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diagnosis, or treatment. The use of any information provided is solely at your own risk,and readers should verify the prescribing information and all data before treating
patients or employing any therapeutic products described in this educational activity.
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DISCLAIMERDISCLAIMERParticipants have an implied responsibility to use the newly acquired information
to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for
patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by
clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s
product information, and comparison with recommendations of other authorities.
DISCLOSURE OF UNLABELED USEDISCLOSURE OF UNLABELED USEThis activity may contain discussion of published and/or investigational uses of
agents that are not indicated by the FDA. IMER does not recommend the use of any agent outside of the labeled indications.
The opinions expressed in the activity are those of the faculty and do not necessarily represent the views of IMER. Please refer to the official prescribing information for
each product for discussion of approved indications, contraindications, and warnings.
Disclosure of Conflicts of InterestDisclosure of Conflicts of Interest Mollie E. Moran, MSN, CNP, AOCNP®, has no real or
apparent conflicts of interest to report.
Michael R. Savona, MD, FACP, reported a financial interest/relationship or affiliation in the form of: Speakers' Bureau, Celgene Corporation, Eisai, Inc.
Kathleen K. Curran, MSN, RN, CRNP, has no real or apparent conflicts of interest to report.
Learning ObjectivesLearning ObjectivesUpon completion of this activity, Upon completion of this activity,
participants should be better able to:participants should be better able to:
Evaluate the efficacy and safety profiles of first and second generation TKIs for the treatment of patients with CML
Apply primary and secondary prevention strategies for TKI-associated side effects that patients with CML experience
Implement effective treatment management and supportive care strategies to optimize patient adherence for CML patients receiving oral therapy
Plan health-literate, culturally-sensitive patient education regarding CML pathogenesis, diagnostics, treatment options, and potential side effects
Cite accruing CML clinical trials, and determine patient enrollment eligibility
Welcome and IntroductionWelcome and Introduction
Mollie E. Moran, MSN, CNP, AOCNP®
The James Cancer Hospital at The Ohio State University
Introduction to Faculty PanelIntroduction to Faculty Panel Mollie E. Moran, MSN, CNP, AOCNP®
– Oncology Nurse Practitioner
– The James Cancer Hospital at The Ohio State University
Michael R. Savona, MD, FACP
– Director of Leukemia Research, Senior Investigator Hematologic Malignancies Research and Drug Development
– Sarah Cannon Research Institute / Sarah Cannon Center for Blood Cancers
Kathleen K. Curran, MSN, RN, CRNP
– Nurse Practitioner
– University of Pittsburgh Medical Center
Activity AgendaActivity Agenda
12:30 – 12:35 pm Introduction
12:35 – 12:55 pm The Evolving Landscape of CML Treatment
12:55 – 1:35 pm Roundtable Workshop: Interactive Case on
Choosing CML Front-Line Therapy
1:35 – 1:55 pm Medication Adherence: Patient and Caregiver Teaching
1:55 – 2:00 pm Audience Questions and Answers
The Evolving Landscape The Evolving Landscape of CML Treatmentof CML Treatment
Michael R. Savona, MD, FACP
Sarah Cannon Research Institute /
Sarah Cannon Center for Blood Cancers
Chronic Myeloid Leukemia (CML)Chronic Myeloid Leukemia (CML)
Image courtesy of Michael R. Savona, MD, FACP.
CMLCML Incidence is 1.6–2.1 / 100,000 annually
Mortality is 0.2 / 100,000 annually in the US
Median age at diagnosis: 66
Female / Male ratio is ~ 1:1.7
Disease at presentation
– Chronic phase 85%–90%
– Accelerated phase and blast crisis 10%–15%
Radich, 2012; Cortes et al, 2011; Jabbour et al, 2012.
Ph+ = Philadelphia chromosome-positive; ALL = acute lymphoblastic leukemia; BCR = breakpoint cluster region.
NCCN, 2012; Martinelli et al, 2005.
Figure modified from Faderl et al, 1999.
ABL
BCR3'
5'
Chromosome 22Chromosome 9
3'
5'
BCR-ABL(Ph chromosome)
Philadelphia Chromosome Results Philadelphia Chromosome Results
From Reciprocal TranslocationsFrom Reciprocal Translocations Occur between chromosomes
9 and 22 to create the BCR-ABL gene transcript
– BCR-ABL fusion protein
– Constitutively activates ABL tyrosine kinase
– Increases cellular proliferation, modifies differentiation, and inhibits apoptosis
– Ph+ is also found in 20% of ALL
Blast Phase• > 30% blasts• ~ 2/3 of BC patients have
myeloid blast crisis • ~ 1/3 have lymphoid blast
crisis• Very poor prognosis
CMP CLP
HSCBCR-ABL
Chronic Phase• Myeloid hyperplasia • 10%–15% blasts• Natural history of
disease progression, 3–5 years
Additionalmutations
Additionalmutations
CML-BP(lymphoid)
CML-BP(myeloid)
Accelerated Phase• > 15%, < 30% blasts• Basophilia• New cytogenetic
abnormalities in 50%–80% of patients
CML-CP
M RBC
Platelets
MEG
T cell B cell
MEPGMP
G
Progression of CMLProgression of CML
RBC
CML-CP
HSC = haematopoietic stem cells; CMP = common myeloid progenitors; GMP = granulocyte/macrophage progenitors; G = granulocytes; M = macrophages; MEP = megakaryocyte/erythrocyte progenitors; RBC = red blood cells; MEG = megakaryocytes; CLP = common lymphoid progenitors.Ren, 2005; Cortes et al, 2006.
