Stephanie A. Gregory, MD, FACP The Elodia Kehm Chair of Hematology Professor of Medicine Rush...

Stephanie A. Gregory, MD, FACPThe Elodia Kehm Chair of Hematology

Professor of Medicine

Rush University Medical Center/Rush UniversityChicago, Illinois, USA

Treatment Strategy of Indolent Treatment Strategy of Indolent Lymphoma and the Role of Lymphoma and the Role of

RadioimmunotherapyRadioimmunotherapy

ObjectivesObjectives

After completing this activity, participants should be able to:

•Assess options for first-line and subsequent lines of therapy for indolent B-cell NHL in order to select the optimal treatment for individual patients

•Explain the rationale for the use of radioimmunotherapy (RIT)

•Describe the efficacy and safety of RIT

•Formulate treatment strategies for relapsed and refractory indolent B-cell NHL using currently available options in order to optimize outcomes for individual patients

•To be knowledgeable regarding potential barriers of use of RIT in the community practice setting

Lecture OutlineLecture OutlineLecture OutlineLecture Outline

1. Overview of Indolent Non-Hodgkin Lymphoma (NHL) with a focus on follicular

lymphoma (FL)

2. Current approaches for initial therapy

3. Approaches for relapsed disease

4. Use of RIT after front-line therapy for indolent NHL and the role of RIT in relapsed disease

2012 Estimated US New Cancer Cases2012 Estimated US New Cancer Cases

Females

Prostate 241,740 29%

Lung & bronchus 116,470 14%

Colon & rectum 73,420 9%

Urinary bladder 55,600 7%

Melanoma of skin 44,250 5%

Kidney & renal pelvis 40,250 5%

Non-Hodgkin 38,160 4%Non-Hodgkin 38,160 4%

lymphomalymphoma

Oral cavity & pharynx 28,540 3%

Leukemia 26,830 3%

Pancreas 22,090 3%

ALL SITES 848,170 100%

Males

BreastBreast 226,870 29% 226,870 29%

Lung & bronchusLung & bronchus 109,690 14% 109,690 14%

Colon & rectumColon & rectum 70,040 9% 70,040 9%

Uterine corpusUterine corpus 47,130 6% 47,130 6%

ThyroidThyroid 43,210 5% 43,210 5%

Melanoma of skinMelanoma of skin 32,000 4% 32,000 4%

Non-Hodgkin Non-Hodgkin 31,970 4% 31,970 4%

lymphomalymphoma

Kidney & renal pelvis 24,520 3%Kidney & renal pelvis 24,520 3%

OvaryOvary 22,280 3% 22,280 3%

PancreasPancreas 21,830 3% 21,830 3%

ALL SITESALL SITES 790,740 100% 790,740 100%

CA: A Cancer Journal for Clinicians, Vol. 62, January/February 2012.

2012 Estimated US Cancer Deaths2012 Estimated US Cancer Deaths

Females

Lung & bronchus 87,750 29%

Prostate 28,170 9%

Colon & rectum 26,470 9%

Pancreas 18,850 6%

Liver & intrahepatic 13,980 5%

bile duct

Leukemia 13,500 4%

Esophagus 12,040 4%

Urinary bladder 10,510 3%

Non-Hodgkin Non-Hodgkin 10,320 3% 10,320 3%

lymphomalymphoma

Kidney & renal pelvis 8,650 3%

ALL SITES 301,820 100%

Males

Lungs & bronchusLungs & bronchus 72,590 26% 72,590 26%

BreastBreast 39,510 14% 39,510 14%

Colon & rectumColon & rectum 25,220 9% 25,220 9%

PancreasPancreas 18,540 7% 18,540 7%

OvaryOvary 15,500 6% 15,500 6%

LeukemiaLeukemia 10,040 4% 10,040 4%

Non-HodgkinNon-Hodgkin 8,620 3% 8,620 3%

lymphomalymphoma

Uterine corpusUterine corpus 8,010 3% 8,010 3%

Liver & intrahepatic 6,570 2%Liver & intrahepatic 6,570 2%

bile duct bile duct

Brain & other nervous 5,980 2%Brain & other nervous 5,980 2%

systemsystem

ALL SITES ALL SITES 275,370 100% 275,370 100%

CA: A Cancer Journal for Clinicians, Vol. 62, January/February 2012.

NHL SubtypesNHL SubtypesNHL SubtypesNHL Subtypes

Percentages of all NHLsMALT=mucosa-associated lymphoid tissue; NHL=non-Hodgkin’s lymphoma NK=natural killerLichtman MA. Williams Hematology. 7th ed. New York, NY: McGraw Hill. 2006;1408.

T and NK cell(12%)

Other subtypes(9%)

Burkitt(2.5%)

Mantle cell(6%)

Diffuse large B cell

(DLBCL)(30%)

Follicular(25%)

Small lymphocytic(7%)

MALT-type marginal-zone

B cell (7.5%)

Nodal-type marginal-zone

B cell (<2%)

Lymphoplasmacytic (<2%)

Follicular Lymphoma (FL)Follicular Lymphoma (FL)Follicular Lymphoma (FL)Follicular Lymphoma (FL)• Most common indolent NHL, accounts for ~22%-25% of

NHL in North America

• Variable presentation and prognosis, but typically advanced stage at presentation

• Often asymptomatic

• Advanced stage FL not curable with standard therapy

• Median survival was about 10 years, but has increased with the advent of rituximab and RIT

• Multiple therapies: no standard, how best to sequence

• Many novel therapies in development

• Reliable biomarkers needed

Modified from Skarin AT, Dorfman DM. CA Cancer J Clin. 1997;47:351-72.

