In 2011, the treatment armamentarium dramatically expanded with the approval of the anti-CTLA4 antibody ipilimumab and the BRAF inhibitor vemurafenib. Oncology nurses who care for patients with melanoma are beginning to administer these new agents and have numerous questions regarding their efficacy, different response patterns, unique toxicity profiles, how they may be integrated into current treatment regimens, and how to educate patients on their benefits and risks. Downloadable slide decks are a great tool for self study and teaching purposes. They are non-certified resources available to enhance your knowledge. Review a downloadable slide deck by Mollie E. Moran, MSN, CNP, AOCNP®, covering the most clinically relevant new data reported from Establishing Best Practices for CML Therapy: A Workshop Symposium for the Advanced Practice Oncology Nurse. Target Audience This activity has been designed to meet the educational needs of oncology advanced practitioners involved in the care of patients with chronic myelogenous leukemia (CML) who are interested in an advanced course on this topic. Slide Deck Disclaimer This 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 the faculty, and not those of IMER, the CE provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should 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. For more information visit: http://imeronline.com/gxpsites/hgxpp001.aspx?11,52,304,O,E,0,,745;561;8471

2. DISCLAIMER
This 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 the
faculty, and not those of IMER, the CME provider, or the commercial supporter. These
materials may discuss therapeutic products that have not been approved by the US
Food and Drug Administration and off-label uses of approved products. Readers
should 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.
Usage Rights
This slide deck is provided for educational purposes and individual slides may be
used for personal, non-commercial presentations only if the content and references
remain unchanged. No part of this slide deck may be published in print or
electronically as a promotional or certified educational activity without prior written
permission from IMER. Additional terms may apply. See Terms of Service on
IMERonline.com for details.

3. DISCLAIMER
Participants 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 USE
This 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.

4. Disclosure 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.

5. Learning Objectives
L
Upon completion of this activity,
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

6. Welcome and Introduction
Mollie E. Moran, MSN, CNP, AOCNP®
The James Cancer Hospital at
The Ohio State University

7. Introduction 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

8. Activity Agenda
A
12:30 – 12:35 pm I
Introduction
12:35 – 12:55 pm T
The Evolving Landscape of CML Treatment
12:55 – 1:35 pm Roundtable Workshop: Interactive Case on
C
Choosing CML Front-Line Therapy
1:35 – 1:55 pm Medication Adherence: Patient and
C
Caregiver Teaching
1:55 – 2:00 pm Audience Questions and Answers

9. The Evolving Landscape
of CML Treatment
Michael R. Savona, MD, FACP
Sarah Cannon Research Institute /
Sarah Cannon Center for Blood Cancers

10. Chronic Myeloid Leukemia (CML)
Image courtesy of Michael R. Savona, MD, FACP.

11. CML
 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.

12. Philadelphia Chromosome Results
From Reciprocal Translocations Chromosome 9
Chromosome 22
 Occur between chromosomes
9 and 22 to create the BCR-
ABL gene transcript 5'
BCR
3'
– BCR-ABL fusion protein
– Constitutively activates ABL
5'
ABL
3'
tyrosine kinase
– Increases cellular proliferation,
modifies differentiation, and
inhibits apoptosis
– Ph+ is also found in 20% of ALL BCR-ABL
(Ph chromosome)
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.

13. Progression of CML
BCR-ABL HSC
CML-BP CML-BP
(myeloid) CMP CLP (lymphoid)
Additional GMP MEP Additional
mutations mutations
MEG
CML-CP
CML-CP
G
M RBC
Chronic Phase RBC T cell B cell
• Myeloid hyperplasia Platelets Blast Phase
• 10%–15% blasts • > 30% blasts
• Natural history of Accelerated Phase • ~ 2/3 of BC patients have
disease progression, G • > 15%, < 30% blasts myeloid blast crisis
• Basophilia • ~ 1/3 have lymphoid blast
3–5 years
• New cytogenetic crisis
abnormalities in 50%–80% • Very poor prognosis
of patients
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.

14. Progression of CML (cont.)
Independence
from addiction
to BCR-ABL
Anaplastic
threshold
Oncogenic
addiction to
BCR-ABL
Time
Image adapted from Savona et al, 2008.

15. Targeted Molecular Therapy
in 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
N
H H
• ARG N N N N
• Kit N O
• PDGFRA, PDGFRB
N
PDGFR = platelet-derived growth factor receptor; ARG = ABL-related gene.
Wong et al, 2004.
Image adapted from O’Hare et al, 2005.