G
Image adapted from Savona et al, 2008.
Progression of CML (cont.)Progression of CML (cont.)
Time
Independence from addiction to BCR-ABL
Anaplastic threshold
Oncogenic addiction to BCR-ABL
N
N
N
HN
HN
O
N
N
PDGFR = platelet-derived growth factor receptor; ARG = ABL-related gene.
Wong et al, 2004.
Image adapted from O’Hare et al, 2005.
Targeted Molecular TherapyTargeted Molecular Therapyin the Management of CMLin the Management of CML
Imatinib
– Small molecule inhibitor of BCR-ABL tyrosine kinase activity
– Binds only to the inactive conformation of BCR-ABL
– Inhibits the activity of multiple kinases
• ABL
• ARG
• Kit
• PDGFRA, PDGFRB
2010 ASH: 116 – CML Outcome in Sweden2010 ASH: 116 – CML Outcome in Sweden3,173 patients (1973–2008); median age 62 yrs3,173 patients (1973–2008); median age 62 yrs
Image adapted from Bjorkholm et al, 2010.
Years Since Diagnosis
P P
Shah, 2005.
P P
P P
P P
Mechanisms of Secondary Mechanisms of Secondary Resistance to ImatinibResistance to Imatinib
Secondary resistance
Kinase domain mutations in BCR-ABL
– Occurs in ~ 50% of patients
Overproduction of native BCR-ABL
– Associated with ~ 10% of patients
BCR-ABL–independent mechanisms (largely uncharacterized)
– Src activation
– Non–BCR-ABL chromosomal translocations (ie, nup98/ddx10 fusion gene)
Shah et al, 2002.
Mutations that directly affect imatinib binding
Mutations that affect the conformation required to bind imatinib
Imatinib
Role of Kinase Conformation Role of Kinase Conformation in Imatinib Resistancein Imatinib Resistance
Point mutations in BCR-ABL kinase domain restricts its ability to adopt an inactive conformation
E355G
M351T
F317L
Y253F
Q252H
G250E
T315I
E255K
WT P210
0
0.2
0.4
0.6
0.8
1
1.2
1.4
0.01 0.1 1 10
Imatinib (M)
Pro
po
rtio
n o
f V
iab
le C
ells
(%
)
Mutations in BCR-ABL Kinase Domain Confer Mutations in BCR-ABL Kinase Domain Confer Varying Degrees of Resistance to ImatinibVarying Degrees of Resistance to Imatinib
In select cases, dose escalation of imatinib may overcome mutation-based resistance, but this has not been seen with mutation T315I
Shah et al, 2002.
Walz et al, 2005; O’Hare et al, 2005.Image modified from Weisberg et al, 2005.
Nilotinib
Imatinib
NilotinibNilotinib
A more selective, imatinib-derived ABL inhibitor
Binds to the inactive conformation of BCR-ABL
Also inhibits PDGFR and Kit kinases
~ 20-fold more potent compared with imatinib
Inhibits kinase activity of most BCR-ABL mutants
– Not including T315I
ABL PDGFR Kit Src-Family Kinases
Cellular IC50 (nM)*
Imatinib 630 30 100 NA
Nilotinib 25 57 60 NA
*Inhibition of cellular proliferation.
Walz et al, 2005.
Comparative ICComparative IC5050 Values for Values for
Targeted Molecules for CMLTargeted Molecules for CML
Shah et al, 2004; O’Hare et al, 2005.Image adapted from O’Hare et al, 2005.
DasatinibDasatinib An oral, multi-kinase inhibitor
Binds to both inactive and active conformations of BCR-ABL
325-fold more potent at inhibiting BCR-ABL kinase activity than imatinib
Active against all BCR-ABL mutants (to imatinib) tested
– 1 exception is mutation T315I
ABL PDGFR Kit Src-Family Kinases
Cellular IC50 (nM)*
Imatinib 630 30 100 NA
Nilotinib 25 57 60 NA
Dasatinib < 1 28† 5 0.5
*Inhibition of cellular proliferation.†PDGFRB.
Walz et al, 2005; Lombardo et al, 2004.
Comparative ICComparative IC5050 Values for Values for
Targeted Molecules for CML (cont.)Targeted Molecules for CML (cont.)
CSF1R = colony stimulating factor 1 receptor; VEGFR = vascular endothelial growth factor receptor; PDGFR = platelet-derived growth factor; ARG = ABL-related gene.
*Sensitive to drug.
Adapted from Walz et al, 2005; Lombardo et al, 2004; Wong at al, 2004.
Src familykinases
Abl* ARG*
YesSrcFynFgr
BlkLck
LynHck
Flk2VEGFR1
VEGFR3
VEGFR2
Kit*
PDGFRB*
PDGFRA*
CSF1R
Imatinib
VEGFR3
VEGFR2
Kit*
PDGFRB*CSF1R
Src familykinases
Abl* ARG*
YesSrcFyn
Fgr
BlkLck
LynHck
Flk2VEGFR1
PDGFRA*
Nilotinib
Src familykinases
Abl* ARG*
Yes*Src*Fyn*Fgr
BlkLck*
Lyn*Hck*
Flk2VEGFR1
VEGFR3
VEGFR2
Kit*
PDGFRB*
PDGFRA*
CSF1R
Dasatinib
Targets of Tyrosine Kinase InhibitorsTargets of Tyrosine Kinase Inhibitors
Saglio et al, 2010; Kantarjian et al, 2010.