Follicular Lymphoma

TransformationAccelerated Indolent10% to 15% 40% to 65% 20% to 60%

A View of the Natural History of A View of the Natural History of Follicular LymphomaFollicular Lymphoma

A View of the Natural History of A View of the Natural History of Follicular LymphomaFollicular Lymphoma

Horning SJ. Semin Oncol. 1993;20(suppl 5):75-88.

0

20

100

80

60

40

0

Pro

bab

ilit

y (%

)

5 10 15 20 25 30

Years

1987-1993 (n=668)

1976-1987 (n=513)

1960-1976 (n=195)

Prognoses in FL Correlated with Gene Expression Prognoses in FL Correlated with Gene Expression Patterns in Tumor-Infiltrating Patterns in Tumor-Infiltrating

Normal Immune CellsNormal Immune Cells

Prognoses in FL Correlated with Gene Expression Prognoses in FL Correlated with Gene Expression Patterns in Tumor-Infiltrating Patterns in Tumor-Infiltrating

Normal Immune CellsNormal Immune Cells

Dave SS, et al. N Engl J Med. 2004;351:2159-69.

Genes Associated with FAVORABLE PROGNOSIS

Genes Associated with POOR PROGNOSIS

NCCN Practice Guidelines forNCCN Practice Guidelines forRelapsed Follicular Lymphoma: 2012Relapsed Follicular Lymphoma: 2012


Additional TherapyAdditional TherapyInitial Therapy

F OLLICULAR

LYMPHOMA

PROGRESSIVE

DISEASE

Stage I, IIStage I, II

Stage II Stage II StageStage III, IV III, IV

• Locoregional RT or • ImmunoRx ± Chemo Rx ± RT • Observe (if tx not indicated)

• Clinical trial or• Local RT• Chemotherapy followed by RIT•Observe (if tx not

indicated)

• Clinical trial or • Chemotherapy

Rituximab or • Rituximab maintenance or• RIT or• Stem Cell Transplant• Local RT• Observe (if tx not indicated)

Without transformation

Transformed to DLBCL

• Clinical trial or

• Rituximab

Chemotherapy ± Rituximab or

• Chemotherapy ± RT

NCCN Practice Guidelines in Oncology, v.2.2012.

Follicular Lymphoma: Factors to Follicular Lymphoma: Factors to Consider When Choosing TherapyConsider When Choosing TherapyFollicular Lymphoma: Factors to Follicular Lymphoma: Factors to

Consider When Choosing TherapyConsider When Choosing Therapy

• PATIENTPATIENT Characteristics

– Age

– Symptoms

– Short & long term goals

– Comorbidity

– Preserve future options • DISEASE DISEASE Characteristics

– Stage

– Grade

– Transformation

– Sites of involvement

Overall Survival According to FLIPI:Overall Survival According to FLIPI:Clinical Prognosis FactorsClinical Prognosis Factors

Overall Survival According to FLIPI:Overall Survival According to FLIPI:Clinical Prognosis FactorsClinical Prognosis Factors

Adapted from Solal-Celigny P, et al. Blood. 2004;104:1258-65.

Su

rviv

al p

rob

abil

ity

Low risk

Intermediate risk

High risk

0

0.2

0.4

0.6

0.8

1.0

Years0 1 2 3 4 5 6 7

No Nodal regions 4

L LDH increased

A Age ≥60

S Stage III/IV

H Hemoglobin <120 g/L

Risk Group No. of Factors % of Pts 5-y OS (%) 10-y OS (%)

Low 0-1 36 90.6 70.7

Intermediate 2 37 77.8 50.9

High 3-5 27 52.5 35.5

p<10-4

FLIPI-2: Risk AssessmentFLIPI-2: Risk AssessmentFLIPI-2: Risk AssessmentFLIPI-2: Risk Assessment

Federico M, et al. J Clin Oncol. 2009;27:4555-62.

• Updated version

• Accounts for immunochemotherapy as a widely used treatment option

• Future treatment guidelines will most likely be based on staging, genetic profiles, and immune response signatures

FLIPI 2Age >60 yrs

BM involvement

Anemia (Hgb <120 g/L)

Nodes >6 cm

β2m > ULN

PFS:

After Staging Evaluation

Advanced stage:low tumor burden

Advanced stage:high tumor burden

Observation Chemo-immuno-

therapyTherapy

RituximabClinical Trial

eg, RESORT Trial orW & W vs. Rituximab

Update on Treatment Options for Update on Treatment Options for Follicular LymphomaFollicular Lymphoma

Update on Treatment Options for Update on Treatment Options for Follicular LymphomaFollicular Lymphoma

Courtesy of Stephanie A. Gregory, MD.

Immunotherapy Targets on B CellsImmunotherapy Targets on B CellsImmunotherapy Targets on B CellsImmunotherapy Targets on B Cells

slg

DR

CD19 CD20

CD22

B lymphocyte

• Surface proteins targeted by immunotherapy– Naked monoclonal

antibodies (mAbs)– Conjugated mAbs

- Radioisotopes

- Drugs

- Toxins

Adapted from Press OW. Cancer J Sci Am. 1998;4(suppl 2):S19-S26.

Friedberg JW. J Clin Oncol.2009;27:1202-08.