16. 2010 ASH: 116 – CML Outcome in Sweden
3,173 patients (1973–2008); median age 62 yrs
Years Since Diagnosis
Image adapted from Bjorkholm et al, 2010.

17. Mechanisms of Secondary
Resistance to Imatinib
 Secondary resistance P P
 Kinase domain mutations in
BCR-ABL
– Occurs in ~ 50% of patients
 Overproduction of native BCR- P P
ABL
– Associated with ~ 10% of patients
 BCR-ABL–independent
P P
P P
mechanisms (largely
uncharacterized)
– Src activation
– Non–BCR-ABL chromosomal
translocations (ie, nup98/ddx10
fusion gene)
Shah, 2005.

18. Role of Kinase Conformation
in Imatinib Resistance
 Point mutations in BCR-ABL kinase domain restricts its
ability to adopt an inactive conformation
Mutations that directly
affect imatinib binding
Imatinib Mutations that affect the
conformation required
to bind imatinib
Shah et al, 2002.

19. Mutations in BCR-ABL Kinase Domain Confer
Varying Degrees of Resistance to Imatinib
1.4
Proportion of Viable Cells (%)
E355G
1.2
M351T
1 F317L
Y253F
0.8
Q252H
0.6 G250E
T315I
0.4
E255K
0.2
WT P210
0
0.01 0.1 1 10
Imatinib (µM)
 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.

20. Nilotinib
 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 Nilotinib
most BCR-ABL mutants Imatinib
– Not including T315I
Walz et al, 2005; O’Hare et al, 2005.
Image modified from Weisberg et al, 2005.

21. Comparative IC50 Values for
Targeted Molecules for CML
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.

22. Dasatinib
 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
Shah et al, 2004; O’Hare et al, 2005.
Image adapted from O’Hare et al, 2005.

23. Comparative IC50 Values for
Targeted Molecules for CML (cont.)
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.

24. Targets of Tyrosine Kinase Inhibitors
Imatinib Nilotinib Dasatinib
Abl* ARG* PDGFRA* Abl* ARG* PDGFRA* Abl* ARG* PDGFRA*
PDGFRB* PDGFRB* Src* Yes* PDGFRB*
Src Yes Src Yes
Fyn CSF1R Fyn CSF1R Fyn* CSF1R
Fgr Kit* Fgr Kit* Fgr Kit*
Blk Blk Blk
Lck VEGFR2 Lck VEGFR2 Lck* VEGFR2
Hck Lyn VEGFR3 Hck Lyn VEGFR3 Hck* Lyn* VEGFR3
VEGFR1 VEGFR1 VEGFR1
Flk2 Flk2 Flk2
Src family Src family Src family
kinases kinases kinases
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.

25. Saglio et al, 2010; Kantarjian et al, 2010.

26. ENESTnd: Cumulative Incidence
of MMR3 (3-log reduction)
n
100 Nilotinib 300 mg BID 282
Nilotinib 400 mg BID 281
90 By 3 Years
Imatinib 400 mg QD 283
80 73%, p < .0001
By 1 Year
70
% With MMR
55%, p < .0001
70%, p < .0001
60
Δ 17%–20%
50
51%, p < .0001 53%
40 Δ 24%–28%
30
20 27%
10
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Months Since Randomization
MMR = major molecular response.
Saglio et al, 2011.

27. DASISION: Cumulative Incidence of MMR3
100 Dasatinib 100 mg QD
Imatinib 400 mg QD
80 By 24 months
65%
% of Patients
By 12 months
60 47% Δ 18%
47%
40 Δ 19%
28%
20
0
0 3 6 9 12 15 18 21 24 27
Months
*Response achieved by 24 months; calculated from randomized subjects with typical BCR-ABL transcripts.
Kantarjian et al, 2011.

28. Hasford Risk:
Age
Spleen size
Platelet count
Basophils
Eosinophils
Myeloblasts
Marin et al, 2011; Hasford et al, 1998.