% W
ith
MM
R
33
Months Since Randomization
73%, p < .0001
70%, p < .0001
53%
By 3 Years
100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 12 15 18 21 24 27 30
55%, p < .0001
51%, p < .0001
27%
By 1 Year
Δ 24%–28%
Δ 17%–20%
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Imatinib 400 mg QD
282
281
283
n
36
MMR = major molecular response.Saglio et al, 2011.
ENESTnd: Cumulative Incidence ENESTnd: Cumulative Incidence of MMR3 (3-log reduction)of MMR3 (3-log reduction)
Months
100
80
60
40
20
0
Dasatinib 100 mg QD
Imatinib 400 mg QD
0 3 6 9 12 15 18 21 24 27
By 24 months65%
47%
By 12 months47%
28%
Δ 19%
Δ 18%
*Response achieved by 24 months; calculated from randomized subjects with typical BCR-ABL transcripts.
% o
f P
atie
nts
DASISION: Cumulative Incidence of MMR3DASISION: Cumulative Incidence of MMR3
Kantarjian et al, 2011.
Marin et al, 2011; Hasford et al, 1998.
Hasford Risk:AgeSpleen sizePlatelet countBasophilsEosinophilsMyeloblasts
CCyR = complete cytogenetic response; CMR = complete molecular response; EFS = event-free survival; OS = overall survival; PFS = progression-free survival; RR = relative risk.Marin et al, 2011.
Assessment of BCR-ABL1 Transcript Levels at Assessment of BCR-ABL1 Transcript Levels at 3 Months Is the Only Requirement for Predicting Outcome 3 Months Is the Only Requirement for Predicting Outcome
for CML Patients Treated With TKIsfor CML Patients Treated With TKIsOutcome RR for Transcript Level (Log) 8-Year Probability of the Outcome
RR p ValueCutoff
(%)
No. of Patients at
RiskPercent
(%) p Value
BCR-ABL1 transcript level at 3 months
OSLow RiskHigh Risk
0.161 < .001≤ 9.84> 9.84
21168
93.356.9
< .001
PFSLow RiskHigh Risk
0.162 < .001≤ 9.54> 9.54
20871
92.857.0
< .001
EFSLow RiskHigh Risk
0.102 < .001≤ 9.84> 9.84
21166
65.16.9
< .001
CCyRLow RiskHigh Risk
5.17 < .001≤ 8.58> 8.58
16979
99.421.7
< .001
MMRLow RiskHigh Risk
12.98 < .001≤ 2.81> 2.81
141137
82.521.1
< .001
CMRLow RiskHigh Risk
10.95 < .001≤ 0.61> 0.61
57222
84.71.5
< .001
How to Choose?How to Choose?
Kantarjian et al, 2010.
Adverse EventsAdverse Events A thorough discussion
on the risks of non-hematologic side effects is necessary
The vastly different side-effect profile between dasatinib and nilotinib/imatinib means near total compliance/tolerance
*ALT = alanine aminotransferase; AST = aspartate aminotransferase.†Nilotinib was administered at a dose of either 300 mg or 400 mg BID, and imatinib at a dose of 400 mg QD.‡Listed are all nonhematologic AEs that occurred in at least 10% of patients in any group.Saglio et al, 2010.
Adverse EventsAdverse Events(cont.)(cont.)
Again, nuances in the AEs seen even between these relatively similar drugs
– These match clinical practice
% PatientsNilotinib
300 mg BID(n = 279)
Nilotinib400 mg BID
(n = 277)
Imatinib400 mg QD
(n = 280)All
GradesGrade
3/4All
GradesGrade
3/4All
GradesGrade
3/4
Nausea 14 < 1 21 1 34 0
Muscle spasms 8 0 7 < 1 27 < 1
Diarrhea 8 < 1 7 0 26 1
Vomiting 5 0 9 1 18 0
Peripheral edema 5 0 6 0 15 0
Facial edema < 1 0 2 0 11 < 1
Eyelid edema < 1 0 2 < 1 16 < 1
Periorbital edema < 1 0 1 0 14 0
Rash 32 < 1 37 3 13 2
Headache 14 1 22 1 9 < 1
Pruritus 16 < 1 13 < 1 6 0
Alopecia 9 0 13 0 5 0
Myalgia 10 < 1 10 0 11 0
Fatigue 11 0 9 < 1 10 < 1
Hughes et al, 2010.
Nilotinib Vs. Imatinib in CML-CPNilotinib Vs. Imatinib in CML-CPDrug-Related AEs (≥ 10% in Any Group)Drug-Related AEs (≥ 10% in Any Group)
Bosutinib Vs. Imatinib: CML Front-Line Bosutinib Vs. Imatinib: CML Front-Line Therapy-Related AEs Therapy-Related AEs 10%10%
Bosutinib(n = 248)
Imatinib(n = 251)
p ValueAE, % Any 3/4 Any 3/4Any AE 96 64 95 47 NS Diarrhea 68 10 21 1 .001 Vomiting 32 3 13 0 .001 Nausea 31 1 35 0 NS Rash 20 1 15 1 NS Pyrexia 16 1 9 1 .022 Abd pain upper 12 0 5 0 .007 Abd pain 12 1 5 0 .005 Fatigue 11 1 12 1 NS Headache 10 1 8 0 NS URI 10 0 6 0 NS Bone pain 4 0 10 1 .004 Muscle cramps 2 0 20 0 .001 Periorbital edema 1 0 14 0 .001
Abd = abdominal; URI = upper respiratory tract infection.
