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

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

Survival in early chronic phase CML Year Total Dead Imatinib era 230 7 1990-2000 960 334 1982-1989 365 265 1975-1981 132 127 1965-1974 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

What to expect with current therapies

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 2009. Abstract 1126.

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 2006 355:23, 2408-17

Risk assessment in CML http://www.icsg.unibo.it/rrcalc.asp Study Calculation Risk Definition Sokal et al, 1984 Exp 0.0116 x (age in years – 43.4) + (spleen in cm – 7.51) + 0.188 x [(platelet count / 700)2 - 0.563] + 0.0887 x (blast cells – 2.10) Low: <0.8 Intermediate: 0.8-1.2 High: >1.2 Hasford et al, 1998 0.666 when age ≥ 50 years + (0.042 x spleen in cm) + 1.0956 when platelet count >1500 x 109/L + (0.0584 x blast cells) + 0.20399 when basophils >3% + (0.0413 x %eosinophils) x 100 Low: ≤780 Intermediate: 781-1480 High: >1480 http://www.icsg.unibo.it/rrcalc.asp http://www.leukemia-net.org/content/leukemias/cml/cml_score/ Sokal JE et al, Blood 1984; 63: 789-799 Hasford J et al, J Nat Cancer Inst 1998; 90: 850-858

Are patients ever cured with TKIs?

When should mutation testing be done?

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%)

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)

Does early molecular response matter?

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

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

Progression-free Survival (PFS) BCR-ABL IS at 3 months ≤10% vs. >10% BCR-ABLIS n 5Y-PFS ≤10% 499 93% >10% 189 87% p-value 0.003

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

What’s coming…

Some practical tips

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

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

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

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

Thank you!