September 2012, Vol 5, No 6

SepteMber 2012 www.theOncologypharmacist.com VOl 5, NO 6

The Indiana University Health Simon Cancer Center was estab-lished in 1992 under the leadership of Stephen D. Williams, MD,and in 1999, the center was designated by the National Cancer

Institute as a clinical cancer center. The Indiana University ResearchInstitute was opened in 1997, financed in part by federal funding. Thename of the center was changed in 2006 to honor the philanthropicsupport of Melvin and Bren Simon.The Simon Cancer Center is a patient care, research, and educa-

tional institution within the Indiana University (IU) School of Medicineon the main campus in Indianapolis. The physicians and scientists

Continued on page 7

The GrowTh of SpecialTy

pharmacy . . . . . . . . . . . . . . . . . . . . . .11What Is the Impact on Patient

Relationships?

proSTaTe cancer

Progress in Treating Prostate

Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Team Approach Enhances

Choice of Observation . . . . . . . . . . . 23

Side effecT manaGemenT . . . 23Chemotherapy-Induced Peripheral

Neuropathy Increases Risk of Falls

and Physical and Functional Problems

immune

ThrombocyTopenia . . . . . . . . . . 24Considerations for Treatment

complimenTary ce . . . . . . . . . . . 28Considerations in Lymphoma—Ask

the Experts: Follicular Lymphoma

I N S I D E

For men with localized prostate can-cer detected by prostate-specific antigen(PSA) level, treatment with radicalprostatectomy did not significantly re-duce mortality compared with observa-tion, according to overall results of thelarge, randomized, controlled PIVOTtrial (Wilt TJ, et al. N Engl J Med. 2012;367:203-213). All-cause mortality andprostate-specific mortality were similar

for the surgery and observation groupsover a 12-year follow-up. Results sug-gest that surgery may be a better optionthan observation for men with inter-mediate- and high-risk localizedprostate cancer, but low-risk localizedprostate cancer can be safely managedwith observation.Overall, absolute differences in mor-

NEWS BRIEFS

By Alice Goodman

Surgery Versus Observation forLocalized Prostate Cancer

Anew appreciation of the pathobio-logical foundation of mucositis,and the application of genomics

to risk assessment, heralds an individual-ized and more effective approach to inter-vention for this costly, often disabling,toxicity, according to specialists who spokeat a session on mucosal injury during the2012 Annual Meeting of the AmericanSociety of Clinical Oncology (ASCO).

New Mechanistic UnderstandingOld concepts are being replaced by a

pathobiological paradigm that bettercaptures the underlying mechanism andallows for more effective interventions.Mucositis is now “about bioinformatics,targeted treatment, risk prediction, andother exciting frontiers,” said DouglasPeterson, DMD, PhD, of the Universityof Connecticut Health Center inFarmington.Stephen T. Sonis, DMD, DMSc, of

Biomodels in Watertown, Massachu setts,described the biological cascade leading tomucosal injury as one involving the mes-

SIDE EFFECT MANAGEMENT

Mucositis Management toBecome More PersonalizedBy Caroline Helwick

Continued on page 36

Continued on page 4

THE PATIENT’S VOICE

Popping Pills andShooting UpBy MMA

Imust admit that I am not a fan of med-ications. I had 4 beautiful childrenmedication-free with midwives. I

drink green tea to get rid of a cold. I eatchocolate to calm a headache. I mi-crowave rice in a sock and place it onsore muscles. Perhaps that is why I resent(yes, I said it, “resent!”) that I have beensent home with 2 medications I must in-

ject into myself twice a day for a total of4 daily injections. When I got sent home from the hospi-

tal after my fourth chemotherapy sessionwith both my regular white bag packedfull of pills plus new injections of bloodthinners and stem cell stimulators (I ampreparing for a stem cell transplant), I feltnervous. Certainly, since the start of my

The oncology pharmacy team at the Indiana University Health Simon Cancer Center.

Photo courtesy of Indiana University Health.

CANCER CENTER PROFILE

Indiana University HealthSimon Cancer CenterAddressing the Needs of the Patient

By Alice Goodman


©2012 Green Hill Healthcare Communications, LLC

APPROVED FO

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SUBCUTANEO

US AND IV

ADMINISTRAT

ION

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VELCADEHCP.COM

5:28 PM

If you define value as an overall survival advantage:VELCADE® (bortezomib) DELIVERED A >13-MONTH OVERALL SURVIVAL ADVANTAGE

At 5-year median follow-up, VELCADE (bortezomib)+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-085]; p<0.05)†

At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you define value as defined length of therapy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you define value as medication cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,471 per 3.5-mg vial as of January 2012

Health plans should consider medication cost, length of therapy, and dosing regimens when determining the value of a prescription drug regimen. This list of considerations is not meant to be all-inclusive; there are multiple other factors to consider when determining value for a given regimen

VELCADE Indication and Important Safety InformationINDICATIONVELCADE is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONSVELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS Peripheral neuropathy, including severe cases, may occur — manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment

Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated

Closely monitor patients with risk factors for, or existing heart disease

Acute diffuse infiltrative pulmonary disease has been reported

Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement

Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment

Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus

Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONSMost commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported

Please see Brief Summary for VELCADE on the next page of this advertisement.

To contact a reimbursement specialist: Please call 1-866-VELCADE, Option 2 (1-866-835-2233).

*Melphalan+prednisone.† VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analyses were performed.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.

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www.TheOncologyPharmacist.com4 sEPTEmbER 2012 I VOL 5, NO 6

News Briefs

tality favoring surgery were less than 3percentage points, explained lead authorTimothy J. Wilt, MD, Min neapolisVeterans Affairs Health Care System,Minnesota. “Surgery might reduce mor-tality for men with higher PSA valuesand possibly among men with higher-

risk tumors, but not among men withPSA levels of ≤10 ng/mL or low-risk tu-mors,” Wilt wrote.He noted that PIVOT was conducted

in the early era of PSA testing, and thatin the current era men suspected of hav-ing prostate cancer undergo repeatedPSA testing and sometimes repeat biop-sies, which detect more indolent cancers.These factors increase the likelihood ofoverdiagnosis and over treatment. “Ourfindings support observation for men

with localized prostate cancer, espe-cially those who have low-risk disease,”he wrote.PIVOT randomized 364 men to radi-

cal prostatectomy and 367 to observa-tion alone. All participants were sus-pected of having prostate cancer basedon PSA testing and had histologicallyconfirmed localized prostate cancer di-agnosed within the previous year. Meanage was 67 years, about one-third wereblack, and median PSA value was 7.8

ng/mL. About 40% of the men had low-risk prostate cancer, 34% intermediate-risk prostate cancer, and 21% high-riskprostate cancer.At a median follow-up of 10 years,

mortality was 47% in the surgery groupversus 49.9% in the observation group,an absolute reduction of 2.9% for sur-gery. The rates of prostate-specific mor-tality were 5.8% for surgery versus 8.4%for observation, an absolute risk reduc-tion of 2.6%. The effect of treatment onall-cause mortality was similar accordingto age, race, coexisting illness, perform-ance status, or histologic tumor features.Radical prostatectomy was associated

with reduced all-cause mortality amongmen with PSA >10 ng/mL and for menwith intermediate- or high-risk tumors.Perioperative adverse events (occur-

ring within 30 days of surgery) were re-ported in 21.4% of men. Rates of urinaryincontinence and erectile dysfunctionwere significantly higher in the radicalprostatectomy group (P <.001 for bothcomparisons vs observation).

Older patientsWith Mantle CelllymphomaR-CHOP (rituximab, cyclophos-

phamide, doxorubicin, vincristine, andprednisone) induction therapy followedby maintenance therapy with rituximabwas more effective than R-FC (ritux-imab, fludarabine, and cyclophos-phamide) followed by maintenancetherapy with interferon alfa in older pa-tients with mantle cell lymphoma, ac-cording to a recently published prospec-tive, randomized, double-blind clinicaltrial (Kluin-Nelemans HC, et al. N EnglJ Med. 2012;367:520-531).“The excellent results with ritux-

imab administered as maintenancetherapy are important. Maintenancetherapy with rituximab showed notonly a progression-free survival benefitbut also a significant survival advan-tage among patients who were success-fully pretreated with R-CHOP,” wrotethe authors.The long-term prognosis is poor for

older patients with mantle cell lym-phoma. Treatment with chemotherapyachieves low rates of complete remission(CR), the authors wrote. Most older pa-tients with mantle cell lymphoma willrelapse, and better therapy is needed forthis group of patients. When the trialwas first initiated, the authors hopedthat the fludarabine-containing regimenwould perform better than it did in thistrial. However, results showed that R-FCwas not more effective than R-CHOP,and the fludarabine-containing regi-men was more toxic. The study enrolled 560 patients aged

60 years or older with stage II to IVmantle cell lymphoma who were ran-

Surgery VersusObservation...Continued from cover

Brief Summary

INDICATIONS:VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE.Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE (bortezomib) 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group.DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.USE IN SPECIFIC POPULATIONS:Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc.All rights reserved. Printed in USA V-12-0095 6/12

News Briefs


EDITOR-IN-CHIEFPatrick Medina,PharmD, BCOPOklahoma UniversityCollege of PharmacyTulsa, OK

ASSOCIATEEDITOR-IN-CHIEFSteve Stricker,PharmD, MS,BCOPSamford UniversityMcWhorter School ofPharmacyBirmingham, AL

John F. Aforismo,BSc Pharm, RPh,FASCPRJ Health SystemsInternational, LLCWethersfield, CT

David Baribeault,RPh, BCOPBoston Medical CenterBoston, MA

Betty M. Chan,PharmD, BCOPUSC/Norris CancerHospitalLos Angeles, CA

Steven L.D’Amato, RPh,BCOPMaine Center for CancerMedicineScarborough, ME

Anjana Elefante,PharmD, BSc,BSc Pharm, RPhRoswell Park CancerInstituteBuffalo, NY

Beth Faiman,PhD(c), MSN,APRN-BC,AOCNCleveland Clinic TaussigCancer InstituteCleveland, OH

ChristopherFausel, PharmDIndiana University Simon Cancer CenterIndianapolis, IN

Rebecca S. Finley,PharmD, MSJefferson School ofPharmacyPhiladelphia, PA

David C. Gammon, BSPhOncologyPharmacist.net Warwick, RI

Lew Iacovelli, BS,PharmD, BCOP,CPP Moses H. Cone HealthSystemGreensboro, NC

Dwight Kloth,PharmD, FCCP,BCOPFox Chase CancerCenterPhiladelphia, PA

Jim Koeller, MSUniversity of Texas atAustinSan Antonio, TX

Christopher J.Lowe, PharmDIndiana UniversityHospitalIndianapolis, IN

Emily Mackler,PharmD, BCOPUniversity of MichiganHealth System & Collegeof PharmacyAnn Arbor, MI

Laura BoehnkeMichaud, PharmD,BCOP, FASHPThe University of TexasMD Anderson CancerCenterHouston, TX

LeAnn BestNorris, PharmD,BCPS, BCOPSouth Carolina Collegeof PharmacyColumbia, SC

Timothy G. Tyler,PharmD, FCSHPDesert Regional MedicalCenterPalm Springs, CA

John M. Valgus,PharmD, BCOPUniversity of NorthCarolina Hospitals andClinicsChapel Hill, NC

Gary C. Yee,PharmD, FCCP,BCOPUniversity of NebraskaCollege of PharmacyOmaha, NE

Burt Zweigenhaft,BSBioPharma Partners LLCNew York, NY

Marlo Blazer, PharmD, BCOPJames Cancer Hospital & Solove ResearchInstituteColumbus, OH

Heidi D. Gunderson, PharmD,BCOPMayo Clinic Cancer CenterRochester, MN

Kamakshi V. Rao, PharmD,BCOPUniversity of North Carolina Hospitals and ClinicsChapel Hill, NC

Editorial Board

www.TheOncologyPharmacist.com sEPTEmbER 2012 I VOL 5, NO 6 5

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The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN1944-9593 (online) is published 8 times a year by GreenHill Healthcare Communications, LLC, 1249 South RiverRoad, Suite 202A, Cranbury, NJ 08512. Telephone:732.656.7935. Fax: 732.656.7938. Copyright ©2012 byGreen Hill Healthcare Communications, LLC. All rightsreserved. The Oncology Pharmacist® logo is a registeredtrademark of Green Hill Healthcare Com munications,LLC. No part of this publication may be reproduced ortransmitted in any form or by any means now or hereafterknown, electronic or mechanical, including photocopy,recording, or any informational storage and retrieval sys-tem, without written permission from the Publisher.Printed in the United States of America.

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6 sEPTEmbER 2012 I VOL 5, NO 6 www.TheOncologyPharmacist.com

In this month’s issue of The Oncology Pharmacist (TOP),we explore the growth of specialty pharmacies and theimplications for our relationship with patients. Author

Lea Ann Hansen discusses the evolution of specialty phar-macy and the function it serves in the treatment of cancerand how this affects patients. As Hansen points out in herarticle, “In many cases, the complicated nature of admin-istration or possible adverse events with specialty drugsnecessitate intensive patient monitoring.” The topic of The Patient’s Voice article revolves around

a patient’s complicated relationship with her oncologydrugs. MMA writes about “popping pills and shooting up”at home. While not directly acknowledging adherence,

MMA shows us how difficult it is to ensure that patientstake medications as prescribed. In our reader survey poll,we ask how you talk to patients about adherence. Go towww.TheOncologyPharmacist.com and tell us how youtry to help patients like MMA overcome their emotionalreactions to taking (or not taking) their medications. We continue our coverage of the news from the 2012

Annual Meeting of the American Society of ClinicalOncology by addressing the topic of mucositis—notingthat the advent of personalized cancer medicine alsomeans personalizing supportive care issues as well.As always, we want to hear from you about what you see

in TOP. Contact us at [email protected]. �

From the Editors

Patrick Medina, PharmD, BCOPEditor-in-Chief

Steve Stricker, PharmD, MS, BCOPAssociate Editor-in-Chief

Recent FDA Newsbosutinib for Chronic Myelogenous leukemiaThe US Food and Drug Administration (FDA) approved

bosutinib tablets (Bosulif; Pfizer) for the treatment of adultswith chronic, accelerated, or blast phase Philadelphia chro-mosome–positive chronic myelogenous leukemia (CML)who did not respond or were resistant to prior therapy.The September 4, 2012, approval was based on the re-

sults of a single-arm, open-label, multicenter trial in 546adults (503 evaluable for efficacy) with chronic, accelerat-ed, or blast phase CML. All patients had been previouslytreated with at least 1 tyrosine kinase inhibitor (TKI). The efficacy end points for patients with chronic phase

CML were the rate of major cytogenetic response (MCyR) atweek 24, and the duration of MCyR. The rate of confirmedcomplete hematologic response (CHR) and overall hemato-logic response (OHR) by week 48 were the efficacy endpoints for patients with accelerated or blast phase CML.For those with chronic phase CML, 33.8% of patients

who had received 1 prior TKI (imatinib) achieved MCyRat week 24 while 26.9% of patients who received prior ther-apy with more than 1 TKI (imatinib followed by dasatiniband/or nilotinib) achieved MCyR by week 24. Among pa-tients with accelerated or blast phase CML who had re-ceived 1 prior TKI, 30.4% and 15%, respectively, achievedCHR response by week 48, while 55.1% and 28.3%, re-spectively, achieved OHR by week 48. Diarrhea, nausea, thrombocytopenia, vomiting, abdomi-

nal pain, rash, anemia, pyrexia, and fatigue were the mostcommon side effects in the safety population of patients. Richard Pazdur, MD, Director of the Office of

Hematology and Oncology Products in the FDA’s Centerfor Drug Evaluation and Research, noted, “With the ap-proval of tyrosine kinase inhibitors, we are seeing improve-ments in the treatment of CML based on a better under-standing of the molecular basis of the disease.”

enzalutamide for Metastatic Castration-resistantprostate CancerThe FDA granted expedited approval for enzalutamide

(Xtandi; Medivation and Astellas Pharma US) on August31, 2012. Enzalutamide was approved for the treatment of

patients with metastatic castration-resistant prostate cancer(CRPC) who have previously received docetaxel.Approval was based on the results of a single randomized,

placebo-controlled, multicenter trial of 1199 patients withmetastatic CRPC. The study was designed to measure over-all survival in men receiving enzalutamide compared withmen receiving a placebo. The median overall survival forthose patients who received enzalutamide was 18.4 months,compared with 13.6 months for those who received placebo.For more information about enzalutamide, please see

page 22.

Carfilzomib for Multiple MyelomaOn July 20, 2012, the FDA granted accelerated approval

to carfilzomib injection (Kyprolis; Onyx Pharmaceuticals)for the treatment of patients with multiple myeloma whohave received at least 2 prior therapies, including bortez -omib and an immunomodulatory agent, and who havedemonstrated disease progression on or within 60 days ofthe completion of their last therapy.The safety and effectiveness of carfilzomib was evaluated

in a study of 266 patients participating in a single-arm, mul-ticenter trial. Patients received carfilzomib intravenouslyfor a 2- to 10-minute period on 2 consecutive days weeklyfor 3 weeks, followed by a 12-day rest period (a 28-day treat-ment cycle). Treatment was continued until disease pro-gression, unacceptable toxicity, or completion of a maxi-mum of 12 cycles.The overall response rate was 22.9% and consisted of 1

complete response, 13 very good partial responses, and 47partial responses. The median response duration was 7.8months. The most common side effects observed in morethan 30% of patients in the study were fatigue, low bloodcell count and blood platelet levels, shortness of breath, di-arrhea, and fever. Serious side effects included heart failureand shortness of breath.As a condition of having received accelerated approval for

carfilzomib, Onyx Pharmaceuticals will submit a completeanalysis of an ongoing randomized phase 3 trial that com-pares lenalidomide plus low-dose dexamethasone to lenalido-mide plus low-dose dexamethasone plus carfilzomib. �

sEPTEmbER 2012 I VOL 5, NO 6 7www.TheOncologyPharmacist.com

Cancer Center Profile

who work at the center are mainly fromthe faculty of the IU School of Medi -cine, the IU Schools of Nursing andDentistry, and the Purdue Univer sitySchool of Science. The staff works witha team of other professionals to addressthe full spectrum of the needs of cancerpatients, including physical, emotional,psychological, and spiritual needs. Over the past decade, many mile-

stones have been reached, includinglaunching of the Indiana GenomicsInitiative, opening of the Biotech -nology Research and Training Center,expanding research space for theWalther Oncology Center, breakingground on a new research facility, dedi-cation of a new 405,000 square foot pa-tient care center, and dedication of thelargest research building on the campus,the Joseph E. Walther Hall, at 238,371square feet.The mission and goals of the Simon

Cancer Center drive the staff to con-duct better research, provide better ed-ucation, and improve patient care. The Oncology Pharmacist spoke with

Patrick Kiel, PharmD, BCPS, BCOP,Cancer Pharmacy Specialist, Hema -tology and Stem Cell Transplant,Indiana University Health SimonCancer Center, about the approach tomanaging patients at the center and hisrole as an oncology pharmacy specialist.

What is the approach to treatingcancer patients at the SimonCancer Center?Patrick Kiel (PK): We are an NCI-

designated cancer center, and we em-ploy a multidisciplinary approach.Physicians handle diagnosis and treat-ment, and the oncology pharmacistsmonitor treatments, develop symptomreports, and participate in developingtreatment algorithms and standard op-erating procedures. Our nursing staff in-cludes magnet-trained nurses, and wehave case managers and social workers.There is a good dynamic between casemanagers and pharmacists at our centerto ensure that patients get their treat-ments covered by insurance, or if not,by assistance programs from the phar-

maceutical company or the SimonCenter to offset costs so that patientscan afford their treatments.

Is cost becoming more of an issuewith regard to treatment?PK: Yes, there is a push nationally as

well as here at our center to containcosts to help doctors and nurses beaware of the direct and associated costsof treatment; for example, considera-tions as to whether a treatment can begiven as inpatient versus outpatient andthe amount and frequency of monitor-ing a treatment requires.

How does this approach translateto better outcomes?PK: The benefit comes from the

more eyes that are on the patient, andthat includes the pharmacist’s eyes.Also, patient education is a multidisci-plinary effort. The pharmacist rein-forces physician’s education about treat-ments and their side effects. I tellpatients, “You are not a car getting atype of oil. You are a person, and when-ever you get a medication, you shouldask what this medication is for, what theside effects are, and how they can helpmonitor for side effects.”

What are you excited about now inthe field of oncology?PK: I am excited about new therapies.

We have already covered the low-hang-ing fruit, that is, treatments that affectmultiple disease states and benefit largenumbers of patients. Those days are over.

Now the emphasis is on targeted treat-ments for subgroups and rarer diseases.Oncology pharmacists are becoming in-

volved in clinical trials and bench re-search. I have just been given a grant towork with a physician scientist on study-ing PARP inhibition in leukemias and

lymphomas. Pharma cists are also in-volved in clinical outcomes research, forexample, on potential treatments to ad-dress neurotoxicity of chemotherapy, orimmune suppression outcomes in stem

cell transplant patients and how we canimprove upon safety.

How has the role of the oncologypharmacist changed over the past 5years?PK: What has changed the most is

going from having oncology pharmacistsat large oncology centers to now having ademand for them from smaller hospital-associated clinics and private practices. Inthese smaller practice settings, pharmacyis becoming integral to the managementof chemotherapy-induced toxicities andmonitoring associated side effects.

What inspired you to become anoncology pharmacist?PK: I was always interested in genet-

ics as well as pharmacotherapy of dis-ease states. At Midwestern UniversityChicago College of Pharmacy, I studiedwith David Frame and Deb Drager(both PharmDs) who taught me how toevaluate clinical trials and the rationalebehind them. I gravitated toward evi-dence-based medicine. Oncology is afield where you can establish long-termrelationships with patients that can lastfor many years. The best experience is aroutine visit from a patient who is doingwell in his or her life after being treatedfor cancer.

What advice would you give an on-cology pharmacist just entering thefield?PK: The most important aspect of

your job is to talk to patients about theirexperiences on therapy and get theirperspective. Always see patients first,and then go to the computer to look uplaboratory reports. The computer is im-portant, but the patient should be thetop priority.

What work would you be doing ifyou weren’t an oncology pharmacist?PK: I have always been interested in

chemistry and food. If I weren’t a phar-macist, I would be a brewmaster or a foodcritic, as long as the food was for free!One of my favorite TV shows is AltonBrown’s “Good Eats.” �

Indiana University Health Simon Cancer Center... Continued from cover

Indiana University Health Simon Cancer Center.Photo courtesy of Indiana University Health.

Photo courtesy of Indiana University Health.

“The most important aspect of

your job is to talk to patients

about their experiences on

therapy and get their

perspective.”

—Patrick Kiel, PharmD, BCPS, BCOP

Take action: get YOUR cancer center profiled!We are looking to interview oncology pharmacists from cancer centers around the country.

It’s an easy process—a short phone interview and you need to submit some photos.

Contact [email protected] for more information.

TREANDA® (bendamustine HCI) for Injection is his chemo. This is his therapy.

S

TRE-2510a August 2012

D

Single-agent TREANDA tripled median PFS*

TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Effi cacy relative to fi rst-line therapies other than chlorambucil has not been established.

20100 30 4025155

PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

35

TREANDA(n=153)

Chlorambucil(n=148)18 months

median PFS

45

0.10.20.30.40.5

Surv

ival

dis

tribu

tion

func

tion

0.60.70.80.91.0

Months

HR†=0.27 (95% CI‡: 0.17, 0.43) P<.0001

6 monthsmedian PFS

*TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6).†HR=hazard ratio.‡CI=confi dence interval.

2

≥≥

Important Safety Information

≥ ≥

LEARN MORE AT WWW.TREANDA.COM

Please see accompanying brief summary of full Prescribing Information.

©2012 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-2510a August 2012

Discover the elements of ef� cacy and safety

1-2 9 11:57 AM

Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions]WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients

Number (%) of patientsTREANDA Chlorambucil(N=153) (N=143)

System organ classPreferred term All Grades Grade 3/4 All Grades Grade 3/4Total number of patients with atleast 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17)Gastrointestinal disordersNausea 31 (20) 1 (<1) 21 (15) 1 (<1)Vomiting 24 (16) 1 (<1) 9 (6) 0Diarrhea 14 (9) 2 (1) 5 (3)General disorders and administration site conditionsPyrexia 36 (24) 6 (4) 8 (6) 2 (1)Fatigue 14 (9) 2 (1) 8 (6) 0Asthenia 13 (8) 0 6 (4) 0Chills 9 (6) 0 1 (<1) 0Immune system disordersHypersensitivity 7 (5) 2 (1) 3 (2) 0Infections and infestationsNasopharyngitis 10 (7) 0 12 (8) 0Infection 9 (6) 3 (2) 1 (<1) 1 (<1)Herpes simplex 5 (3) 0 7 (5) 0InvestigationsWeight decreased 11 (7) 0 5 (3) 0Metabolism and nutrition disordersHyperuricemia 11 (7) 3 (2) 2 (1) 0Respiratory, thoracic and mediastinal disordersCough 6 (4) 1 (<1) 7 (5) 1 (<1)Skin and subcutaneous tissue disordersRash 12 (8) 4 (3) 7 (5) 3 (2)Pruritus 8 (5) 0 2 (1) 0

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil.