Gambacorti-Passerini et al, 2010.
CML Prevalence and Choice of TherapyCML Prevalence and Choice of TherapyHow Does Growing Prevalence Effect Our Choice?How Does Growing Prevalence Effect Our Choice?
~ 5,000 ~ 120,000
2001 2010 2020 2030
HHT = Homoharringtonine; Hsp = heat shock proteins; Sfb = sorafenib; mTOR = mammalian target of rapamycin;HDAC = Histone deacetylases.
Adapted from Cooper et al, 2009.
Rational Design of Future CML Rational Design of Future CML TherapyTherapy
HHT
HspInh
HDAC I
Crcm
JAK2-I
PEITCFTY720
AKIMKISPI
SfbFTI
mTOR
Translation
Post-translationalmodification
BCR-ABLT315I
Degradation and Direct Inhibition of
BCR-ABLT315I
Inhibition of BCR-ABLT315I
Protein Synthesis
Transcription of BCR-ABLT315I
How to Address the Leukemia Stem CellHow to Address the Leukemia Stem Cell
Wnt
Hedgehog
Ideal Targetable Stem Cell Pathways…
Pathway known to regulate self-renewal, differentiation, and proliferation in stem cells that are necessary for embryogenesis, hijacked in carcinogenesis, and unnecessary/superfluous in homeostasis
NotchTu, 2010; Images courtesy of national geography, Copyright (c) Kanehisa Laboratories - www.kegg.org. Used with permission.
Adapted from Crompton et al, 2007.act = activated form; GLI = glioma-associated oncogene; PTCH = patched; SMO = smoothened; rep = repressor form; SHH = sonic hedgehog.
Smoothened (SMO) Regulates Cancer Stem Cells
SHH GradientPF-04449913
GLIact
GLIrep
SHH-producing cell
GLI2, GLI3
GLI3 (GLI2)
PKA
GLI3rep (GLI2)
PP
GLI1-GLI3
GLI1act-GLI3act
PTCH1SMO
SHH
Hedgehog Inhibition: Novel Mechanism With Hedgehog Inhibition: Novel Mechanism With Applications Across a Broad Range of Cancers Applications Across a Broad Range of Cancers Hedgehog inhibition plays a key role in regulating cancer stem cell
survival and disrupting Hedgehog signaling in the malignant niche that contributes to disease resistance
ECOG PS = Eastern Cooperative Oncology Group performance status; HH = hedgehog.Jamieson et al, 2011.
PF04449913 – HH Inhibition in Myeloid DiseasePF04449913 – HH Inhibition in Myeloid Disease
Major Inclusion Criteria
– ≥ 18 years
– Previously treated (including transplant) or untreated select hematologic malignancies including:
• Myelodysplastic syndrome (MDS)
• Myelofibrosis (MF)
• Chronic myelomonocytic leukemia (CMML)
• CML, including T315I mutants
• AML
– ECOG PS: 0–2
– Adequate organ function (renal, hepatic, cardiac)
Major Exclusion Criteria
– Active graft vs. host disease
– Life-threatening or clinically significant uncontrolled infection
– Active central nervous system involvement by leukemia
Well ToleratedWell Tolerated
1 case of grade 3 hypoxia
Jamieson et al, 2011.
Photo courtesy of of Michael R. Savona, MD, FACP, national geography.
Event, n (%) Grade 1 Grade 2 Grade 3 Grade 4
Dysgeusia 4 (11%) 2 (6%) 0 0
Alopecia 3 (9%) 0 0 0
Muscle spasms 1 (3%) 1 (3%) 0 0
Nausea 2 (6%) 0 0 0
Vomiting 2 (6%) 0 0 0
AML: Reduction in Blasts (7 of 20)AML: Reduction in Blasts (7 of 20)
Jamieson et al, 2011.
Key TakeawaysKey Takeaways
CML is characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 t(9;22)(q34;q11) that causes fusion of the BCR and ABL genes
There are a number of oral TKIs available for effectively treating CML-CP
Roundtable Workshop: Roundtable Workshop: Interactive Case on Choosing Interactive Case on Choosing
CML Front-Line TherapyCML Front-Line Therapy
Mollie E. Moran, MSN, CNP, AOCNP®
The James Cancer Hospital at The Ohio State University
Case Study Case Study A 48-year-old flight attendant presents for her annual physical
exam. She is in her usual state of health and is without complaints. She is found to have a palpable spleen at 5 cm below the LCM.
– WBC 38,000 K/uL
• Basophils 2%
• Eosinophils 2%
• Blasts 7%
– Platelets 550,000 K/uL
– LDH 250 U/L (range 100–190 U/L)
– UA 7.8 mg/dL (range 4.47.6 mg/dL)
– Remainder of labs normal
– Physical exam normal except as noted above
WBC = white blood count; LDH = lactate dehydrogenase; UA = uric acid.
Case Study (cont.)Case Study (cont.)
– Medical History
• Type II DM controlled with metformin
• HTN controlled with lisinopril and HCTZ
– Family History
• Negative for leukemia or lymphoma
• 2 brothers and 1 sister, all AW
CML is suspected
Case Study (cont.)Case Study (cont.)
