12/7/2012 1 12/7/2012 Chronic Myeloid Leukemia Chronic Myeloid - PDF document

12/7/2012 1

12/7/2012 Chronic Myeloid Leukemia Chronic Myeloid Leukemia Diagnosis and Treatment Update Diagnosis and Treatment Update Neil Shah, MD PhD Division of Hematology/Oncology UCSF School of Medicine San Francisco, California CML - clinical features CML - clinical features • approximately 4500 new US cases per year • median age at presentation: 53 years • men comprise approximately 60 percent of cases • disease is clinically divided into two general phases � chronic phase � accelerated/ blast crisis phase 2

12/7/2012 CML - chronic phase CML - chronic phase • approximately 40 percent of patients are without symptoms (fatigue) • 85 percent of newly diagnosed CML cases are in chronic phase • median duration of chronic phase (prior to 2000) approximately 4-6 years � After 2000 - unknown, greater than 10 years • interventions can lead to durable responses in chronic phase � Medical therapy (interferon, TKIs) � Stem cell transplantation Clinical Course: Phases of CML Advanced phases Chronic phase Accelerated phase Blastic phase (blast crisis) Median duration Median survival Median 4–6 years up to 1 year 3–6 months stabilization Cooperating mutations* *loss of p53; trisomy 8; second Ph; PAX5 deletion; others 3

12/7/2012 The Philadelphia chromosome is nearly always The Philadelphia chromosome is nearly always The Philadelphia chromosome is nearly always The Philadelphia chromosome is nearly always detected in patients with CML detected in patients with CML detected in patients with CML detected in patients with CML 46,XX,t(9;22)(q34;q11.2) Forrest et al, 2008; Bakshi et al, 2008; Image courtesy of Larry Beauregard, Jr., PhD. The Philadelphia (Ph) Chromosome Results in the The Philadelphia (Ph) Chromosome Results in the BCR-ABL Fusion Gene BCR-ABL Fusion Gene BCR BCR ABL ABL Ph chromosome Ph chromosome BCR BCR- -ABL ABL (activated activated tyrosine kinase) tyrosine kinase) CML CML 4

12/7/2012 CML - diagnosis CML - diagnosis • Bone marrow biopsy should be performed at the time of suspected diagnosis • The presence of the Philadelphia chromosome translocation or other strong evidence of the BCR- ABL fusion gene is required to make the diagnosis of CML CML was the first cancer to be treated CML was the first cancer to be treated with a tyrosine kinase inhibitor (TKI) with a tyrosine kinase inhibitor (TKI) 5

12/7/2012 Imatinib (Gleevec) - Clinical Efficacy Phase III Trials (Chronic Phase CML) Response Rate (%) Treatment Hematologic Major Cytogenetic Imatinib 94 83 Interferon + Ara-C 55 20 O � � � Brien et al, NEJM, 2003 � FDA Approval, May 2001 6

12/7/2012 IMATINIB AS FRONTLINE THERAPY IMATINIB AS FRONTLINE THERAPY FOR CML FOR CML 7- -8 year update of newly 8 year update of newly- -diagnosed diagnosed Chronic Phase CML patients treated Chronic Phase CML patients treated with 400 mg daily imatinib with 400 mg daily imatinib O � Brien et al. ASH 2008, Abstract 186 Overall Survival (ITT Principle): Imatinib Arm 100 90 80 % Without Event 70 Estimated overall survival 60 at 8 years is 85% 50 (93% considering only 40 CML-related deaths) 30 Survival: deaths associated with CML 20 Overall Survival 10 0 0 12 24 36 48 60 72 84 96 Months Since Randomization �� Deininger et al. ASH 2009, Abstract 1126 7

12/7/2012 Expectations on Imatinib: IRIS 8-Yr Update Shows 37% Have Unacceptable Outcome No CCyR: 17%* Sustained CCyR on study: 53% Lost CCyR: 15%* Safety: 5%* Lost � regained CCyR + CCyR: 3% other: 7% *Unacceptable outcome. Deininger M, et al. ASH 2009. Abstract 1126. Most Frequently Reported AEs: First-Line Imatinib Most Common Grade 3/4 AE � � s All Grade AEs � � Adverse Events (by Patients, % Patients % 5 Years) Superficial Edema 60 2 Nausea 50 1 Muscle cramps 49 2 Musculoskeletal pain 47 5 Diarrhea 45 3 Rash/skin problems 40 3 Fatigue 39 2 Headache 37 <1 Abdominal pain 37 4 Joint pain 31 3 • Only Serious Adverse Events (SAEs) were collected after 2005 • Grade 3/4 adverse events decreased in incidence after years 1-2 O � Brien et al. ASH 2008, Abstract 186 �� 8

