ASCO 2011: Leukemia. Disclosures

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1 ASCO 2011: Leukemia E.J. Feldman M.D Weill-Cornell Medical College Disclosures Speaker does not report any affiliations 1

2 V617F JAK2 mutation in MPDs JAK STAT PATHWAY Signal transducers and activators of transcription JAKs crucially important in intracellular growth-factor & cytokine signalling In the JAK system there are 3 JAKs (1,2,3) and one tyrosine kinase (TYR2) JAK2 involved in TPO, EPO, GM-CSF signalling JAK2 has an: Active kinase domain Inactive psuedokinase domain which turns off signalling Molecular abnormality is a phenylaline substitution for valine at codon 617, nucleotide 184g, giving rise to V617F mutation Nomenclature is JAK2 V617F 2

3 Figure 2 Janus homology domains of the JAK family of kinases Levine, R. L. et al. Blood 2008;112: Copyright 2008 American Society of Hematology. Copyright restrictions may apply. Jak-2 + Chronic MPD Polycythemia Vera Essential Thrombocytosis Primary Myelofibrosis 3

4 Erythrocytosis Thrombocytosis Leukocytosis Early MPD ** Risk of thrombosis Advanced Myelofibrosis Weight loss Cachexia Fever/Nightsweats Splenic pain/fullness/early satiety Marrow failure AML 4

5 Ruxolitinib in MF-Open Label Ruxolitinib ( INC424) vs best Supportive care in PMF ( Harrison et al Randomized trial:1:1 219 Pts Endpoint: > 35% reduction in spleen size 5

6 COMFORT-II Study Design Patients with MF, PPV-MF, PET-MF with intermediate-2 or high risk prognostic factors Palpable splenomegaly 5 cm below the costal margin JAK2V617F positive or negative 2:1 Randomization Ruxolitinib Starting dose based on baseline platelet counts Randomized Treatment Phase (RTP) Best Available Therapy (BAT) As selected by the investigator Discontinuation Qualifying event of disease progression Extension Phase (EP) Ruxolitinib treatment Discontinuation Progression events that qualified for the EP: Splenectomy Progressive splenomegaly as defined by a 25% increase in spleen volume compared with the onstudy nadir (including baseline) Progression events that did not qualify for the EP: Splenic irradiation Leukemic transformation as defined by a bone marrow blast count of 20% at any time during the study Peripheral blood blast count of 20%, sustained for 8 weeks Demographics and Baseline Patient Characteristics Ruxolitinib N = 146 BAT N = 73 Age, median (years) Male, n (%) 83 (57) 42 (58) Caucasian*, n (%) 118 (81) 67 (92) Myelofibrosis type, n( %) PMF PPV-MF PET-MF Palpable spleen size, median (cm) below coastal margin 77 (53) 48 (33) 21 (14) 39 (53) 20 (27) 14 (19) Spleen volume, median (cm 3 )** Prior HU, n (%) 110 (75) 50 (69) Median duration of treatment: 51 weeks (ruxolitinib); 45 weeks (BAT) Normal spleen volume is 150 to 200 cm 3 HU, hydroxyurea *Race was not recorded for patients from France. 6

7 Patient Treatments on BAT Arm ATC class BAT (N = 73) n (%) Anti-neoplastic agents 37 (50.7) Glucorticoids 12 (16.4) Epoetin alfa 5 ( 6.8) Immunomodulators 5 (6.8) Purine analogs 4 (5.5) Androgens 3 (4.1) Interferons 3(41) (4.1) Nitrogen mustard 2 (2.7) analogs Pyrimidine analogs 2 (2.7) 49 (67.1) patients received BAT medication 24 (33.9) patients received no BAT medication COMFORT-II Efficacy Results n % With 35% Spleen Volume Reduction Primary Endpoint P <.0001 n % With 35% Spleen Volume Reduction 15 Key Secondary Endpoint P < % 31.9% 20 Ruxolitinib BAT Week Ruxolitinib BAT Week 24 7

8 COMFORT-II: Ruxolitinib vs BAT in MF Percent Change From Baseline in Spleen Volume at Week 48 in Individual Patients 80 cent change from baseline e Per Primary endpoin -80 Ruxolitinib BAT Ruxolitinib BAT spleen volume as best percentage change from BL 132 (97%) 35 (56%) spleen volume as best percentage change from BL 4 (3%) 28 (44%) COMFORT-II: Ruxolitinib vs BAT in MF Duration of Response Loss of response: < 35% reduction from baseline that was also 25% increase from nadir Median duration of response was not reached with 55 patients (79.7%) still responding and 14 patients (20.3%) having lost their response 8