Observation(Watch and Wait)

18%

Radiotherapy 6%

Rituximab Monotherapy14%

Chemotherapy +Rituximab

52%

Chemotherapy 3%

Clinical trial6%

Other 2%

Initial Treatment – All PatientsInitial Treatment – All PatientsInitial Treatment – All PatientsInitial Treatment – All Patients

Current Practice: the LymphoCare StudyCurrent Practice: the LymphoCare Study2004-2007 n=2728 at 265 US Sites: 80% Nonacademic, 20% Academic

Treatment Deferral vs. Initiation: Treatment Deferral vs. Initiation: GELF CriteriaGELF Criteria

Treatment Deferral vs. Initiation: Treatment Deferral vs. Initiation: GELF CriteriaGELF Criteria

All of the Following:

Maximum diameter of disease <7 cmFewer than 3 nodal sitesNo systemic symptomsSpleen <16 cm on computed tomography (CT)No significant effusionsNo risk of local compressive symptomsNo circulating lymphoma cells

Brice P, et al. J Clin Oncol. 1997;15:1110-1117.

GELF, Groupe pour l’Etude de Lymphome Folliculaire

Randomized Trials with the Watch-and-Wait Approach vs. Chemotherapy for

Asymptomatic Patients with Advanced FL

Randomized Trials with the Watch-and-Wait Approach vs. Chemotherapy for

Asymptomatic Patients with Advanced FL

Study NChemotherapy

RegimenOS With Chemotherapy

OS with Watch-and-Wait Approach

Ardeshna et al 309Chlorambucil (Leukeran®)

Median:5.9 y

Median: 6.7 y

Brice et al 193Prednimustine 5 y: 70%

5 y: 78%IFN- 5 y: 84%

Young et al 104 ProMACE-MOPP Median: NR Median: NR

Ardeshna KM, et al. Lancet. 2003:362:516-22; Brice P, et al. J Clin Oncol. 1997;15:1110-7; Young RC, et al. Semin Hematol. 1988;25:11-6.

IFN=interferon; MOPP=mechlorethamine, vincristine, procarbazine, prednisone; NR=not reached; ProMACE=prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide.

Rituximab (R) vs. a “Watch and Wait” Strategy in Rituximab (R) vs. a “Watch and Wait” Strategy in Patients with Stage II-IV Asymptomatic, Patients with Stage II-IV Asymptomatic,

Nonbulky FLNonbulky FL

Rituximab (R) vs. a “Watch and Wait” Strategy in Rituximab (R) vs. a “Watch and Wait” Strategy in Patients with Stage II-IV Asymptomatic, Patients with Stage II-IV Asymptomatic,

Nonbulky FLNonbulky FL

Intervention Observe R x 4 weeks R x 4 weeks

Maintenance --- --- R q 2 mos. x 2 years

Number 187 84 192

CR/PR (%) 2/3 43/30 54/33

3-year PFS 33% 60% 81%

Time to next treatment 33 months Not reached Not reached

• Patients had: stage II–IV, asymptomatic, non-bulky low-grade FL• Improved PFS in rituximab arms (p ≤0.001)• Time to initiation of new treatment in the rituximab arms

• 33 months vs. not reached at 4 years (p ≤0.001)• No difference in OS (p ≥0.5)• Quality of life no worse

Ardeshna KM, et al. ASH 2010. abstr 6 (oral, Plenary Session).

Observation vs. Single-Agent RituximabObservation vs. Single-Agent RituximabObservation vs. Single-Agent RituximabObservation vs. Single-Agent Rituximab

Watch and Wait = 52%Rituximab = 20%Rituximab and maintenance rituximab = 9%

0 1 2 3 4 5

Years from Randomization

Time to initiation of new therapy

Ardeshna K, et al. ASH 2010. abstr 6 (oral, Plenary Session).

Initial Therapy for Low Tumor Burden: Initial Therapy for Low Tumor Burden: Follicular LymphomaFollicular Lymphoma

Initial Therapy for Low Tumor Burden: Initial Therapy for Low Tumor Burden: Follicular LymphomaFollicular Lymphoma

• Rituximab as first-line therapy for indolent lymphoma

Regimen n ORR CR TTF/PFS (months)

Rituximab monotherapy(patients with low tumor burden)

Colombat P, et al. ASH. 2006, abstr 486.

49 74% 49% 24

Rituximab monotherapy

Witzig TE, et al. J Clin Oncol. 2005;23:1103-8.

37 72% 36% 26

Chemoimmunotherapy in Chemoimmunotherapy in Follicular NHL PatientsFollicular NHL Patients

Chemoimmunotherapy in Chemoimmunotherapy in Follicular NHL PatientsFollicular NHL Patients

• CHOPCHOP ++ RituximabRituximab

• BendamustineBendamustine + + RituximabRituximab (Treanda(Treanda®®))

• CVPCVP ++ RituximabRituximab

• FNDFND ++ RituximabRituximab

• BVRBVR ++ RituximabRituximab

• FCMFCM ++ RituximabRituximab

• FludarabineFludarabine ++ RituximabRituximab


0102030405060708090

100

CHOP-R FND-R Fludarabine-R

PR

CR

CHOP-RCHOP-R FN-R CVP-R

Chemo Rituximab Trials for Chemo Rituximab Trials for Initial Therapy Initial Therapy of Follicular NHLof Follicular NHL

Czuczman Zinzani 1 McLaughlin Czuczman

Hiddemann Zinzani 2 Marcus Rummel

Bendamustine-R

Fludarabine (Fludara®).Courtesy of Oliver W. Press, MD, PhD, and Stephanie A. Gregory, MD.