BMB + for CML
– 8% blasts
– 2% basophils
Cytogenetics 46 XX t(9:22;11) 20/20 cells
FISH 98% + BCR-ABL metaphases
BCR-ABL fusion transcript is positive by RT-PCR
Diagnosis of CML is confirmed
RT-PCR = real-time PCR.
Diagnostic Evaluation: Peripheral BloodDiagnostic Evaluation: Peripheral BloodDiagnostic Study Clinical Significance
CBC, differential, plts, reticulocyte count with evaluation of the peripheral smear
Evaluate for the presence of leukocytosis, basophilia,thrombocytosis, monocytosis, peripheral blasts, morphological abnormalities, cytopenias
Establish baseline for monitoring of treatment-induced cytopenias
LDH, UA, PO4, Ca++, K+ Elevated LDH is a poor prognostic indicator – indicative of higher cell turnover or tumor burden and increased risk for tumor lysis
Baseline hepatic, renal, and electrolyte profiles
Lipase for nilotinib
Mild and transient transaminitis is common with imatinib therapy
Mild hyperbilirubinemia is reported with imatinib, dasatinib, and nilotinib
Elevated lipase levels have been reported with nilotinib
Renal toxicities are rare, but patients requiring diuretic therapies will need continued monitoring
HLA typing For possible BMT
BCR-ABL by PCR
Consistent lab recommended
Establish baseline for continued evaluation of molecular response
PO4 = phosphate; Ca++ = calcium; K+ = potassium; HLA = human leukocyte antigen; BMT = bone marrow transplant. Kurtin, 2010; Druker et al, 2008.
Diagnostic Evaluation: Diagnostic Evaluation: Bone Bone MarrowMarrow
Diagnostic Study Clinical Significance
Aspirate Evaluation of morphological abnormalities of hematopoietic precursors (myeloid vs. lymphoid and stage of maturation)
Used for flow cytometry, FISH, or PCR analysis and cytogenetics
Biopsy Evaluate cellularity, topography, presence of fibrosis
Cytogenetics Evaluate for possible non-random chromosomal abnormalities – based on evaluation of 20 metaphases > 2 metaphases is considered non-randomMost useful in initial diagnostic evaluation for t(9;22)Useful for detection of emerging chromosomal abnormalities in patients with evidence of persistent leukemic clone by RQ-PCR
FISH 5%–10% false positive rateDoes not replace regular cytogenetics to detect additional cytogenetic abnormalities
RQ-PCR = real-time quantitative-PCR.Druker et al, 2008.
Typical Laboratory Parameters Typical Laboratory Parameters by Phase of CMLby Phase of CML
Parameter Chronic Accelerated Blast Crisis
WBC 20 x 109/L — —
Blasts 1%–15% 15% 30%
Basophils 20% —
Platelets or normal or
Bone marrow Myeloid hyperplasia
Cytogenetics Ph+
BCR-ABL + + +
Phase of CML
CMLalliance.net.
50
Chronic Accelerated Blastic
• Asymptomatic (if treated)
• None of criteria for accelerated or blast blast phase
• Blasts 15%
• Bl + pros 30%
• Basophils 20%
• Plts < 100,000/mcl
• Clonal evolution
• Blasts 30%
• Extramedullary
disease with localized
immature blasts
CML PhasesCML Phases
Past 3–5 years 12–18 months 3–9 months
Present 25+ years 4–5 years 6–12 months
NCCN, 2012.
Adapted form Kantarjian et al, 2012.
Survival in Early CP-CMLSurvival in Early CP-CML
Years
Sokal and Hasford ScoresSokal and Hasford Scores
Calculated at diagnosis to predict prognosis
Sokal Index
– Percent of peripheral blasts
– Platelet count
– Spleen size
– Age
Hasford includes the above and
– Eosinophils
– Basophils
Hiwase et al, 2011.
Thomas et al, 2001.
How to Calculate the Sokal and Hasford ScoresHow to Calculate the Sokal and Hasford ScoresHasford score0.6666 x age (0 when < 50 years, 1 otherwise)
+ 0.042 x spleen size (cm below costal margin)
+ 0.0584 x blasts (%)+ 0.0413 x eosinophils (%)+ 0.2039 x basophils
(0 when < 3%, 1 otherwise)+ 1.0956 x platelet count
(0 when < 1,500, 1 otherwise)X 100
≤ 780 low risk group> 780 and ≤ 1,480 intermediate risk group> 1,480 high risk group
Sokal scoreExp. (0.0116 (age – 4.34))
+ 0.0345 (spleen – 7.51)+ 0.188 (platelets/700)2 – 0.563)0.0887 (percentage of blasts – 2.1)
< 0.8 good prognosis0.8–1.2 moderate prognosis> 1.2 poor prognosis
Case Study (cont.)Case Study (cont.)
Sokal
– 0.97
– Intermediate Risk
Hasford
– 785
– Intermediate Risk
Case Study (cont.)Case Study (cont.)
