Chronic myeloid leukemia and myeloproliferative neoplasms. Gregor Verhoef 16th Post-ASH Meeting Friday 10 January 2014

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1 Chronic myeloid leukemia and myeloproliferative neoplasms Gregor Verhoef 16th Post-ASH Meeting Friday 10 January 2014

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10 IHD=Ischemic Heart disease ICVE=ischemic cardiovascular events PAD=peripheral arterial disease

11 Abstract 257: Hadsijusufovic Emir et al. Nilotinib (n=34): AOD (artherial occlusive disease): 26.5% (median observation time 24 months) Studies on: cultured human umbilical vein endothelial cells Human coronary artery-derived endothelial cells Human microvascular endothelial cell line HMEC-1 Mouse model of himlimb ischemia Nilotinib exerts direct pro-atherogenic and antiangiogenic effects on vascular endothelial cells which might explain the cardiovascular events in patients treated with nilotinib

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13 653 Four-Year (Yr) Follow-Up of Patients (Pts) With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Receiving Dasatinib or Imatinib: Efficacy Based on Early Response J. Cortes, 1 A. Hochhaus, 2 D.-W. Kim, 3 N.P. Shah, 4 J. Mayer, 5 P. Rowlings, 6 H. Nakamae, 7 M.B. Bradley-Garelik, 8 H. Mohamed, 9 H. Kantarjian, 1 G. Saglio 10 1 University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; 2 Universitätsklinikum Jena, Jena, Germany; 3 Seoul St. Mary's Hospital, Seoul, Republic of Korea; 4 UCSF School of Medicine, San Francisco, CA, USA; 5 Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czech Republic; 6 Calvary Mater Newcastle Hospital, University of Newcastle, Australia; 7 Osaka City University Hospital, Osaka, Japan; 8 Bristol-Myers Squibb, Wallingford, CT, USA; 9 Bristol-Myers Squibb, Plainsboro, NJ, USA; 10 University of Turin, Turin, Italy ASH

14 DASISION (CA ) Study Design Treatment-naive CML-CP patients (N=519) 108 Centers 26 Countries Enrollment: September 2007 December 2008 a Stratified by EURO (Hasford) risk score Randomized a Dasatinib 100 mg QD (n=259) Imatinib 400 mg QD (n=260) Long-term follow-up Primary end point: confirmed CCyR by 12 months 77% dasatinib versus 66% imatinib (P=0.007) 1 1. Kantarjian H, et al. N Engl J Med. 2010;362: DASISION (CA ): NCT ; CCyR = complete cytogenetic response. 14

15 % With MMR Cumulative Rate of MMR 100 P< Dasatinib 100 mg QD Imatinib 400 mg QD Fold higher likelihood of achieving MMR with dasatinib; HR=1.55 ( ) 46% 64% 46% 69% 55% 74% 60% 76% 63% 20 23% MMR = major molecular response, BCR-ABL (IS) 0.1%; IS = International Scale Months Hasford Risk Score MMR 4-y cumulative rates Low Intermediate High Dasatinib 90% 70% 65% Imatinib 69% 63% 52% 15

16 Patients, n Transformation to AP/BP CML by 4 Years Dasatinib 100 mg QD 8 (3.1%) On Study 14 (5.4%) Imatinib 400 mg QD 12 (4.6%) Including Follow-up Beyond Discontinuation (ITT) a One patient (on imatinib) transformed on study between 3 and 4 years 18 (6.9%) a Yearly evaluations after discontinuation are currently stipulated per protocol; additional information on patient status may be provided by investigators at other times. 16

17 Overall Survival and Progression-Free Survival Dasatinib 100 mg QD (n=259) Imatinib 400 mg QD (n=260) Hazard ratio Total number of deaths, a n Estimated 4-year OS, % 92.9 ( ) 92.1 ( ) HR=0.91 ( ) Estimated 4-year PFS, b % 90.0 ( ) 90.2 ( ) HR=1.04 ( ) a On-study treatment and in follow-up after discontinuation of randomized treatment. b Progression was defined as doubling of WBC count, loss of CHR, increase in Ph-positive metaphases to >35%, transformation, or death from any cause. 17