GELA PRIMA Phase III Study: GELA PRIMA Phase III Study: Rituximab Maintenance in FLRituximab Maintenance in FLGELA PRIMA Phase III Study: GELA PRIMA Phase III Study: Rituximab Maintenance in FLRituximab Maintenance in FL

CHOP x 6 +Rituximab x 8

CVP x 8 +Rituximab x 8

FCM x 6 +Rituximab x 8

Patients with previously untreated grade I–III FL

(n = 1,200)

CR/CRu, PR

RANDOMIZED

Maintenance Rituximab 375 mg/m2 q2mos x 2 yrs

Observation

Salles GA, et al. Lancet. 2011;377:42-51.

• 1,217 patients in 223 centers– 43% FLIPI 3-5

– Median age 56 y

– 90% stage III-IV

PRIMA Study: ResultsPRIMA Study: ResultsPRIMA Study: ResultsPRIMA Study: Results

• The risk of progression was significantly reduced for the rituximab maintenance group (HR 0.55, 95% CI: 0.44–0.68)

74.9%

57.1%

Salles GA, et al. Lancet. 2011;377:42-51.

Parameter Rituximab Observation HR P value

3-yr PFS 78.6% 60.3% 0.55 <0.0001

Deaths 6% 5% 0.87

CR/CRu 75% 55% <0.0001

FDA approved rituximab for front-line maintenance therapy in advanced FL in January, 2011

BendamustineBendamustineBendamustineBendamustine• Alkylating agent

– Induces durable DNA damage resulting in apoptosis and mitotic catastrophe

• Lacks cross resistance with other agents (including alkylators)

Rummel MJ, et al. J Clin Oncol. 2005;23:3383-9; Friedberg JW, et al. Blood. 2005;106:abstr#229; Chovan JP, et al. Drug Metab Dispos. 2007;35:1744-53; Weide R. Ther Clin Risk Manag. 2008;4:727-32; Cheson BD, Rummel MJ. J Clin Oncol. 2009;27:1492-501.

O

O

C

N

N

N

Cl

Cl

Nitrogen mustard

Carboxylic acid

Untreated pts with

indolent and MCL

(n=513)

RANDOMIZE

BR (× 6 cycles)Bendamustine: 90 mg/m2:

day 1-2, q4w+

Rituximab: 375 mg/m2

day 1, q4w

R-CHOP (× 6 cycles)Rituximab: 375 mg/m2

day 1, q3w+

CHOP (standard)day 1, q3w

Primary objective: To prove a non-inferiority of BR vs R-CHOP in PFS (defined as a difference of less than 15% in PFS after 3 years)Secondary objectives: ORR, OS, relapse-free survival, and safety

n=260

n=253

Evaluable patients

Rummel MJ, et al. Blood. 2009;114:168-169;abstr #405.

Phase III Study of First-line Phase III Study of First-line Bendamustine/Rituximab (B-R) Versus R-CHOP Bendamustine/Rituximab (B-R) Versus R-CHOP

in Indolent NHL: Final Results in Indolent NHL: Final Results

Phase III Study of First-line Phase III Study of First-line Bendamustine/Rituximab (B-R) Versus R-CHOP Bendamustine/Rituximab (B-R) Versus R-CHOP

in Indolent NHL: Final Results in Indolent NHL: Final Results

Key Eligibility Criteria:

• CD20+ FL (grade 1/2), MCL, MZL, WM, SLL, other LPL

• Stage III/IV

• No prior therapy

• Age ≥18 years

Bendamustine/Rituximab Versus R-CHOP for the Bendamustine/Rituximab Versus R-CHOP for the Frontline Treatment of Follicular Lymphoma: PFSFrontline Treatment of Follicular Lymphoma: PFS

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Su

rviv

al P

rob

abili

ty

0 12 24 36 48 60 72

Bendamustine/Rituximab(N=260)

R-CHOP (n=253)

*p=0.0281HR=0.63 (95% CI, 0.42-0.95)

RegimenMedian PFS*

ORR CR

R-CHOP 46.7 mos 91.3% 30.0%

Bendamustine/Rituximab NR 92.7% 39.6%

P value NS 0.026

• Significantly less adverse events with bendamustine/rituximab: alopecia, paresthesias, stomatitis, erythema, allergic reactions, and infectious complications

Time (Months)


Phase III Study of First-line Bendamustine/Rituximab Phase III Study of First-line Bendamustine/Rituximab (B-R) Versus R-CHOP in Indolent NHL: Safety(B-R) Versus R-CHOP in Indolent NHL: Safety

Phase III Study of First-line Bendamustine/Rituximab Phase III Study of First-line Bendamustine/Rituximab (B-R) Versus R-CHOP in Indolent NHL: Safety(B-R) Versus R-CHOP in Indolent NHL: Safety

Will B+R replace R+CHOP/CVP???Await formal publication and closer analysis of Rummel trial… long-term F/U?