She is initiated on one of the following therapies for CML:
– Imatinib 400 mg po daily
– Imatinib 800 mg po daily
– Dasatinib 100 mg po daily
– Nilotinib 300 mg BID
Roundtable Discussion TopicsRoundtable Discussion Topics
Patient and disease characteristics
– Influence on choice of front-line therapy
Lab values and diagnostic interpretation
Cytogenetic evaluation
– FISH and RT-PCR
Treatment selection rationale
Response Definitions and Response Definitions and Monitoring of CMLMonitoring of CML
Hematologic Cytogenetic Molecular
Definitions
Complete: Plts < 450 x 109/L WBC < 10 x 109/L differential without immature granulocytes nonpalpable spleen
Complete: Ph+ 0% Partial: Ph+ 1%–35% Major: Ph+ 36%–65% Minor: Ph+ 66%–95%
Complete: BCR-ABL undetectable by RT-PCRMajor: ≥ 3-log reduction in BCR-ABL mRNA
Monitoring
Check q2wks until CR achieved and confirmed, then q3mos unless otherwise required
Check at 6, 12, achieved and confirmed, then at least q12mos
Check q3mos; mutational analysis in case of failure, suboptimal response, or transcript level increase
CR = complete response; mRNA = messenger ribonucleic acid. NCCN, 2012.
Roundtable Discussion Topics Roundtable Discussion Topics (cont.)(cont.)
Adverse events
– Primary prevention strategies/cautions and contradictions with TKI use
– Monitoring protocols
– Overall side-effect management
Dose adjustment protocols
Evaluation and monitoring of response
Treatment failure/resistant disease
Patient education
Roundtable DiscussionsRoundtable Discussions
(10 minutes)
Faculty Roundtable Faculty Roundtable Presentations Presentations
(20 minutes)
Results With Imatinib in Results With Imatinib in Early CML-CP: IRIS Trial at 8 YearsEarly CML-CP: IRIS Trial at 8 Years 304 (55%) patients on imatinib on study
Projected results at 8 years
– CCyR: 83%
• 82 (18%) lost CCyR, 15 (3%) progressed to AP/BP
– EFS: 81%
– TFS: 92%
• If MMR at 12 mos: 100%
– Survival: 85% (93% CML-related)
Annual rate of transformation: 1.5%, 2.8%, 1.8%, 0.9%, 0.5%, 0%, 0%, 0.4%
CCyR = complete cytogenic response; AP = accelerated phase; BP = blast phase; EFS = event-free survival; TFS = transformation-free survival; IRIS = International Randomized Study of Interferon and STI571.Deininger et al, 2009.
Long-Term Outcome With Imatinib Long-Term Outcome With Imatinib in Early CML-CP (ITT)in Early CML-CP (ITT)
Pro
bab
ility
(%
)
1.0
0.8
0.6
0.4
0.2
0.1
0.9
0.7
0.5
0.3
6054481260
Time From Start of Imatinib Therapy (months)
4236302418
SurvivalPFS
EFSCHR
Loss of MCyR
63%
ITT = intent-to-treat.
de Lavallade et al, 2008.
Criteria for Failure and Suboptimal Criteria for Failure and Suboptimal Response to ImatinibResponse to Imatinib
Time (months)
Response
Failure Suboptimal Optimal
3 No CHR No CG Response < 65% Ph+
6 No CHR> 95% Ph+ ≥ 35% Ph+ ≤ 35% Ph+
12 ≥ 35% Ph+ 1%–35% Ph+ 0% Ph+
18 ≥ 5% Ph+ No MMR MMR
AnyLoss of CHRLoss of CCyRMutation CE
Loss of MMRMutation
Stable or Improving MMR
Baccarani et al, 2009.
High-Dose Imatinib as Initial Therapy in CMLHigh-Dose Imatinib as Initial Therapy in CML 281 patients Rx’d with imatinib 400 mg (n = 73) or 800 mg (n = 208)Overall Response (%) 400 mg 800 mg p ValueCCyR 87 91 .49MMR 78 87 .06CMR 39 49 .21
CMR = complete molecular response.
Pemmaraju et al, 2010.
0 12 24 36 48 60 72 84 96 108 1200.0
0.2
0.4
0.6
0.8
1.0
400mg 800mg
Total73
208
No.event1522
p = 0.01
0 12 24 36 48 60 72 84 96 108 120
1
0.8
0.6
0.4
0.2
0
800 mg 400 mg
Total CMR 206 100 71 28
p = 0.04
Time to CMR EFS
TOPS: Rate of MMR Over Time TOPS: Rate of MMR Over Time by Imatinib Dose (ITT)by Imatinib Dose (ITT)
476 patients with early CML-CP randomized to imatinib 400 mg daily vs. 800 mg daily
Outcome at 24 monthsPercent (%)
400 mg 800 mg
CCyR 76 76
MMR 54 51
EFS 95 95
PFS 97 98
Significant impact of dose intensity/treatment interruptions on MMR rate
TOPS = tyrosine kinase inhibitor optimization and selectivity; PFS = progression-free survival.Baccarani et al, 2009.
Dasatinib Vs. Imatinib Study inDasatinib Vs. Imatinib Study inTreatment-Naïve CML (DASISION) Trial Design Treatment-Naïve CML (DASISION) Trial Design
Primary end point: Confirmed CCyR by 12 mos
Secondary/other end points: Rates of CCyR and MMR; times to confirmed CCyR, CCyR, and MMR; time in confirmed CCyR and CCyR; PFS; OS
Follow-Up
5 yrsRandomizeda
Imatinib 400 mg QD (n = 260)
Dasatinib 100 mg QD (n = 259)N = 519
108 centers
26 countries
aStratified by Hasford risk score.DASISION = dasatinib vs. imatinib study in treatment-naive CML patients.Kantarjian et al, 2011.