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19 New ELN 2013 Definition of response to 1 st -line TKI Definition of response of response to 1 st -line TKIs to in 1CP-CML st -line TKIs in CP-CML Time Optimal Warning Failure Diagnosis _ High risk, or CCA in Ph+ major route _ 3 months BCR-ABL1 10% And/or Ph+ 35% BCR-ABL1 >10% And/or Ph % Non CHR And/or Ph+ >95% 6 months BCR-ABL1 <1% And/or Ph+ 0 BCR-ABL1 1-10% And/or Ph+ 1-35% BCR-ABL1 >10% And/or Ph+ >35% 12 months BCR-ABL1 0.1% BCR-ABL % BCR-ABL1 >1% And/or Ph+ >0 >12 months, and at any time BCR-ABL1 0.1% CCA/Ph- (-7, or 7q-) Loss of CHR Loss of CCyR Confirmed loss of MMR* Mutations CCA/Ph + *In two consecutive tests, of which one with a BCR-ABL1 transcripts level 1%. NA = Not Applicable. MMR = Major molecular response (BCR-ABL1 0.1% = MR3.0 or better). CCA/Ph+ = Clonal Chromosome Abnormalities in Ph+ cells. CCA/Ph- = Clonal Chromosome Abnormalities in Ph- cells OPTIMAL response is associated with the best long-term outcome Adapted from: Baccarani M, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: Blood 2013;122:

20 Recommended testing for disease monitoring adapted from NCCN (2013) and ELN (2009 and 2013). Oehler V G Hematology 2013;2013: by American Society of Hematology

21 Choosing frontline TKI treatment Patient s long-term goals Treatment-free remission? Overall survival? Long-term safety? Intrinsic risk profile of the disease Sokal risk score (high versus intermediate-low) IC 50 analysis OCT-activity, CIP2A, GFI-1, omics, BIM polymorphism Patient s comorbidities (availability of TKI s (budget)

22 Proposed schema for individualizing therapy based on comorbidities, goals of therapy, and disease risk profile. Hughes T, and White D Hematology 2013;2013: by American Society of Hematology

23 Timeline of gene discovery efforts in patients with MPNs. The MPNs were initially grouped together based on prescient clinical insights by William Dameshek in The earliest insights into the genetic causes for the MPNs were then made in 1976 to 1981, CALR mutation Kim E, and Abdel-Wahab O Hematology 2013;2013: by American Society of Hematology

24 Another piece of the MPN puzzle MPN without JAK2 or MPL mutation Klampfl et al. performed exome sequencing of paired MPN and normal DNA to identify recurrent mutations in the CALR gen on samples of 6 patients and then targeted sequencing of a large cohort of patients Nangalia et al. performed exome sequencing on samples from 151 patients with MPN

25 Mutations in CALR and the Generation of a Novel C-Terminal Peptide in the Calreticulin Protein. Klampfl T et al. N Engl J Med 2013;369:

26 Frequency of CALR Mutations in Myeloid Neoplasms. Klampfl T et al. N Engl J Med 2013;369:

27 Mutational Profile of 151 Myeloproliferative Neoplasms. Nangalia J et al. N Engl J Med 2013;369:

28 Frequency of CALR Mutations in Samples Obtained from Patients with Myeloproliferative Neoplasms or Other Disorders and from Controls. Nangalia J et al. N Engl J Med 2013;369:

29 CALR mutations in MPN Only in patients with ET and PMF (73%) without the JAK-2 or MPL < 10% of patients with ET-IMF have no JAK-2, MPL or CALR mutations No patients with PV, CML, MDS (or very rare), CMML or AML, lymphoma, solid tumors Some patients with RARS-T Probably an early (and stable) event in early progenitor cells ET-Patients with CALR mutations have a lower Hb and WBC count, and higher Platelet count than patiens with JAK-2 mutation

30 Estimated Overall Survival and Cumulative Incidence of Thrombosis among Patients with CALR, JAK2, or MPL Mutations. Klampfl T et al. N Engl J Med 2013;369:

31 CALR mutations in MPN CALR-mutated cells are independent of IL-3 JAK-STAT signaling is responsible for cytokineindependent growth of cells expressing CALR mutation CALR can activate STAT signaling in hemopoietic cells but how is not clear CALR function: Within the endoplasmatic reticulum: appropriate folding of newly synthesized glycoproteins. Calcium homeostasis Without the endoplasmatic reticulum: proliferation, apoptosis and immune respons Will potentially used as a diagnostic test and might guide therapeutic-decision making