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study

TREANDA Chlorambucil(N=150) (N=141)

Laboratory AbnormalityAll Grades Grade 3/4 All Grades Grade 3/4

n (%) n (%) n (%) n (%)Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9)Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10)Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3)Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4)Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21)

In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions]OVERDOSAGE: The intravenous LD50 of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Reconstitution/Preparation for Intravenous Administration. Aseptically

Sterile Water for Injection, USP Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be

immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The

reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride

drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period.DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder.HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

Distributed by:Cephalon, Inc.Frazer, PA 19355TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved.©2008-2012 Cephalon, Inc., or its affiliates. TRE-2500 April 2012(Label Code: 00016287.06) This brief summary is based on TRE-006 TREANDA full Prescribing Information.

TRE-2511a August 2012

This brief summary is based on TRE-2527 TREANDA full Prescribing Information.


The past decade has seen a dramat-ic upsurge in the utilization ofspecialty pharmacies for all types

of therapeutic modalities, includingthose for cancer. The cost of cancer caremay rise from about $125 billion in 2010to $207 billion by the end of the decade.By that time, specialty drugs are predict-ed to account for 2 of every 5 pharmacydollars spent.1 The purpose of this articleis to explain the evolution of the spe-cialty pharmacy and the functions it canserve in the treatment of cancer and todiscuss the potential benefits and chal-lenges of the system from the point ofview of the patient.

the evolution of Specialty Drugsand Specialty pharmacyThere is a lack of consensus on the def-

inition of a specialty drug. The US Foodand Drug Administration has not definedthe term. Initially, the label was virtuallysynonymous with biotechnology products,either proteins produced by recombinantDNA techniques or monoclonal anti bod-ies produced with cellular hybridomas,but this is no longer the case. The 2007Medicare Modernization Act defined aspecialty drug as “a part D drug with plan-negotiated prices that exceed $400 permonth.”2 Other health plans may definespecialty drugs differently. In general, theyare high cost, administered by injection orinfusion, require special handling, or areused for complex diseases that require spe-cial monitoring. In oncology, however, themost common agents dispensed by a spe-cialty pharmacy provider (SPP) are thenewer targeted agents that are adminis-tered orally. After a systematic review ofthe literature, one academic group of au-thors proposed the most critical descriptorsof a specialty drug to be3:• High cost (prescriptions cost morethan $600 per month)

• Difficult medication delivery, such as– Special handling requiring stricttemperature control

– Restricted location for medicationpreparation or distribution site

– Restricted location for medicationadministration

• Complex treatment maintenance, in-cluding– Personalized or frequent dosing, dos-ing adjustments, and administrationprotocols

– Clinical management or patientsupport programs to monitor for se-rious side effects and adherence

The EMD Serono Specialty Digest con-tains survey data from 93 health plansrepresenting over 115 million covered in-

dividuals.4 This source lists high cost asthe most common reason a plan woulddesignate a drug as “specialty,” in that80% of the plans ranked high cost as 4 or5 on a 5-point impact scale. Self-admin-istration of an injectable, office adminis-tration of an injectable, and treatment ofa rare disease are other characteristicsthat are commonly considered when des-ignating drugs as “specialty.”Specialty drugs have been the fastest

growing segment in the pharmacy benefitsector. The number of specialty drugs onthe market in the United States hasgrown from about 10 in 1990 to morethan 250 in 2010.4 From 2008 to 2009,spending per healthcare plan member peryear increased by 19.5% for specialtydrugs, compared with an increase of 4.8%for traditional drugs.5 Even though lessthan 3% of the private healthcare popu-lation uses specialty pharmaceuticals,they account for as much as 25% of alloutpatient pharmacy spending.6 With

more than 600 specialty agents in the re-search pipeline, it is not surprising thatpayers have been focused on methods tomanage these costs most effectively.3SPPs are a diverse group of companies in-volved in overseeing distribution, man-agement, and reimbursement of specialtypharmaceuticals.6 These companies havetheir origins in a number of lines of busi-ness, including community pharmacies,chain pharmacies, home infusion compa-nies, wholesale drug distributors, andpharmacy benefit managers (PBMs). In2006, 78% of surveyed health plans hadcontracted with or were in the process ofcontracting with an SPP for specialtydrug distribution.6 As of January 2011,88% are utilizing SPPs, 7% manage thedistribution of specialty drugs in-house,and only 5% have no contractual rela-tionship with SPPs. Forty-three percentcontract with a single SPP, a proportionthat has been decreasing over the past3 years.4Mandatory use of an SPP for dis-pensing is in place for at least one thera-py category in 59% of commercial payers,64% of Medicare Advantage plans, and71% of Medicaid plans.

SPPs are often able to acquire drugproducts with a volume discount unavail-able to most pharmacies, hospitals, andphysician offices. Health plans are alsoable to implement formulary policiesmore easily with a few contracted SPPsthan with hundreds of local pharmacies.Another commonly discussed strategy tomanage specialty drugs is to move themto the pharmacy benefit, relying heavilyon SPPs, rather than covering themunder the medical benefit.7 This has beenreferred to as medical channel manage-ment.1 SPPs have the advantage to payersthat claims are submitted via an electron-ic, real-time process, whereas medicalclaims are typically batched with no con-current review. The strategy also allowsplans to shift from the traditional physi-cian reimbursement model of “buy andbill” to a more controllable system. Onemanaged care organization with approxi-mately 4.6 million members reported anestimated $15.5 million in savings in drugcosts by converting 50 drugs to an SPP.8The trends in this activity are shown inthe Figure.4Some health plans mandate that pa-

tients use a single, or one of a few, con-tracted SPPs for specialty drugs. Most inthe EMD Serono survey agreed that sucha mandate is an effective strategy forachieving their overall specialty drugmanagement goals, and currently 59%use this approach for at least one thera-peutic class.4 In some states, “AnyWilling Provider” legislation and certifi-cates of coverage prevent the practice insome situations. Health plans indicatethat monitoring of health outcomes, suchas decreases in disease progression and se-rious adverse event rates, for specialtydrugs is of increasing interest. SPPs offeroutcome measurements, predictive mod-eling, and comparative prescribing analy-sis, but health plans report the least satis-faction with these services. Based onthese findings and the overall drug devel-opment landscape, it is apparent thatSPPs will remain in the healthcare envi-ronment for the foreseeable future.

Specialty Drugs in OncologySPPs have growing significance for per-

sons with cancer for several reasons.9 In anumber of malignancies, the treatmentparadigm is shifting from a single course ofchemotherapy lasting a few months toone more analogous to treatment for achronic disease involving long-term, dailytherapy with transitions from one drugto another as the disease progresses. Thebreakthrough medications that haveachieved this possibility are expensive:

In oncology, the most

common agents

dispensed by a specialty

pharmacy provider are

the newer targeted

agents that are

administered orally.

SPPs are often able to

acquire drug products

with a volume discount

unavailable to most

pharmacies, hospitals,

and physician offices.

the Growth of Specialty pharmacy: What Is the Impacton patient relationships?Lea Ann Hansen, PharmD, BCOPAssociate Professor, Virginia Commonwealth University

Lea Ann Hansen



90% of oncology drugs approved duringthe last 5 years cost more than $20,000 fora 3-month course of therapy.1Oncolo gy iscurrently dominating research and devel-opment in the pharmaceutical industry,with 125 drugs in phase 3 clinical trials,38 of which are oral medications.Additionally, cancers are increasinglybeing characterized by complex tumorbiomarkers which will, in some cases,guide treatment. The strategies used byhealth plans to manage these moleculardiagnostic tests, which are themselves ex-pensive, are evolving. Many have not im-plemented policies as of yet, but most planto do so within the next 12 to 24 months.4Currently, 77% of health plans classify

oral oncology agents as specialty drugs,and they represent some of the most com-monly used agents in the category.4Spending on oral cancer agents morethan doubled between 2002 and 2006.9Examples of drugs dispensed throughSPPs, with their most common oncologyindications, are shown in the Table.4,10-25Some health plans include injectable

chemotherapy agents in the specialty druggenre under a medical channel manage-ment strategy, even though they are notself-administered. These include paclitax-el protein-bound particles, ixabepilone,cabazitaxel, mitoxantrone, bendamustine,pralatrexate, azacitidine, decitabine, ofatu-mumab, bevacizumab, cetuximab, panitu-mumab, trastuzumab, romidepsin, leupro-lide acetate, aldesleukin, temsirolimus,and bortezomib.10 Injectable agents forsupportive care of cancer patients, such asepoetin alfa, darbepoetin, sargramostim,filgrastim, and pegfilgrastim, are consid-ered specialty drugs by 78% of healthplans. In addition, 59% of the survey re-

spondents currently place some palliativecare and end-of-life therapies in the spe-cialty category or plan to increase focus onthis area in the future. Currently, approxi-mately 40% of health plans require an SPPbe used for some or all specialty drugs inthe oncology category.4

benefits and Challenges of Specialtypharmacy to the patient With CancerLearning of a cancer diagnosis and re-

ceiving treatment represent a series ofstressful events for patients and their fam-ilies. The entire diagnostic experience im-merses them in an unfamiliar world ofmedical specialists, testing procedures,medical jargon, and health insurancerules. Often the cancer diagnosis was pre-ceded by an insidious onset of vaguesymptoms in an otherwise healthy person,so patients may be relatively naive to nav-igating the healthcare system. Coexistingconcerns about employment, child care,and other responsibilities add to the bur-den. Therefore, it is important for healthprofessionals to be aware of benefits andchallenges introduced by each type ofservice entity that is utilized in the care ofthe cancer patient, including SPPs.

Since most SPPs are in a location re-mote from the patient, the prescriberand/or the prescriber’s staff will usuallycommunicate with patients electronical-ly. The SPP would typically be more fa-miliar with the particular specialty drugthey have been contracted to providethan a general service pharmacy. Manyprior authorization or reimbursement is-sues can be addressed by the SPP, pre-scriber, and health plan without direct in-volvement of the patient. In some cases,when high-cost specialty drugs that areadministered by infusion are assigned tothe pharmacy benefit, via an SPP, ratherthan to the medical benefit, the overallout-of-pocket expense to the patient canbe reduced. Some SPPs have realizedcost savings through dispensing cus-tomized quantities with close monitor-ing for regimen changes or discontinua-tion.26 However, this benefit may not betransmitted to the patient if the healthplan requires a copayment each time aprescription is dispensed. The drug product will subsequently be

delivered directly to the patient’s home.This represents a valuable conveniencefor the patient who may be fatigued bydisease, travel, and medical procedures.In many cases, the complicated natureof administration or possible adverseevents with specialty drugs necessitateintensive patient monitoring. MostSPPs offer patient education and 24/7support lines staffed by a pharmacist ornurse. Some provide proactive refill pro-grams, while others monitor for adher-ence based on refill patterns. Better ad-herence to specialty drugs with SPPsthan with community pharmacies hasbeen described in poster presentationsand Internet Web sites.1,27While there are many potential bene-

fits to patients with cancer when theyutilize an SPP, a number of concernshave been raised by other healthcaregroups. The National ComprehensiveCancer Network (NCCN), a not-for-profit alliance of 21 cancer centers thatare designated at the highest level by theNational Cancer Institute, conducts ini-tiatives in order to “improve the quality,effectiveness, and efficiency of oncologypractice so patients can live betterlives.”28 In 2010, the NCCN convened atask force on the topic of specialty phar-macy. The majority of their recommenda-tions involve communication, coordina-tion of care, and pharmacy practice issuesas described below.When an SPP assumes the primary re-

sponsibility for delivering the anticancermedication, the potential for fragmenta-tion of care between the SPP and the restof the oncology care team arises.Questions regarding quantities dispensed,communication of dosage changes ormodifications, and delays in treatmentinitiation may be difficult to resolve since

the Growth of Specialty pharmacy

Figure. How Health Plans Typically Cover Specialty Drugs

Adapted from EMD Serono. EMD Serono Specialty Digest, 7th Edition. http://specialtydigest. emdserono.com. M indicates medical benefit; OAA, office-administered agent; P, pharmacy benefit; S, specialtybenefit; SAA, self-administered agent.

100

90

80

70

60

50

40

30

20

10

0SAA 2008 SAA 2012 OAA 2008 OAA 2010

S Both P & M M P

% of P

lans

29

13

58

15

7

73

25

71

1

29

62

6

Since most SPPs are in a

location remote from the

patient, the prescriber

and/or the prescriber’s

staff will usually

communicate with

patients electronically.

While there are many

potential benefits to

patients with cancer

when they utilize an SPP,

a number of concerns

have been raised by

other healthcare groups.

Continued from page 11

each SPP and health plan will have dif-ferent procedures. Even within a healthplan, logistic procedures may be differentfor each drug or class of drugs, and solvinga problem can consume considerableprovider time. Better informatics systemsare needed to facilitate information flowand delineation of roles between SPPsand the healthcare team, especially sinceoncology patients have a frequentlyevolving medication regimen.28 Otherspecific recommendations have beenmade by the NCCN Specialty PharmacyTask Force to decrease the risk of patientfrustration, adverse events, and waste.These include:• SPP practitioners who care for patientswith cancer should have specific ex-pertise in oncology

• Distribution models for SPPs shouldminimize delay in initiating therapy,and an appropriate estimate of drug de-livery should be given to the providerand patient; this is important becausemany therapeutic regimens involvemultiple drugs on a precise scheduleand should not be initiated if availabil-ity of a specialty drug will be delayed

• SPP should dispense small quantitieson the first fill without penalties tothe patient

• If a self-injectable medication is sentdirectly to the patient, the SPP or thePBM should have the responsibility toeducate the patient regarding self-ad-ministration techniques

• Only agents that can be safely and ap-propriately self-administered should bedispensed through the SPP model

• Medications requiring sterile com-pounding before infusion or those thata patient cannot self-administer shouldnot be distributed through an SPP,since the process of “brown bagging,”by which patients deliver drugs to theclinical setting, creates obvious risk toproduct integrity and additional bur-den on the patient

• Preparation of injectables by the SPPand dispensing directly to the hospital,clinic, or physician office (“white bag-ging”) does not necessarily eliminatethe concerns of brown bagging and cre-ates potential waste when dose modifi-cation or discontinuation based on pa-tient-specific data occurs

• SPPs should develop and implementprocedures for proper handling anddisposal of chemotherapy agents theydispense

• All pharmacies, including SPPs, shouldparticipate in national incident report-ing databases to include medication er-rors, adverse events, and near missesA roundtable convened by the

American Society of Health-SystemPharmacists outlined a number of addi-tional concerns related to drug distribu-tion and handling that impact patientwelfare and the oncology workforce.29

One participant stated, “Specialty phar-macies provide a recipe for profound clin-ical problems for our patients as decisionsare made to carve select components ofthe total care process out of our health-system setting.” A number of potentialnegative effects were noted:

• Supply chain control is disruptedwhen a patient receives a drug froman SPP and brings it to the institu-tion for the injection, leading to thepossibility of improper storage andhandling and introduction of coun-terfeit drugs into the system



Table. Oral Anticancer Agents Often Classified as Specialty Drugs*

Imatinib11 • Newly diagnosed Philadelphia chromosome–positive chronic myelogenousleukemia (Ph+ CML)

• Ph+ CML after failure of interferon-alpha therapy• Relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL)• Kit (CD117)+ unresectable and/or metastatic malignant gastrointestinal stromalcell tumors (GISTs)

• Adjuvant treatment following resection of Kit (CD117)+ GISTDasatinib12 • Newly diagnosed Ph+ CML

• Ph+ CML when not benefitting from, or not tolerating, other treatment • Ph+ ALL when not benefitting from, or not tolerating, other treatment

Nilotinib13 • Newly diagnosed Ph+ CML in chronic phase• Ph+ CML resistant or intolerant to prior therapy that included imatinib

Erlotinib14 • Maintenance therapy of locally advanced or metastatic non–small cell lung cancer(NSCLC) when disease has not progressed after 4 cycles of chemotherapy

• Locally advanced or metastatic NSCLC after failure of at least 1 priorchemotherapy regimen

• First-line treatment of locally advanced, unresectable, or metastatic pancreaticcancer in combination with gemcitabine

Sorafenib15 • Unresectable hepatocellular carcinoma• Advanced renal cell carcinoma

Sunitinib16 • GIST after disease progression or intolerance to imatinib• Advanced renal cell carcinoma• Progressive, well-differentiated pancreatic neuroendocrine tumors (PNETs)that are unresectable or metastatic

Pazopanib17 • Advanced renal cell carcinoma• Advanced soft tissue carcinoma, after at least 1 prior chemotherapy

Everolimus18 • Advanced renal cell carcinoma after failure of sunitinib or sorafenib• Advanced hormone receptor–positive, HER2- breast cancer after failure withletrozole or anastrozole, in combination with exemestane

• PNETs that are unresectable, locally advanced, or metastatic• Renal angiomyolipoma and tuberous sclerosis complex, not requiring immediatesurgery

Lapatinib19 • Advanced or metastatic HER2+ breast cancer after prior therapy with ananthracycline, a taxane, and trastuzumab, in combination with capecitabine

• Metastatic, postmenopausal, hormone-positive HER2+ breast cancer, incombination with letrozole

Thalidomide20 • Newly diagnosed multiple myeloma (MM), in combination with dexamethasoneLenalidomide21 • MM, in combination with dexamethasone, after at least 1 prior therapy

• Transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplasticsyndromes associated with deletion 5q abnormality

Temozolomide22 • Newly diagnosed glioblastoma multiforme, concomitantly with radiotherapyand then as maintenance treatment

• Refractory anaplastic astrocytoma after progression on a regimen containingnitrosourea and procarbazine

Capecitabine23 • Adjuvant treatment of Dukes C colon cancer• First-line treatment of metastatic colorectal cancer when a fluoropyrimidinetherapy alone is preferred

• Metastatic breast cancer, in combination with docetaxel after failure of prioranthracycline-containing therapy

• Metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing regimen

Topotecan24 • Relapsed small cell lung cancerVorinostat25 • Cutaneous manifestations of cutaneous T-cell lymphoma, with progressive,

persistent, or recurrent disease on or following 2 systemic therapies

*For complete FDA-approved indications and usages, please visit the manufacturers’ Web sites.


Even within a health plan,

logistic procedures may

be different for each drug

or class of drugs, and

solving a problem can

consume considerable

provider time.

• Some drugs provided by an SPP areaccompanied by an infusion devicethat local staff is unfamiliar withusing or replenishing

• These concerns lead many hospitalsto adopt policies preventing suchmedications from being adminis-tered within the institution, creatingfrustration for the patient who mayhave been required to follow this ap-proach by his or her health plan

• Increases in bureaucracy, paperwork,and inefficiencies are created forclinic nurse managers, physicians,and pharmacy managers in deter-mining where to obtain the drug foreach patient

• Patients become dissatisfied becauseof the disruptions and delays causedby the complicated process and diffi-culty obtaining accurate informationabout their out-of-pocket expenses

When patients are treated for cancer,an entire team of professionals overseestheir care. Inclusion of an additional ordifferent entity, such as an SPP, into thesystem increases the potential for missedinformation, frustration, and even devas-tating consequences. In order to realizepotential cost and clinical benefits whilealso supporting patients through a devas-tating cancer diagnosis, it is imperativethat professionals providing care are wellinformed about all of the elements of thehealthcare system and effectively delivernecessary information, training, and serv-ices to their patients.

ConclusionAt the core of the debate around spe-

cialty pharmaceuticals is the question ofvalue and control in healthcare.Clinicians have typically been trained to

emphasize patient outcome with relativelylittle concern for costs. Coverage policiesin health plans have not typically beendesigned to evaluate the therapeuticvalue of particular treatments relative totheir direct or indirect cost. At times, pa-tient demand for a new product that ap-pears to be a therapeutic breakthroughswells to a level not justified by the avail-able outcomes data. The intersection ofthese circumstances in the wake of high-technology cancer innovations will re-quire investment of all groups in order toensure that individuals with cancer re-ceive care that has clinical value, financialvalue, and above all, humanistic value. �

references1. Medco 2011 Drug Trend Report. Drug Trend ReportWeb site. http://www.drugtrendreport.com/2011-report.Accessed November 29, 2011.2. Centers for Medicare & Medicaid Services. MedicareModernization Act: 2007 Final Guidelines—Formularies,CY07 Formulary Guidance. Washington, DC: CMS; 2006.3. Blaser DA, Lewtas AJ, Ousterhout MM, et al. How todefine specialty pharmaceuticals—a systematic review.Am J Pharm Benefits. 2010;2:371-380.4. EMD Serono. EMD Serono Specialty Digest, 7th Edition.http://specialtydigest.emdserono.com/. Accessed Novem -ber 28, 2011. 5.Miller S, Cox E, Nease B, et al. 2009 Drug Trend Report:Solving for America's $163 Billion in Pharmacy-RelatedWaste: A Market and Behavioral Analysis. St. Louis, MO:Express Scripts, Inc; 2010. http://www.express-scripts.com/research/research/dtr/archive/2009/dtrFinal.pdf.Accessed September 11, 2012.6. Stern D, Reissman D. Specialty pharmacy cost man-agement strategies of private health care payers. J ManagCare Pharm. 2006;12:736-744.7.Robinson JC. Insurers’ strategies for managing the use andcost of bio-pharmaceuticals. Health Aff. 2006;25:1205-1207.8. Baldini CG, Culley EJ. Estimated cost savings associ-ated with the transfer of office-administered specialtypharmaceuticals to a specialty pharmacy provider in amedical injectable drug program. J Manag Care Pharm.2011;17:51-59.9. Weingart SN, Brown E, Bach PG. NCCN Task ForceReport: oral chemotherapy. J Natl Compr Canc Netw. 2008;6(suppl):S1-S14.10. LM Healthworks. Learn about your specialty phar-macy benefit. https://host1.medcohealth.com/art/open_enrollment/Lockheed_SPharm_Benefit.pdf. AccessedNovember 27, 2011.

11. Gleevec Prescribing Information. Novartis Pharma -ceuticals Corporation Web site. http://www.pharma.us.novartis.com/product/pi/pdf/gleevec_tabs.pdf. AccessedNovember 29, 2011.12. Sprycel Prescribing Information. Bristol-Myers SquibbWeb site. http://packageinserts.bms.com/pi/pi_sprycel.pdf.Accessed November 29, 2011. 13. Tasigna Prescribing Information. Novartis Pharma -ceuticals Corporation Web site. http://www.pharma.us.novartis.com/product/pi/pdf/tasigna.pdf. AccessedNovember 29, 2011.14. Tarceva Prescribing Information. Genentech Website. http://www.gene.com/gene/products/information/pdf/tarceva-prescribing.pdf. Accessed November 29, 2011.15. Nexavar Prescribing Information. http://www.univgraph.com/bayer/inserts/nexavar.pdf. Accessed Novem ber29, 2011.16. Sutent Prescribing Information. Pfizer Web site.http://labeling.pfizer.com/ShowLabeling.aspx?id=607.Accessed November 29, 2011.17.Votrient Prescribing Information. GSK Source Web site.https://www.gsksource.com/gskprm/htdocs/documents/VOTRIENT-PI-MG.PDF. Accessed September 11, 2012.18. Afinitor Prescribing Information. Novartis Pharma -ceuticals Corporation Web site. http://www.pharma.us.novartis.com/product/pi/pdf/afinitor.pdf. Accessed Sep -tember 11, 2012.19. Tykerb Prescribing Information. GlaxoSmithKlineUSA Web site. http://us.gsk.com/products/assets/us_tykerb.pdf. Accessed November 29, 2011.20. Thalomid Prescribing Information. http://www.thalomid.com/pdf/Thalomid%20PI%2072991-10.pdf.Accessed November 29, 2011.21.Revlimid Prescribing Information. http://www.revlimid.com/pdf/REVLIMID_ PI.pdf. Accessed November 29, 2011.22. Temodar Prescribing Information. http://www.spfiles.com/pitemodar.pdf. Accessed November 29, 2011.23. Xeloda Prescribing Information. Genentech Web site.http://www.gene.com/gene/products/information/xeloda/pdf/pi.pdf. Accessed November 29, 2011.24. Hycamtin Prescribing Information. GlaxoSmithKlineUSA Web site. http://us.gsk.com/products/assets/us_hycamtin_capsules.pdf. Accessed November 29, 2011.25. Zolinza Prescribing Information. Merck Web site.http://www.merck.com/product/usa/pi_circulars/z/zolinza/zolinza_pi.pdf. Accessed November 29, 2011.26. Frederick J. Walgreens promotes big savings via mon-itored oncology Rx therapy. Drug Store News Web site.http://www.drugstorenews.com/article/walgreens-promotes-big-savings-monitored-oncology-rx-therapy. AccessedNovember 30, 2011.27. Allen JD, Zabriski S, Brown J. Effectiveness of a di-rect-to-patient specialty pharmacy compliance program. JManag Care Pharm. 2005;11:602. Abstract.28. Schwartz RN, Eng KJ, Frieze DA, et al. NCCN TaskForce Report: specialty pharmacy. J Natl Compr CancNetw. 2010;8(suppl 4):S1-S12.29.Armistead J, Lloyd L, Pane F, et al. Implications of thespecialty drug marketplace for health-system pharmacy: aroundtable discussion. Am J Health Syst Pharm. 2007;64:2364-2372.