Dasatinib Vs. Imatinib in Dasatinib Vs. Imatinib in Newly Diagnosed CML-CPNewly Diagnosed CML-CP
519 patients randomized to dasatinib 100 mg QD (n = 259) or imatinib 400 mg QD (n = 260)
Median follow-up: 24 months
Outcome Dasatinib 100 Imatinib 400
% CCyR 86 82
% MMR 64 46
% BCR-ABL ≤ 0.0032% 17 8
% Discontinued Therapy 23 25
New Mutations (No.) 10 10
Kantarjian et al, 2011.
Nilotinib Vs. Imatinib in Nilotinib Vs. Imatinib in Newly Diagnosed CML-CPNewly Diagnosed CML-CP
846 patients randomized to nilotinib 300 mg BID (n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg QD (n = 283)
Minimum follow-up: 24 months
Outcome Nilotinib 300 Nilotinib 400 Imatinib 400
% CCyRa 87 85 77
% MMRa 71 67 44
% BCR-ABL ≤ 0.0032%a 26 21 10
% Discontinued Treatment 18 21 22
New Mutation (No.) 10 8 20
aBy 24 months.Larson et al, 2011; Kantarjian, Hochhaus, et al, 2011.
Known Mechanisms of Imatinib ResistanceKnown Mechanisms of Imatinib Resistance
Branford et al, 2003; Weisberg et al, 2000; Donato et al, 2003.
Time of Therapy
TKI CML Phase
CP (%) AP (%) BP (%)
Newly Diagnosed
Imatinib 75 20 10
Nilotinib 95
Dasatinib 95
Resistance or Progression
Nilotinib 45 20 30
Dasatinib 50 30 30
Radich, 2010.
CCyR Rates for Approved TKIsCCyR Rates for Approved TKIs
EFS by Treatment in Early CML-CPEFS by Treatment in Early CML-CP
Adapted from Cortes et al, 2009.
Time (months)
Pro
bab
ility
EF
S (
%)
Toxicity ProfilesToxicity ProfilesGRADE 3/4 HEM (%) NON-HEM (%)
Imatinib Anemia (5–7)
Neutropenia (20)
Thrombocytopenia (9–10)
Fluid Retention/Edema (39–42)
Nausea (20–21)
Diarrhea (17–21)
Rash (11–17)
Elevated Amylase (18)
Dasatinib Anemia (10)
Neutropenia (21)
Thrombocytopenia (19)
Fluid Retention/Edema (19)
Pleural Effusion (10, no grade 3/4)
Nausea (8)
Diarrhea (17)
Rash (11)
Elevated Amylase (not listed)
Nilotinib Anemia (3)
Neutropenia (10–12)
Thrombocytopenia (10–12)
Fluid Retention/Edema (7–8)
Nausea (11–19)
Diarrhea (6–8)
Rash (31–36)
Elevated Amylase (12–15)
QTc > 500 msec• Nilotinib trial: 1 patient on imatinib, no patients on nilotinib• Dasatinib trial: 1 patient on imatinib, 1 patient on dasatinib
Gleevec® prescribing information, 2012; Sprycel® prescribing information, 2012; Tasigna® prescribing information, 2012.
MyelosuppressionMyelosuppression Generally occurs in the first few months Mild-to-moderate in severity (grade 1–2) and self-limiting Monitoring of blood counts can detect serious events
– Weekly during the first and/or second months
– Monthly during second and third months
– Every 3 months thereafter
Serious events can be managed by dose reduction or interruption– Per agent-specific prescribing information
Use of growth factors may be used to manage
Jabbour et al, 2011; NCCN, 2012; Tasigna® prescribing information, 2012.
Neutropenia Dasatinib, Imatinib, Nilotinib
Thrombocytopenia Dasatinib, Nilotinib
General Fluid RetentionGeneral Fluid Retention Patient education key to allow patients to recognize
and report symptoms
CXR = chest X-ray.Jabbour et al, 2011; NCCN, 2012.
Symptoms of Fluid Retention Management of Peripheral Edema or Rapid Weight Gain
Rapid weight gain Peripheral and peri-orbital edema Heart- and lung-associated symptoms
Diuretic therapy Limit salt intake CXR for patients with symptoms suggestive of pleural effusion (dyspnea or dry cough) Dose reduction, interruption, or discontinuation
Management of QTc ProlongationManagement of QTc Prolongation Prolongation of the QTc interval can occur with nilotinib
(black box warning) or dasatinib Prior to initiation of therapy, check serum potassium and
magnesium levels as well as other medications In case of severe events
– Therapy should be withheld until resolution and serum potassium and magnesium levels are corrected
– Check concomitant medications
Take caution in prescribing to patients at risk for or with known QTc prolongation
– Hypokalemia, hypomagnesemia, or congenital long QT syndrome
– Patients taking medicines known to prolong QT including antiarrhytmic drugs, azoles
Tasigna® prescribing information, 2012; Sprycel® prescribing information, 2012.
Cutaneous ReactionsCutaneous Reactions
Jabbour et al, 2011; Sprycel® prescribing information, 2012; Tasigna® prescribing information, 2012; Gleevec® prescribing information, 2012.