9 COMFORT-II: Ruxolitinib vs BAT in MF Red Blood Cell Transfusion Dependency Patients receiving 1PRBC transfusions while on treatment: t t Ruxolitinib: 75 (51.4%) BAT: 28 (38.4%) Mean number of transfusions/month: Ruxolitinib: 0.86 BAT: 0.91 PRBC, packed red blood cell. Ruloxitinib ( INC1824) in Myelofibrosis: ( Verstovsek et al) Phase 3 trial: ruloxitinib mg twice daily versus placebo Endpoints: >35% reduction in spleen size > 50% reduction in symptom score 309 Pt randomized 1:1 Response: 41.9% versus 0.7% spleen reduction 46% vs 5.3% reduction in symptoms *** Adverse events; anemia, thrombocytopenia, fatigue, diarrhea, peripheral edema 9

10 CYT387 in MF: Pardnani et al Jak-1/2 inhibitor 108 patients t in int/high h risk MF MTD 300 mg daily ( hyperlipasemia, headache) Response: -42 anemic Pts 50% erythroid response ( 58% in RBC-Tx-dependent Pts) Spleen response: 45% SB1518 in MF: Deeg et al Jak-2 inhibitor Phase 2 trial: endpoint: reduction in spleen size 33 patients Response: 57% had spleen reduction > 25% Adverse effects: nausea, fatigue Significant cytopenias not seen 10

11 The Ph Chromosome and the bcr-abl Gene: The t(9;22) Translocation Chromosome 9 q+ Chromosome 9 Philadelphia Chromosome (or 22q-) Chromosome 22 abl bcr bcr-abl FUSION PROTEIN WITH CONSTITUTIVE TYROSINE KINASE ACTIVITY Melo. Blood. 1996;88:2375. Pasternak et al. J Cancer Res Clin Oncol. 1998;124:643. Nilotinib Vs Imatinib Outcome at 24 months Nilotinib Nilotinib Imatinib P value 600 mg 800 mg 400 mg MMR 71% 67% 44% P<.0001 CMR-IS 26% 21% 10% P <.0001 FFP AP/BC P =.006/.01 OS 97.4% 97.8.% 96.3% P=.64/.21 CMR: 4.5 IS 11

12 Larson RA, et al. J Clin Oncol. 2011;29(15s):421s [abstract 6511]. ENESTnd 24-month Update Cumulative Incidence of MMR* U % Pat ients With MMR, Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD 283 n By 12 months 55%, P < %, P <.0001 Δ 24%-28% 27% By 24 months 71%, P < %, P <.0001 Δ 23%-27% 44% Time Since Randomization, Months * Intent-to- treat (ITT) population used for all efficacy analyses. 23 Dasatinib vs Imatinib: Outcome at 24 months Dasatinib Imatinib P value 100 mg 400 mg CCyr 86% 82% P=.09 MMR/CMR 64%/17% 46%/8% P=.0001 AP/BC 2.3% 3.5% P=NS OS 96% 97.9% P=NS CMR: 4.5 IS 12

13 Bosutinib Vs Imatinib: Outcome at 1.5 yr Bosutinib Imatinib 400 mg P value CCyR 62% 67% P=NS MMR 55% 45% P=.002 AP/BC 2% 5% P=.053 *** adverse events Bosutinib-25%, Imatinib-13.5% ***Discontinuation: Bosutinib 29%, Imatinib 20% Acute Myeloid Leukemia 13

14 Abstracts for Discussion Faderl et al. Clofarabine+cytarabine vs. cytarabine alone in older rel/ref AML Thomas et al. Decitabine vs. supportive care or low-dose cytarabine in newly dx d elderly AML Pollyea et al. Sequential azacitidine and lenalidomide in elderly AML AML Survival: Patients 60 years Burnett et al. Semin Hematol 2006:43(2):96-106, 14

15 30-Day Early Mortality of AML Induction: Effects of age and performance status Performance Status < 56 y (N=364) y (N=242) y (N=270) >75 y (N=79) 0 3/129 (2)* 8/72 (11) 9/73 (12) 2/14 (14) 1 6/180 (3) 6/112 (5) 20/126 (16) 7/40 (18) 2 1/46 (2) 6/34 (18) 16/52 (31) 7/14 (50) 3 0/9 (0) 7/24 (29) 9/19 (47) 9/11 (82) All 3% 11% 20% 32% Appelbaum et al. Blood 2006; 107: 3481 * Deaths/Patients (%) A Comparison of Low-Dose Cytarabine and Hydroxyurea With or Without All-Trans Retinoic Acid for AML - De novo or secondary AML and high-risk MDS - Cytarabine 20 mg SC BID X 10 vs. Hydrea Regimen Age Distribution N Complete Response Overall Survival Low-Dose Ara-C < % 65 weeks Hydroxyurea < % Time to CR 114 days - Duration of CR 36 weeks - No CR in patients with adverse karyotype yp Burnett et al, Cancer, 2007, 109 (6);