14 sEPTEmbER 2012 I VOL 5, NO 6 www.TheOncologyPharmacist.com


The evolution of drug research anddevelopment toward oral thera-pies for cancer over the past

decade has created a number of ques-tions for the oncology healthcareprovider. Will insurance companies payfor these exceptionally expensive med-ications? How and when will patients re-ceive their medication? Who will be re-sponsible for ensuring patient educationand monitoring to maximize safe drugadministration and patient compliance?In the accompanying article, Dr Hansenbuilds a case for specialty pharmacyproviders (SPPs) to assume these re-sponsibilities in a marketplace increas-

ingly focused on reducing drug costswhile also remaining committed to phar-macovigilance. When appropriately uti-

lized, the SPP can become a benefit tothe healthcare team and an additional

resource at the disposal of the oncologypharmacist.When a patient is initially introduced

to the concept of oral chemotherapy, itoften becomes the duty of the oncologypharmacist to ensure that the patient andfamily are well educated with regard tothe dosage, schedule, and side effects re-lated to the new medication. As thesedrugs are often used in the second-line(or beyond) setting, frequently counsel-ing sessions are undertaken while pa-tients are still processing the news thattheir cancer has returned or worsened.Thus, it becomes important that patientsare provided with written education ma-

Steve Stricker

A pharmacist’s perspective Steve Stricker, PharmD, MS, BCOP

Many SPPs have

pharmacists available

24 hours a day to be

responsive to the needs

of their customers and

patients.

It is imperative that

professionals providing

care are well informed

about all of the elements

of the healthcare system

and effectively deliver

necessary information,

training, and services to

their patients.




66%OF U.S. HOSPITALS SURVEYEDFACED SHORTAGES OFONCOLOGY PRODUCTS1 APP® increased oncolytics supply

up to 45% to meet this vital need2

ONCOLOGY

NO SHORTAGE OF COMMITMENT.

DROP-BY-DROP. VIAL-BY-VIAL. A VITAL FOCUS ON SAFETY AND SUPPLY.

APP® and are trademarks of Fresenius Kabi USA, LLC.©2012, Fresenius Kabi USA, LLC. All Rights Reserved. 0351DR1-APPF-05-05/12

References:1.2.

terials and have an available “life line”when questions arise regarding these oraldrugs. While a provider from our practiceis always available to the patient and fam-ily around the clock, the availability ofadditional highly reliable patient re-sources can play a significant role in en-suring that patients receive timely adviceor an appropriate answer to a question or

concern in the event that they feel un-comfortable asking us directly. The SPPmay then provide education as an exten-sion of the oncology team rather thanhaving the patient seek out informationor anecdotes from the Internet or othersuch unreliable references.As Dr Hansen notes, “The SPP would

typically be more familiar with the partic-

ular specialty drug they have been con-tracted to provide than a general servicepharmacy.” In addition to enhancedknowledge of these drugs, many, if not all,SPPs have pharmacists available 24 hoursa day to be responsive to the needs oftheir customers and patients. This is a sig-nificant advantage in contrast to the




pharmacist in a traditional communitypharmacy where patients may, otherwise,feel inclined to seek additional drug in-formation. In an article in the Journal ofthe American Pharmacists Association in2008, O’Bryant and Crandell surveyedcommunity pharmacists’ knowledge andattitudes toward oral chemotherapy andconcluded that only 45% of communitypharmacists were knowledgeable regard-ing adverse events of these drugs. Theyalso reported a low level of comfort indispensing these highly specialized oralmedications (mean 2.4; Likert scale 1[low] to 5 [high]).1 Thus, an insurancecompany that contracts an SPP to pro-vide dispensing services for these drugsalso is more likely to ensure that patients

will be the beneficiaries of competentdrug information. While the SPP may play a favorable role

in patient education, there are obviousconcerns related to the possibility of frag-mentation of care ultimately related tocommunication issues. In my opinion, it isimportant for the oncology pharmacist inthe ambulatory care setting to be aware ofthe SPPs used by insurance plans com-monly encountered in a community.Oncology pharmacists would be wellserved to communicate directly with theSPPs, become knowledgeable in the drugsand services offered by specific SPPs, andmaintain open channels of communica-tion to ensure that when questions ariserelated to quantities dispensed, dosage

changes, or delays in treatment, this infor-mation may be exchanged in a cordial andprofessional manner, no differently thancommunicating with a community phar-macy down the street. We must, as a pro-fession, recognize that SPPs will remain asignificant factor in the dispensing of ex-pensive, highly specialized oral oncologydrugs for the foreseeable future. Thus, ourresponsibility should be to utilize the SPPas a resource to enhance care for the pa-tient with cancer rather than view theSPP as an insurmountable barrier to pa-tient care. �

reference1. O’Bryant CL, Crandell BC. Community pharmacists’knowledge of and attitudes toward oral chemotherapy.J Am Pharm Assoc. 2008;48:632-639.

illness I have been charged with takingpills at home. If I had to rank myself ona scale of 1 to 10, with 1 being a patientwho constantly forgets to take his/hermedicine and 10 being the highly con-scientious patient who never missesmedicine time while following all the di-rections about eating, drinking, and driv-ing exactly, I would place myself arounda 7 or 8. Honestly, I don’t forget to takethe medicine; sometimes, probably forsome psychological reason, I resist takingit. That means, if the pharmacist or nursewrote on my medicine sheet to take a pill(or series of them) every day at 9:00 inthe morning, some days I may take it at11:00, even if the bottle is sitting right infront of me for those extra 2 hours.Furthermore, if the bottle says not to eatfor a half hour after taking the pill, Ioften wait only 20 minutes. I cannot ex-plain my behavior. I know I am onlyhurting myself. Nonetheless, I just do itthat way, sometimes. The injections, which I had been

taught to give myself in the hospital,presented an entirely new challenge.First of all, I have a deep-seated fear ofneedles. When the nurse first told me Iwould need to inject myself, I startedto cry and sweat. She tried to calm meby telling me the needle was verysmall. That did nothing. She broughtme the fake skin to place on my bellyto practice injecting myself without ac-tually doing it. The doctor even camein to tell me that because of the size ofthe needle, even if I jammed the injec-

tion into myself, I would not hit a vitalorgan. Then, after about a hundredpractice runs, the nurse watched as Icleaned off my own skin with an alco-hol wipe, pinched the skin 2 inchesfrom my belly button, counted “1-2-3”and stuck the needle into my virginbelly skin.Yet, this self-injection bothers me not

only because of my fear of needles, butalso because I honestly think I shouldnot have to do it. I think the hospitalshould either do the injections so as notto force me into this masochistic routinemorning and afternoon, or give me an-other pill that I can take relatively ontime every day. Perhaps some peopleprefer to be able to self-inject at homeinstead of having to go back to the hos-pital, but I do not fall into that category.I find it very hard to understand how—with all the advances in medicine, withall the brilliant minds working on hard-core issues such as finding cures for can-cer, with all the nurses who spend yearsin school, and with all the specializedfields within pharmacology—I am stillrequired to “shoot up” in my own bath-room as part of my treatment. Perhaps I should feel lucky that I

have access to medical care (and I do).Perhaps I should stop whining andthink of all the millions of people withdiabetes who have to inject themselvesevery day for the rest of their lives (andI do). Perhaps I should think of all thosewho have passed away from my illnessand be thankful I have the opportunity

to receive medications that may saveme (and I do/am). Perhaps I shouldsomehow look on the bright side andbreathe a sigh of relief that at least theinjections are not another pill I need toremember to take (unfortunately, I can-not). The truth of the matter is, thatwhile I am pretty comfortable with pop-ping pills, I am not at all comfortable

with shooting up in my bathroom evenafter a month of doing so. Can someoneplease invent something that makes itunnecessary while still maintaining thesame level of care? �

Popping Pills and Shooting Up... Continued from cover

MMA is undergoing treatment forcancer. She wishes to use her initials.

The Patient’s Voice


Reader PollDo you talk to patients about the importance of

adherence to their medications? r Yesr No

Go to www.TheOncologyPharmacist.comto cast your vote and add your comments.Please tell us what your patients are tellingyou, directly or indirectly, about how they

take their medications.

THE AFINITOR DUAL BENEFIT CO-PAY CARD

RxBIN:RxPCN:RxGrp:RxID:Suf:

601341OHCP

[OHXXXXXXX][000000000000]

01

With this co-pay assistance card, most eligible patients will pay $25 per 28-day prescription of AFINITOR® (everolimus) Tablets when they visit their pharmacy. The card also provides up to $50 off their co-pay for generic exemestane when prescribed with AFINITOR.

Novartis Pharmaceuticals Corporation will pay the balance of your eligible patient’s out-of-pocket expenses, up to a maximum of $1200 per month for the AFINITOR prescription and up to $50 per month for generic exemestane when prescribed with AFINITOR. Not valid for prescriptions for which payment may be made in whole or in part under federal or state healthcare programs, including, but not limited to, Medicare or Medicaid. The exemestane offer is not valid in Michigan. Patients can obtain the co-pay card at their physician’s offi ce or at www.AFINITOR.com. This program will expire on June 30, 2014.

Please see accompanying Important Safety Information and Brief Summary of Prescribing Information for AFINITOR on the following pages.

The AFINITOR Dual Benefi t Co-Pay Card

THE AFINITOR® (everolimus) TABLETS DUAL BENEFIT CO-PAY CARD FROM NOVARTIS PHARMACEUTICALS CORPORATION Designed to help make treatment more affordable for your eligible AFINITOR patients

Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936-1080 © 2012 Novartis 9/12 AFB-1046627

Helping make access to AFINITOR easier

For more information about AFINITOR access services, please visit www.AFINITOR.com.

Novartis Oncology shares your commitment to helping patients living with cancer receive the medicines they need. Patient Assistance Now Oncology offers quick and easy access to information about the broad array of support and reimbursement programs available for patients.

S

AFINITOR® (everolimus) Tablets is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Important Safety Information

AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Noninfectious Pneumonitis: Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed. If symptoms are moderate, patients should be managed with dose interruption until symptoms improve. The use of corticosteroids may be indicated. For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve. For grade 3 cases, interrupt AFINITOR until resolution to grade 1. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose.

Infections: AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred. Some of these infections have been severe (eg, leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Treatment of preexisting invasive fungal infections should be completed prior to starting treatment. Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered. Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment.

Oral Ulceration: Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 86% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients. In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed.

Renal Failure: Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR.

Geriatric Patients: In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent discontinuation occurred in 33% of patients 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended.

Laboratory Tests and Monitoring: Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have been reported. Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine), blood glucose, lipids,

and hematologic parameters should be evaluated prior to treatment and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR.

Drug-Drug Interactions: Avoid coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole). Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4 and/or PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). Avoid coadministration with strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, increase the AFINITOR dose from 10 mg daily up to 20 mg daily, using 5-mg increments.

Hepatic Impairment: Exposure of everolimus was increased in patients with hepatic impairment. For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended.

Vaccinations: The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR.

Embryo-Fetal Toxicity: Fetal harm can occur if AFINITOR is administered to a pregnant woman. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment.

Adverse Reactions: The most common adverse reactions (incidence 30%) were stomatitis (67%), infections (50%), rash (39%), fatigue

(36%), diarrhea (33%) and decreased appetite (30%). The most common grade 3/4 adverse reactions (incidence 2%) were stomatitis (8%), infections (5%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%) and diarrhea (2%).

Laboratory Abnormalities: The most common laboratory abnormalities (incidence 50%) were hypercholesterolemia (70%), hyperglycemia (69%), increased aspartate transaminase (AST) concentrations (69%), anemia (68%), leukopenia (58%), thrombocytopenia (54%), lymphopenia (54%), increased alanine transaminase (ALT) concentrations (51%), and hypertriglyceridemia (50%). The most common grade 3/4 laboratory abnormalities (incidence 3%) were lymphopenia (12%), hyperglycemia (9%), anemia (7%), decreased potassium (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%).

Please see accompanying Brief Summary of Prescribing Information for AFINITOR on the following pages.

S

AFINITOR (everolimus) tablets for oral administrationInitial U.S. Approval: 2009Brief Summary of Prescribing Information. See full prescribing information for complete product information. 1 INDICATIONS AND USAGE

AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failureof treatment with letrozole or anastrozole.

4 CONTRAINDICATIONSHypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients.Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea,flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratoryimpairment) have been observed with everolimus and other rapamycin derivatives.

5 WARNINGS AND PRECAUTIONSNon-infectious PneumonitisNon-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectiouspneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidenceof Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and upto 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information].Fatal outcomes have been observed.Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratorysigns and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neo-plastic, and other causes have been excluded by means of appropriate investigations. Advise patients toreport promptly any new or worsening respiratory symptoms.Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or nosymptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate theincidence of clinical pneumonitis.If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of cortico -steroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower thanthe dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribinginformation].For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Cortico steroids may be indicateduntil clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR untilresolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately50% lower than the dose previously administered depending on the individual clinical circumstances[see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs atgrade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported evenat a reduced dose.InfectionsAFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, orprotozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2,6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumo-nia, mycobac terial infections, other bacterial infections, invasive fungal infections, such as aspergillosisor candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patientstaking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic fail-ure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR.Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR.While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection ismade, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR.If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appro-priate antifungal therapy.Oral UlcerationMouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an inci-dence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-8% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Insuch cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashesshould be avoided as they may exacerbate the condition. Antifungal agents should not be used unlessfungal infection has been diagnosed [see Drug Interactions].Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed inpatients treated with AFINITOR [see Laboratory Tests and Monitoring].Geriatric PatientsIn the randomized advanced hormone receptor positive, HER2-negative breast cancer study, the incidenceof deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years ofage compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatmentdiscontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 yearsof age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended[see Dosage and Administration (2.2) in the full prescribing information, Use in Specific Populations].Laboratory Tests and MonitoringRenal FunctionElevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reac-tions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, includingmeasurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended priorto the start of AFINITOR therapy and periodically thereafter.Blood Glucose and LipidsHyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [seeAdverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fastingserum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodicallythereafter. When possible, optimal glucose and lipid control should be achieved before starting a patienton AFINITOR.Hematologic ParametersDecreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [seeAdverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of completeblood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.Drug-drug InteractionsDue to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitorsshould be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information and DrugInteractions].A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4and/or PgP inhibitor [see Dosage and Administration (2.2, 2.4) in the full prescribing information andDrug Interactions].An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer[see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions].Hepatic ImpairmentExposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology(12.3) in the full prescribing information].For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients withsevere hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desiredbenefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B)

hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and ClinicalPharmacology (12.3) in the full prescribing information].For SEGA patients with severe hepatic impairment, AFINITOR is not recommended. For SEGA patientswith mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to thestarting dose may not be needed; however subsequent dosing should be individualized based on thera-peutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information].VaccinationsThe use of live vaccines and close contact with those who have received live vaccines should be avoidedduring treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps,rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.The timing of routine vaccinations in pediatric patients with SEGA should be considered prior to the startof everolimus therapy.Embryo-fetal ToxicityThere are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based onthe mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities inanimals at maternal exposures that were lower than human exposures. If this drug is used during preg-nancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of thepotential hazard to a fetus. Women of childbearing potential should be advised to use an effectivemethod of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use inSpecific Populations].

6 ADVERSE REACTIONSThe efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placeboplus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients withadvanced or metastatic hormone-receptor-positive, HER2-negative breast cancer. The median age ofpatients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months.The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diar-rhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) werestomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most commonlaboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST,anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The mostcommon grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, ane-mia, decreased potassium, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%)compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergentadverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemes-tane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions orreductions) were more frequent among patients in the AFINITOR plus exemestane arm than in theplacebo plus exemestane arm (63% versus 14%).Table 3 compares the incidence of treatment-emergent adverse reactions reported with an incidence of≥10% for patients receiving AFINITOR 10 mg daily versus placebo.

Table 3: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC*AFINITOR (10 mg/day) Placebo

+ exemestanea + exemestanea

N=482 N=238All grades Grade 3 Grade 4 All grades Grade 3 Grade 4

% % % % % %Any adverse reaction 100 41 9 90 22 5Gastrointestinal disorders

Stomatitisb 67 8 0 11 0.8 0Diarrhea 33 2 0.2 18 0.8 0Nausea 29 0.2 0.2 28 1 0Vomiting 17 0.8 0.2 12 0.8 0Constipation 14 0.4 0 13 0.4 0Dry mouth 11 0 0 7 0 0

General disorders and administration site conditionsFatigue 36 4 0.4 27 1 0Edema peripheral 19 1 0 6 0.4 0Pyrexia 15 0.2 0 7 0.4 0Asthenia 13 2 0.2 4 0 0

Infections and infestationsInfectionsc 50 4 1 25 2 0

InvestigationsWeight decreased 25 1 0 6 0 0

Metabolism and nutrition disordersDecreased appetite 30 1 0 12 0.4 0Hyperglycemia 14 5 0.4 2 0.4 0

Musculoskeletal and connective tissue disordersArthralgia 20 0.8 0 17 0 0Back pain 14 0.2 0 10 0.8 0Pain in extremity 9 0.4 0 11 2 0

Nervous system disordersDysgeusia 22 0.2 0 6 0 0Headache 21 0.4 0 14 0 0

Psychiatric disordersInsomnia 13 0.2 0 8 0 0

Respiratory, thoracic and mediastinal disordersCough 24 0.6 0 12 0 0Dyspnea 21 4 0.2 11 0.8 0.4Epistaxis 17 0 0 1 0 0Pneumonitisd 19 4 0.2 0.4 0 0

Skin and subcutaneous tissue disordersRash 39 1 0 6 0 0Pruritus 13 0.2 0 5 0 0Alopecia 10 0 0 5 0 0

Vascular disordersHot flush 6 0 0 14 0 0Median Duration of Treatmente 23.9 weeks 13.4 weeks

CTCAE Version 3.0*160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks)a Exemestane (25 mg/day)b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulcerationc Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common

being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneu-monia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%).

d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosise Exposure to AFINITOR or placebo

Key observed laboratory abnormalities are presented in Table 4. Table 4: Key Laboratory Abnormalities Reported in ≥ 10% of

Patients with Advanced HR+ BCLaboratory parameter AFINITOR (10 mg/day) Placebo

+ exemestanea + exemestanea

N=482 N=238All grades Grade 3 Grade 4 All grades Grade 3 Grade 4

% % % % % %Hematologyb

Hemoglobin decreased 68 6 0.6 40 0.8 0.4WBC decreased 58 1 0 28 5 0.8Platelets decreased 54 3 0.2 5 0 0.4Lymphocytes decreased 54 11 0.6 37 5 0.8Neutrophils decreased 31 2 0 11 0.8 0.8Clinical ChemistryGlucose increased 69 9 0.4 44 0.8 0.4Cholesterol increased 70 0.6 0.2 38 0.8 0.8Aspartate transaminase (AST)increased 69 4 0.2 45 3 0.4

Alanine transaminase (ALT)increased 51 4 0.2 29 5 0

Triglycerides increased 50 0.8 0 26 0 0Albumin decreased 33 0.8 0 16 0.8 0Potassium decreased 29 4 0.2 7 1 0Creatinine increased 24 2 0.2 13 0 0CTCAE Version 3.0a Exemestane (25 mg/day)b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia,

and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.

7 DRUG INTERACTIONSEverolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multi drug effluxpump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.Agents that may Increase Everolimus Blood ConcentrationsCYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases ineverolimus exposure when AFINITOR was coadministered with:

max

max

max

Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage and Administration (2.2, 2.4)in the full prescribing information and Warnings and Precautions].Use caution when AFINITOR is used in combination with moderate CYP3A4 and/or PgP inhibitors. Ifalternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration(2.2, 2.4) in the full prescribing information and Warnings and Precautions].Agents that may Decrease Everolimus Blood ConcentrationsCYP3A4 Inducers

CYP3A4, decreasedeverolimus AUC and Cmax by 63% and 58% respectively, compared

treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably andshould be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information].Agents whose Plasma Concentrations may be Altered by EverolimusStudies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions

kinetic analyses also detected no influence ofsimvastatin (a CYP3A4 substrate) on the clearance of AFINITOR.

max and a 30% increase in.

Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%.However, the corresponding estradiol levels at steady state (4 weeks) were not different between the twotreatment arms. No increase in adverse

Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%. 8 USE IN SPECIFIC POPULATIONS

Pregnancy Pregnancy Category D [see Warnings and Precautions].

the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman.

exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the

should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment.In animal reproductive studies, oral administration of everolimus to female rats before mating and

retarded skeletal development. These efftoxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately4% of the exposure (AUC ) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered toSEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternaltoxicities.

tion. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or

developmental parameters (morphological development, motor activity, learning, or fertility assessment)in the offspring.Nursing MothersIt is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passedinto the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because manydrugs are excreted in human milk and because of the potential for serious adverse reactions in nursinginfants from everolimus, a decision should be made whether to discontinue nursing or to discontinue thedrug, taking into account the importance of the drug to the mother.Pediatric UseAFINITOR is recommended for use only in patients with SEGA who are aged ≥ 3 years.

Geriatric Use

≥ 65 years of age, while 15% were 75 and over. No overall differences ineffectiveness were observed between elderly and younger subjects. The incidence of deaths due to anycause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in

33% of patients ≥ [see Warnings andPrecautions].

pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and≥ 65

treated patients were ≥ 65 years of age, while 7% were 75 and over. Other reported clinical experience has not identified differences in response between the elderly andyounger patients, but greater sensitivity of some older individuals cannot be ruled out macology (12.3) in the full prescribing information].

ate dose adjustments for adverse reactions is recommended. [see Dosage and Administration (2.2),Clinical Pharmacology (12.3) in the full prescribing information].Renal ImpairmentNo clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal

ommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribinginformation].Hepatic ImpairmentThe safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose

tion.

scribing information].For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients withsevere hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the

dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information].

[see Dosage and Administration (2.4ing information].

10 OVERDOSAGEIn animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity wereobserved in either mice or rats given single oral doses of 2000 mg/kg (limit test).Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have beenadministered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose.

Manufactured by:Novartis Pharma Stein AG

Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936© Novartis

July 2012


domized to receive either 6 cycles of R-FC every 28 days or to 8 cycles of R-CHOP every 21 days. Responders (n =316) were randomized to maintenancetherapy with rituximab or interferonalfa, and treatment was continued untildisease progression.Median age was 70 years, about 70%

were male, and about 80% were stageIV at baseline. An intent-to-treatanalysis for response was based on 532patients. Rates of CR were similar forthe regimens: 40% for R-FC and 34%for R-CHOP. However, more patientsprogressed on R-FC (14% vs 5% withR-CHOP). Four-year survival rates weresignificantly lower on R-FC: 47% versus62%, respectively (P = .10). Also, morepatients treated with R-FC died duringfirst remission (10% vs 4%, respective-ly). Hematologic adverse events werereported more frequently in the R-FCgroup than in the R-CHOP group, butthe rates of infection were similar (17%for R-FC and 14% for R-CHOP).In the analysis of responders, mainte-

nance therapy with rituximab reducedthe risk of progression or death by 45%:progression or death occurred in 58% ofthose on maintenance with interferonalfa versus 29% of those on mainte-nance rituximab (P = .01). Among re-sponders to R-CHOP, maintenancetherapy with rituximab significantly im-proved overall survival at 4 years from63% with interferon alfa maintenanceto 87% (P = .005).Toxic effects during the maintenance

phase were more pronounced in the in-terferon alfa group, with more patientshaving leukocytopenia, thrombocyto -penia, and fatigue, whereas rituximabwas associated with more infections.These observed differences led to differ-ences in adherence, with an overall me-dian treatment duration of 25 monthswith rituximab versus 7 months with in-terferon alfa.

blood test forOvarian CancerThe OVA1 blood test had a high

chance of correctly identifying whetheran ovarian mass was malignant prior tosurgery, according to results of theOVA500 clinical trial. In a study of 494patients, the test had 94% sensitivity inpremenopausal women and 91% sensi-tivity in the early-stage ovarian cancergroup, for an overall sensitivity of 96%.The OVA1 blood test had a negativepredictive value of 98%.OVA500 was designed to evaluate the

test in 2 subgroups: those with early-stageovarian cancer, where about 50% of pa-

tients have a normal CA125 level, andpremenopausal women, who typicallyhave a high incidence of benign cystsand a low incidence of ovarian cancer.OVA1 is the first US Food and Drug

Administration–approved blood test forovarian cancer; the test has a high sen-sitivity to determine if cancer is presentin women with an ovarian mass prior tosurgery. OVA1 is an in vitro diagnostic

test that combines results of 5 immuno -assays using a proprietary algorithm tocome up with a single numerical scoreindicating a woman’s likelihood of hav-ing ovarian cancer.Vermillion, Inc, the diagnostic compa-

ny that is marketing OVA1, released pre-liminary results of OVA500 and said thatfurther details of the study have beensubmitted to a peer-review publication.