Primary AE Drug Specific Considerations
Dermatologic Toxicity
Imatinib 12.7% of patients reported with rash grade 1/240.9% incidence of depigmentation3.6% hyperpigmentation
Dasatinib 22% incidence of rash (grade 1/2)0.5% (grade 3/4)
Nilotinib 30% incidence of rash (grade 1/2)2% (grade 3/4)
Numerous Drug InteractionsNumerous Drug InteractionsIMATINIB DASATINIB NILOTINIB
PPI ↑ Exposure (inhibit Pgp) ↓ Absorption
(decreased solubility)
↑ Exposure (inhibit Pgp)
H2-antagonists ↑ Exposure (inhibit Pgp)
↓ Intracellular exposure
(inhibit hOCT-1)
↓ Absorption
(decreased solubility)
↑ Exposure (inhibit Pgp)
↑ Exposure (inhibit CYP 3A4)
Metoclopromide ↑ QTc ↑ QTc ↑ QTc
Metformin ↓ Intracellular exposure
(inhibit hOCT-1)
Warfarin ↑ Increased anticoagulation
(↑ CYP 2C9 by TKI)
↑ Increased anticoagulation
(↑ CYP 2C9 by TKI)
Haouala et al, 2011.
And many more….
General Patient EducationGeneral Patient Education
Do not crush or cut tablets Missed doses should not be made up, instruct patient
not to double the doses Should not be administered to pregnant women Dasatinib: Antacid 2 hours pre- or post-dose, avoid
medications that reduce stomach acid Nilotinib: No food 2 hours prior and 1 hour after dose No grapefruit juice Notify staff of current, new, and OTC medications
that are being consumed
OTC = over-the-counter.Sprycel® prescribing information, 2012; Tasigna® prescribing information, 2012; Gleevec® prescribing information, 2012.
Medication Adherence:Medication Adherence:Patient and Caregiver TeachingPatient and Caregiver Teaching
Kathleen K. Curran, MSN, RN, CRNPUniversity of Pittsburgh Medical Center
““Drugs DonDrugs Don’’t Work in Patients Who Dont Work in Patients Who Don’’t t Take Them.Take Them.”” – C. Everett Coop, MD – C. Everett Coop, MD
Low-adherence to prescribed treatments is very common
– Typical adherence rate for medication to treat chronic disease is about 50%
Success rate for TKIs are high, but require long-term administration in responsive patients
Patients may feel that ‘drug holidays’ are to be expected when patients are advised to hold their dose to control neutropenia or side effects. They may feel that skipping doses is acceptable.
Sackett, 1978; Guilhot, 2004.
Oral Therapy AdherenceOral Therapy Adherence
About 25% of patients being treated for CML did not take imatinib as prescribed
Lack of compliance had adverse effect on cytogenetic and molecular responses
– Patients who look < 90% of their imatinib (missing 3 doses in 1 month) had worse responses than those who were 100% compliant
– None who took < 80% of imatinib had a complete response
Bazeos et al, 2009.
As Many Reasons as SnowflakesAs Many Reasons as Snowflakes
There is not one intervention that will work for all people
Patients must be included when adherence methods are being evaluated
Patients who miss their appointments are at high risk for non-adherence to medication
Patients with complex regimens are at high risk for missed doses
What Works?What Works?
Identify patients at high risk—missed appointments, missed refills, evaluate barriers
Evaluate your patients and discuss their feelings about the need for treatment
Make the regimen as simple as possible
– Look at all the medications that have been prescribed and look for ways to simplify
Listen to the patient and family and align identified behaviors that may decrease forgetfulness
Osterberg et al, 2005.
Interventions to TryInterventions to Try
Patients will bring ALL of their medication to clinic visits
Calling the patient frequently to assess side effects and adherence
Medication reminder systems
Recruit assistance from the pharmacist
Have the patient identify what will help
ConsiderConsider
Health literacy
Health beliefs
Patient-practitioner relationship
Depression
Support system or lack of support
Financial barriers and privacy concerns
Denial of illness and its severity
Compliance-Adherence-PersistenceCompliance-Adherence-Persistence
Compliance implies paternalism and obedience
Adherence is the extent to which a person’s behavior—taking medication, following a diet, making lifestyle changes—corresponds with agreed recommendations from a health-care provider
Persistence is the ability of a person to continue taking medication for the intended course of therapy
WHO, 2003.
Three Decades of ResearchThree Decades of Research
Many, many, many interventions have been tried to assist people with medication adherence have proven:
– Nothing works for every person
Find what works for some of your patients; find something else that works for other patients; then combine other strategies to work for the rest of them
Medication Adherence Medication Adherence DiscussionsDiscussions
1) Roundtable Discussion (5 minutes)
– Best practices for ensuring oral therapy adherence
2) Microphone Session (10 minutes)
– Volunteers to share their best practices with the audience
Possible Discussion Topics
– Medication precautions/drug interactions
– Strategies to improve compliance and adherence
– The “how to” on recording and reporting adverse reactions/keeping a diary
– Healthy literacy and cultural sensitivities
Final Key TakeawaysFinal Key Takeaways There are a number of oral TKIs available for effectively
treating CML-CP
Patients require close monitoring for response, resistance, and tolerance to optimize potential for a complete response to therapy
Nurses play a key role by monitoring effective treatment management and implementing supportive care strategies to optimize patient adherence for CML patients receiving oral therapy
Nurses can plan health-literate, culturally-sensitive patient education regarding CML pathogenesis, diagnostics, treatment options, and potential side effects to support patients receiving therapy for CML
Final Key Takeaways (cont.)Final Key Takeaways (cont.)
Patients who were not 100% compliant did not achieve CR in clinical trials
Assess every patient’s risk of medication non-adherence with every encounter
For every patient, for every visit… have them bring in all medications. Assess for compliance and interactions.
Excellent symptom management of side effects can assist patients to tolerate medication
The nurse is at the perfect position to assist patients to achieve the best possible outcome
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