12/7/2012 Long-Term Adherence to Imatinib Is Critical for Achieving Molecular Response � Adherence to imatinib tracked for 3 months in 87 consecutive CML patients with CCyR using microelectronic monitoring devices MMR CMR Adherence > 90% (n = 64) Adherence > 90% (n = 64) 1.0 1.0 Adherence � 90% (n = 23) Adherence � 90% (n = 23) Probability of MMR Probability of CMR 0.8 0.8 P < .001 P = .002 0.6 0.6 0.4 0.4 0.2 0.2 0 0 0 6 12 18 24 30 36 42 48 54 60 66 72 0 6 12 18 24 30 36 42 48 54 60 66 72 Mos Since Start of Imatinib Therapy Mos Since Start of Imatinib Therapy Marin D, et al. J Clin Oncol. 2010;28:2381-2388. Imatinib - Conclusions Imatinib - Conclusions • Imatinib is effective for a large proportion of chronic phase CML patients • 85% overall survival with imatinib exceeds that of all other CML therapies, with 7% patients dying from CML after eight years • 82% of patients treated with imatinib achieved a CCyR � 55% of all imatinib randomized patients are still on study treatment, and nearly all of these are in CCyR • Responses are typically durable, and the annual risk of progression generally decreases with time • Adherence appears to be critical for achieving optimal responses • While many patients have side effects, there have been no new concerning safety findings with long term follow-up 9

12/7/2012 Chronic Phase CML – response definitions Chronic Phase CML – response definitions • Complete hematologic response: normal white blood cell count and differential, platelet count not elevated • Complete cytogenetic response (CCyR): lack of Ph chromosome in at least 20 bone marrow metaphases � Major cytogenetic response (MCyR): � 35% Ph metaphases • Major molecular response (MMR): three log (1000- fold) reduction in BCR-ABL transcript level from baseline � Complete molecular response (CMR): BCR-ABL no longer detectable by PCR NCCN – monitoring guidelines NCCN – monitoring guidelines • Complete blood count and differential should be performed regularly • Molecular monitoring of BCR-ABL levels in the blood by PCR should be performed every three months for at least the first 3 years after initiating treatment • Bone marrow biopsy should be performed: � If a one-log reduction level in BCR-ABL is not achieved at 3 months � After 12 months, in any patient who has not had a documented CCyR or MMR � In the event of loss of response (one-log increase in PCR) or disease transformation 10

12/7/2012 Why do some patients not achieve deep Why do some patients not achieve deep responses on imatinib? responses on imatinib? Why do some patients lose an initial Why do some patients lose an initial response despite continuing imatinib? response despite continuing imatinib? Imatinib Failure - Causes Imatinib Failure - Causes • Drug-resistant mutations in BCR-ABL develop (most common) � Close to 100 different drug-resistant mutations have been identified in patients with resistant disease • BCR-ABL overexpression develops • Apparent lack of normal hematopoietic stem cells • Non-adherence to treatment • Undefined mechanisms 11

12/7/2012 Imatinib Failure – Treatment Options Imatinib Failure – Treatment Options • Second-generation TKIs � Dasatinib � Nilotinib � Bosutinib • These drugs are vulnerable to about 5 drug-resistant mutations • These drugs are ineffective against the imatinib-resistant T315I mutation • Omacetaxine (protein synthesis inhibitor) • Interferon • Stem cell transplantation • Clinical trial Imatinib Failure – Response Rates Imatinib Failure – Response Rates • TKIs: � Dasatinib: 50% CCyR; 42% MMR � Nilotinib: 45% CCyR; 28% MMR � Bosutinib: 41% CCyR; 31% MMR • These drugs are vulnerable to about 5 drug-resistant mutations • These drugs are ineffective against the imatinib-resistant T315I mutation • Omacetaxine (protein synthesis inhibitor) in T315I+ patients: 16% CCyR; 13% MMR • Interferon (anecdotal experience) • Stem cell transplantation • Clinical trial (ponatinib, active against T315I mutation) 12