OVA500 follows a previous studypublished online in Obstetrics &Gynecology in March 2011 showing thatuse of OVA1 in place of the CA125 testcorrectly identified ovarian cancer 94%of the time versus 77% for CA125 in516 women having surgery. The compa-ny hopes that results of OVA500 willsupport adoption and reimbursementfor this blood test. �

NOWAVAILABLE

©2012 Onyx Pharmaceuticals, Inc., South San Francisco, CA 1111-CARF-147a July 2012 Printed in USA KYPROLIS.com

News Briefs

Older patientsWith Mantle Cell...Continued from page 4


Two studies presented at the 2012American Society of ClinicalOncology (ASCO) Annual Meet -

ing suggested that abiraterone acetate(AA; Zytiga), an androgen biosynthesisinhibitor,1 has the potential to be usedearlier in the course of prostate cancerthan its current US Food and DrugAdministration (FDA) indication (ie,after failure of chemotherapy in menwith metastatic castration-resistantprostate cancer [CRPC]). A second in-terim analysis of a phase 3 trial had posi-tive outcomes with AA in men withmetastatic CRPC who had not yet re-ceived chemotherapy,1 and a preliminaryphase 2 study suggested AA may have arole in the neoadjuvant setting beforeradical prostatectomy is performed inmen with early-stage localized high-riskprostate cancer.2 In addition, secondaryresults from the AFFIRM trial confirmedthe superiority of enzalutamide to place-bo in men with CRPC following treat-ment with docetaxel.3

Abiraterone in Chemotherapy-Naive Metastatic CrpC1

Results of the second interim analy-sis of COU-AA-302 showed that AAplus prednisone significantly improvedradiographic progression-free survival(rPFS), with a strong trend toward in-creased overall survival (OS) comparedwith placebo plus prednisone in menwith metastatic CRPC who had not re-ceived chemotherapy. This study evalu-ated earlier use of AA than the currentFDA indication for use following failureof chemotherapy in CRPC.“This is the first randomized trial to

demonstrate both an overall survivaland progression-free survival benefit inchemotherapy-naive patients withmetastatic CRPC and show that inhi-bition of persistent extragonadal an-drogen synthesis significantly delaysinitiation of cytotoxic chemotherapy,”stated lead author Charles J. Ryan,MD, of the University of CaliforniaSan Francisco. The study enrolled 1088 patients at

151 centers in 12 countries. Patientswere randomized 1:1 to AA (1 g) plusprednisone (5 mg BID) versus placeboplus prednisone. The Independent DataMonitoring Committee unblinded thestudy early, when all primary and sec-ondary outcomes were seen to favorAA, and patients were allowed to crossover from placebo to the AA arm. At a median follow-up of 22.3

months, median rPFS was not yetreached in the AA arm versus 8.3months in the placebo arm (P <.0001).Median OS was not yet reached in the

AA arm and was 27.2 months in theplacebo arm (P = .0097). The interim analysis also confirmed

the acceptable tolerability and safetyprofile of AA in this setting.

Neoadjuvant Abiraterone Acetate2

Another study of even earlier use ofAA suggests that the drug will find arole prior to the development ofmetastatic prostate cancer. Preadjuvanttreatment with 6 months of AA givenconcurrently with leuprolide acetate(LHRHa), a hormonal therapy, andprednisone prior to radical prostatecto-my successfully eradicated prostate can-cer cells in about 30% of men withhigh-risk early prostate cancer in a ran-domized phase 2 trial.“These results are particularly amaz-

ing in this incredibly high-risk group ofpatients, and suggest that this combina-tion therapy could improve outcomesfor a substantial number of men withearly high-risk prostate cancer,” statedlead author Mary-Ellen Taplin, MD, ofHarvard Medical School and the Dana-Farber Cancer Institute in Boston, Mas -sachusetts. This is a preliminary study,and larger, longer trials will be neededto establish a role for AA plus hormonetherapy in the neoadjuvant setting.The phase 2 trial included 58 men

who were defined as high risk becausethey had at least 1 of the following fea-tures: ≥3 positive biopsies; Gleasonscore ≥7 (71% of men had scores of8-10); prostate-specific antigen (PSA)>20 ng/mL (19%); T3, T4 bulky disease(24%); or PSA velocity >2 ng/mL/year(16%). Men with extranodal diseasewere allowed to enroll. The men were randomized to receive

3 months of treatment with LHRHaalone or 3 months of LHRHa plus AAplus low-dose prednisone. Prednisone 5mg/day was given with AA to preventside effects associated with this drug.After 3 months, a prostate biopsy wasperformed to measure serum testos-terone and dihydrotestosterone levels,after which the men received 12 moreweeks of LHRHa/AA/prednisone.

At 3 months, 10% of the men whowere treated with LHRHa/AA/pred-nisone had pathologic complete re-sponse (pCR), compared with 4% ofthose treated with LHRHa alone; near

pCR was observed in 24% and 11%,respectively.

enzalutamide in Metastatic CrpC3

Enzalutamide, an androgen receptorsignaling inhibitor, was superior toplacebo for both the primary and sec-ondary end points in the phase 3 AF-FIRM trial in men with progressiveCRPC. Primary end point results for OSreported earlier showed that enzalu-tamide significantly improved OS by4.8 months compared with the placebogroup; the risk of death was reduced by37% in men randomized to enzalu-tamide (P <.0001).4,5

“These are the best survival rates wehave seen in the post-chemotherapysetting,” said Johann S. de Bono, MD,ChB, of the Institute for CancerResearch and the Royal Marsden NHSFoundation Trust, United Kingdom.

At the ASCO Annual Meeting, deBono presented new data on secondaryoutcomes in AFFIRM. Enzalutamide wassuperior to placebo for the followingmeasures: PSA response, soft tissue objec-tive response, and quality-of-life responseas assessed by FACT-P, as well as such in-dicators of disease progression as rPFSand time to first skeletal-related event.AFFIRM randomized 800 patients to

enzalutamide and 399 to placebo.Median age was 69 years. At baseline,both groups were well matched for de-mographic and disease characteristics.Almost 50% of the group assigned toenzalutamide had received prior hor-mone therapy compared with 53% ofplacebo patients; median number ofprior chemotherapy regimens was simi-lar between groups. PSA response to enzalutamide was

high; 54% of patients in the enzalutamidegroup had >50% declines in PSA level.Following a prespecified interim

analysis, the Independent Data Moni -toring Committee recommended thatthe AFFIRM trial be halted and un-blinded, and eligible patients in theplacebo arm were allowed to cross overto enzalutamide.Enzalutamide was well tolerated. A

greater percentage of patients in thetreated group reported fatigue, and 5patients had seizures versus none withplacebo. On August 31, 2012, enzalutamide

(Xtandi; Medivation) was approved bythe FDA for the treatment of patientswith metastatic CRPC who have previ-ously received docetaxel. �

references1. Ryan CJ, Smith MR, de Bono JS, et al; on behalf ofthe COU-AA-302 Investigators. Interim analysis (IA)results of COU-AA-302, a randomized, phase 3 study ofabiraterone acetate (AA) in chemotherapy-naïve pa-tients (pts) with metastatic castration-resistant prostatecancer (mCRPC). Presented at: 2012 Annual Meetingof the American Society of Clinical Oncology; June2012; Chicago, IL. Abstract LBA4518.2. Taplin M-E, Montgomery RB, Logothetis C, et al.Effect of neoadjuvant abiraterone acetate (AA) plusleuprolide acetate (LHRHa) on PSA, pathological com-plete response (pCR), and near pCR in localized high-risk prostate cancer (LHRPC): results of a randomizedphase II study. Presented at: 2012 Annual Meeting ofthe American Society of Clinical Oncology; June 2012;Chicago, IL. Abstract 4521.3. de Bono JS, Fizazi K, Saad F, et al; for the AFFIRMInvestigators. Primary, secondary, and quality-of-lifeendpoint results from the phase III AFFIRM study ofMDV3100, an androgen receptor signaling inhibitor.Presented at: 2012 Annual Meeting of the AmericanSociety of Clinical Oncology; June 2012; Chicago, IL.Abstract 4519.4. Scher HI, Fizazi K, Saad F, et al; for the AFFIRMInvestigators. Effect of MDV3100, an androgen receptorsignaling inhibitor (ARSI), on overall survival in pa-tients with prostate cancer postdocetaxel: results fromthe phase III AFFIRM study. J Clin Oncol. 2012;30(suppl 5):Abstract LBA1.5. Scher HI, Fizazi K, Saad F, et al; the AFFIRMInvestigators. Increased survival with enzalutamide inprostate cancer after chemotherapy [published onlineahead of print August 15, 2012]. N Engl J Med.

Prostate Cancer

progress in treating prostate CancerBy Alice Goodman

“These are the best

survival rates we have

seen in the post-

chemotherapy setting.”

—Johann S. de Bono, MD, ChB

“These results…suggest that

this combination therapy could

improve outcomes for a

substantial number of men with

early high-risk prostate cancer.”

—Mary-Ellen Taplin, MD

Photo © ASCO/Silas Crews 2012.

Photo © ASCO/Silas Crews 2012.

Thrombopoietin Mimetics Thrombopoietin mimetics increase platelet count

in patients with chronic ITP and reduce the risk ofbleeding.2,4 Nplate®, a thrombopoietin mimetic,increases platelet production by binding to and acti-vating the thrombopoietin receptor, a mechanismanalogous to endogenous thrombopoietin.5 Inpatients who have had an insufficient response tocorticosteroids or immunoglobulins, Nplate® mayoffer the potential for effective maintenance treat-ment in patients who wish to avoid or defer splenec-tomy or in whom splenectomy is contraindicated.5,7

Continuous weekly treatment with Nplate® increas-es platelet counts in many patients who have chron-ic ITP with an acceptable safety profile.4

Important Safety Information • In Nplate® clinical trials of patients with myelo -dysplastic syndromes (MDS) and severe throm-bocytopenia, progression from MDS to acutemyelogenous leukemia (AML) has been ob serv -ed. Nplate® is not indicated for the treatment ofthrombocytopenia due to MDS or any cause ofthrombocytopenia other than chronic ITP.

• Additional serious adverse reactions associatedwith Nplate® are Thrombotic/ThromboembolicCom plica t ions, Bone Marrow Reticulin For -m a tion and Risk for Bone Marrow Fibrosis,Worsened Thrombo cytopenia after Cessationof Nplate®, and Lack or Loss of Response toNplate®.

• In the placebo-controlled studies, headachewas the most commonly reported adverse drugreaction.

Please see additional Important Safety Informa -tion on pages 3 and 4.

Two 6-month, Phase 3 Pivotal Trials 2,5

The results from the SOC study should beviewed in context with the prior pivotal, prospec-tive, multicenter, randomized, placebo-controlled,international, double-blind phase 3 studies thatevaluated Nplate® and placebo, one in splenec-tomized and one in nonsplenectomized patients.The primary end point was durable plateletresponse (weekly platelet responses of ≥ 50 × 109/Lduring 6 or more weeks of the last 8 weeks of treat-ment; no rescue therapy at any time during study).The secondary end point was overall plateletresponse (durable plus transient* rates of plateletresponse). In nonsplenectomized patients:• Durable platelet response was 61% (25/41) ofpatients on Nplate® versus 5% (1/21) of thecontrol group (P < 0.0001).

• Overall platelet response was 88% (36/41) ofpatients on Nplate® versus 14% (3/21) of thecontrol group (P < 0.0001).

In splenectomized patients:• Durable platelet response was 38% (16/42) ofpatients on Nplate® versus 0% (0/21) of thecontrol group (P = 0.0013).2

• Overall platelet response was 79% (33/42) ofpatients on Nplate® versus 0% (0/21) of thecontrol group (P < 0.0001).

In the pivotal trials for Nplate®, prior ITP treat-ments in the Nplate® and control groups includedcorticosteroids, immunoglobulins, rituximab, cyto-toxic therapies, danazol, and azathioprine. Patientsreceiving corticosteroids, azathioprine or danazolat a constant dosing schedule were allowed to con-tinue receiving these medical treatments through-out the studies.The recommended starting dose for Nplate® is

1 µg/kg. See the Nplate® prescribing informationfor complete dosing instructions, including guide-lines for dose adjustments. In the pivotal trials, themedian dose of Nplate® was 2 µg/kg (25th–75thpercentile: 1–3 µg/kg) in the study of nonsplenec-tomized patients and 3 µg/kg (25th–75th per-centile: 2–7 µg/kg) in the study of splenectomizedpatients.

Study Design3

• This was a multicenter, randomized, con-trolled, 52-week, open-label study designed toassess the efficacy and safety of Nplate® orSOC in adult patients with ITP.

• Patients were randomized, in a 2:1 ratio, toreceive Nplate® (n=157) or SOC (n=77).

© 2012 Amgen, Inc. • © 2012 Green Hill Healthcare Communications, LLC

�mmune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts dueto both increased platelet destruction and suboptimal platelet production.1 Many therapies are aimedat reducing platelet destruction.2 Treatments aimed at increasing platelet production, alone or in com-

bination with existing therapies, provide an opportunity to improve outcomes in patients with ITP.2 Thethrombopoietin mimetic Nplate® (romiplostim) is an Fc-peptide fusion protein that stimulates plateletproduction by binding the thrombopoietin receptor, thereby increasing the body’s natural production ofplatelets.3 Nplate® is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopeniain patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins,or splenectomy. Nplate® is not indicated for the treatment of thrombocytopenia due to myelodysplasticsyndrome (MDS) or any cause of thrombocytopenia other than chronic ITP. Nplate® should be used onlyin patients with ITP whose degree of thrombocytopenia and clinical condition increase their risk forbleeding. Nplate® should not be used in an attempt to normalize platelet counts.A summary of the trial that compares Nplate® to medical standard of care (SOC) in patients with

ITP published in the New England Journal of Medicine is presented. The design of the trial does notallow for the comparison of Nplate® to the individual treatments received in the SOC arm.

Evidence-based Results From a 1-Year Trial Evaluating Nplate® (romiplostim) or Medical Standard of Care inNonsplenectomized Patients With Immune Thrombocytopenia (ITP)A summary of the Romiplostim or Standard of Care in Patients with Immune Thrombocytopenia article previously published.3

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Nplate or SOC Study Design

Nplate® (n=157)Weekly SC injections starting at 3 µg/kg; dose adjustments

based on platelet count

Medical SOC (n=77)Prescribed by investigatoraccording to standardinstitutional practices ortherapeutic guidelines

1-year treatment period

6-month post-treatment

safety monitoring period

End of trial

Randomization 2:1

ITP diagnosis based on

ASH guidelines

Platelet count < 50 x 10

9 /Land

≥ 1 prior ITP treatment

The recommended starting dose for Nplate® is 1 µg/kgbased on actual body weight. Use the actual bodyweight at initiation of therapy, then adjust the weeklydose of Nplate® by increments of 1 µg/kg until thepatient achieves a platelet count ≥ 50 x 109/L as nec-essary to reduce the risk for bleeding; do not exceeda maximum weekly dose of 10 µg/kg. In clinical stud-ies, most patients who responded to Nplate® achievedand maintained platelet counts ≥ 50 x 109/L with amedian dose of 2 µg/kg.5

Patients already receiving ITP therapies at baseline(21/157 in Nplate® group; 5/77 in SOC group) couldcontinue receiving these treatments throughout the trial.

ASH, American Society of Hematology SC, subcutaneous

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S

N

•

•

•

• To detect antibody formation, submit bloods

• Discontinue Nplate®

• Obtain CBCs, including platelet counts,w

• Most common adverse reactions (≥

Patient Population3

• The clinical diagnosis of ITP was based on aplatelet count < 150 × 109/L without any otherclearly associated cause.

• Patients must not have undergone splenectomy. • Patients with a history of ≥ 1 type of therapyfor ITP and a pretreatment platelet count of < 50 × 109/L.

• A bone marrow–biopsy specimen was requiredto confirm the diagnosis of ITP in patients > 60 years of age.

• Key exclusion criteria were previous splenecto-my, active cancer or stem cell disorder, historyof cancer, previous exposure to a thrombopoi-etin mimetic, pregnancy, and lactation.

• At the time of enrollment, patients could havebeen receiving any therapy for ITP, except ex -perimental treatments.

• Median duration of treatment for ITP at thetime of study entry was approximately 2 years,but 36% of patients (85/234) entered the studyafter having ITP for a year or less (median dura-tion in this subgroup, 0.25 years).

• Treatment groups did not differ significantly

with respect to any baseline characteristics.• Median age across the 2 groups was 57 years(with 36% of patients > 65 years of age and18% > 75 years).

Primary and Secondary End Points3

• There were 2 coprimary end points:• Incidence of treatment failure was defined asa platelet count of ≤ 20 × 109/L for 4 consec-utive weeks at the highest recommendeddose, a major bleeding event, or requirementfor a change in therapy (including splenecto-my) because of an adverse event (AE) orbleeding symptom.

• Incidence of splenectomy.• A patient who had received any study treat-ment and had then discontinued the studywas counted as having had both treatmentfailure and splenectomy.

• Secondary efficacy end points included: • Time to splenectomy • Platelet count • Platelet response (platelet count > 50 × 109/Lat any scheduled visit, excluding countsobtained after discontinuation of the ran-domized treatment or within 8 weeks afterreceipt of rescue medications)

• Safety end points: bleeding events, blood-product transfusions, and laboratory results

Study Results 3: Platelet Count Over 1 YearThe mean platelet count was higher in the romi-

plostim group than in the SOC group throughoutthe treatment period.• Platelet response from week 2 through the end ofthe 1-year treatment period ranged from 71%(108/152 patients) to 92% (127/138 patients) inthe romiplostim group and 26% (16/62 patients)to 51% (26/51 patients) in the SOC group.

• Median platelet count was 108 × 109/L to 176× 109/L in the romiplostim group and 35 ×109/L to 52 × 109/L in the SOC group.

• The mean (± standard error) weekly dose was3.9 ± 2.1 µg/kg.

Treatment Failure and SplenectomyThe incidence of treatment failure was signifi-

cantly lower among patients receiving romiplostim(18/157 [11%]) than among those receiving SOC(23/77 [30%], P < 0.001).The time to treatment failure was significantly

longer in the Nplate® group than in the SOC group(P = 0.02).Incidence of splenectomy was significantly

lower among patients receiving romiplostim(14/157 [9%]) than among those receiving SOC(28/77 [36%], P < 0.001). Time to splenectomywas also significantly longer in the romiplostimgroup than in the SOC group (P < 0.001).Throughout the study, all patients could receive

additional therapies for ITP (including short-termrescue therapies, such as intravenous immune glob-ulin, but excluding other thrombopoietin mimeticsand investigational products) if they were deemedmedically necessary by the investigator.

Platelet Count Over 1 Year

Mean (SE)

platelet cou

nt (1

09/L)

SOC n =

Nplate® n =

250

200

150

100

50

01 4 8 12 16 20 24 28 32 36 40 44 48 52

Incidence of Treatment Failure at 1 Year

Patie

nts (%

)

80

60

40

20

0Nplate® SOC

69%relative risk reduction

Odds ratio: 0.31(95% Cl:0.15–0.61)

P < 0.001

30%

11%23/77

18/157

Analysis of Additional Treatments During the Study (percentage of patients)

Patients could receive ≥1 types of SOC therapies, including watchful waiting.

Corticosteriods‡

Immunoglobulins§

Rituximab¶

Azathioprine

Danazol

Other agentsll

Platelet transfusions#

The trial design did not allow for comparison of Nplate® with individual treatments received in the SOC arm.

‡Including betamethasone, dexamethasone, methylprednisolone,prednisolone, and prednisone.

§Including anti-D immunoglobulin and intravenous immunoglobulin.

¶Rituximab is not FDA approved for treatment of ITP.

llIncluding vincristine, cyclosporine, tranexamic acid, ascorbic acid,calcium, ethamsylate, pantoprazole, and Expasyl®. (Expasyl® is aregistered trademark and entire property of Pierre Rolland.)

#Including therapeutic and prophylactic transfusions.

37%63%

7%33%

1%20%

1%9%

2%7%

6%19%

6%16%

72 68 62 59 57 54 53 54 51 51 49 51 48 38

153 150 148 148 141 137 137 135 132 135 126 127 130 122I bars indicate standard errors.

SOCNplate®

SOC

Nplate®

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Safety3

• Headache and fatigue were the most commonAEs reported during treatment.

• SAEs occurred in 23% of patients (35/154)receiving Nplate® and in 37% of patients(28/75) receiving SOC.

• Treatment-related SAEs occurred in 5% ofpatients (7/154) receiving Nplate® and 8% ofpatients (6/75) receiving SOC.

• Treatment-related SAEs reported in > 1 sub-ject in the Nplate® group included pulmonaryembolism (3 subjects) and deep vein throm-bosis (2 subjects).3

• Thrombocytopenia was the most commonSAE, occurring in 3% of patients (5/154) re -ceiving Nplate® and in 12% of patients (9/75)receiving SOC.

• The Nplate® group had significantly loweradjusted incidences of overall bleeding events(P = 0.001) and bleeding events of grade 3 orhigher (P = 0.02) as compared with the SOCgroup.

• There were no significant differences betweenthe treatment groups regarding less severebleeding (P = 0.17).

• A total of 41 blood transfusions were admin-istered to 12/154 patients (8%) receivingNplate®, and 76 blood transfusions were admin-istered to 13/75 patients (17%) receiving SOC.

• There were 3 deaths, not considered to berelated to treatment, which occurred duringthe treatment period: 1 in the Nplate® groupand 2 in the SOC group.

IndicationNplate® is a thrombopoietin receptor agonist

indicated for the treatment of thrombocytopeniain patients with chronic immune thrombocytope-nia (ITP) who have had an insufficient response tocorticosteroids, immunoglobulins, or splenectomy. Nplate® is not indicated for the treatment of

thrombocytopenia due to myelodysplastic syn-drome (MDS) or any cause of thrombocytopeniaother than chronic ITP. Nplate® should be usedonly in patients with ITP whose degree of throm-bocytopenia and clinical condition increase therisk for bleeding. Nplate® should not be used in anattempt to normalize platelet counts.

�� Important Safety Information

Risk of Progression of Myelodysplastic Syn dromes to Acute Myelogenous Leukemia• In Nplate® clinical trials of patients with my -e l o dysplastic syndromes (MDS) and severethrombo c ytopenia, progression from MDS toacute myelogenous leukemia (AML) has beenob served.

• Nplate® is not indicated for the treatment ofthrombocytopenia due to MDS or any causeof thrombocytopenia other than chronic ITP.

Thrombotic/Thromboembolic Complications• Thrombotic/thromboembolic complicationsmay result from increases in platelet countswith Nplate® use. Portal vein thrombosis hasbeen reported in patients with chronic liverdisease receiving Nplate®. Nplate® should beused with caution in patients with ITP andchronic liver disease.

• To minimize the risk for thrombotic/thrombo-embolic complications, do not use Nplate® inan attempt to normalize platelet counts.Follow the dose adjustment guidelines toachieve and maintain a platelet count of ≥ 50× 109/L.

Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis• Nplate® administration may increase the riskfor development or progression of reticulinfiber formation within the bone marrow. Thisformation may improve upon discontinuationof Nplate®.

• In a clinical study, one patient with ITP andhemolytic anemia developed marrow fibro-sis with collagen during Nplate® therapy.Clin i cal studies are in progress to assess therisk of bone marrow fibrosis and clinical con-sequences with cytopenias.

• If new or worsening morphological abnormal-ities or cytopenia(s) occur, consider a bonemarrow biopsy to include staining for fibrosis.

Worsened Thrombocytopenia after Cessation of Nplate®

• In clinical studies of patients with chronicITP who had Nplate® discontinued, four of 57patients developed thrombocytopenia ofgreater severity than was present prior toNplate® therapy. This worsened thrombocy-topenia resolved within 14 days.