29. Assessment of BCR-ABL1 Transcript Levels at
3 Months Is the Only Requirement for Predicting Outcome
for CML Patients Treated With TKIs
Outcome RR for Transcript Level (Log) 8-Year Probability of the Outcome
No. of
Cutoff Patients at Percent
RR p Value (%) Risk (%) p Value
BCR-ABL1 transcript level at 3 months
OS 0.161 < .001 < .001
Low Risk ≤ 9.84 211 93.3
High Risk > 9.84 68 56.9
PFS 0.162 < .001 < .001
Low Risk ≤ 9.54 208 92.8
High Risk > 9.54 71 57.0
EFS 0.102 < .001 < .001
Low Risk ≤ 9.84 211 65.1
High Risk > 9.84 66 6.9
CCyR 5.17 < .001 < .001
Low Risk ≤ 8.58 169 99.4
High Risk > 8.58 79 21.7
MMR 12.98 < .001 < .001
Low Risk ≤ 2.81 141 82.5
High Risk > 2.81 137 21.1
CMR 10.95 < .001 < .001
Low Risk ≤ 0.61 57 84.7
High Risk > 0.61 222 1.5
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.

30. How to Choose?

31. Adverse 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
Kantarjian et al, 2010.

32. Adverse Events
(cont.)
 Again, nuances in the
AEs seen even
between these
relatively similar drugs
– These match
clinical practice
*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.

33. Nilotinib Vs. Imatinib in CML-CP
Drug-Related AEs (≥ 10% in Any Group)
Nilotinib Nilotinib Imatinib
% Patients 300 mg BID 400 mg BID 400 mg QD
(n = 279) (n = 277) (n = 280)
All Grade All Grade All Grade
Grades 3/4 Grades 3/4 Grades 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.

34. Bosutinib Vs. Imatinib: CML Front-Line
Therapy-Related AEs ≥ 10%
Bosutinib Imatinib
(n = 248) (n = 251)
AE, % Any 3/4 Any 3/4 p Value
Any 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.

35. CML Prevalence and Choice of Therapy
How Does Growing Prevalence Effect Our Choice?
~ 5,000 ~ 120,000
2001 2010 2020 2030

36. Rational Design of Future CML
Therapy
Translation
HHT
Post-translational
Hsp modification
Inh
Transcription of
Sfb BCR-ABLT315I HDAC I AKI
FTI MKI
mTOR SPI
BCR-ABLT315I
Crcm PEITC
Inhibition of
BCR-ABLT315I FTY720
Protein
Degradation and
Synthesis
Direct Inhibition of JAK2-I
BCR-ABLT315I
HHT = Homoharringtonine; Hsp = heat shock proteins; Sfb = sorafenib; mTOR = mammalian target of rapamycin;
HDAC = Histone deacetylases.
Adapted from Cooper et al, 2009.

37. How to Address the Leukemia Stem Cell
Ideal Targetable Stem Cell
Pathways…
Pathway known to regulate
self-renewal, Hedgehog
differentiation, and
proliferation in stem cells
that are necessary for
embryogenesis, hijacked Wnt
in carcinogenesis, and
unnecessary/superfluous
in homeostasis
Tu, 2010; Images courtesy of national geography, Copyright (c) Kanehisa Laboratories - www.kegg.org.
Used with permission. Notch

38. Hedgehog Inhibition: Novel Mechanism With
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
Smoothened (SMO) Regulates Cancer Stem Cells
PF-04449913
PTCH1 SHH
SHH Gradient
SMO
GLI
rep
GLI2, GLI3
PKA
GLI1-GLI3
P GLI3 (GLI2)
P
GLI
act GLI3rep (GLI2) GLI1act-GLI3act
SHH-producing cell
Adapted from Crompton et al, 2007.
act = activated form; GLI = glioma-associated oncogene; PTCH = patched; SMO = smoothened; rep = repressor form; SHH = sonic hedgehog.

39. PF04449913 – HH Inhibition in Myeloid Disease
 Major Inclusion Criteria  Major Exclusion Criteria
– ≥ 18 years – Active graft vs. host disease
– Previously treated (including – Life-threatening or clinically
transplant) or untreated select significant uncontrolled
hematologic malignancies infection
including: – Active central nervous system
• Myelodysplastic syndrome involvement by leukemia
(MDS)
• Myelofibrosis (MF)
• Chronic myelomonocytic
leukemia (CMML)
• CML, including T315I mutants
• AML
– ECOG PS: 0–2
– Adequate organ function
(renal, hepatic, cardiac)
ECOG PS = Eastern Cooperative Oncology Group performance status; HH = hedgehog.
Jamieson et al, 2011.

40. Well Tolerated
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
 1 case of grade 3 hypoxia
Jamieson et al, 2011.
Photo courtesy of of Michael R. Savona, MD, FACP, national geography.

41. AML: Reduction in Blasts (7 of 20)
Jamieson et al, 2011.

42. Key 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

43. Roundtable Workshop:
Interactive Case on Choosing
CML Front-Line Therapy
Mollie E. Moran, MSN, CNP, AOCNP®
The James Cancer Hospital at
The Ohio State University

44. 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.

