1. 18th NOCR Meeting
Las Vegas, Nevada – February 2012
An Update in Chronic Myeloid Leukemia (CML): The Clever ‘Stupid Cancer’
David Steensma, MD FACP
Associate Professor of Medicine, Harvard Medical School
Adult Leukemia Program, Dana-Farber Cancer Institute

2. CML: a disease of “firsts”
1845 – first clear description of leukemia
1960/1972 – first association of a recurrent chromosomal abnormality (“Philadelphia chromosome”) with cancer…
and second to be recognized as a reciprocal translocation (t(9;22), found after t(8;21))
1982 – first fusion protein associated with cancer (BCR/ABL)
1999 – first tyrosine kinase inhibitor with clinical activity against a fusion protein (CGP57148b=STI571=imatinib)
2000 – first description of “Darwinian” emergence of molecular resistance to a targeted agent (e.g., T315I ABL mutation)
David Craigie
John Hughes Bennett
Rudolf Virchow
Peter Nowell and David Hungerford
Janet Rowley
Annalies de Klein
Nora Heisterkamp
John Groffen
Brian Druker
Imatinib

3. Survival in early chronic phase CML
Year
Total
Dead
Imatinib era
230 7
960
334
365
265
132
127
123
122
1.0
95%
0.8
0.6
Proportion surviving
Interferon α, cytarabine, allogeneic stem cell transplant
0.4
0.2
Hydroxyurea, busulfan, splenectomy 2 4 6 8 10 12 14
Years from referral

4. What to expect with current therapies

5. Estimated overall survival
IRIS Phase III trial of imatinib vs. cytarabine/interferon: overall survival (ITT) in imatinib arm
100 90 80 70
Estimated overall survival
at 8 years was 85%
(93%, considering only
CML-related deaths) 60
Alive, % 50 40 30
Survival, deaths associated with CML
Overall Survival 20 10 12 24 36 48 60 72 84 96
108
Months Since Randomization
ITT: intent-to-treat; OS: overall survival
O’Brien SG, et al. American Society of Hematology annual meeting Abstract 1126.

6. IRIS Study: imatinib patient status at 60 months
Continued Imatinib 4% 3%
11%
Withdrew consent
Death
Protocol violation
SCT 5% 2% 3%
Adverse Event
Crossed over to IFN
Unsatisfactory
therapeutic effect
69%
Cumulative failure rate ~30%
Druker B et al. NEJM :23,

7. Risk assessment in CML http://www.icsg.unibo.it/rrcalc.asp
Study
Calculation
Risk Definition
Sokal et al, 1984
Exp x (age in years – 43.4) + (spleen in cm – 7.51) x [(platelet count / 700) ] x (blast cells – 2.10)
Low: <0.8
Intermediate:
High: >1.2
Hasford et al, 1998
0.666 when age ≥ 50 years + (0.042 x spleen in cm) when platelet count >1500 x 109/L + ( x blast cells) when basophils >3% + ( x %eosinophils) x 100
Low: ≤780
Intermediate:
High: >1480
Sokal JE et al, Blood 1984; 63:
Hasford J et al, J Nat Cancer Inst 1998; 90:

8. Are patients ever cured with TKIs?

9. When should mutation testing be done?

11. N positive for KD mutation (%)
Factor Analyzed N
N positive for KD mutation (%)
De novo CP CML 58
1 (2%)
De novo AP/BC CML 12
2 (17%)
IM Failure (ELN criteria)
166
45 (27%)
Suboptimal IM Response (ELN)
233
11 (5%)
Rise in PCR without loss of MMR 70
0 (0%)
Rise in PCR with loss of MMR 89
4 (5%)
NIL/DAS ‘Failure’ (ELN criteria) 19
11 (58%)
NIL/DAS ‘Suboptimal’ (ELN criteria)
4 (21%)

13. Treatment options based on BCR-ABL kinase domain mutation status
Treatment recommendation
T315I
Stem cell transplant or clinical trial (e.g., ponatinib, omacetaxine)
V299L, T315A, F317L/V/I/C
Consider nilotinib; likely resistant to dasatinib
Y253H, E255K/V, F359V/C/I
Consider dasatinib; likely resistant to nilotinib
Any other mutation
Unclear; consider high-dose imatinib, nilotinib, dasatinib
Based on NCCN and ELN guidelines (Soverini S et al Blood 2011)