Additional TherapyAdditional TherapyInitial Therapy

F OLLICULAR

LYMPHOMA

PROGRESSIVE

DISEASE

Stage I, IIStage I, II

Stage II Stage II StageStage III, IV III, IV

• Locoregional RT or • ImmunoRx ± Chemo Rx ± RT • Observe (if tx not indicated)

• Clinical trial or• Local RT• Chemotherapy followed by RIT•Observe (if tx not

indicated)

• Clinical trial or • Chemotherapy

Rituximab or • Rituximab maintenance or• RIT or• Stem Cell Transplant• Local RT• Observe (if tx not indicated)

Without transformation

Transformed to DLBCL

• Clinical trial or

• Rituximab

Chemotherapy ± Rituximab or

• Chemotherapy ± RT


Recurrent Follicular Lymphoma: Recurrent Follicular Lymphoma: Recommended TreatmentRecommended Treatment

Recurrent Follicular Lymphoma: Recurrent Follicular Lymphoma: Recommended TreatmentRecommended Treatment

• Conventional strategies– Rituximab ± maintenance– Chemoimmunotherapy

± maintenance– Radioimmunotherapy– External-beam

radiotherapy– Autologous transplantation– Allogeneic transplantation

• Novel strategies– Novel monoclonal

antibodies– Bortezomib (Velcade®)– Bendamustine– Lenalidomide

(Revlimid®)– Others

• Clinical trial

NCCN. Available at: http://www.nccn.org.

FDA-Approved Agents (US) for FDA-Approved Agents (US) for Rituximab-Refractory* Indolent, Rituximab-Refractory* Indolent,

Follicular NHLFollicular NHL

FDA-Approved Agents (US) for FDA-Approved Agents (US) for Rituximab-Refractory* Indolent, Rituximab-Refractory* Indolent,

Follicular NHLFollicular NHL

• Chemotherapy: bendamustine

•Radioimmunotherapy: I-131 tositumomab (Bexxar®) & Y-90 ibritumomab tiuxetan (Zevalin®)

* Defined as: No response to last rituximab treatment or relapse within 6 months of last rituximab

Bendamustine MonotherapyBendamustine MonotherapyBendamustine MonotherapyBendamustine Monotherapy

• Single-arm, multicenter trial in patients with rituximab-refractory indolent NHL – Eligible patients were 18 years of age, had a

WHO PS 2, at least one lesion measuring 2 cm, and had received 1 to 3 previous chemotherapies

• Bendamustine 120 mg/m2 on days 1 and 2, q21 days x 6-8 cycles

Kahl BS, et al. Cancer 2010; 116:106-14.

Bendamustine Monotherapy ResultsBendamustine Monotherapy ResultsBendamustine Monotherapy ResultsBendamustine Monotherapy Results

Efficacy by NHL type ORR, % (CR/CRu)

Follicular (62%)

Small lymphocytic (21%)

Lymphoplasmacytic (1%)

LN marginal zone (9%)

Ex-LN marginal zone (7%)

Total (100%)

74 (15/5)

71 (5/0)

100 (0/0)

78 (11/0)

86 (43/0)

*75 (14/3)

ORR=overall response rate; CR=complete response; CRu=unconfirmed CR.

Kahl BS, et al. Cancer 2010;116:106-14.

*95% CI, 65% to 83%.

• N=101 patients– Median age, 60 years; 76% with advanced-stage disease; FL (n=63);

marginal zone lymphoma (n=16); SLL (n=21); lymphoplasmacytoid lymphoma (n=1)

– Median number of prior chemotherapy regimens = 2

Radioimmunotherapy (RIT)Radioimmunotherapy (RIT)Radioimmunotherapy (RIT)Radioimmunotherapy (RIT)

Radiolabeled Monoclonal Antibodies for Radiolabeled Monoclonal Antibodies for RadioimmunotherapyRadioimmunotherapy

Radiolabeled Monoclonal Antibodies for Radiolabeled Monoclonal Antibodies for RadioimmunotherapyRadioimmunotherapy

• Proliferating tumor cells are inherently sensitive to radiation

• Continuous rather than intermittent RT

• Crossfire effect—kill tumor cells a few mm from the bound antibody & antigen-negative tumor cells

Crossfire Enhances EfficacyCrossfire Enhances EfficacyCrossfire Enhances EfficacyCrossfire Enhances Efficacy

Unlabeled “Cold” Antibody Radiolabeled Antibody

Courtesy of Andrew D. Zelenetz, MD, PhD.

Radiolabeled Monoclonal AntibodiesRadiolabeled Monoclonal AntibodiesRadiolabeled Monoclonal AntibodiesRadiolabeled Monoclonal Antibodies

Monoclonal Monoclonal antibodyantibody

Bond or Bond or ChelatorChelator RadionuclideRadionuclide

RadiationRadiation

RIT Historical TimelineRIT Historical TimelineRIT Historical TimelineRIT Historical Timeline

1985 1990 1995 2000 2005 2010

Trials of RIT begin

Phase I/II trial of I-131 tositumomab begins at Michigan

Phase I/II trial of Y-90 ibritumomab begins

FDA approvals of both agents in 2002 & 2003

First reports of frontline RIT

Randomized trial of RIT consolidation reported

Frontline trial of 131I tositumomab begins (1996)

Chemo + RIT in frontline begins (2000)

Durable remissions from all previous studies continue

Courtesy of Mark S. Kaminski, MD.