45. 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

46. 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.

47. Diagnostic Evaluation: Peripheral Blood
Diagnostic Study Clinical Significance
CBC, differential, plts, Evaluate for the presence of leukocytosis, basophilia,
reticulocyte count with thrombocytosis, monocytosis, peripheral blasts, morphological
evaluation of the peripheral abnormalities, cytopenias
smear
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 Mild and transient transaminitis is common with imatinib therapy
electrolyte profiles
Mild hyperbilirubinemia is reported with imatinib, dasatinib, and
Lipase for nilotinib 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 Establish baseline for continued evaluation of molecular response
Consistent lab
recommended
PO4 = phosphate; Ca++ = calcium; K+ = potassium; HLA = human leukocyte antigen; BMT = bone marrow transplant.
Kurtin, 2010; Druker et al, 2008.

48. Diagnostic Evaluation:
Bone Marrow
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-random
Most 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 rate
Does not replace regular cytogenetics to detect additional cytogenetic
abnormalities
RQ-PCR = real-time quantitative-PCR.
Druker et al, 2008.

49. Typical Laboratory Parameters
by Phase of CML
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 + + +
CMLalliance.net.

50. CML Phases
Chronic Accelerated Blastic
Past 3–5 years 12–18 months 3–9 months
Present 25+ years 4–5 years 6–12 months
• Asymptomatic • Blasts ≥ 15% • Blasts ≥ 30%
(if treated) • Bl + pros ≥ 30%
• Basophils ≥ 20% • Extramedullary
• None of criteria for
accelerated or blast • Plts < 100,000/mcl disease with localized
blast phase • Clonal evolution immature blasts
50
NCCN, 2012.

51. Survival in Early CP-CML
Years
Adapted form Kantarjian et al, 2012.

52. Sokal 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.

53. How to Calculate the Sokal and Hasford Scores
Hasford score Sokal score
0.6666 x age (0 when < 50 years, 1 otherwise) Exp. (0.0116 (age – 4.34))
+ 0.042 x spleen size + 0.0345 (spleen – 7.51)
(cm below costal margin) + 0.188 (platelets/700)2 – 0.563)
+ 0.0584 x blasts (%) 0.0887 (percentage of blasts – 2.1)
+ 0.0413 x eosinophils (%)
+ 0.2039 x basophils < 0.8 good prognosis
(0 when < 3%, 1 otherwise) 0.8–1.2 moderate prognosis
+ 1.0956 x platelet count > 1.2 poor prognosis
(0 when < 1,500, 1 otherwise)
X 100
≤ 780 low risk group
> 780 and ≤ 1,480 intermediate risk group
> 1,480 high risk group
Thomas et al, 2001.

54. Case Study (cont.)
 Sokal  Hasford
– 0.97 – 785
– Intermediate Risk – Intermediate Risk

55. 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

56. Roundtable 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

57. Response Definitions and
Monitoring of CML
Hematologic Cytogenetic Molecular
Definitions Complete: Complete: Ph+ 0% Complete: BCR-ABL
Plts < 450 x 109/L Partial: Ph+ 1%–35% undetectable by
WBC < 10 x 109/L Major: Ph+ 36%–65% RT-PCR
differential without Minor: Ph+ 66%–95% Major: ≥ 3-log reduction
immature granulocytes in BCR-ABL mRNA
nonpalpable spleen
Monitoring Check q2wks until Check at 6, 12, Check q3mos;
CR achieved and achieved and mutational analysis in
confirmed, then q3mos confirmed, then at case of failure,
unless otherwise least q12mos suboptimal response, or
required transcript level increase
CR = complete response; mRNA = messenger ribonucleic acid.
NCCN, 2012.

58. Roundtable Discussion Topics
(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

59. Roundtable Discussions
(10 minutes)

60. Faculty Roundtable
Presentations
(20 minutes)

61. Results With Imatinib in
Early 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.

62. Long-Term Outcome With Imatinib
in Early CML-CP (ITT)
1.0
0.9
0.8
Probability (%)
0.7
0.6
0.5 Survival 63%
PFS
0.4
CHR
0.3 EFS
Loss of MCyR
0.2
0.1
0 6 12 18 24 30 36 42 48 54 60
Time From Start of Imatinib Therapy (months)
ITT = intent-to-treat.
de Lavallade et al, 2008.