• Following discontinuation of Nplate®, obtainweekly CBCs, including platelet counts, for atleast 2 weeks and consider alternative treat-ments for worsening thrombocytopenia,according to current treatment guidelines.

Lack or Loss of Response to Nplate®

• Hyporesponsiveness or failure to maintain aplatelet response with Nplate® should prompta search for causative factors, including neu-

tralizing antibodies to Nplate®. • To detect antibody formation, submit bloodsamples to Amgen (1-800-772-6436). Amgenwill assay these samples for antibodies toNplate® and thrombopoietin (TPO).

• Discontinue Nplate® if the platelet count doesnot increase to a level sufficient to avoid clin-ically important bleeding after 4 weeks at thehighest weekly dose of 10 mcg/kg.

Laboratory Monitoring• Obtain CBCs, including platelet counts,weekly during the dose adjustment phase ofNplate® therapy and then monthly followingestablishment of a stable Nplate® dose.

• Obtain CBCs, including platelet counts,weekly for at least two weeks following dis-continuation of Nplate®.

Adverse Reactions • In the placebo-controlled studies, headachewas the most commonly reported adverse drugreaction, occurring in 35% of patients receiv-ing Nplate® and 32% of patients receivingplacebo. Headaches were usually of mild ormoderate severity.

• Most common adverse reactions (≥ 5% high-er patient incidence in Nplate® versus place-bo) were arthralgia (26%, 20%), dizziness(17%, 0%), insomnia (16%, 7%), myalgia(14%, 2%), pain in extremity (13%, 5%) ,abdominal pain (11%, 0%), shoulder pain(8%, 0%), dyspepsia (7%, 0%), and paresthe-sia (6%, 0%).

Please see Brief Summary of the Prescribing In -formation on the next page.

References:1. Nugent D, McMillan R, Nichol JL, Slichter SJ. Pathogenesisof chronic immune thrombocytopenia: increased plateletdestruction and/or decreased platelet production. Br JHaematol 2009;146:585-96.

2. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostimin patients with chronic immune thrombocytopenic purpu-ra: a double-blind randomised controlled trial. Lancet 2008;371:395-403.

3. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or stan-dard of care in patients with immune thrombocytopenia. NEngl J Med 2010;363:1889-99. Kuter DJ, Rummel M, BocciaR, et al. Romiplostim or standard of care in patients withimmune thrombocytopenia. N Engl J Med 2010;363:1889-99. http://www.nejm.org/doi/full/10.1056/NEJMoa1002625.Accessed July 31, 2012.

4. Kuter DJ, Bussel JB, Newland A, et al. Long-term efficacyand safety of romiplostim treatment of adult patients withchronic immune thrombocytopenia (ITP): a final reportfrom an open-label extension study. Blood. 2010;116:Abstract 68. [Pre sented at 52nd American Society ofHematology Annual Meeting and Exposition; Orlando, FL;December 4-7, 2010.]

5. Nplate® (romiplostim) [prescribing information]. ThousandOaks, CA: Amgen.

6. Bussel JB, Kuter DJ, Pullarkat V, Lyons RM, Guo M, NicholJL. Safety and efficacy of long-term treatment with romi-plostim in thrombocytopenic patients with chronic ITP.Blood 2009;113:2161-71. [Erratum, Blood 2009b;113:4822.]

7. Provan D, Stasi R, Newland AC, et al. International con-sensus report on the investigation and management of pri-mary immune thrombocytopenia. Blood. 2010;115:168-186.

Bleeding Events

Rate of b

leed

ing even

ts

per 1

00 patient-w

eeks 1.0

0.80.6

0.4

0.20

≥ Grade 2 bleeding events

≥ Grade 3 bleeding events

34 events in 7294

patient-weeks

8 events in 7294

patient-weeks

21 events in 3050

patient-weeks

10 events in 3050

patient-weeks

Grade 2 = moderate; grade 3 = severe grade; grade 4 = life-threatening;grade 5 = fatal Rate = Adverse event rate per 100 patient-weeks on study medication. Rate was calculated by dividing the total number of reported events by thetotal number of patient-weeks and then multiplying by 100.

SOC (n=75)Nplate® (n=154)

P = 0.17

0.47

0.69

0.11

0.3367%

lessP = 0.02

S

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BRIEF SUMMARY OF PRESCRIBING INFORMATION Nplate® (romiplostim), for subcutaneous injectionWARNINGS AND PRECAUTIONSRisk of Progression of Myelodysplastic Syndromes to Acute Myelogenous LeukemiaProgression from myelodysplastic syndromes (MDS) to acute myelogenous leukemia (AML) has been observed in clinical studies with Nplate®. A randomized, double-blind, placebo-controlled study enrolling patients with severe thrombocytopenia and International Prognostic Scoring System (IPSS) low or intermediate-1 risk MDS was terminated due to more cases of AML observed in the Nplate® treatment arm. At the time of an interim analysis, among 219 MDS patients randomized 2:1 to treatment with Nplate® or placebo (147 Nplate®: 72 placebo), 11 patients showed progression to AML, including nine on the Nplate® arm versus two on the placebo arm. In addition, in peripheral blood counts, the percentage of circulating myeloblasts increased to greater than 10% in 28 patients, 25 of whom were in the romiplostim treatment arm. Of the 28 patients who had an increase in circulating myeloblasts to greater than 10%, eight of these patients were diagnosed to have AML, and 20 patients had not progressed to AML. In four patients, increased peripheral blood blast cell counts decreased to baseline after discontinuation of Nplate®. In a single-arm study of Nplate® given to 72 patients with thrombocytopenia related to MDS, eight (11%) patients were reported as having possible disease progression, and three patients had confirmation of AML during follow-up. In addition, in three patients, increased peripheral blood blast cell counts decreased to baseline after discontinuation of Nplate®. Nplate® is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP.Thrombotic/Thromboembolic ComplicationsThrombotic/thromboembolic complications may result from increases in platelet counts with Nplate® use. Portal vein thrombosis has been reported in patients with chronic liver disease receiving Nplate®. Nplate® should be used with caution in patients with ITP and chronic liver disease. To minimize the risk for thrombotic/thromboembolic complications, do not use Nplate® in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain a platelet count of 50 x 109/L [see Dosage and Administration].Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis Nplate® administration may increase the risk for development or progression of reticulin fiber formation within the bone marrow. This formation may improve upon discontinuation of Nplate®. In a clinical study, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during Nplate® therapy. Clinical studies are in progress to assess the risk of bone marrow fibrosis and clinical consequences with cytopenias.If new or worsening morphological abnormalities or cytopenia(s) occurs, consider a bone marrow biopsy to include staining for fibrosis [see Adverse Reactions]. Worsened Thrombocytopenia after Cessation of Nplate®

In clinical studies of patients with chronic ITP who had Nplate® discontinued, four of 57 patients developed thrombocytopenia of greater severity than was present prior to Nplate® therapy. This worsened thrombocytopenia resolved within 14 days. Following discontinuation of Nplate®, obtain weekly CBCs, including platelet counts, for at least 2 weeks and consider alternative treatments for worsening thrombocytopenia, according to current treatment guidelines [see Adverse Reactions].Lack or Loss of Response to Nplate®

Hyporesponsiveness or failure to maintain a platelet response with Nplate® should prompt a search for causative factors, including neutralizing antibodies to Nplate® [see Adverse Reactions]. To detect antibody formation, submit blood samples to Amgen (1-800-772-6436). Amgen will assay these samples for antibodies to Nplate® and thrombopoietin (TPO). Discontinue Nplate® if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks at the highest weekly dose of 10 mcg/kg.Laboratory MonitoringObtain CBCs, including platelet counts, weekly during the dose adjustment phase of Nplate® therapy and then monthly following establishment of a stable Nplate® dose. Obtain CBCs, including platelet counts, weekly for at least 2 weeks following discontinuation of Nplate® [see Dosage and Administration and Warnings and Precautions].

ADVERSE REACTIONSClinical Studies ExperienceSerious adverse reactions associated with Nplate® in ITP clinical studies were bone marrow reticulin deposition and worsening thrombocytopenia after Nplate® discontinuation [see Warnings and Precautions].The data described below reflect Nplate® exposure to 271 patients with chronic ITP, aged 18 to 88, of whom 62% were female. Nplate® was studied in two randomized, placebo-controlled, double-blind studies that were identical in design, with the exception that Study 1 evaluated nonsplenectomized patients with ITP and Study 2 evaluated splenectomized patients with ITP. Data are also reported from an open-label, single-arm study in which patients received Nplate® over an extended period of time. Overall, Nplate® was administered to 114 patients for at least 52 weeks and 53 patients for at least 96 weeks. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction, occurring in 35% of patients receiving Nplate® and 32% of patients receiving placebo. Headaches were usually of mild or moderate severity. Table 2 presents adverse drug reactions from Studies 1 and 2 with a 5% higher patient incidence in Nplate® versus placebo. The majority of these adverse drug reactions were mild to moderate in severity.

Table 2. Adverse Drug Reactions Identified inTwo Placebo-Controlled Studies

Among 142 patients with chronic ITP who received Nplate® in the single-arm extension study, the incidence rates of the adverse reactions occurred in a pattern similar to those reported in the placebo-controlled clinical studies.Postmarketing Experience The following adverse reactions have been identified during post approval use of Nplate®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

ImmunogenicityAs with all therapeutic proteins, patients may develop antibodies to the therapeutic protein. Patients were screened for immunogenicity to romiplostim using a BIAcore-based biosensor immunoassay. This assay is capable of detecting both high- and low-affinity binding antibodies that bind to romiplostim and cross-react with TPO. The samples from patients that tested positive for binding antibodies were further evaluated for neutralizing capacity using a cell-based bioassay.In clinical studies, the incidence of preexisting antibodies to romiplostim was 8% (43/537) and the incidence of binding antibody development during Nplate® treatment was 6% (31/537). The incidence of preexisting antibodies to endogenous TPO was 5% (29/537) and the incidence of binding antibody development to endogenous TPO during Nplate® treatment was 4% (21/537). Of the patients with positive binding antibodies that developed to romiplostim or to TPO, two (0.4%) patients had neutralizing activity to romiplostim and none had neutralizing activity to TPO. No correlation was observed between antibody activity and clinical effectiveness or safety. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay used in detection and may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to romiplostim with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONSNo formal drug interaction studies of Nplate® have been performed.USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category CThere are no adequate and well-controlled studies of Nplate® use in pregnant women. In animal reproduction and developmental toxicity studies, romiplostim crossed the placenta, and adverse fetal effects included thrombocytosis, postimplantation loss, and an increase in pup mortality. Nplate® should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.Pregnancy Registry : A pregnancy registry has been established to collect information about the effects of Nplate® use during pregnancy. Physicians are encouraged to register pregnant patients, or pregnant women may enroll themselves in the Nplate® pregnancy registry by calling

In rat and rabbit developmental toxicity studies no evidence of fetal harm was observed at romiplostim doses up to 11 times (rats) and 82 times (rabbits) the maximum human dose (MHD) based on systemic exposure. In mice at doses 5 times the MHD, reductions in maternal body weight and increased postimplantation loss occurred. In a prenatal and postnatal development study in rats, at doses 11 times the MHD, there was an increase in perinatal pup mortality. Romiplostim crossed the placental barrier in rats and increased fetal platelet counts at clinically equivalent and higher doses.Nursing MothersIt is not known whether Nplate® is excreted in human milk; however, human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Nplate®, a decision should be made whether to discontinue nursing or to discontinue Nplate®, taking into account the importance of Nplate® to the mother and the known benefits of nursing.Pediatric UseThe safety and effectiveness in pediatric patients (< 18 years) have not been established.Geriatric UseOf the 271 patients who received Nplate® in ITP clinical studies, 55 (20%) were age 65 and over, and 27 (10%) were 75 and over. No overall differences in safety or efficacy have been observed between older and younger patients in the placebo-controlled studies, but greater sensitivity of some older individuals cannot be ruled out. In general, dose adjustment for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.Renal ImpairmentNo clinical studies were conducted in patients with renal impairment. Use Nplate® with caution in this population.Hepatic ImpairmentNo clinical studies were conducted in patients with hepatic impairment. Use Nplate® with caution in this population.OVERDOSAGEIn the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In this case, discontinue Nplate® and monitor platelet counts. Reinitiate treatment with Nplate® in accordance with dosing and administration recommendations [see Dosage and Administration].Rx Only. Consult package insert for complete Prescribing Information.Manufactured by:Amgen Inc.One Amgen Center DriveThousand Oaks, California 91320-1799This product, its production, and/or its use may be covered by one or more U.S. Patents, including U.S. Patent Nos. 6,835,809, 7,189,827, 7,994,117 and 8,044,174, as well as other patents or patents pending.© 2008-2012 Amgen Inc. All rights reserved.www.nplate.comv5

Preferred Term Nplate®

(n = 84)Placebo(n = 41)

Arthralgia 26% 20%Dizziness 17% 0%Insomnia 16% 7%Myalgia 14% 2%

13% 5%Abdominal Pain 11% 0%Shoulder Pain 8% 0%

Dyspepsia 7% 0%Paresthesia 6% 0%

64256-R2-V1

• © 2012 Green Hill Healthcare Communications, LLC

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Prostate Cancer

Motor toxicities of chemothera-py-induced peripheral neu-ropathy (CIPN) are likely to

lead to falls, deficits in physical per-formance (PP), and functional losses,according to a substudy of a phase 3clinical trial in patients with CIPN re-ported at the 2012 Annual Meeting ofthe American Society of ClinicalOncology.1“This study suggests that cancer sur-

vivors who have received chemothera-py should be evaluated over time notonly for CIPN toxicities, but also forphysical functioning and falls,” citedSupriya Gupta Mohile, MD, of theUniversity of Rochester Medical Schoolin Rochester, New York. Mohile sug-gested that balance and mobility train-ing should be considered during chemo -therapy to reduce the risk of falls.Falls and PP problems are common in

cancer patients, and older patients aremore likely to fall than age-matchedpeers without cancer. Falls are a signifi-cant cause of morbidity. Prior to thisstudy, data were limited on the relation-ships between CIPN and falls, PPdeficits, and functional problems. The study enrolled 461 patients who

participated in a randomized, double-blind, placebo-controlled clinical trial

to evaluate a topical cream in cancersurvivors with CIPN. All participantshad completed chemotherapy, were noton medications for pain or neuropathy,and had self-reported painful CIPN atbaseline, as reflected by daily painscores of >4 on an 11-point scale from 0

to 10 for severity. Patients also complet-ed sensory and motor subscales of theEuropean Organisation for Researchand Treatment of Cancer quality-of-lifequestionnaire for neuropathy toxicitiesand self-reported falls. A primary outcome measure was self-

reported falls in the previous 3 months.A PP deficit was defined as finding itdifficult or being unable to perform any

of 6 physical tasks, including lifting ob-jects, walking a quarter of a mile, reach-ing arms above shoulder level, andstooping, crouching, or kneeling.Functional losses were defined as hav-ing difficulty or being unable to performany of 5 functional tasks: managingmoney, bathing, light housework, walk-ing across the room, and shopping. Patients who reported falls and/or PP

deficits were compared with those whodid not. A logistic regression analysiswas performed to examine the associa-tion of baseline characteristics andCIPN toxicities with falls, PP deficits,and functional losses. Among the studypopulation, 11.9% experienced recentfalls, 58.6% reported a PP deficit, and26.6% reported a functional loss.Patients who reported falls and/or PP

deficits were significantly more likely tobe older (P = .02), female (P = .03),have less education (P <.01), and tohave higher severity of CIPN toxicities:pain (P <.001), sensory (P <.001), andmotor (P <.001) neuropathy (in an un-adjusted analysis). Groups with fallsand/or PP deficits and without thesefactors did not differ according to can-cer and chemotherapy history. An analysis adjusted for age, gender,

race, ethnicity, marital status, educa-

tion, history of taxane therapy, previousradiation therapy, cancer diagnosis,pain, and sensory neuropathy found fac-tors independently and significantly as-sociated with falls were a history ofbreast cancer (P = .045) and motor neu-ropathy (P = .006). Factors independ-ently associated with having a PPdeficit were previous surgery (P = .013)and motor neuropathy (P <.001).Factors that were significantly associat-ed with functional losses included non-white race (P = .01), Hispanic ethnici-ty (P = .048), PP deficit (P <.0001), andmotor neuropathy (P = .0001).The study was limited by its hetero-

geneous cancer sample; its cross-sec-tional nature, which did not allow forassessment of causality and temporal re-lationships; and the self-reporting ofCIPN toxicities. Nevertheless, thestudy confirmed that CIPN toxicities,primarily motor related, are significant-ly associated with falls, PP deficits, andfunctional losses.—AG �

reference1.Mohile SG, Fan L, Gewandter JS, et al. Falls, physicalperformance deficits, and functional losses in cancer sur-vivors with chemotherapy-induced neuropathy (CIPN):a University of Rochester CCOP study. Presented at: 2012Annual Meeting of the American Society of ClinicalOncology; June 2012; Chicago, IL. Abstract 9014.

Chemotherapy-Induced peripheral NeuropathyIncreases risk of Falls and physical and Functionalproblems, especially in Older patients

Men diagnosed with low-riskprostate cancer are more likelyto choose active surveillance

as their primary treatment if their careis managed by a multidisciplinary team,according to a recent study (Aizer AA,et al. J Clin Oncol. 2012;30:3071-3076).In 2012, about 240,000 men in the

United States will be diagnosed withprostate cancer. About 70% will be lowrisk, but more than 90% of these menwill opt for definitive treatment with ra-diation or radical prostatectomy. Neitherof these treatments is superior to activesurveillance in reducing prostate can-cer–specific mortality. Active surveil-lance entails observation with moni-

toring for disease progression and initi-ating curative therapy at the earliestsign of progression.“Efforts to prevent unnecessary treat-

ment are crucial from medical, social, andeconomic standpoints,” wrote the authors.Multidisciplinary teams provide a

balanced view of the risks and benefitsof various treatment options, while asingle specialist tends to recommendthe treatment he or she is trained to de-liver, the investigators wrote.Author Jason Efstathiou, MD, Mas -

sachusetts General Hospital, Boston,and colleagues analyzed choices made by701 men with low-risk prostate cancerwho were treated at 3 different Boston

area hospitals. Low risk was defined asGleason score of 6 or less, prostate-spe-cific antigen level of 10 ng/mL or less,and clinical stage T1c or T2a.At baseline, the groups were similar

for age, comorbidity score, family histo-ry of prostate cancer, race, marital sta-tus, and annual income.One-third were managed by a multi-

disciplinary team of doctors (urologic,radiologic, and medical oncologists),and 43% of this group opted for activesurveillance rather than surgery or radi-ation. By contrast, only 22% of menseen by individual practitioners optedfor active surveillance. The proportionof men treated with radiation or prosta-

tectomy declined by about 30% in theactive surveillance group.In a multivariate analysis, older age,

being unmarried, increased comorbidi-ties, fewer positive cores on biopsy, andconsultation with a multidisciplinaryteam were significantly associated withchoice of active surveillance. Efstathiou commented that a visit to

a multidisciplinary clinic allowed thepatient to hear multiple views about ap-propriate management choices and forimproved informed decision making.He said this was the first study to showthat multidisciplinary care may reducebias of specialists toward the type of carethey deliver. �

team Approach enhances Choice of Observation inMen With low-risk prostate CancerBy Alice Goodman

Side Effect Management

Falls and physicalperformance problemsare common in cancer

patients, and olderpatients are more likely

to fall than age-matchedpeers without cancer.


SG is a 29-year-old female, recentlymarried, who was referred to the hema-tology clinic due to a platelet count of 11× 109/L. Additionally, she recently had 3nosebleeds and heavy menstrual bleeding.She had dismissed them as another sign ofstress from her hectic schedule, includingher recent wedding, teaching full-time,and evening graduate school. A detailedand extensive review of her history andphysical, serum chemistries, CBC, andperipheral smear does not reveal any po-tential underlying causes for her thrombo-cytopenia. She is negative for HCV andHIV, and her blood type is AB negative.Because her platelet count is <100 ×109/L without an identifiable cause, she isdiagnosed with primary immune throm-bocytopenia. What are considerations forappropriate first-line therapy?

Regardless of the stage of immunethrombocytopenia (ITP), previouslyreferred to as idiopathic thrombocy-topenic purpura, treatment decisionsmust take into account an individual’spreferences as well as comorbidities,bleeding, the urgency to increase theplatelet count, and potential advan-tages and adverse effects of each treat-ment. The goal of therapy is to preventmajor bleeding, and because mostmajor bleeds are associated withplatelet counts <20-30 × 109/L, treat-ment is generally instituted at aplatelet level <30 × 109/L. In this pa-tient with newly diagnosed (within 3months of diagnosis) ITP requiring ini-tial therapy, evidence-based practiceguidelines suggest prednisone 1 mg/kgdaily for 21 days with a subsequenttaper.1 Other acceptable options in-clude dexamethasone 40 mg PO dailyfor 4 days, or intravenous immunoglob-ulin (IVIg) 1 g/kg × 1; however, thelonger course of corticosteroids ispreferable due to longer response.Though anti-D Ig has demonstrated ef-ficacy, SG would not be a candidatebecause she is Rh-negative. Anti-Dtherapy also carries a risk of severe he-molysis and should be used only incarefully selected patients.1

As SG did not have any contraindica-tions to steroid therapy (eg, uncontrolleddiabetes mellitus, active infection), shereceived a 21-day course of prednisone,which was quickly tapered over the subse-

quent week. One month after startingtherapy, her platelet count increased to>100 × 109/L, with no further bleedingepisodes for the next 2 months. At thattime, her platelet count had dropped to9 × 109/L. She received IVIg 1 g/kg × 1,which increased her platelet count to 35 ×109/L one week later. Does she need fur-ther therapy, and if so, what options doesshe have at this time?

Because of her young age, lack of re-cent bleeding episodes, and plateletcount >30 × 109/L, SG does not receivefurther treatment, but again receives ex-tensive counseling regarding monitor-ing for signs and symptoms of bleedingand use of bleeding precautions.Though IVIg rapidly increases theplatelet count, response is not durable,typically lasting only 2 to 4 weeks.2 SGbegins wearing a stylish medical alertbracelet, a present from her husband.

Four months later she reports mucosalbleeding (nosebleed and gum bleeding),and her platelet count has dropped to 7 ×109/L. She and her husband are very anx-ious and would like to know her options fortreatment at this time.

The 2011 American Society ofHematology evidence-based guidelinesrecommend either a splenectomy forpatients failing corticosteroid therapy(grade 1B) or a thrombopoietin recep-tor agonist (romiplostim or eltrom-bopag) if the patient has relapsed aftersplenectomy or has a contraindicationto splenectomy and has failed ≥1 othertherapy (1B). Other options includeromiplostim or eltrombopag in a patientwho has failed ≥1 other therapy andhas not undergone splenectomy, or ri - tuximab in a patient who has failed ≥1other therapy such as corticosteroids,IVIg, or splenectomy, though the

strength of these recommendations islower (grade 2C).1For several decades, splenectomy has

been considered the gold standard forsecond-line treatment of ITP. Themajor advantage of a splenectomy isthat approximately two-thirds of pa-tients achieve a long-term response ofat least 5 to 10 years.3 Laparoscopicsplenectomy is associated with fewer

complications than open splenectomyand is often the preferred approach inappropriate patients. The major risks as-sociated with splenectomy includebleeding and infections. Additionalcom plications include transfusion-relat-ed adverse events, thrombosis requiringanticoagulant therapy, adhesions/ob-struction, hernia formation, and nervepalsies. To minimize risk of infection, allpatients should receive recommendedimmunizations preoperatively (at leastpneumococcal, meningococcal, andHaemophilus influenzae) as well as exten-sive counseling regarding the need forearly detection and treatment for infec-tions.4 Because patients may sponta-neously go into remission, splenectomymay be deferred until 1 to 2 years afterdiagnosis, but there are no specific rec-ommendations for optimal timing. Thispatient is young and without comor-bidities, and she would likely tolerate asplenectomy.

Though splenectomy is not a con-traindication, SG does not want to un-dergo surgery at this time, due to her busywork and school schedules. She and herhusband have done much research on theInternet and have many questions aboutthe potential benefits and risks associatedwith the thrombopoietin receptor ago-nists. She is 7 months postdiagnosis and isconsidered to have persistent ITP, as shehas not had a spontaneous remission or a

complete response to therapy. What areconsiderations before initiating romi-plostim or eltrombopag therapy?

