DISCLAIMERDISCLAIMERThis slide deck in its original and unaltered format is for educational purposes and is

current as of May 2012. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME provider, or the commercial supporter. Thesematerials may discuss therapeutic products that have not been approved by the US

Food and Drug Administration and off-label uses of approved products. Readersshould not rely on this information as a substitute for professional medical advice,

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