14. Does early molecular response matter?

15. Molecular and Cytogenetic Response at 3 Months of Imatinib Predicts Progression-free Survival (PFS) and Overall Survival (OS) – a Follow-Up Analysis of the Randomized CML-Study IV
Benjamin Hanfstein, MD, Martin C. Müller, MD, Philipp Erben, MD, Michael Lauseker, Susanne Saussele, MD, Ulrike Proetel, MD, Susanne Schnittger, PhD, Claudia Haferlach, MD, Hans-Jochem Kolb, MD, Stefan W. Krause, MD, Christoph Nerl, MD, Dominik Heim, MD, Gabriela M. Baerlocher, MD, Jörg E. A. Schubert, MD, Hermann Einsele, MD, Mathias Hänel, MD, Jolanta Dengler, MD, Christiane Falge, MD, Lothar Kanz, MD, Andreas Neubauer, MD, Michael Kneba, MD, Frank Stegelmann, MD, Michael Pfreundschuh, MD, Cornelius F. Waller, MD, Markus Pfirrmann, PhD, Jörg Hasford, MD, Wolf-Karsten Hofmann, MD, Rüdiger Hehlmann, MD, Andreas Hochhaus, MD, for The SAKK and for The German CML Study Group

16. Median age 52 years (16-85), 39% female
Patients and samples
N = 1,223 (assigned by April 30, 2010)
Median age 52 years (16-85), 39% female
Median observation time 4.8 years
Treatment:
Imatinib 400 mg/d n = 335 (27%)
Imatinib 400 mg/d + Interferon alpha n = 366 (30%)
Imatinib + Cytarabine n = 149 (12%)
Imatinib 800 mg/d n = 373 (30%) 16

17. Progression-free Survival (PFS) BCR-ABL IS at 3 months ≤10% vs. >10%
BCR-ABLIS n 5Y-PFS
≤10% %
>10% %
p-value
0.003

18. Overall Survival (OS) BCR-ABLIS at 3 months ≤10% vs. >10%

19. What’s coming…

20. Some practical tips

21. What is needed at initial diagnosis?
CBC+differential; complete metabolic profile including liver tests
Bone Marrow Aspirate and Biopsy
Cytogenetics (20 metaphases)
?FISH, ?QPCR
Why is a bone marrow necessary?
Need to exclude AP/BP-CML.
Sokal/Hasford score predictive of response to TKIs
Helpful to review entire karyotype (useful for comparison at time of relapse)
FISH important for “cytogenetic negative” CML (<5%)
FISH may have some role in prognosis, e.g., del9q+
NCCN Guidelines 2012 21

22. How do I choose initial therapy?
Imatinib at 400 mg daily remains the ‘standard of care’
But it will fail ~30% of patients
And it is rarely curative
However, reasonable to choose a 2nd Generation TKI:
Especially for higher-risk disease based on Sokal or Hasford scores
Young patient, as 2nd generation TKI best chance of obtaining CMR and MMR, and reduces progression to AP/BP
Nilotinib and dasatinib likely very similar, and differences largely from different trial designs and/or locations; choose based on adverse event profile
NCCN Guidelines 2011. 22

23. How to follow your patient?
CBC+differential, complete metabolic profile
Every 3 months; maybe more frequent earlier on
Bone Marrow Aspirate and Biopsy with Cytogenetics (20 metaphases)
Every 6 months until Complete Cytogenetic Remission (CCR)
Further bone marrow exams PRN
Quantitative RT-PCR
Every 3 months indefinitely
Can go to every 6 months, after 2 years of major molecular response
FISH not as helpful
Only follow in patients with cytogenetic negative CML (<5%)
NCCN Guidelines 2012 23

24. Pearls Maximize patient adherence by managing adverse events
“The most important cell in CML resistance is the neuron”
“Once disease is in advanced phase, the game is largely over”
Never dose reduce imatinib below 300 mg daily or nilotinib below 400 mg daily or dasatinib below 50 mg daily
Heme toxicities (ANC < 1000; Plts < 75K): rare, usually early, and easily managed
Never change dose or therapy based solely on a single PCR
Repeat in 1 month
Confirm with bone marrow exam before changing therapy
Mutational Analysis
Not useful at initial diagnosis or in responding patients
Send at time of any change in therapy (increase in dose or 2nd TKI)
Stem Cell Transplant
Refer at time of 1st failure (want to know donor status)
Refer to transplant in patients who fail 2nd TKI, have a T315I or AP/BP-CML 24

25. Thank you!