Both romiplostim and eltrombopaghave demonstrated efficacy in bothsplenectomized and nonsplenectomizedpatients.5,6 In a prospective, random-ized, open-label study of 234 patientswith ITP without splenectomy, Kuterand colleagues assigned 157 patients toweekly romiplostim and 77 patients tostandard of care for 52 weeks.6 Thetreatment in the standard-of-care armwas left to the investigator’s decision.The group receiving romiplostim ex-hibited a significantly lower incidenceof treatment failure than those receiv-ing standard of care (11% vs 30%, re-spectively; P <.001), and they were lesslikely to require a splenectomy (9% vs36%, respectively; P <.001). The rateof platelet response (to a level >50 ×109/L) was 2.3 times that in the stan-dard-of-care arm, and fewer patients re-quired blood transfusions (8% vs 17%).At any given time between weeks 2 and52, 71% to 92% of patients had an ade-quate platelet response. This study didallow short-term treatment with othertherapies (most commonly glucocorti-coids), which was required in 44% ofthe romiplostim group versus 79% ofthose receiving standard of care.

Despite the evidence that romi-plostim is effective, there are importantconsiderations before initiating thera-py. Romiplostim is given as a subcuta-neous injection and requires weeklyplatelet counts until dosage is stabi-lized. For some, this may be an incon-venience or burden that would rule outthis therapy. Compliance is particularlyimportant, because upon discontinua-tion of romiplostim, the platelet countwill likely drop, in some cases to levelslower than when initiated. Cost is usu-

Considerations for treatment of Immunethrombocytopenia

By Kathy Hogan Edwards, PharmD, BCPSClinical Pharmacy SpecialistHollings Cancer CenterMedical University of South CarolinaCharleston, South Carolina

Immune Thrombocytopenia

Treatment decisions must take into account anindividual’s preferences as well as comorbidities,

bleeding, the urgency to increase the platelet count, and potential advantages and adverse effects

of each treatment.

Both romiplostim andeltrombopag have

demonstrated efficacy inboth splenectomized and

nonsplenectomizedpatients.


ally an additional factor, and dependingon the insurance coverage and copays,the patient may be responsible for ex-traordinary out-of-pocket copays. Thereare excellent patient assistance pro-grams to help qualified patients withexpenses, and these should be fully in-vestigated before ruling out this therapybased on cost alone.For most people receiving romi-

plostim, the dose usually stabilizes afterthe first 12 weeks or so, and frequencyof platelet counts may be extended toonce every 4 weeks. In an open-labelextension study, 63% of patients werestabilized on a dosage and were able toself-administer romiplostim at home.7Although this would provide a con-venient option for appropriate pa-tients, self-administration of romi-plostim is not approved by the USFood and Drug Administration at thistime.8 From 2008 to 2011, romiplostimwas available only through the restric-tive Nplate NEXUS (REMS) Program,which required enrollment of the pa-tient, prescriber, and pharmacy. Sincetermination of the program in 2011,however, any prescriber or institutioncan now order romiplostim, allowingfor greater flexibility for patients to ob-tain treatment.9In the short term, romiplostim is well

tolerated, with primary side effectsbeing headache, fatigue, arthralgia, in-somnia, myalgia, and dyspepsia.8 A sig-nificant concern is formation of retic-ulin and development of fibrosis in thebone marrow; the long-term incidenceand significance of this is unknown atthis time.8 Other serious, yet rare, po-tential risks include development ofthrombosis from elevated counts. Forthese reasons, romiplostim should beused only at the lowest dosage necessaryto minimize bleeding by maintainingthe platelet count >50,000 × 109; it isnot the goal of romiplostim therapy tonormalize the platelet count.8Another concern for this patient is

that romiplostim is not indicated dur-ing pregnancy and should be discon-tinued beforehand. Romiplostim cross-es the placenta, though the effects onthe fetus are unknown at this time.8Current evidence-based guidelines sug-gest treatment with corticosteroids orIVIg during pregnancy and lactation.1There are a multitude of additionalconsiderations regarding ITP and preg-nancy and delivery, and these shouldbe discussed and planned for with ex-perienced physicians.In addition to romiplostim, several

other second-line treatment optionsare available to treat ITP, including el-trombopag, rituximab, azathioprine,cyclosporine A, cyclophosphamide,mycophenolate mofetil, danazol, dap-sone, vinblastine, and vincristine.1,2Eltrombopag, an oral agent taken oncedaily, also demonstrates efficacy and

toxicities similar to romiplostim, withthe exception of an increased incidenceof elevated liver function tests, requir-ing close monitoring.1,3 Rituximab, aCD20 monoclonal antibody typically

administered once weekly for 4 weeks,also has demonstrated efficacy, with re-ports of long-term response. Concernswith rituximab include infusion reac-tions and increased infections.3Many ofthe studies for the additional agents aresmall and nonrandomized, using manydifferent inclusion, exclusion, and as-sessment criteria. Thus, the heterogene-ity of the data makes it difficult to con-

fidently predict outcomes with many ofthese treatment options. Fortunately for patients with ITP,

there are more options than ever fortreatment. When deciding on a courseof therapy, the pros and cons of eachoption should be discussed with the pa-tient, and a realistic plan should be for-mulated. Treatment decisions may beheavily influenced by patient prefer-ences, as well as lifestyle, socioeconom-ic, and other practical considerations, inaddition to existing comorbidities. Aswe do not have a means to predict whowill have the best responses with theleast toxicity, the approach to ITP treat-ment remains individualized.3

SG and her husband elect to begintherapy with romiplostim. She worksnear the clinic, and brief weekly visits willnot be a burden, particularly if she hasher platelet count drawn the day beforeher injection, omitting the need to waitfor results. Her insurance covers the costswith minimal copay. The couple are dili-gent about using effective contraceptionand do not plan to have children for a fewyears. They continue to hope she willachieve a remission and that the romi-

plostim will buy them this time to perhapsavoid splenectomy, to plan for splenecto-my at a better time, or to await for addi-tional treatment options. �

references1.Neunert C, Lim W, Crowther M, et al. The AmericanSociety of Hematology 2011 evidence-based practiceguideline for immune thrombocytopenia. Blood. 2011;117(16):4190-4207.2. Provan D, Stasi R, Newland AC, et al. Internationalconsensus report on the investigation and managementof primary immune thrombocytopenia. Blood. 2010;115(2):168-186.3. Ghanima W, Godeau B, Cines DB, et al. How I treatimmune thrombocytopenia: the choice betweensplenectomy or a medical therapy as a second-line treat-ment. Blood. 2012;120(5):960-969.4. Stasi R, Newland A, Thornton P, et al. Should med-ical treatment options be exhausted before splenectomyis performed in adult ITP patients?: a debate. AnnHematol. 2010;89(12):1185-1195.5. Imbach P, Crowther M. Thrombopoietin-receptor ag-onists for primary immune thrombocytopenia. N Engl JMed. 2011;365(8):734-741.6. Kuter DJ, Rummel M, Boccia R, et al. Romiplostimor standard of care in patients with immune thrombo-cytopenia. N Engl J Med. 2010;363(20):1889-1899.7. Bussel JB, Kuter DJ, Pullarkat V, et al. Safety and ef-ficacy of long-term treatment with romiplostim inthrombocytopenic patients with chronic ITP. Blood.2009;113(10):2161-2171.8. Nplate [package insert]. Thousand Oaks, CA:Amgen Inc; December 2011.9. Amgen Inc. Important prescribing information:Nplate® (romiplostim) REMS Program (Nplate®NEXUS Program): elimination of prescriber, institu-tion, and patient enrollment requirements to prescribeand receive Nplate; serious risks associated with Nplate[letter]. http://www.amgen.com/pdfs/products/Nplate_REMS_DHCP_12-06-2011.pdf. Published December 6,2011. Accessed September 4, 2012.

Immune Thrombocytopenia

SAVE THE DATE

July 26-28, 2013Hyatt Regency La Jolla at Aventine3777 La Jolla Village Drive San Diego, California

Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma Squamous Cell Carcinoma • Merkel Cell Carcinoma

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SECOND ANNUAL CONFERENCE

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When deciding on acourse of therapy, thepros and cons of each

option should bediscussed with the

patient, and a realisticplan should be

formulated.


Noteworthy Numbers

The ratio is 1:6 that a manwill be diagnosed withprostate cancer in his life-time.

More than 80% of thoseprostate cancer diagnosesare made in patients aged65 years or older.

Overall, approximately241,740 men in the US willbe diagnosed with prostatecancer in 2012.

The ratio of men who willdie of prostate cancer is1:36.

Thus, the number of deathsfrom prostate cancer in2012 in the US is estimatedto be 28,170.

Compared with white men,African American men aremore likely to be diagnosedwith prostate cancer andhave a mortality rate 2times higher.

As researchers strive for acure, prostate cancer treat-ments—including newdrugs, surgical approaches,and improved radiothera-py—continue to expand.Due to these medical advances and others, thereare more than 2.5 millionmen diagnosed withprostate cancer in the USwho are still alive today.

However, estimates showthat about 20% to 30% ofmen will relapse 5 yearsafter initial treatment andbegin to show signs ofdisease recurrence.

Therefore, most doctorsrecommend prostate-spe-cific antigen tests aboutevery 6 months for the first5 years after treatment,and at least yearly afterthat.

Sourceshttp://www.cancer.net/cancer-types/prostate-cancer/statistics; http://www.cancer.org/Cancer/ProstateCancer/DetailedGuide/prostate-cancer-key-statistics; http://www.cancer.net/cancer-types/prostate-cancer/risk-factors-and-prevention; http://seer.cancer.gov/statfacts/html/prost.html;http://www.pcf.org/site/c.leJRIROrEpH/b.5822791/k.1DC2/Recurrence.htm; http://www.cancer.org/Cancer/ProstateCancer/DetailedGuide/prostate-cancer-after-follow-up.

Although the 10-year survival rate for prostate cancer is 98%, the disease is still the second leading cause of cancer death for men in the United

States. With each new treatment developed, vaccine examined, and screening test created, scientists draw closer to the day when the survival rate

for all patients with prostate cancer will be 100%. The following numbers reflect today’s prostate cancer statistics.

�� Editor in ChiefSagar Lonial, MDProfessorVice Chair of Clinical AffairsDepartment of Hematology and Medical OncologyWinship Cancer InstituteEmory University School of Medicine

Editor in ChiefStephanie A. Gregory, MDThe Elodia Kehm Chair of Hematology Professor of MedicineDirector, Lymphoma ProgramRush University Medical Center/Rush University

Topics include:• Newly Diagnosed Patients• Maintenance Settings• Transplant-Eligible and -Ineligible Patients• Retreatment Settings• Bone Health

Newsletter Series

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Topics include:• Mantle Cell Lymphoma• Follicular Lymphoma

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AccreditationThese activities will be accredited for physicians, nurses, and pharmacists.

For complete accreditation information, please refer to each activity.

This activity is jointly sponsored by Medical Learning Institute, Inc.and Center of Excellence Media, LLC.

ALL NEW CONTENT FOR 2012

YOUR QUESTIONS ANSWERED

COEAsize71912AskExperts

These activities are supported by educational grants from Millennium: The Takeda Oncology Company

and Spectrum Pharmaceuticals.

These activities are supported by educational grants from Millennium: The Takeda Oncology Company

and Celgene Corporation.

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CONTINUING EDUCATION

CONSIDERATIONSINLymphoma™

4th Annual

ASK THE EXPERTS: Follicular Lymphoma

Christopher R. Flowers, MD, MS Associate Professor of Hematology and Medical Oncology Emory School of MedicineWinship Cancer InstituteAtlanta, GA

Supported by educational grants fromMillennium: The Takeda Oncology Company

and Spectrum Pharmaceuticals

PUBLISHING STAFF

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LETTER FROM THE EDITOR-IN-CHIEF

According to recent estimates from the American Cancer Society, approximately 70,130 individuals will be diagnosedwith non-Hodgkin lymphoma (NHL) in 2012 and about 18,940 deaths will be attributed to the disease. There has beensignificant progress in the treatment of these hematologic malignancies, including the development and approval of new,highly effective therapies. However, more progress is needed and numerous questions remain unanswered regarding theapplication and interpretation of recent clinical advances.The goal of our 4th annual “Considerations in Lymphoma” newsletter series is to provide clinicians with the latest evi-

dence-based strategies for managing NHL in the era of novel agents. To address the needs of key members of the interdis-ciplinary team, frequently asked questions have been posed to physicians, midlevel providers, and pharmacists from leadingcancer centers specializing in the treatment of lymphoma. In this second issue, experts from Winship Cancer Institute atEmory University discuss the effective management of follicular lymphoma. It is our hope that the insight, knowledge, andprofessional experience offered by these professionals will facilitate the optimal care of your patients with NHL.

Sincerely,

Stephanie A. Gregory, MDThe Elodia Kehm Chair of HematologyProfessor of MedicineDirector, Lymphoma ProgramRush University Medical Center/Rush UniversityChicago, IL

This activity is jointly sponsored by Medical Learning Institute, Inc., and Center of Excellence Media, LLC.

FACULTY

SEPTEMBER 2012 • VOLUME 4 • NUMBER 2

Loretta J. Nastoupil, MD Hematology/Oncology FellowEmory School of Medicine, Winship Cancer InstituteAtlanta, GA

Lisa Anderson, RN, BSN, OCNClinic NurseEmory Bone Marrow and Stem Cell Transplant CenterWinship Cancer InstituteAtlanta, GA

Nassoma King, PA-CPhysician AssistantWinship Cancer InstituteEmory UniversityAtlanta, GA

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CONSIDERATIONS IN LYMPHOMA

IntroductionOver the past several years, the treatment paradigm for patients

with follicular lymphoma (FL) has undergone significant changes, with

the development of effective new agents that are now being used

in the frontline, maintenance, and relapsed settings. Although these

new therapies have led to improvements in patient outcomes,

numerous questions remain regarding their optimal use. In this article,

Christopher Flowers, MD, MS and Loretta Nastoupil, MD, discuss results

from recent clinical trials evaluating novel agents and combination

regimens for FL and provide their professional insights on future direc-

tions related to the management of this disease.

Is there a standard approach to the initial treatment of patientswith FL?

The American Cancer Society estimates that 70,130 new cases of non-Hodgkin lymphoma (NHL) and 18,940 NHL-related deaths will occur in2012 in the United States.1 FL is the second most frequently occurring NHLsubtype worldwide, with an increasing incidence in Western nations over the

last 2 decades.2 It accounts for approximately 22% of all NHLs.2 Most patientswith FL have stage III or IV disease at the time of diagnosis.3,4

Depending on stage and presenting characteristics, there are numerousavailable options for the initial management of FL. These include observation(ie, watchful waiting), radiation alone, single-agent chemotherapy, single-agent rituximab, and rituximab-chemotherapy combinations (ie, immuno -chemotherapy).5 According to data from the National LymphoCare Study(NLCS), there is no single standard of care for frontline management of FL inthe United States.6

Stage I/II FL is often managed with radiation therapy, based on observation-al studies indicating long-term disease-free survival for select patients.5 Forexample, a British National Lymphoma Investigation study reported that, fol-lowing radiation therapy for stage I FL, relapse was rare after 10 years of fol-low-up.7 However, emerging data on practice patterns from the NLCS suggestthat other management strategies for patients with localized disease may pro-duce outcomes similar to those achieved with radiation.8

Regarding stage III/IV disease, preliminary NLCS data also indicate thatoutcomes for patients with high-risk scores on the Follicular LymphomaInternational Prognostic Index (FLIPI) differ depending on the type ofimmunochemotherapy selected.9,10 For high-risk FLIPI patients, rituximabplus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)improves progression-free survival (PFS) and overall survival (OS) comparedwith rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP).9,10 A third combination, rituximab plus fludarabine, produces a signifi-cantly longer PFS and time to next treatment compared with R-CVP; how-ever, it is also associated with more frequent treatment discontinuation.10 The

New Treatment Paradigms inFollicular Lymphoma

Christopher R. Flowers, MD, MS1 and Loretta Nastoupil, MD2

1Associate Professor of Hematology and Medical Oncology,Emory School of Medicine, Winship Cancer Institute, Atlanta, GA; 2Hematology/Oncology Fellow, Emory University, Winship Cancer Institute, Atlanta, GA

SponsorThis activity is jointly sponsored by Medical Learning Institute Inc andCenter of Excellence Media, LLC.

Target AudienceThe activity was developed for physicians, nurses, and pharmacistsinvolved in the treatment of patients with follicular lymphoma.

Educational ObjectivesUpon completion of this activity, the participant will be able to:• Review current and novel treatment approaches for optimizing clinicaloutcomes in patients with follicular lymphoma (FL)

• Summarize expert guideline recommendations and clinical trial datato determine appropriate treatment plans for patients with newlydiagnosed and relapsed/refractory FL

• Formulate strategies for incorporating consolidation and maintenancetherapy in appropriate patients with FL

• Discuss clinical issues of importance in the treatment paradigm for FL,including the timing of initial therapy, the role of transplantation, andthe management of adverse events

Commercial Support AcknowledgmentThis activity is supported by educational grants from Millennium: TheTakeda Oncology Company and Spectrum Pharmaceuticals.

Instructions for Credit

There is no fee for this activity. To receive credit after reading this CME/CEactivity in its entirety, participants must complete the pretest, posttest, andevaluation. The pretest, posttest, and evaluation can be completed online atwww.mlicme.org/P12031.html. Upon completion of the evaluation andscoring 70% or better on the posttest, you will immediately receive your cer-tificate online. If you do not achieve a score of 70% or better on the posttest,you will be asked to take it again. Please retain a copy of the Certificate foryour records.

For questions regarding the accreditation of this activity, please contactMLI at 609-333-1693 or [email protected].

Physician Credit DesignationThe Medical Learning Institute Inc designates this enduring material fora maximum of 1.0 AMA PRA Category 1 Credits™. Physicians shouldclaim only the credit commensurate with the extent of their participationin the activity. This activity has been planned and implemented in accor-

dance with the Essential Areas and policies of the Accredi tation Councilfor Continuing Medical Education (ACCME) through the joint sponsor-ship of the Medical Learning Institute Inc and the Center of ExcellenceMedia, LLC. The Medical Learning Institute Inc is accredited by theACCME to provide continuing medical education for physicians.

Registered Nurse DesignationMedical Learning Institute IncProvider approved by the California Board of Registered Nursing, Pro -vider Number 15106, for 1.0 contact hour.

Registered Pharmacy DesignationMedical Learning Institute Inc is accredited by the Accredi tationCouncil for Pharmacy Education (ACPE) as a provider of continu-

ing pharmacy education. Completion of this knowledge-based activity pro-vides for 1.0 contact hour (0.1 CEU) of continuing education credit. Theuniversal activity number for this activity is 0468-9999-12-027-H01-P.

DisclosuresBefore the activity, all faculty and anyone who is in a position to have con-trol over the content of this activity and their spouse/life partner will dis-close the existence of any financial interest and/or relationship(s) theymight have with any commercial interest producing healthcare goods/ser-vices to be discussed during their presentation(s): honoraria, expenses,grants, consulting roles, speakers’ bureau membership, stock ownership, orother special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vettedby Medical Learning Institute Inc for fair balance, scientific objectivity ofstudies mentioned in the materials or used as the basis for content, andappropriateness of patient care recommendations.

Planners’ and Managers’ DisclosuresDana Delibovi, Medical Writer, has nothing to disclose.William J. Wong, MD, MLI Reviewer, has nothing to disclose.Ryan Sims, CRNA, MS, MLI Reviewer, has nothing to disclose.Shelley Chun, PharmD, MLI Reviewer, has nothing to disclose.

Faculty DisclosuresStephanie A. Gregory, MD, is on the advisory board for Genentech/Roche, and Spectrum Pharmaceuticals, and on the data safety monitor-ing board for Genentech/Roche.*Christopher R. Flowers, MD, MS, is a consultant for Celgene,Genentech/Roche, and Millennium: The Takeda Oncology Company,

and has re ceived research support from Celgene, Gilead Sciences,Janssen Biotech, and Millennium: The Takeda Oncology Company.

Loretta Nastoupil, MD, is a consultant for Genentech/Roche.

Lisa Anderson, RN, BSN, OCN, has nothing to disclose.

Nassoma King, PA-C, has nothing to disclose.

*Content will include non–FDA-approved uses.

The associates of Medical Learning Institute Inc, the accreditedprovider for this activity, and Center of Excellence Media, LLC, do nothave any financial relationships or relationships to products or deviceswith any commercial interest related to the content of this CME/CEactivity for any amount during the past 12 months.

Disclaimer The information provided in this CME/CE activity is for continuingeducation purposes only and is not meant to substitute for the inde-pendent medical judgment of a healthcare provider relative to diagnos-tic and treatment options of a specific patient’s medical condition. Rec -ommendations for the use of particular therapeutic agents are based on the bestavailable scientific evidence and current clinical guidelines. No bias toward orpromotion for any agent discussed in this program should be inferred.

Agenda: 1 hourArticles/Commentaries: 45 minutesEvaluation/Posttest: 15 minutes

Date of original release: September 14, 2012Valid for CME/CE credit through: September 14, 2013

SCAN HERE to Download the PDF or Apply for Credit.

To use 2D barcodes, download the ScanLife app:• Text “scan” to 43588• Go to www.getscanlife.com on your smartphone’s

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above findings have been corroborated by a secondary analysis of the PrimaryRituximab and Maintenance (PRIMA) trial, which reported that R-CHOPproduces both higher response rates and longer PFS than does R-CVP, withcomparable tolerability.11

Recent findings from the FOLL05 study, a clinical trial evaluating frontlineimmunochemotherapy regimens, provided a definitive comparison.12 In thisstudy, previously untreated patients with advanced-stage FL (N=534;178/arm), the majority of whom had high-risk FLIPI scores, were randomlyassigned to receive R-CVP, R-CHOP, or rituximab plus fludarabine andmitoxantrone (R-FM), with no maintenance therapy. Significant differencesbetween regimens—favoring R-CHOP and R-FM—were observed in terms of3-year time to treatment failure (TTF), the primary endpoint (Figure). Thetrial also showed superior 3-year PFS with R-CHOP and R-FM compared withR-CVP; 3-year OS rates, on the other hand, were comparable among groups.Unfortunately, R-FM was associated with a higher rate of grade 4 neutropeniathan R-CVP or R-CHOP (64%, 28%, and 50%, respectively).Rummel and colleagues investigated a regimen of bendamustine plus ritux-

imab (BR) versus R-CHOP for indolent lymphomas (FL and other subtypes,N=549), with favorable outcomes.13,14 At a median follow-up of 45 months,median PFS was 69.5 in the BR group versus 31.2 months in the R-CHOPgroup, representing a significant prolongation of PFS with BR (P<.001).14 Inthe FL subgroup, PFS benefit was independent of FLIPI risk.14 In comparisonto R-CHOP, BR was associated with less hematologic toxicity and no alopeciagreater than grade 1.13 No significant difference in OS was reported betweengroups, although the authors suggest that interpretation of OS may be con-founded by the fact that 21% of patients treated with R-CHOP also receivedBR as a salvage treatment.14 Although the FL cohort undergoing collection inthis trial was small, results showed that stem cells could be harvested ade-quately from patients treated with either regimen. In addition, the occurrenceof second malignancies, including myelodysplastic syndromes and acutemyeloid leukemia, were similar in both groups.

What are the latest data on maintenance and consolidation strate-gies in FL?

Results from the PRIMA trial showed significant improvements in PFS withrituximab maintenance versus observation following first-line induction with a

variety of immunochemotherapy regimens.15 Although BR was not one of theinduction regimens offered in PRIMA, an ongoing trial by the EasternCooperative Oncology Group (ECOG) is evaluating the safety and efficacy ofthis combination, followed by maintenance rituximab with or without lenalido-mide.16 This randomized phase 2 trial (ECOG E2408) is enrolling high-riskpatients with FL who will be randomized to either BR followed by rituximabmaintenance; bortezomib, bendamustine, and rituximab (VBR) followed by rit-uximab maintenance; or BR followed by maintenance with lenalidomide plusrituximab (RR).16 Study results should be available for analysis by August 2016.The phase 3 ECOG 4402 RESORT trial was designed to determine whether

a maintenance rituximab strategy following induction rituximab couldimprove TTF compared with a rituximab retreatment strategy in patients withlow tumor burden FL.17 At 3 years of follow-up, 95% of patients receivingmaintenance rituximab and 86% of patients randomized to rituximab retreat-ment remained free of cytotoxic chemotherapy. However, the authors report-ed that rituximab retreatment was as effective as maintenance rituximab interms of TTF, which was the primary endpoint of this study, and was the pre-ferred strategy for this patient population.Radioimmunotherapy (RIT), which combines a radiation-emitting radio -

nuclide with an antibody, continues to be evaluated as consolidation in FL. Inthe FIT trial, 414 patients with advanced-stage FL, who had achieved a com-plete response (CR)/unconfirmed complete response (CRu) or partial re -sponse (PR) to frontline chemotherapy (with or without rituximab), were ran-domized to either 90Y-ibritumomab tiuxetan (90Y-IT) or observation. In thistrial, only 31 patients received rituximab-based frontline therapy.