Regulatory Status of Anti-CD20 RadioimmunotherapyRegulatory Status of Anti-CD20 RadioimmunotherapyRegulatory Status of Anti-CD20 RadioimmunotherapyRegulatory Status of Anti-CD20 Radioimmunotherapy

• Y-90 ibritumomab tiuxetan– 2002 FDA approval: relapsed or refractory, low grade or

follicular NHL – 2009 FDA approval: treatment of previously untreated

follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy

• I-131 tositumomab– 2003 FDA approval: treatment of patients with CD20

antigen-expressing relapsed/refractory, low grade, follicular, or transformed NHL, including rituximab-refractory NHL

• Not indicated for first-line treatment of CD20+ NHL

I-131 Tositumomab & I-131 Tositumomab & Y-90 Ibritumomab Tiuxetan Y-90 Ibritumomab Tiuxetan

I-131 Tositumomab & I-131 Tositumomab & Y-90 Ibritumomab Tiuxetan Y-90 Ibritumomab Tiuxetan

• I-131 Tositumomab – Mouse anti CD20– Direct iodination of tyrosine

amino acids on the antibody, subject to dehalogenation

& 1 mm emission– 8.0 day half life– Thyroid uptake of free 131I – 50%-90% of 131I cleared in

urine within 48 hour – Scans needed to determine

residence time and rate of clearance

• Y-90 Ibritumomab tiuxetan– Mouse anti CD20– Indirect linkage via tiuxetan

linker chelated to 90Y and covalently linked to lysine and arginine amino acids

– 5 mm emission length– 2.7 day half-life– 5%-10% of 90Y-chelate

cleared in urine, some through bowel

– No scans needed

Clinical Criteria for Radioimmunotherapy Clinical Criteria for Radioimmunotherapy in Lymphomain Lymphoma

Clinical Criteria for Radioimmunotherapy Clinical Criteria for Radioimmunotherapy in Lymphomain Lymphoma

• Relapsed low-grade, follicular, and/or transformed low grade B-cell lymphoma

• Normocellular marrow

• Bone marrow involvement 25%

• ANC >1500/mm3

• Platelet count 150,000/mm3 (lower dose if 100k-149k)

• Peripheral blood lymphocytes <5000/mm3

• No human anti-mouse antibodies (HAMA)

• No prior radioimmunotherapy (preferred)

• No prior stem cell transplant (preferred)

Efficacy of RIT in Patients with Relapsed or Efficacy of RIT in Patients with Relapsed or Refractory CD20+ B-cell NHLRefractory CD20+ B-cell NHL

Efficacy of RIT in Patients with Relapsed or Efficacy of RIT in Patients with Relapsed or Refractory CD20+ B-cell NHLRefractory CD20+ B-cell NHL

Reference n Patient Characteristics

Median Number of Prior

Therapies

ResponseRate

ORR CRDisease Control

Median Duration of Response

I-131 tositumomab

Horning SJ, et al. J Clin Oncol 2005;23:712-9

40 CD20+ small cleaved or mixed lymphoma, de novo follicular large cell, or transformed lymphoma; relapsed or refractory after ≥ 1 course of standard rituximab

4 65% 38% Median PFS: 10.4 months (24.5 months for responders; NR for CR patients after median 39 months of follow-up)

NR in patients with grade 1 or 2 FL and tumor bulk ≤ 7 cm

Kaminski MS, et al. J Clin Oncol 2001;19:3918-28

60 Relapsed or refractory low-grade or transformed low-grade CD20+ B-cell NHL

4 65% 20% Median PFS: 8.4 months

6.5 months (NR for CR patients with >47 months of follow-up)

Witzig TE, et al. Leukemia Lymphoma. 2011;52:1188-99.

Efficacy of RIT in Patients with Relapsed/Refractory CD20+ B-cell NHLEfficacy of RIT in Patients with Relapsed/Refractory CD20+ B-cell NHL Efficacy of RIT in Patients with Relapsed/Refractory CD20+ B-cell NHLEfficacy of RIT in Patients with Relapsed/Refractory CD20+ B-cell NHL

Reference nPatient

Characteristics

Median Number of

Prior Therapies

Response Rate

ORR CRDisease Control

Median Duration of Response

Y-90 ibritumomab tiuxetan

Witzig TE, et al. J Clin Oncol 1999;17:3793-803

51 Relapsed or refractory low-grade or follicular NHL or intermediate-grade or mantle-cell NHL

2 67% 26% Median TTP: 12.9+ months

11.7+ months

Witzig TE, et al. J Clin Oncol 2002;20:2453-63

143 Relapsed or refractory low-grade, follicular, or transformed NHL

2 80% CR 30%; CRu 4%Rand Trial of Zevalin vs. Rituximab

Median TTP: 11.2 months

14.2 months

Wiseman GA, et al. Blood 2002;99:4336-42

30 Relapsed or refractory low-grade, follicular, or transformed CD20+ NHL and mild thrombocytopenia

2 83% CR: 37%; CRu: 6.7%

Median TTP: 9.4 months (12.6 months in responders)

11.7 months

Witzig, et al. J Clin Oncol 2002;20:3262-9

54 Rituximab-refractory follicular B-cell NHL

4 74% 15% Median TTP: 6.8 months (8.7 months in responders)

6.4 months

Gordon LI, et al. Blood 2004;103:4429-31

51 Relapsed or refractory low-grade or follicular B-cell NHL

2 73% CR: 29%; CRu: 22%

Median TTP: 9.3 months (12.6 months in responders)

11.7 months

Witzig TE, et al. Leukemia Lymphoma. 2011;52:1188-99.