32 Pre- and on-treatment considerations with use of JAK inhibitors in MF. Gotlib J Hematology 2013;2013: by American Society of Hematology

33 Long-Term Outcomes of Ruxolitinib Therapy in Patients with Myelofibrosis: 3-Year Update From COMFORT-I Srdan Verstovsek, 1 Ruben A. Mesa, 2 Jason Gotlib, 3 Richard S. Levy, 4 Vikas Gupta, 5 John F. DiPersio, 6 John V. Catalano, 7 Michael W.N. Deininger, 8* Carole B. Miller, 9 Richard T. Silver, 10 Moshe Talpaz, 11 Elliott F. Winton, 12 Jimmie H. Harvey, Jr., 13 Murat O. Arcasoy, 14 Elizabeth O. Hexner, 15 Roger M. Lyons, 16 Azra Raza, 17 Kris Vaddi, 4 William Sun, 4 Wei Peng, 4 Victor Sandor, 4 and Hagop Kantarjian, 1 for the COMFORT-I investigators 1 The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2 Mayo Clinic, Scottsdale, AZ, USA; 3 Stanford Cancer Institute, Stanford, CA, USA; 4 Incyte Corporation, Wilmington, DE, USA; 5 Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada; 6 Washington University School of Medicine, St. Louis, MO, USA; 7 Frankston Hospital and Department of Clinical Haematology, Monash University, Frankston, Australia; 8* Oregon Health and Science University, Portland, OR, USA; 9 Saint Agnes Cancer Institute, Baltimore, MD, USA; 10 Weill Cornell Medical Center, New York, NY, USA; 11 University of Michigan, Ann Arbor, MI, USA; 12 Emory University School of Medicine, Atlanta, GA, USA; 13 Birmingham Hematology and Oncology, Birmingham, AL; 14 Duke University Health System, Durham, NC, USA; 15 Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; 16 Cancer Care Centers of South Texas/US Oncology, San Antonio, TX, USA; 17 Columbia Presbyterian Medical Center, New York, NY, USA *Currently at Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

34 Background COMFORT-I (abstract 396) Placebo-controlled, randomized, double-blind, phase III study Primary analysis (median follow-up 32 weeks) 1 Significant improvements in spleen volume, MF-related symptoms, and QoL measures with ruxolitinib compared with placebo Ruxolitinib treatment was associated with an overall survival advantage relative to placebo at a median follow-up of 51 weeks 1 2-Year analysis (median follow-up 102 wks): 2 Durable spleen volume reductions and QoL improvements Continued overall survival advantage despite placebo crossover Objective To report longer-term efficacy, overall survival, and safety of ruxolitinib in patients from the COMFORT-I study 1. Verstovsek S, et al. N Engl J Med. 2012; 366: Verstovsek S, et al. Haematologica Sept 13. Epub ahead COMFORT of print. PMID I Year Update

35 Patient Disposition Ruxolitinib (n = 155) Placebo (n = 151) Placebo Placebo Ruxolitinib (n=111) Median exposure, weeks Still on treatment, n (%) 77 (49.7) 0 57 (51.4) Crossed over, n (%) 111 (73.5) Discontinued, n (%) 78 (50.3) 40 (26.5) 54 (48.6) Primary reasons for discontinuation, n (%)* Death 15 (19.2) 7 (17.5) 11 (20.4) Adverse event 15 (19.2) 9 (22.5) 8 (14.8) Consent withdrawn 12 (15.4) 7 (17.5) 11 (20.4) Disease progression 18 (23.1) 13 (32.5) 15 (27.8) All patients originally randomized to placebo crossed over or discontinued within 3 months of the primary analysis Median time to crossover: 41.1 weeks * Percentages are calculated based on the number COMFORT of patients I who - 3 Year discontinued Update within the respective treatment group.