16 Clofarabine Deoxyadenosine analog designed to improve fludarabine and cladribine FDA-approved for pediatric ALL Developed to have increased resistance to deamination and phosphorolysis; higher affinity to deoxycytidine kinase; inhibition of DNA synthesis and ribonucleotide reductase Avoids anthracycline-related cardiotoxicity Clofarabine in Older AML Patients Regimen Author N CR/C Ri Clofarabine 30 mg/m 2 QD X 5 vs. Clofarabine 30 mg/m 2 QD X 5 + Ara-C 20 mg/m 2 SC X 14 Faderl et al % 63% OS same Clofarabine 30 mg/m 2 QD X 5 Burnett et al % Clofarabine 40 mg/m 2 QD X 5, 1 hour infusion, 4 hours later Ara-C 1,000 mg/m 2 QD IV over 2 hours Agura et al 3 12 untreated 67% Clofarabine 30 mg/m 2 QD X 5 Kantarjian et al % -definitely active in AML -remissions in patients with adverse cytogenetics, age>70, PS 2, AHD -myelosuppressive -renal and hepatic dysfunction 1. Faderl et al, Blood, 2008, 112 (5); Burnett et al, Journal of Clinical Oncology, 2010, 28 (14); Agura et al, Oncologist, 2011, 16 (2); Kantarjian et al, Journal of Clinical Oncology, 2010, 28 (4);

17 Faderl et al: Classic I Trial 326 pts 55 yrs, 1 prior AML induction ECOG PS 0-2, good renal/hepatic function Clo 40 mg/m 2 IV X 5 + Ara-C C1 g/m 2 IV X 5 vs. Placebo + Ara-C 1 g/m 2 CR higher in Clo-treated pts, 47% vs. 23%, including 46% in previously treatment refractory patients 4 month EFS higher in Clo-treated pts, but still only 38%, so if bridge to transplant, need to hurry No difference in overall survival Higher mortality and more safety issues for the Clo arm Clofarabine: Where Do We Stand? Definitely active in AML, both as single agent and in combination Major question: is it low-intensity or intensive? Target population: Elderly single agent, induction for pts with cardiac issues, bridge to transplant for relapsed patients?? FDA mandated randomized trial for approval ECOG randomized trial vs. 7+3 ongoing in newly diagnosed patients 17

18 Thomas et al: Decitabine vs. Supportive care or LDAC in Newly Diagnosed Elderly AML DNA methyltransferase inhibitor approved for treatment t t of MDS Several regimens studied, most common in MDS 20 mg/m 2 IV X 5 days Multicenter phase II using this regimen in newly diagnosed elderly AML: 24% CR, med OS 7.7 mos, induction mortality 7% 1 1 Cashen et al. J Clin Oncol 28(4):556-61, Thomas et al: Decitabine vs. Supportive care or LDAC in Newly Diagnosed Elderly AML 485 newly dx d AML pts age 65, PS 0-2 Randomized Decitabine 20 mg/m 2 X 5 vs. supportive care or ara-c 20 mg/m 2 SC X 10 Initially trend toward improved OS, reached statistical significance in later analysis, 7.7 vs. 5 mos CR 18% decitabine, 8% ara-c Generally well-tolerated 18

19 Where are we with decitabine in Newly- Diagnosed Older AML Patients? -Decitabine 20 mg/m 2 QD X 10 by 1-hour infusion - Ohio State experience 1-53 patients, med age 74 yrs - CR 47% -Med OS 14 mos -Higher levels of mir-29b (targets DNA methyltransferases) may predict response 1 Blum et al, PNAS, 2010, 107 (16); Cornell experience 2-52 Patients New CALGB trial Mean age 74 years Decitabine vs. Decitabine+bortezomib t ib - CR 38% Primary Endpoint Overall Survival - Median time to CR 8 NO PS restriction and enrollment of very weeks elderly pts encouraged - 30 day mortality 5.8% Extensive geriatric assessments and - 60 day mortality 13.5% Correlative scientific studies 2 Roboz et al, submitted for publication Azacitidine and Lenalidomide in AML Regimen Author N CR Median Overall Survival Azacitidine 75mg/m 2 SC X 7 Fenaux 55 18% 24.5 months (<30% blasts) et al 1 Lenalidomide 50mg QD X 28 (5q AML only) Lenalidomide 50mg QD X 28 (better with lower blasts) Sekeres 37 14% et al 3 (PR+CR) 2 months Fehniger 33 30% 4 months (16 mos for et al 4 responders) 1. Fenaux et al, Journal of Clinical Oncology, 2010, 28 (4); Sekeres et al, Journal of Clinical Oncology, 2010, 28 (13); Sekeres et al, Blood, prepublished online May 6, Fehniger et al, 2011, Blood, 117 (6);

20 Pollyea et al: Phase I sequential azacitidine and lenalidomide in elderly AML Both have activity in AML Hypothesis that sequential rx would give additive upregulation of silenced tumor suppressor genes Aza 75 mg/m 2 days 1-7, len 0-50 mg days 8-28 PS 0-2, WBC <10,000/μL 18 patients, no MTD reached ORR 10/18 (56%), 11% early death, OS 8.2 mos Phase II dose/sched aza 75 mg/m 2 D1-7, len 50 mg D8-28, observation D29-42 Methylation and cytokine profiles may predict response 20