63. Criteria for Failure and Suboptimal
Response to Imatinib
Time Response
(months) Failure Suboptimal Optimal
3 No CHR No CG Response < 65% Ph+
No CHR
6 ≥ 35% Ph+ ≤ 35% Ph+
> 95% Ph+
12 ≥ 35% Ph+ 1%–35% Ph+ 0% Ph+
18 ≥ 5% Ph+ No MMR MMR
Loss of CHR
Loss of MMR Stable or
Any Loss of CCyR
Mutation Improving MMR
Mutation CE
Baccarani et al, 2009.

64. High-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 Value
CCyR 87 91 .49
MMR 78 87 .06
CMR 39 49 .21
Time to CMR EFS
1
1.0
Total CMR
800 mg 206 100 p = 0.04
0.8 400 mg 71 28 0.8
0.6
0.6
0.4 0.4
Total No.event
400mg 73 15 p = 0.01
800mg 208 22
0.2 0.2
0 0.0
0 12 24 36 48 60 72 84 96 108 120 0 12 24 36 48 60 72 84 96 108 120
CMR = complete molecular response.
Pemmaraju et al, 2010.

65. TOPS: Rate of MMR Over Time
by Imatinib Dose (ITT)
476 patients with early CML-CP randomized to imatinib 400 mg
daily vs. 800 mg daily
Percent (%)
Outcome at 24 months
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.

66. Dasatinib Vs. Imatinib Study in
Treatment-Naïve CML (DASISION) Trial Design
Dasatinib 100 mg QD (n = 259)
 N = 519
Follow-Up
 108 centers Randomized a
5 yrs
 26 countries Imatinib 400 mg QD (n = 260)
 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
Stratified by Hasford risk score.
a
DASISION = dasatinib vs. imatinib study in treatment-naive CML patients.
Kantarjian et al, 2011.

67. Dasatinib Vs. Imatinib in
Newly 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.

68. Nilotinib Vs. Imatinib in
Newly 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
a
By 24 months.
Larson et al, 2011; Kantarjian, Hochhaus, et al, 2011.

69. Known Mechanisms of Imatinib Resistance
Branford et al, 2003; Weisberg et al, 2000; Donato et al, 2003.

70. BCR-ABL Point Mutations
 Point mutations in ABL kinase alter TKI binding
– Most frequent mechanism of resistance
– Maintains the “active” or “open” conformation of the BCR-ABL protein
– Interrupts critical contact points preventing imatinib binding
– Imatinib binds to the BCR-ABL protein in the “closed” or “inactive”
conformation
 P-loop mutations
– Located along the adenosine triphosphate (ATP) binding site
– Destabilize conformation necessary for imatinib binding
– Shift kinase to favor “active” state
 Activation loop mutations
– Maintain the active conformation, preventing imatinib from binding
Weisberg et al, 2007.

71. CCyR Rates for Approved TKIs
Time of TKI CML Phase
Therapy
CP (%) AP (%) BP (%)
Newly Imatinib 75 20 10
Diagnosed
Nilotinib 95
Dasatinib 95
Resistance or Nilotinib 45 20 30
Progression
Dasatinib 50 30 30
Radich, 2010.

72. EFS by Treatment in Early CML-CP
Probability EFS (%)
Time (months)
Adapted from Cortes et al, 2009.

73. Toxicity Profiles
GRADE 3/4 HEM (%) NON-HEM (%)
Imatinib Anemia (5–7) Fluid Retention/Edema (39–42)
Neutropenia (20) Nausea (20–21)
Thrombocytopenia (9–10) Diarrhea (17–21)
Rash (11–17)
Elevated Amylase (18)
Dasatinib Anemia (10) Fluid Retention/Edema (19)
Neutropenia (21) Pleural Effusion (10, no grade 3/4)
Thrombocytopenia (19) Nausea (8)
Diarrhea (17)
Rash (11)
Elevated Amylase (not listed)
Nilotinib Anemia (3) Fluid Retention/Edema (7–8)
Neutropenia (10–12) Nausea (11–19)
Thrombocytopenia (10–12) 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.

74. Myelosuppression
 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
Neutropenia Dasatinib, Imatinib, Nilotinib
Thrombocytopenia Dasatinib, Nilotinib
Jabbour et al, 2011; NCCN, 2012; Tasigna® prescribing information, 2012.