Patients in the 90Y-IT consolidation arm had a high conversion rate fromPR to CR/CRu (77%) and a high overall CR rate (89%). RIT consolidationalso significantly prolonged median PFS compared with no further treatmentin patients who were responsive to frontline therapy.18 For all patients, at 8years of follow-up, 41% who received consolidation were still free of relapsecompared with 22% in the control group. There was no statistically significantdifference between groups regarding the occurrence of secondary malignan-cies. There was also no difference in OS.

What treatment options are available for patients in the relapsedsetting?

Despite the substantial improvements in PFS with frontline immuno -chemo therapy and maintenance regimens, nearly all patients with FL eventu-ally relapse. Therefore, strategies aimed at treating relapsed disease are thefocus of numerous investigations. Allogeneic stem cell transplantation (allo-SCT) is the only approach that is demonstrably curative.5 However, it carriessignificant morbidity and mortality risks and is therefore reserved for young,highly motivated patients with relapsed or resistant FL. Alternatively, reducedintensity conditioning (RIC) regimens are associated with lower transplant-related mortality. For example, single-center studies and registry analyses indi-cate that long standing disease control can be achieved in 40% to 75% ofpatients with FL following RIC and allo-SCT.19 Therefore, this appears to bea promising approach for select populations of patients.19,20

Figure. Comparison of immunochemotherapy regimens forfrontline therapy of advanced FL: results of FOLL05.12

FL indicates follicular lymphoma; OS, overall survival; R-CHOP, rituximab, cyclophosphamide,doxorubicin, vincristine, prednisone; R-CVP, rituximab, cyclophosphamide, vincristine, prednisone; R-FM, rituximab, fludarabine, mitoxantrone; TTF, time to treatment failure.

Patie

nts

(%)

100

80

60

40

20

0

P=0.021

P=0.007 P=0.969

46%

64% 61%

98% 95% 93% R-CVPR-CHOPR-FM

3-Year TTF 3-Year OS

Despite the substantial improvements in PFS with frontline immuno chemo therapy and maintenance regimens, nearly all patients with FL eventually relapse.

� ��



Regimens using molecularly targeted agents, such as bortezomib andlenalidomide, have also emerged as useful options in the management ofrelapsed FL. For example, in the phase 2 VERTICAL trial, treatment withVBR was shown to be active in previously treated patients, producing an 88%overall response rate (ORR), a 53% CR rate, and a median PFS of 14.9months.21 A randomized trial in recurrent FL from the Cancer and LeukemiaGroup B (CALGB 50401) reported that RR yielded a greater response rateand a longer event-free survival than single-agent rituximab (Table).22

In addition, several novel antibody therapies are being studied in FL. Recenttrials include a phase 1/2 study of veltuzumab in relapsed/refractory B-cellNHL, including 55 FL patients, showing good response with no adverse eventsgrade 3 or higher, despite short infusion times.23 Subcutaneous dosing of thisagent is also being explored.24 Ofatumumab has shown activity in patients withrituximab-refractory FL25 and has also yielded promising results in frontline usewith CHOP.26 It is still uncertain as to whether the efficacy of adding an anti-body to chemotherapy is a class effect common to all B-cell–targeted antibod-ies. This question will remain unanswered pending randomized trials compar-ing the monoclonal antibody rituximab to other antibodies plus chemotherapy.In addition, defining the mechanisms of action and resistance for emergingantibodies across lymphoma subtypes will become increasingly important.Another intriguing approach to the treatment of FL is the use of drugs that

target B-cell receptor signaling. CAL-101 (GS-1101) is an orally bioavailable,small-molecule inhibitor that selectively targets phosphatidylinositol 3-kinase-delta, which regulates survival and proliferation of normal and malig-nant B cells.27 An early phase 1 study of this inhibitor demonstrated substan-tial clinical activity in patients with hematologic malignancies.27 In asubsequent phase 1 study that evaluated CAL-101 in combination with ritux-imab, bendamustine, or both drugs in patients with extensively pretreatedindolent NHL, all evaluable patients had reductions in lymphadenopathy,resulting in an ORR of >65% for all regimens.7 CAL-101 is thus an attractiveagent, given its reported favorable safety profile28 and lack of overlapping tox-icity, allowing delivery at a full single-agent dose even when coadministeredwith immunochemotherapy in heavily pretreated patients.PCI-32765 is an orally bioavailable, small-molecule inhibitor of Bruton’s

tyrosine kinase, a downstream mediator of B-cell receptor signaling.29 A phase1 study of PCI-32765 in patients with relapsed/refractory B-cell malignanciesreported a 43% ORR.29 Durable responses occurred at all dose levels andacross various histologic subtypes, irrespective of pretreatment risk factorssuch as performance status, lactate dehydrogenase levels, or disease burden.With its good safety profile and lack of cumulative hematologic toxicities,PCI-32765 warrants further studies in patients with FL. It is hoped that thesestudies, along with those of other novel agents, will reveal new strategies thatcontinue to enhance outcomes in FL. �

References1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012.2. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s

lymphoma: The Non-Hodgkin’s Lymphoma Classification Project. Blood. 1997;89:3909-3918.3. Smith SM. What is the best strategy for incorporating new agents into the current treatment of

follicular lymphoma? ASCO Educational Book. 2012:481-487.4. Solal-Céligny P, Roy P, Colombat P, et al. Follicular Lymphoma International Prognostic Index.

Blood. 2004;104:1258-1265.5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN

Guidelines®): Non-Hodgkin’s Lymphoma. Version 3.2012. www.nccn.org. Accessed May 14, 2012.6. Friedberg JW, Taylor MD, Cerhan JR, et al. Follicular lymphoma in the United States: first report

of the National LymphoCare Study. J Clin Oncol. 2009;27:1202-1208.7. Vaughan Hudson B, Vaughan Hudson G, MacLennan KA, Anderson L, Linch DC. Clinical stage 1

non-Hodgkin’s lymphoma: long-term follow-up of patients treated by the British NationalLymphoma Investigation with radiotherapy alone as initial therapy. Br J Cancer. 1994;69:1088-1093.

8. Friedberg JW, Byrtek M, Link BK, et al. Effectiveness of first-line management strategies for stageI follicular lymphoma: analysis of the National LymphoCare Study [published online ahead of printAugust 20, 2012). J Clin Oncol. doi:10.1200/JCO.2011.40.6546.

9. Nastoupil L, Sinha R, Byrtek M, et al. A comparison of the effectiveness of first-line chemoim-

munotherapy regimens for follicular lymphoma (FL) used in the United States. Blood (ASHAnnual Meeting Abstracts). 2011;118:Abstract 97.

10. Nastoupil L, Sinha R, Byrtek M, et al. Effectiveness of first-line chemoimmunotherapy regimens forpatients diagnosed with follicular lymphoma (FL) in the US: data from the National LymphoCareStudy (NLCS). Haematologica (EHA Annual Meeting Abstracts). 2012;97:Abstract 0800.

11. Morschhauser F, Seymour J, Feugier P, et al. Impact of induction chemotherapy regimen on response,safety and outcome in the PRIMA Study. Ann Oncol (ICML Annual Meeting Abstracts). 2011;22(suppl 4):Abstract 022.

12. Federico M, Luminari S, Dondi A, et al. R-CVP versus R-CHOP versus R-FM as first-line therapyfor advanced-stage follicular lymphoma: final results of FOLL05 trial from the Fondazione ItalianaLinfomi (FIL). J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(15 suppl):Abstract 8006.

13. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respectof progression free survival and CR rate when compared to CHOP plus rituximab as first-line treat-ment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of arandomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood(ASH Annual Meeting Abstracts). 2009;114:Abstract 405.

14. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab (B-R) versus CHOPplus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lym-phomas (MCL): updated results from the StiL NHL1 study. J Clin Oncol (ASCO Annual MeetingAbstracts). 2012;30(15 suppl):Abstract 3.

15. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with hightumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): aphase 3, randomised controlled trial. Lancet. 2011;377:42-51.

16. National Cancer Institute. Bendamustine hydrochloride and rituximab with or without bortezomibfollowed by rituximab with or without lenalidomide in treating patients with high-risk stage II, stageIII, or stage IV follicular lymphoma (E2408). www.clinicaltrials.gov. Accessed August 10, 2012.

17. Kahl BS, Hong F, Williams ME, et al. Results of Eastern Cooperative Oncology Group Protocol E4402(RESORT): a randomized phase III study comparing two different rituximab dosing strategies for lowtumor burden follicular lymphoma. Blood (ASH Annual Meeting Abstracts). 2011;118:LBA 6.

18. Morschhauser F. Y-90 Ibritumomab tiuxetan consolidation in follicular lymphoma: the 7-year up -date of the FIT trial. Oral presentation at: 17th Congress of the European Hematology Association(EHA); June 14-17, 2012; Amsterdam, the Netherlands.

19. Dreger P. Role of allotransplantation for non-Hodgkin lymphoma and chronic lymphocyticleukemia. Ann Oncol. 2011;22(suppl 4):iv36-iv39.

20. Khouri IF, McLaughlin P, Saliba RM, et al. Eight-year experience with allogeneic stem cell trans-plantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine,cyclophosphamide, and rituximab. Blood. 2008;111;5530-5536.

21. Fowler N, Kahl BS, Lee P, et al. Bortezomib, bendamustine, and rituximab in patients with relapsedor refractory follicular lymphoma: the phase II VERTICAL study. J Clin Oncol. 2011;29:3389-3395.

22. Leonard J, Jung S-H, Johnson JL, et al; Alliance for Clinical Trials in Oncology. CALGB 50401: a ran-domized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent fol-licular lymphoma. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(15 suppl):Abstract 8000.

23. Morschhauser F, Leonard JP, Fayad L, et al. Humanized anti-CD20 antibody, veltuzumab, in refrac-tory/recurrent non-Hodgkin’s lymphoma: phase I/II results. J Clin Oncol. 2009;27:3346-3353.

24. Negrea GO, Elstrom R, Allen SL, et al. Subcutaneous injections of low-dose veltuzumab (human-ized anti-CD20 antibody) are safe and active in patients with indolent non-Hodgkin’s lymphoma.Haematologica. 2011;96:567-573.

25. Czuczman M, Fayad L, Delwail V, et al. Ofatumumab monotherapy in rituximab-refractory follic-ular lymphoma: results from a multicenter study. Blood. 2012;119:3698-3704.

26. Czuczman MS, Hess G, Gadeberg OV, et al. Chemoimmunotherapy with ofatumumab in combi-nation with CHOP in previously untreated follicular lymphoma. Br J Haematol. 2012;157:438-445.

27. Kahl B, Byrd JC, Flinn IW, et al. Clinical safety and activity in a phase 1 study of CAL-101, an iso-form-selective inhibitor of phosphatidylinositol 3-kinase P110�, in patients with relapsed or refrac-tory non-Hodgkin lymphoma. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 1777.

28. de Vos S, Schreeder MT, Flinn IW, et al. A phase 1 study of the selective phosphatidylinositol 3-kinase-delta (PI3K�) inhibitor, CAL-101 (GS-1101), in combination with rituximab and/or ben-damustine in patients with previously treated, indolent non-Hodgkin lymphoma (iNHL). Blood(ASH Annual Meeting Abstracts). 2011;118:Abstract 2699.

29. Fowler N, Porte Sharman J, Smith SM, et al. The Btk inhibitor, PCI-32765, induces durableresponses with minimal toxicity in patients with relapsed/refractory B-cell malignancies: resultsfrom a phase I study. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 964.

Table. Efficacy and Tolerability of Lenalidomide Alone or WithRituximab in Recurrent FL: Results of CALGB 5040122

Regimens

LenalidomideLenalidomide + Rituximab P Value

OR rate 49% 75% NR

CR rate 13% 32% NR

Median EFS 1.2 years 2.0 years .0063

Grade 3/4 AEs NS• Overall 49% 52%• Neutropenia 16% 19%• Fatigue 9% 14%• Thrombosis 16% 4%

AEs indicates adverse events; CALGB, Cancer and Leukemia Group B; CR, completeresponse; EFS, event-free survival; FL, follicular lymphoma; NR, not reported; NS, not sig-nificant; OR, objective response.

��

3-Year TTF 3-Year OS

��



IntroductionFollicular lymphoma (FL), one of the most common forms of non-

Hodgkin lymphoma (NHL), comprises approximately 1 in 5 of all cases

of the disease.1 FL is slow growing and incurable, and it typically must

be treated over a period of several years. As a result, effective man-

agement of patients requires that nurses be aware of the latest treat-

ment approaches as well as effective strategies for the prevention and

management of adverse events (AEs). In this article, Lisa Anderson, RN,

BSN, OCN, discusses these key issues related to the administration of

newer therapies for FL.

What are some of the toxicities and risks related to the use ofbendamustine?

Hematologic toxicities are common AEs associated with the alkylatingagent bendamustine. In a recent multicenter study by Kahl and colleagues,the efficacy and toxicity of this agent as monotherapy was evaluated inpatients with rituximab-refractory indolent B-cell lymphoma.2 Among 100patients aged 31 to 84 years who received bendamustine 120 mg/m2 (days 1and 2 every 21 days for 6-8 cycles), 61% experienced grade 3/4 neutropenia,resulting in filgrastim or pegfilgrastim administration in 38% of cases; grade3/4 thrombocytopenia occurred in 25% of patients (Figure).2

Combination therapy with bendamustine plus rituximab (BR) is associatedwith less hematologic and nonhematologic toxicity than is a regimen of ritux-imab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). In the phase 3 study by Rummel and colleagues, which includedpatients with FL and other indolent lymphomas, serious AEs were less frequentwith BR than with R-CHOP. The rate of grade 3/4 neutropenia was 10.7%with BR versus 46.5% with R-CHOP (P<.0001).3 Incidence rates of alopecia,infectious complications, peripheral neuropathy (PN), and stomatitis were alsolower with BR, although this regimen produced more skin reactions.Bendamustine has been associated with tumor lysis syndrome (TLS) in

both clinical trials and postmarketing reports.3,4 If TLS occurs, it generallyappears within the first treatment cycle and may be life-threatening if clini-cians do not intervene.3 To prevent TLS, it is crucial to maintain adequatevolume status and closely monitor blood potassium, uric acid, and otherchemistries.3,5 In addition, allopurinol or rasburicase can be used prophylac-tically at the start of bendamustine therapy to help prevent TLS.5 If a TLSevent should occur, management requires aggressive hydration, diuresis, andtreatment with allopurinol or rasburicase.5,6 Caution must be used, however,as there may be an elevated risk of potentially fatal skin toxicity when ben-damustine and allopurinol are coadministered; toxicity syndromes includeStevens-Johnson syndrome and toxic epidermal necrolysis.3

How do you monitor and manage AEs related to the use of bor -tezomib and lenalidomide?

Hematologic toxicities, including neutropenia, thrombocytopenia, and ane -mia, may occur with other agents being used to treat FL, including bortezo -mib and lenalidomide.7,8 Management of these AEs may require dose inter-ruption and/or dose reduction.7,8 At our center, we ensure that patients havecomplete blood counts weekly for the first 8 weeks of treatment, and thenmonthly thereafter. Since neutropenia increases infection risk, patientsreceiving lenalidomide or bortezomib are given sulfamethoxazole/trimetho-prim (for pneumonia prophylaxis) on Monday, Wednesday, and Friday of thetreatment week. We also reinforce bleeding precautions at each patient visit,and thrombocytopenic patients receive transfusions when their plateletcount falls to �20,000 cells/mm3. For anemia, we transfuse patients at hema-tocrit �26% to 27%.Neuropathy is a common AE among patients receiving bortezomib-based

therapy.7 Preexisting neuropathic symptoms are a potential but unconfirmedrisk factor for treatment-induced PN,9,10 with a recent animal model demon-strating a more marked effect of bortezomib on peripheral nerves when base-line neuropathy is moderate or severe.10 Following a baseline neuropathyassessment, we monitor all of our bortezomib-treated patients for symptomssuch as burning sensation, hyperesthesia, hypoesthesia, paresthesia, neuro-pathic pain, or weakness. If we identify PN, we follow recommendations forreducing, interrupting, or discontinuing the dose, depending on the severity.Our goal is amelioration of bortezomib-induced PN, which can be reversiblewhen promptly managed.7,11

Herpes zoster reactivation has been documented in patients receivingbortezomib, but the occurence of this AE can be reduced with antiviral pro-phylaxis.7,12,13 For example, in a trial of bortezomib in combination therapyfor multiple myeloma, incidence of zoster reactivation was 13% before but7% after the introduction of antiviral prophylaxis into the protocol.13 At ourinstitution, patients are given acyclovir 400 mg BID while receiving bor -tezomib treatment, with dose adjusted for renal insufficiency.Risk of venous thromboembolic events (VTEs)—deep vein thromboses and

pulmonary emboli—may be elevated in patients treated with lenalidomide,and the drug carries a boxed warning for this AE.8,14 Therefore, we administerprophylactic aspirin at either 81 mg or 325 mg daily for patients receiving thisagent.14,15 Hormone-containing medications, such as oral contraceptives,should be avoided in female patients to minimize the risk of VTE.16

Lenalidomide also has a boxed warning for human birth defects risk.8

Specific risk evaluation and mitigation strategies for nurse/pharmacist coun-seling, pregnancy prevention, and avoidance of sperm donation are offeredvia the manufacturer’s RevAssist program.8

Managing Treatment-Related Adverse Eventsin Follicular Lymphoma

Lisa Anderson, RN, BSN, OCNClinic NurseEmory Bone Marrow and Stem Cell Transplant CenterWinship Cancer Institute, Atlanta, GA

Caution must be used, however, as there may be an elevated risk of potentially fatal skin toxicity whenbendamustine and allopurinol are coadministered.

� ��


What are necessary precautions that need to be discussed withpa tients receiving rituximab maintenance therapy?

There is concern that maintenance rituximab therapy has the potential forcausing additional hematologic and nonhematologic toxicities.17 At our cen-ter, each patient who starts or resumes rituximab therapy receives written andverbal education from the nurse and outpatient pharmacist at the time of thefirst clinic visit, followed by reinforcement education on the day of the firsttreatment in the infusion center. Potential AEs related to the use of ritux-imab are reviewed with the patient at each additional clinic visit. Mucocutaneous reactions, some with fatal outcome, may occur with ritux-

imab (Table).18 We are vigilant in monitoring for these reactions because oftheir potential severity. Serious reactions of this kind require discontinuationof rituximab.18

We also carefully observe rituximab-treated patients for blood-countchanges and other signs of infection. Serious infections may occur duringand after rituximab-based therapy18; postmarketing reports have document-ed infections in some patients, with prolonged hypogammaglobulinemia>11 months after exposure to rituximab.19 The 5 most frequent infectionsreported in the rituximab maintenance arm of the PRIMA trial were bron-chitis, upper respiratory tract infections, sinusitis, urinary tract infections,and nasopharyngitis.20

Vaccination with live-virus vaccines is not recommended in patientsreceiving rituximab.18 For example, in a study of NHL patients in remissionwho had been treated with rituximab-containing immunochemotherapy,humoral response to influenza vaccine was significantly reduced for a pro-longed period versus healthy controls.21

ConclusionNovel and targeted therapies have enhanced outcomes in FL, but they

present unique challenges in the occurrence and management of AEs. Newertherapies are associated with myelosuppression and potentially elevatedinfection risks. Patients may also be at risk for potentially serious nonhema-

tologic toxicities, notably skin reactions, TLS, PN, and VTEs. Best nursingpractices include frequent counseling, preventive strategies, and promptintervention to minimize AEs, maintain quality of life, and allow for contin-uation of therapy. �

References1. The Non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the Interna -

tional Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood. 1997;89:3909-3918.

2. Kahl BS, Bartlett NL, Leonard JP, et al. Bendamustine is effective therapy in patients with ri -tuximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a multicenter study.Cancer. 2010;116:106-114.

3. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior inrespect of progression free survival and CR rate when compared to CHOP plus rituximab asfirst-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas:final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas,Germany). Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 405.

4. Treanda [package insert]. Frazer, PA: Cephalon Inc; July 2010.5. Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of

pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26:2767-2778.

6. Hummel M, Buchheidt D, Reiter S, Bergmann J, Adam K, Hehlmann R. Recurrent chemo -therapy-induced tumor lysis syndrome (TLS) with renal failure in a patient with chronic lym-phocytic leukemia—successful treatment and prevention of TLS with low-dose rasburicase.Eur J Haematol. 2005;75:518-521.

7. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals Inc; June 2012.8. Revlimid [package insert]. Summit, NJ: Celgene Corporation; May 2012.9. Argyriou AA, Iconomou G, Kalofonos HP. Bortezomib-induced peripheral neuropathy in mul-

tiple myeloma: a comprehensive review of the literature. Blood. 2008;112:1593-1599.10. Bruna J, Alé A, Velasco R, Jaramillo J, Navarro X, Udina E. Evaluation of pre-existing neu-

ropathy and bortezomib retreatment as risk factors to develop severe neuropathy in a mousemodel. J Periph Nerv Syst. 2011;16:199-212.

11. Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibilityof peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib.J Clin Oncol. 2006;24:3113-3120.

12. Vickrey E, Allen S, Mehta J, Singhal S. Acyclovir to prevent reactivation of varicella zostervirus (herpes zoster) in multiple myeloma patients receiving bortezomib therapy. Cancer. 2009;115:229-232.

13. Mateos MV, Hernández JM, Hernández MT, et al. Bortezomib plus melphalan and prednisonein elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study.Blood. 2006;108:2165-2172.

14. Palumbo A, Rajkumar SV, Dimopoulos MA, et al; International Myeloma Working Group.Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423.

15. Niesvizky R, Martínez-Baños D, Jalbrzikowski J, et al. Prophylactic low-dose aspirin is effectiveantithrombotic therapy for combination treatments of thalidomide of lenalidomide in myelo-ma. Leuk Lymphoma. 2007;48:2330-2337.

16. Koopman K, Uyttenboogaart M, Vroomen PC, van der Meer J, De Keyser J, Luijckx GJ. Riskfactors for cerebral venous thrombosis and deep venous thrombosis in patients aged between15 and 50 years. Thromb Haemost. 2009;102:620-622.

17. Fowler NH. Role of maintenance rituximab (Rituxan) therapy in the treatment of follicularlymphoma. P T. 2011;36:590-598.

18. Rituxan [package insert]. South San Francisco, CA: Genentech Inc; July 2012.19. US Food and Drug Administration. Rituxan (rituximab) intravenous injection: detailed view:

safety labeling changes approved by FDA Center for Drug Evaluation and Research (CDER).FDA Web site. www.fda.gov/Safety/MedWatch/SafetyInformation/ucm296234.htm. UpdatedMarch 28, 2012. Accessed August 29, 2012.

20. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with hightumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): aphase 3, randomised controlled trial. Lancet. 2011;377:42-51.

21. Bedognetti D, Zoppoli G, Massucco C, et al. Impaired response to influenza vaccine associatedwith persistent memory B cell depletion in non-Hodgkin’s lymphoma patients treated withrituximab-containing regimens. J Immunol. 2011;186:6044-6055.


Table. Serious Mucocutaneous Reactions Associated withRituximab Use18

Reactions Symptom patterns that raise suspicionLichenoid dermatitis BlisteringParaneoplastic pemphigus Painful sores/ulcers on skin, lips, mouthStevens-Johnson syndrome Peeling skinToxic epidermal necrolysis PustulesVesiculobullous dermatitis Rashes

Figure. Incidence of Grade 3/4 Hematologic Adverse Eventsin a Multicenter Study of Single-Agent Bendamustine (N=100)2

Patients (%

)

40

30

20

10

0

7%

Grade 3Grade 4

Anemia Thrombocytopenia Neutropenia

3%

19%

6%

38%

23%

��

��



IntroductionDespite recent advancements, the management of follicular lym-

phoma (FL) remains challenging for many reasons. Physician assistants

(PAs) play an essential role in improving patient outcomes by provid-

ing continuity of care before, during, and after treatment. In this arti-

cle, Nassoma King, PA-C, responds to questions pertaining to the care

of patients with FL, including the need for pretreatment assessments,

education and counseling, follow-up care, and the prevention and

management of treatment- and disease-related complications.

What is the role of the PA in the management of patients with FL?