I-131 Tositumomab and Y-90 Ibritumomab Tiuxetan I-131 Tositumomab and Y-90 Ibritumomab Tiuxetan Are Active in Patients with Follicular Lymphoma Who Are Active in Patients with Follicular Lymphoma Who

Are Refractory to Rituximab (No Response or Are Refractory to Rituximab (No Response or Duration <6 Months)Duration <6 Months)

I-131 Tositumomab and Y-90 Ibritumomab Tiuxetan I-131 Tositumomab and Y-90 Ibritumomab Tiuxetan Are Active in Patients with Follicular Lymphoma Who Are Active in Patients with Follicular Lymphoma Who

Are Refractory to Rituximab (No Response or Are Refractory to Rituximab (No Response or Duration <6 Months)Duration <6 Months)

• I-131 tositumomab – 40 patients (35 fit criteria)– Median age 57 y– 4 prior chemo median– 28% >7cm bulk– 32% BM involved– 68% response rate, 30% CR – 14.7 mos median duration of

response– >2 yrs CR durationHorning SJ, et al. J Clin Oncol

2005;23:712-9

• Y-90 ibritumomab tiuxetan– 54 patients– Median age 54 y– 4 prior chemo med– 44% >7cm bulk– 32% BM involved– 74% response rate, 15%

CR – 6.4 mos median duration

of response – 7.2 mos CR duration Witzig TE, et al. J Clin Oncol.

2002;20:3262-9

Responses Are Durable: PFS for Patients Treated Responses Are Durable: PFS for Patients Treated with I-131 Tositumomab Across Multiple Studieswith I-131 Tositumomab Across Multiple Studies

Fisher RI, et al. J Clin Oncol. 2005;23:7565-73.

PFS for Patients Treated with PFS for Patients Treated with Y-90 Y-90 Ibritumomab TiuxetanIbritumomab Tiuxetan

PFS for Patients Treated with PFS for Patients Treated with Y-90 Y-90 Ibritumomab TiuxetanIbritumomab Tiuxetan

Zevalin Package Insert. Spectrum Pharmaceuticals, Inc. 2011.

HR = 0.46 [95% CI: 0.35,0.60]; P <0.0001

Earlier Is Better: Higher Responses with Earlier Is Better: Higher Responses with Y-90 Ibritumomab Tiuxetan if Fewer Prior Y-90 Ibritumomab Tiuxetan if Fewer Prior

Chemotherapy Regimens Chemotherapy Regimens

Earlier Is Better: Higher Responses with Earlier Is Better: Higher Responses with Y-90 Ibritumomab Tiuxetan if Fewer Prior Y-90 Ibritumomab Tiuxetan if Fewer Prior

Chemotherapy Regimens Chemotherapy Regimens

1 prior (n=63)2 (n=148)

Com

plet

e R

espo

nder

s (%

)

CR Patients

Number of prior chemotherapy regimens

P<0.01

Emmanouilides C, et al. Leuk Lymphoma. 2006;47:629-36.

Number of prior regimens

Time to progression

1 12.6 mos

≥2 7.9 mos

P value <0.05

Efficacy by Treatment EncounterEfficacy by Treatment EncounterEfficacy by Treatment EncounterEfficacy by Treatment Encounter

I-131 Tositumomab Use by Treatment SequenceI-131 Tositumomab Use by Treatment Sequence

11stst Line Line(n=141)(n=141)

22ndnd Line Line(n=226)(n=226)

33rdrd Line Line (n=228)(n=228)

44thth+ Line + Line (n=540)(n=540)

Response rate, % Response rate, % 9595 7373 5858 4646

Median duration of Median duration of response, moresponse, mo NRNR 3535 1616 1212

Complete response (CR), Complete response (CR), % % 7878 4646 3232 2323

Median duration of CR, Median duration of CR, momo NRNR NRNR 3535 5959

PFS >1 year, % PFS >1 year, % 82 82 5959 4242 2727

All differences are statistically significant (p <0.001). All differences are statistically significant (p <0.001).

Gregory SA, et al. Proc Am Soc Clin Oncol. 2005;24:Abstr #6561.

Event-Free Survival for Event-Free Survival for I-131 Tositumomab by Line of TherapyI-131 Tositumomab by Line of Therapy

Event-Free Survival for Event-Free Survival for I-131 Tositumomab by Line of TherapyI-131 Tositumomab by Line of Therapy

0000

2020

4040

6060

8080

100100

11 22 33 44 55 66 77Time from treatment, yearsTime from treatment, years

Ev

ent-

fre

e s

urv

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l, %

pa

tie

nts

Ev

ent-

fre

e s

urv

iva

l, %

pa

tie

nts

11stst line (n = 141) line (n = 141)

22ndnd line (n = 291) line (n = 291)

33rdrd line (n = 260) line (n = 260)

≥ ≥ 44thth line (n = 484) line (n = 484)

Gregory SA, et al. Proc Am Soc Clin Oncol. 2005;24:Abstr #6561.

Low Incidence of Secondary Malignancies After RITLow Incidence of Secondary Malignancies After RITLow Incidence of Secondary Malignancies After RITLow Incidence of Secondary Malignancies After RIT

131I Tositumomab trials(n = 1071)

90Y IT registrational trials (n = 211)

Median follow-up, (range) 2.1 years3.2 years (1.2-75.5)

MDS/AML cases, n 35 7

Crude incidence of MDS/AML 3.3% 3.3%

Annualized incidence of MDS/AML

1.4% per year 0.70% per year

• MDS/AML with chemotherapy (no high-dose therapy)– Cumulative incidence 4% to 8%– Annualized incidence 1% to 1.5%

Bennett JM, et al. Blood. 2005;105:4576-82; Emmanoulides C, et al. Proc Am Soc Clin Oncol. 2004;23: Abstr #6696; Pedersen-Bjergaard, et al. Ann Intern Med. 1985;103:195-200; Greene MH, et al. Cancer Res. 1983;43:1891-8; Kantarjian HM, et al. Semin Oncol. 1987;14:435-43.