75. General Fluid Retention
 Patient education key to allow patients to recognize
and report symptoms
Symptoms of Fluid Retention Management of Peripheral Edema
or Rapid Weight Gain
 Rapid weight gain  Diuretic therapy
 Peripheral and peri-orbital  Limit salt intake
edema  CXR for patients with
 Heart- and lung-associated symptoms suggestive of
symptoms pleural effusion (dyspnea or
dry cough)
 Dose reduction, interruption,
or discontinuation
CXR = chest X-ray.
Jabbour et al, 2011; NCCN, 2012.

76. Pleural Effusion
 Patients should be aware of symptoms
– Chest pain
– Dry cough
– Dyspnea
 Pleural effusions are manageable by
– Dose interruption/reduction
– Supportive measures (diuretics, steroids)
 Severe pleural effusion may be require
thoracentesis and oxygen therapy
Jabbour et al, 2011; NCCN, 2012; Sprycel® prescribing information, 2012.

77. Metabolic Abnormalities
 Nilotinib
– Mild-to-moderate in severity
– Lipase or amylase elevation
• Generally self-limiting
– Use with caution in patients with a history of pancreatitis
– Lipase and amylase levels should be checked as
indicated
 Hypokalemia, hypomagnesium
– Mild-to-moderate in severity
– Supplement if necessary
Jabbour et al, 2011; Tasigna® prescribing information, 2012.

78. Management 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.

79. QTc Prolongation (cont.)
 Obtain EKG at baseline; at 7 days after any
dose adjustment
 QTcF interval ≥ 480 msec, monitor electrolytes
periodically and review concomitant medications
 If QTcF returns to < 450 msec and to within
20 msec of baseline within 2 weeks, restart at
previous dose
 QTcF is between 450 msec and 480 msec after
2 weeks reduce the dose to 400 mg QD
EKG = electrocardiogram; QTcF = QT interval corrected for heart rate using Fridericia’s formula.
Tasigna® prescribing information, 2012.

80. Managing Gl and Musculoskeletal Toxicities
 Gl toxicities include nausea,  Musculoskeletal toxicities
vomiting, diarrhea include muscle cramps/bone
– Take dose with a meal and pain/arthralgia
large glass of water (imatinib) – Ca2+ supplements
– Take at least 2 hours before – NSAIDs
bedtime • Mild narcotics
– Use antiemetic and – Quinine/tonic water
antidiarrheal medications for
severe effects  Hepatic toxicity
– ± Proton pump inhibitors – With grade 2–3, dose
• H2 inhibitors ± histamine interruptions, reductions, and
potentially discontinuation
– With grade 4, should consider
alternative agent
GI = gastrointestinal; NSAIDs = nonsteroidal anti-inflammatory drugs.
Deininger et al, 2003.

81. Muscle-Related AEs
 Grade 3/4 are infrequent
 Symptomatic relief may be achieved with
calcium and magnesium supplements
 Quinine
– Tonic water
Jabbour et al, 2011.

82. Cutaneous Reactions
Primary AE Drug Specific Considerations
Dermatologic Imatinib 12.7% of patients reported with rash grade 1/2
Toxicity 40.9% incidence of depigmentation
3.6% 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)
Jabbour et al, 2011; Sprycel® prescribing information, 2012; Tasigna® prescribing information, 2012; Gleevec® prescribing information, 2012.

83. Numerous Drug Interactions
IMATINIB DASATINIB NILOTINIB
PPI ↑ Exposure (inhibit Pgp) ↓ Absorption
(decreased solubility)
↑ Exposure (inhibit Pgp)
H2-antagonists ↑ Exposure (inhibit Pgp) ↓ Absorption ↑ Exposure (inhibit
(decreased solubility) CYP 3A4)
↓ Intracellular exposure
(inhibit hOCT-1) ↑ Exposure (inhibit Pgp)
Metoclopromide ↑ QTc ↑ QTc ↑ QTc
Metformin ↓ Intracellular exposure
(inhibit hOCT-1)
Warfarin ↑ Increased ↑ Increased
anticoagulation anticoagulation
(↑ CYP 2C9 by TKI) (↑ CYP 2C9 by
TKI)
And many more….
Haouala et al, 2011.

84. General 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.

85. Medication Adherence:
Patient and Caregiver Teaching
Kathleen K. Curran, MSN, RN, CRNP
University of Pittsburgh Medical Center

86. “Drugs Don’t Work in Patients Who Don’t
Take Them.” – 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.

87. Oral 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.

88. As 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

89. 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.

90. Interventions 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

91. Consider
 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

92. Compliance-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.

93. Three 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

94. Medication Adherence
Discussions
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

95. Final 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

96. 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