As members of the interdisciplinary care team, PAs can be involved in allaspects of care for patients with FL. Working collaboratively with the super-vising physicians, we order and review tests, set up treatment schedules andfollow-up visits, and arrange appropriate restaging studies. PAs also enhancecare by performing health assessments and physical examinations, orderingchemotherapy and other medications, and helping patients cope with thenumerous challenges related to their diagnosis and treatment. At our institu-tion, we provide individuals with counseling and education and work withthem to set realistic expectations both during and after therapy. Our centeralso offers patients and their families a “pretreatment” visit, which gives usthe opportunity to discuss treatment-related adverse events (AEs), nutritionand exercise, potential drug–drug interactions, and sexuality/fertility issues.During this meeting, a social worker, a nutritionist, and a pharmacist are alsoavailable to provide more in-depth evaluation if necessary. These visits areinstrumental in identifying additional needs as well as any possible barriers tosuccessful outcomes.PAs also assume the role of “coordinator of care.” Frequently, after their

initial visit with the oncologist, patients may feel overwhelmed by a diagnosisof lymphoma. As a result, it may be difficult for them to process all of theinformation they have received. Regardless of whether the oncologist pre-scribes a “watch and wait” approach or active treatment, the PA will reviewthe established plan of care and schedule necessary visits and studies. Forpatients who are scheduled to undergo active therapy, all required testingmust be ordered and evaluated prior to the first treatment cycle. During fol-low-up visits, PAs will address treatment-related AEs and other concerns andarrange appropriate referrals. We encourage our patients’ caregivers to attendclinic visits to help reiterate instructions and information. Our institutionalso provides additional assistance in the way of caregiver support groups,massage therapy sessions, and social worker services.After a patient has completed therapy, PAs continue to manage several

aspects of care. In particular, they are an important bridge between the pri-mary care physician (PCP) and the oncology team. As recommended in

From Cancer Patient to Cancer Survivor: Lost in Transition,1 cancer patientswho have finished primary therapy should be given a summary of their treat-ments and a comprehensive plan for follow-up.2 To achieve this goal at ourcenter, we have instituted survivorship clinics, where we provide patientswith treatment summaries detailing their chemotherapy and/or radiationschedules (including specific doses), as well as any complications that mayhave occurred and information regarding short- and long-term AEs. We alsogive these summaries to the patient’s PCP and referring oncologist, whichhelps to close the communication gap posttreatment.

What are the greatest challenges patients face during therapy?

With FL, the goal of therapy is to maintain optimal quality of life and totreat only when patients develop symptoms. Any alteration to this approachrequires demonstration of improved survival with early institution of therapy,or identification of criteria that define patients at a sufficiently high risk tomerit early intervention.3 Numerous therapeutic options for FL are nowavailable, ranging from radiotherapy to single-agent chemotherapy to combi-nation regimens.3 For patients who undergo active treatment, the greatestchallenges are often related to physical and psychosocial changes. It is well known that certain chemotherapeutic agents destroy normal cells

as well as malignant cells, resulting in numerous AEs, including nausea andvomiting, reduced appetite, hair loss, and mouth sores.4 Damage to healthyimmune cells may also place patients at greater risk for infection.4 Single-agentrituximab is generally well tolerated but may cause infusion-related complica-tions and myelosuppression.5,6 Radioimmunotherapy may also result in thedevelopment of AEs such as transient bone marrow depression, fatigue, fever,chills, sweating, rash, arthralgias, erythema, and edema.7 It is therefore criticalfor PAs and other members of the oncology care team to be familiar with thetoxicity profiles associated with these therapies so they can initiate appropriateinterventions, including growth factor support to manage infection, erythro-poietin to treat anemia, and antiemetics to relieve nausea and vomiting.Psychosocial changes, which are often triggered by the AEs described

above, may cause patients to feel emotionally distraught.8 Interpersonal rela-tionships may become strained due to disruptions in everyday life, job loss,decreased finances, and changes in family dynamics. Depression, fatigue, andchanges in physical appearance often lead to sexual dysfunction and poorbody image. Chemotherapy is often associated with loss of libido anddecreased physical intimacy for both men and women. Combining psychoso-cial therapy with treatment for the disease itself can help to alleviate emo-tional distress. Our team, which includes a social worker and a psychiatrist,provides individual and family counseling, as well as support groups gearedtoward addressing many of the psychosocial issues related to chemotherapy.We offer an in-house boutique that provides hair and make-up classes, as wellas hair prostheses and accessories. Elderly patients may be more difficult to treat due to preexisting comorbidi-

ties, diminished organ function, altered drug metabolism, and irregular drugclearance rates.9 They may often present with poor performance status andunderlying cardiac or renal dysfunction. In addition, the risk of developingtreatment-related AEs and the inability to tolerate full doses of therapeutic

Improving Patient Outcomes in FollicularLymphoma

Nassoma King, PA-CPhysician Assistant,Winship Cancer InstituteEmory University, Atlanta, GA

��



agents generally increases with age, and cure and remission rates usuallydecrease.9 The key to maintaining quality of life and helping patients reap theoptimal benefits of therapy involves good communication between members ofthe oncology team and their patients regarding AEs and other complications.

What special considerations are necessary for patients who under-go transplantation?

Although patients with FL typically demonstrate good response to induc-tion therapy, most will eventually relapse. When this occurs, cure is veryunlikely; the median survival after disease recurrence is approximately 4.5years.10 There are several options available to patients who relapse, includingchemotherapy, radioimmunotherapy, and stem cell transplant.Investigators addressed the role of autologous stem cell transplantation

(ASCT) in the European CUP trial, which randomized patients with relapsedFL to undergo chemotherapy alone (C), ASCT with an unpurged autograft(U), or ASCT with a purged autograft (P).11 The 2-year progression-free sur-vival (PFS) rates were 26% (C), 58% (U), and 55% (P), whereas 4-year overallsurvival (OS) rates were 46% (C), 71% (U), and 77% (P). No difference inPFS or OS was seen between the transplant groups. However, a significantreduction in hazard ratios for both PFS and OS was observed in the combinedgroups of patients undergoing ASCT compared with the chemotherapy group.Allogeneic stem cell transplantation (allo-SCT) may be a viable option forpatients whose lymphoma is behaving in an aggressive fashion (ie, early recur-rence after intensive frontline or salvage therapy). However, due to relativelyhigh treatment-related mortality, patients must have an excellent performancestatus, minimal comorbidities, and an human leukocyte antigen–identicaldonor (related or unrelated) to be considered for this procedure.12

For transplant-eligible patients, it is important to consider factors such asnutritional status prior to transplant, neutropenic precautions during trans-plant, and posttransplant changes. Patients must undergo a rigorous pretrans-plant evaluation, which includes testing to assess organ function and diseasestatus. It is also necessary to arrange a meeting with a social worker to addresspsychosocial needs. At our institution, patients typically meet with a nutri-tionist to help improve their performance status prior to transplant, becausedisease status, the amount of time since the last cycle of chemotherapy, infec-tion, and anorexia can all significantly impact nutritional status.13 Mal -nutrition prior to transplantation has been reported to increase the length ofhospital stay and can be a negative prognostic factor for survival.13

Opportunistic infections remain a significant cause of morbidity and mor-tality related to transplant.14 The conditioning regimen causes pancytopenia,impaired phagocytosis, and damaged mucocutaneous barriers.15 Venous accessdevices may also place patients at an increased risk for infection, as they serveas another portal of entry for opportunistic pathogens from organisms coloniz-ing the skin (eg, coagulase-negative staphylococci, Staphylococcus aureus,Candida species, and enterococci).15 At our center, we start patients on pro-phylactic antibiotics on day 1, continuing until engraftment of white bloodcells. If patients develop fever, we order a culture and initiate broad spectrumantibiotics until the pathogen is identified. Upon discharge from the hospital,patients who have undergone ASCT will usually continue acyclovir for her-pes simplex virus prophylaxis; whereas patients who have undergone allo-SCT will continue with both acyclovir and fluconazole. The Centers forDisease Control and Prevention has established extensive guidelines for theprevention of opportunistic infections following transplantation, includinghospital infection control, food safety, pet and travel safety, vaccinations, andgeneral infection precautions.15

It is important to be cognizant of the fact that patients and families mayhave unrealistic expectations after transplant. For example, they may beunder the impression that life will return to normal as soon as the procedureis complete. Some of the common difficulties that patients face posttrans-plant include the inability to resume social roles, concerns about the future,work-related problems, infertility, fear of relapse, and anxiety and depres-sion.16 In addition, fatigue may last anywhere from 3 to 6 months posttrans-plant for recipients of ASCT and up to 2 years or more for recipients of allo-SCT. For patients who develop graft-versus-host disease, fatigue may lasteven longer. As a result, they may be unable to return to their jobs or mayneed to perform their responsibilities in a limited capacity, causing addition-al financial stress. At our center, an oncology supportive care team consist-ing of social workers and psychiatrists works collaboratively with the med-ical team to help patients and caregivers address physical, emotional, andfinancial stressors.

ConclusionBecause many patients with FL face physical, financial, and emotional

challenges before, during, and after treatment, it is essential that they feelcomfortable contacting the nurse practitioner or PA regarding any and allconcerns. In addition to providing information on external support groups,we employ an interdisciplinary approach to tackle issues preemptively. It iscritical to recognize that each patient has specific needs and that each shouldbe cared for in a way that addresses those needs appropriately. �

References1. Hewitt M, Greenfield S, Stovall E, eds. From Cancer Patient to Cancer Survivor: Lost in Transi tion.

Washington, DC: The National Academies Press; 2005. www.nap.edu/catalog.php?record_id=11468. Accessed August 29, 2012.

2. Bhatia S, Landier W; on behalf of the Children’s Oncology Group (COG) Nursing Disciplineand Late Effects Committees. Appendix F: treatment summary forms developed by theChildren’s Oncology Group (COG). In: A National Coalition for Cancer Survivorship andInstitute of Medicine National Cancer Policy Forum Workshop, The Lance ArmstrongFoundation and The National Cancer Institute, Hewitt M, Ganz PA, eds. Implementing CancerSurvivorship Care Planning. Washington, DC: The National Academies Press; 2007.www.nap.edu/openbook.php?record_id=11739&page=288. Accessed August 29, 2012.

3. Gribben JG. How I treat indolent lymphoma. Blood. 2007;109:4617-4626. 4. American Cancer Society. Chemotherapy principles: an in-depth discussion. American Can -

cer Society Web site. www.cancer.org/Treatment/TreatmentsandSideEffects/TreatmentTypes/Chemotherapy/ChemotherapyPrinciplesAnIn-depthDiscussionoftheTechniquesanditsRoleinTreatment/chemotherapy-principles-indepth-toc. Accessed August 29, 2012.

5. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with hightumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): aphase 3, randomized controlled trial. Lancet. 2011;377:42-51.

6. Martinelli G, Schmitz SF, Utiger U, et al. Long-term follow-up of patients with follicular lym-phoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J ClinOncol. 2010;28:4480-4484.

7. Buchegger F, Antonescu C, Helg C, et al. Six of 12 relapsed or refractory indolent lymphomapatients treated 10 years ago with 131I-tositumomab remain in complete remission. J NuclMed. 2011;52:896-900.

8. Bergeson B. Emotional effects of chemotherapy. Livestrong.com Web site. www.livestrong.com/article/143086-emotional-effects-chemotherapy/#ixzz23NwEZ4LT. Updated June 8, 2010.Accessed August 29, 2012.

9. Cabanillas ME, Lu H, Fang S, Du XL. Elderly patients with non-Hodgkin lymphoma whoreceive chemotherapy are at higher risk for osteoporosis and fractures. Leuk Lymphoma.2007;48:1514-1521.

10. Thieblemont C, Coiffier B. Lymphoma in older patients. J Clin Oncol. 2007;25:1916-1923.11. Schouten HC, Qian W, Kvaloy S, et al. High-dose therapy improves progression-free survival

and survival in relapsed follicular non-Hodgkin’s lymphoma: results from the randomizedEuropean CUP trial. J Clin Oncol. 2003;21:3918-3927.

12. van Besien K. Allogeneic stem cell transplantation in follicular lymphoma: recent progress andcontroversy. Hematology Am Soc Hematol Educ Program. 2009:610-618.

13. Horsley P, Bauer J, Gallagher B. Poor nutritional status prior to peripheral blood stem celltransplantation is associated with increased length of hospital stay. Bone Marrow Transplant.2005;35:1113-1116.

14. Nevill TJ, Shepherd JD, Nantel SH, et al. Stem cell transplant-related mortality (TRM) 1985-1996: the Vancouver experience. Blood. 1997;90(10)(suppl 1 [part 2 of 2]):4426.

15. Centers for Disease Control and Prevention; Infectious Disease Society of America; AmericanSociety of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infectionsamong hematopoietic stem cell transplant recipients. MMWR Recomm Rep. 2000;49:1-125.

16. Hjermstad MJ, Evensen SA, Kvaløy SO, Fayers PM, Kaasa S. Health-related quality of life 1year after allogeneic or autologous stem-cell transplantation: a prospective study. J Clin Oncol.1999;17:706-718.

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enchyme, extracellular matrix, and ep-ithelium; the local environment; and themicroflora. Once thought of as a directepithelial process in which chemo thera-py or radiotherapy killed cells, the devel-opment of mucositis is actually a multi-factorial process within the diverse tissuesof the submucosa, he said.

“The cascade of events starts with ox-idative stress, followed by an innate im-mune response, leading to a primarydamage response, initiation of signalingpathways, amplification and feedback,then ulceration, surface colonization,and healing,” Sonis said. The involvement of so many process-

es means, he said, “that in developingdrug targets and in looking for risk pre-dictors, we have a bigger palette to goafter, versus just focusing on epithelialcells, as in the historical paradigm.”Emerging areas of research are the

local environment of the gastrointesti-nal tract and mouth, especially salivary

and intestinal proteins secreted in re-sponse to mucosal injury, as well aschanges in bacterial flora, Sonis said.

targeted Agents May Not be MuchbetterDorothy Keefe, MD, MBBS, of Royal

Adelaide Hospital in Australia, cau-tioned against thinking that new target-ed agents will carry less risk of mucosi-tis. The mTOR inhibitors, for example,produce a unique mucositis pattern.“Every new drug class brings new tox-

icities, despite the temptation to thinkthat ‘targeted’ equals ‘nontoxic,’ ” shesaid. The toxicities of targeted therapiesare often clinically significant, long-lasting, and not reversible, she added. Keefe pointed out that signaling

pathways may be related to both thetoxicity and oncogenesis, and interfer-ing with pathways is “tricky territory.”Under standing of mechanisms, she said,is key to optimal management.“Time-tested empiric foundational

approaches” that have been used fordecades will continue to be importantin the new frontier of targeted cancertherapies and their toxicities, Petersonsaid. These include patient educationand compliance, simple wound care ap-proaches, structured approaches to paincontrol, adequate hydration and nutri-tional support, surveillance, and treat-ment of infectious complications.“The problem is that these approach-

es are not fundamentally targeting thepathobiology,” he said. “The new worldorder, where we are headed, will includeindividualized risk profiles and cus-tomized therapies.”

risk prediction“Personalized cancer medicine in-

volves both tumor and toxicity. It is notgood enough to personalize the cancertreatment. We have to personalize thesupportive care as well, and risk predic-tion for toxicity is becoming a reality,”Keefe said. “We are at a very serendipitous time,”

Sonis agreed. “Risk prediction has be-come possible through the evolution ofgenomics.” Single-nucleotide polymorphisms

(SNPs) are the most common form ofvariation in the genome. SNPs can re-side intracellularly (and affect transcrip-tion) or extracellularly (and be an indi-cator of toxicity risk).Advances in bioinformatics are mak-

ing it possible to select clusters of SNPs,out of millions, that can predict for tox-icity. This is already possible for patientsundergoing conditioning regimens forautologous stem cell transplant, 40% ofwhom will develop severe mucositis and60% of whom will therefore be treatedunnecessarily, he said.

Mucositis Management to Become More Personalized... Continued from cover


TARGET AUDIENCEThis initiative will target medical oncologists, hematologists, breast surgeons, radiationoncologists, oncology nurses, advanced practice nurses, nurse practitioners, physicianassistants, oncology pharmacists, managed care professionals, and others with clinicalresearch and management interest in treatment of ductal carcinoma in situ (DCIS) andearly-stage breast cancer.

STATEMENT OF NEEDAbility to detect DCIS has dramatically improved in recent decades, and the current inci-dence of DCIS is several-fold higher than in the 1970s and 1980s, largely due to increaseduse of mammography screening.1,2 However, attempts to identify subsets of DCIS womenwho may be spared radiotherapy and perhaps treated with surgery alone have heretoforebeen unsuccessful. This inability to predict which patients will develop recurrent DCIS orinvasive disease has complicated DCIS management. Many clinicians and other health-care professionals dealing with patients diagnosed with DCIS are unaware or incomplete-ly knowledgeable about the most recent results from a clinical trial examining the abilityof the 12-gene assay, using a prespecified DCIS algorithm, to predict recurrence risk, andthe implications these findings may have for management of their patients with DCIS. 1. Kerlikowske K. Epidemiology of ductal carcinoma in situ. J Natl Cancer Inst Monogr. 2010;2010:139-141.2. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence,treatment, and outcomes. J Natl Cancer Inst. 2010;102:170-178.

EDUCATIONAL OBJECTIVESAfter completion of this activity, participants will be better able to:

• Identify approaches currently available or in development to predict recurrence riskin DCIS patients

• Explain how the 12-gene expression assay for DCIS was developed and how it compares with the 21-gene assay for early invasive breast cancer

• Describe the design and findings of the ECOG 5194 validation study• Apply the 12-gene assay for DCIS into clinical decision-making• Explain relevant information about the 12-gene DCIS assay and DCIS score topatients

Individualizing Treatment for DCIS of the Breast: New Molecular Approaches

www.coexm.com/ace09LOG ON TODAY TO PARTICIPATE

Release Date: May 8, 2012Expiration Date: May 7, 2013

FACULTYChair:Lawrence J. Solin, MD, FACR,FASTROChairman Department of Radiation OncologyAlbert Einstein Medical CenterPhiladelphia, PA

E. Shelley Hwang, MD, MPHProfessor and Chief, Breast SurgeryDuke University Medical CenterDurham, NC

Kathy D. Miller, MDAssociate Professor Department of MedicineIU School of MedicineIndianapolis, IN

ACCREDITATIONPhysicians: Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Continuing MedicalEducation (ACCME) to provide continuing medical education for physicians. CEC designates this enduring educational activityfor a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of theirparticipation in the activity.Nurses:CEC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s (ANCC)Commission on Accreditation. CEC provides this activity for 1.0 contact hour. Learners are advised that accredited status doesnot imply endorsement by the provider or ANCC of any commercial products displayed in conjunction with an activity.Case Managers: This activity has been approved for 1.0 clock hour through 12/31/12 by the Commission for Case ManagerCertification. Case Managers number 790005057.

This activity is supported by an educational grant from Genomic Health, Inc.

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The Oncology Pharmacist is pleased to announce the 2013

T.O.P. Pharmacist Award, sponsored by Teva Oncology.

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research, or education in 2012.

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In a retrospective analysis of myelo-ma and lymphoma patients undergoingtransplant at a single center, Sonis andhis team identified 51 patients who de-veloped oral mucositis and 102 who didnot. They looked for SNPs in the DNAof patients’ saliva and found that a clus-ter of 82 SNPs that predicted for mu-cositis with 99.3% accuracy.

The area under the ROC (receiveroperating characteristic) curve was0.997 (0.9-1.0 is considered an excel-lent predictor). The ROC for mammog-raphy is 0.74, he noted for comparison.A multicenter study of the model isplanned, and this model is being furtherdeveloped for commercialization.“We were thrilled,” Sonis comment-

ed. “This approach should be a gamechanger in terms of our ability to predictmucositis and other biologically basedtoxicities. This means we can be muchmore precise in developing risk assess-ments, understanding the patient’s re-sponse to risk, and being able to favor-ably impact toxicity with targetedinterventions for the patient at risk.” �


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Novel Mouthrinse reducesCourse andSeverity of OralMucositisTopical administration of a

novel mouth rinse, AG013, ap-pears safe, well tolerated, and ef-fective in reducing the severityand course of oral mucositis (OM)in patients receiving inductionchemo therapy in a study present-ed at the 2012 ASCO AnnualMeeting (Abstract 9024).AG013 is a mouth rinse com-

posed of a recombinant Lactococcuslactis engineered to secrete humantrefoil factor 1 (hTFF1) and defi-cient in the gene encodingthymidylate synthase. TFFs havewound-healing properties and areprotective of mucosal tissues. Thecompound was evaluated in 25patients who developed sympto-matic oral mucositis after induc-tion chemotherapy for head andneck cancer in a phase 1B, multi-center, single-blind, placebo-con-trolled study reported by SewantiAtul Limaye, MD, of the Dana-Farber Cancer Institute in Boston,Massachusetts.

Three dosing cohorts were eval-uated and compared with placeborecipients. Patients receivingAG013 on any dosing schedulehad a lower percentage of dayswith OM and fewer unplanned of-fice and emergency room visitscompared with patients who re-ceived placebo. Responses (≤1day of ulcerative OM) were ob-served in 29% of AG013 patientsbut in none of the placebo pa-tients. Ulcerative OM was observed during 35% to 40% ofstudy days for patients receivingthe mouth rinse, compared with60% of study days in the placebogroup. The absolute reduction inthe percentage of days with ulcer-ative OM, with the use of thenovel mouth rinse, was 35%. Nodifferences were noted in mouthand throat soreness, opioid use, orgastrostomy tube placement.

Mucositis Management to Become More Personalized... Continued from page 36


Three dosing cohortswere evaluated and

compared withplacebo recipients.

BRIEF SUMMARYCONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Docetaxel Injection, USP safely and effectively. See full prescribing information for Docetaxel.

Docetaxel Injection, USPFor intravenous infusion only. Initial U.S. Approval: 1996

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID

RETENTION

See full prescribing information for complete boxed warning

docetaxel at 100 mg/m2 (5.1)

treatment cycle (8.6)

< 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4)

dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection, USP and administration of appropriate therapy (5.4)

polysorbate 80 (4)

(5.5)

CONTRAINDICATIONS

3

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, www.fda.

gov/medwatch


HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Gemcitabine Injection safely and effectively. See full prescribing information for Gemcitabine Injection.

Gemcitabine InjectionFor Intravenous Infusion Only.Must Be Diluted Before Use.Initial U.S. Approval: 1996

INDICATIONS AND USAGE

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS


ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact

at [email protected], or FDA at www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION

Revised: 09/2011


HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Oxaliplatin safely and effectively. See full prescribing information for Oxaliplatin.

Oxaliplatin for Injection,

Oxaliplatin Injection,solution for intravenous use

Initial U.S. Approval: 2002

WARNING: ANAPHYLACTIC REACTIONSSee full prescribing information for complete boxed warning.

Anaphylactic reactions to Oxaliplatin have been

administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms. (5.1)

INDICATIONS AND USAGE

CONTRAINDICATIONS


ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact Hospira

See 17 for PATIENT COUNSELING INFORMATION and FDA approved patient labeling.

Revised: 04/2011

Zydus Hospira

Hospira, Inc. Manufactured for:Hospira, Inc.

Reference: 1. Data on fi le. Hospira, Inc.

Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045 P12-3707-11.125x14.125-Jul., 12

For more information, contact your

Hospira representative or call 1-877-946-7747. Or visit us at products.hospira.com.

As the complexity of healthcare evolves,

we’re doing our part to improve cost savings,

optimize workfl ow and enhance patient care.

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FOR PHARMACISTS—FAMILIAR STRENGTHS AND FLEXIBLE DOSING

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FOR ADMINISTRATORS—MULTIPLE-DOSE VIALS LEAD TO LESS WASTE

FOR YOUR INSTITUTION—HIGH-QUALITY MEDICATION AT A LOWER COST

AVAILABLE FROMHOSPIRA

160 mg/16 mL multiple-dose vial

80 mg/8 mL multiple-dose vial

20 mg/2 mL single-dose vial

See Black Box Warning Below

DOCETAXEL INJECTION (10 mg/mL)

2 g/52.6 mL single-dose vial

1 g/26.3 mL single-dose vial

200 mg/5.26 mL single-dose vial

GEMCITABINE INJECTION(38 mg/mL)



OXALIPLATIN INJECTION(5 mg/mL)

See Black Box Warning Below

OXALIPLATIN INJECTIONOXALIPLATIN INJECTIONOXALIPLATIN INJECTION

1 PVC BOTTOM offers shatter resistance.

2 SHRINK-WRAPPED SLEEVE provides surface protection that acts as a barrier between any cytotoxic residue that may remain on the surface of the vial and persons handling the products.

3 GLASS CLARITY allows for easy inspection of the vial as a fi nal safety check before administration.

4 PREWASHED VIALS reduce cytotoxic residue.

UNIQUE ONCO-TAIN SAFETY FEATURES

Docetaxel:WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTIONOxaliplatin:WARNING: ANAPHYLACTIC REACTIONS

Please refer to Black Box Warnings and see Brief Prescribing Informations on back page.

September 2012, Vol 5, No 6

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