Subsequent Chemotherapy Regimens Are Subsequent Chemotherapy Regimens Are Well-Tolerated After RadioimmunotherapyWell-Tolerated After RadioimmunotherapySubsequent Chemotherapy Regimens Are Subsequent Chemotherapy Regimens Are Well-Tolerated After RadioimmunotherapyWell-Tolerated After Radioimmunotherapy

• 58 patients (Mayo Clinic) who had disease progression after previous treatment with Y-90 ibritumomab tiuxetan

– Median of 2 prior therapies before RIT: 54 CHOP, 35 CVP, 24 rituximab, 20 chlorambucil, 11 fludarabine

– 1-7 subsequent chemo regimens, median 2• Grade IV toxicity: 25% platelets, 33% ANC • 1/3 required CSF &/or hospitalized for febrile neutropenia and/or

bleeding• similar to contemporary cohort controls without RIT

– 8 had autologous stem cell transplants (7 PBSC)

Ansell SM, et al. J Clin Oncol. 2002;20:3885-90.

Chemotherapy, Radiation Therapy Chemotherapy, Radiation Therapy and Rituximab Can Be Effective and Rituximab Can Be Effective

After RadioimmunotherapyAfter Radioimmunotherapy

Chemotherapy, Radiation Therapy Chemotherapy, Radiation Therapy and Rituximab Can Be Effective and Rituximab Can Be Effective

After RadioimmunotherapyAfter Radioimmunotherapy

• 153/521 (29%) patients received other treatment after Y-90 ibritumomab tiuxetan

• Response data for 100/153 patients: first subsequent therapy after Y-90 ibritumomab tiuxetan 60/100 (60%) ORR

– 20/25 (80%) RR to focal radiation therapy– 25/49 (53%) RR to chemotherapy– 15/26 (58%) RR to rituximab

Schilder RJ [abstract #1064], Saleh F [abstract #30], ASCO 2002.

Algorithm for the Treatment of Relapsed or Algorithm for the Treatment of Relapsed or Refractory Follicular LymphomaRefractory Follicular Lymphoma

RIT

RITRIT

RIT

Witzig TE, et al. Leuk Lymphoma. 2011;52:1188-99.

Has the Natural History of Follicular NHL Changed?Has the Natural History of Follicular NHL Changed?

Reproduced with permission from Fisher RI, et al. J Clin Oncol. 2005;23:8447-52.

OS According to Treatment Program

Sur

viva

l (%

)

Time After Registration (Years)

OS by Treatment Program

CHOP + MoAb

ProMACE

CHOPPts Deaths

4-Year Estimate

179 18 91%

425 189 79%

356 226 69%

100

80

60

40

20

02 4 6 8 10

CHOP=cyclophosphamide, doxorubicin, vincristine, prednisone; MoAb=monoclonal antibody.

SummarySummarySummarySummary

• Many options of therapy exist for patients with follicular lymphoma

• There is no standard of care for both front-line and relapsed disease

• Radioimmunotherapy is an effective therapy for indolent B cell lymphoma

– One course of therapy is as effective as multiple courses of chemotherapy

– Patient selection is important to maximize benefit and minimize toxicity

– New approaches include frontline treatment with RIT and RIT consolidation after chemotherapy for frontline treatment of follicular lymphoma

Case StudyCase Study

• Walter: 59 year-old male diagnosed with stage 4, grade II follicular lymphoma 3 years ago

• At time of diagnosis, FLIPI score was low-risk

• Patient and his physician chose a watch and wait approach

• Patient has now developed progressive disease with multiple areas of lymphadenopathy but not systemic symptoms

What Would You Do Next?What Would You Do Next?

A. Continue to watch and wait

B. Single-agent rituximab

C. Rituximab + chemotherapy

D. Radioimmunotherapy


• Single-agent rituximab was prescribed because patient had a low tumor volume

• He had a good partial response to treatment, tolerated it well, and was left further untreated

• One year later he developed progressive disease with extensive lymphadenopathy (the largest mass measured 7 cm)

– 10% bone marrow involvement– Rebiopsy confirmed grade II follicular lymphoma

Now What?Now What?

A. Another course of single-agent rituximab

B. Rituximab + chemotherapy

C. Chemotherapy + radiation

D. Radioimmunotherapy


• Walter and his doctor decided to go with radioimmunotherapy

What Are Some Considerations When Choosing RIT?

What Are Some Considerations When Choosing RIT?

A. Percentage of bone marrow involvement

B. Platelet count

C. Absolute neutrophil count

D. Age of patient

E. Comorbidities of patient

If Walter Relapses After RIT, What Other Treatment Options

Available?

If Walter Relapses After RIT, What Other Treatment Options

Available?

A. Single-agent rituximab

B. Chemoimmunotherapy

C. Stem cell transplant

D. Repeat RIT

Questions?Questions?

Stephanie A. Gregory, MD, FACP The Elodia Kehm Chair of Hematology Professor of Medicine Rush...

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