36 Mean Percentage Change from Baseline Mean Percentage Change from Baseline Percentage Change in Spleen Size Mean reductions in spleen volume and palpable spleen length with ruxolitinib were stable over time Spleen Volume Spleen Length 10 Ruxolitinib Placebo 10 Ruxolitinib Placebo 0 n = n = Weeks -60 COMFORT I - 3 Year Update Weeks

37 Mean Change From Baseline Mean Change From Baseline Mean Change From Baseline Mean Change From Baseline Improvements in EORTC QLQ-C30 Over Time Global Health Status/QoL Weeks Role Functioning Weeks 10 RUX PBO Arrows indicate improvement COMFORT I - 3 Year Update Fatigue Weeks Physical Functioning Weeks

38 Probability Overall Survival Overall survival favored patients originally randomized to ruxolitinib compared with patients originally randomized to placebo Randomized to Ruxolitinib 0.6 Randomized to Placebo Ruxolitinib * HR=0.69 (95% CI: 0.46, 1.03); P=0.067 No. of deaths: Ruxolitinib=42; Placebo=54 Median follow-up: 149 weeks Percent of at-risk placebo who crossed over or discontinued Number of patients at risk Ruxolitinib Weeks Placebo COMFORT I - 3 Year Update *By week 80, all patients originally randomized to placebo discontinued or crossed over to ruxolitinib therapy 38

39 COMFORT-I 3-Year: Conclusions Reductions in spleen volume and improvements in symptoms and QoL measures were sustained with longer-term therapy Overall survival favored patients originally randomized to ruxolitinib compared with those originally randomized to placebo Results from exploratory analyses suggest cross over leads to an underestimation of the true survival difference between ruxolitinib and placebo The incidence of new onset grade 3 or 4 anemia and thrombocytopenia decreased with longer-term therapy There was no change in the rate, distribution, or severity of nonhematologic adverse events in patients originally randomized to ruxolitinib with longer-term treatment Collectively, these data reinforce the durable efficacy and longer-term safety of ruxolitinib in patients with myelofibrosis COMFORT I - 3 Year Update

40 JAK inhibitors in patients with MF (PMF, PPV, PET) JAK inhibitor Key study Patients enrolled Trial design Ruxolitinib (JAK {2,1,3}, TYK2) Comfort INT-2/High risk Phase III placebo Comfort-II 219 INT-2/High risk Phase III, 2:1 BAC Phase I/II study 153 High risk Dose escalation Fedratinib (JAK {2,1,3}, TYK2) Phase III Jakarta 225 INT-2/High risk 400 mg/500 mg/placebo Phase II 31 INT-2/High risk Randomized, dose ranging Phase I/II 59 INT-2/High risk Dose escalation Momelotinib(JAK {2,1,3) Phase I/II 166 INT-2/High risk Dose escalation/confirmation Phase III trial Momelotinib versus ruxolitinib Pacritinib(JAK {2,1,3) Phase II 34 Low-high Dose 400 mg Phase I/II 33 Dose escalation mg Phase III studies initiated INCB (JAK-1 inhibitor) Phase II 65 INT-2/High risk Dose escalation mg BMS (JAK-2 inhibitor Phase I/II 84 INT-2/High risk Dose escalation Ly27845 (JAK2 inhibitor) Phase I 38 INT-2/High risk Dose escalation

41 JAK inhibitors in patients with MF (PMF, PPV, PET) JAK inhibitor Key study Key efficacy findings Key safety findings Ruxolitinib Comfort-I Anemia 45% Comfort-II Thrombopenia 13% Survival advantage Phase I/II study Fedratinib Phase III Jakarta Anemia 35% Phase II Trombopenia 20% (dose depending) Wernicke s encephalopathy (rare) Phase I/II Decrease in JAK2 V617F burden Momelotinib Phase I/II Anemia 2% Increase Hb (53%) Thrombopenia 24% Constitutional Peripheral neuropathy Pacritinib Phase I/II Anemia: none Thrombopenia 15% INCB Phase II Spleen volume symptoms BMS Phase I/II Decrease in JAK2 V617F burden Ly27845 Phase I

42 Novel agents targeting pathways downstream of the JAK/STAT signaling pathway in MF. Activated JAK2 signals through and activates downstream signaling intermediates such as STAT5, RAS/MAPK, and PI3K/AKT/mTOR pathways, leading to effects on proliferation and... Odenike O Hematology 2013;2013: by American Society of Hematology

43 How I treat MF in the JAK inhibitor era. DIPSS score points Hb<10g/dL 2 Age >65 yr 1 WBC>25x109/L 1 Circulating blasts 1% 1 Constitutional sympt 1 Odenike O Hematology 2013;2013: