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MDS and MPD ASH 2013

MDS and MPD ASH 2013. Katherine Walsh MD Katherine.Walsh@osumc.edu . No conflicts of interest to disclose. Off-label use of: azacitidine , vorinostat, and lenalidomide. Objectives. To discuss new insights into the diagnosis of MDS and MPD focusing on new genomic analyses

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MDS and MPD ASH 2013

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  1. MDS and MPDASH 2013 Katherine Walsh MD Katherine.Walsh@osumc.edu No conflicts of interest to disclose. Off-label use of: azacitidine, vorinostat, and lenalidomide

  2. Objectives • To discuss new insights into the diagnosis of MDS and MPD focusing on new genomic analyses • To discuss updates on current treatment options and new treatment strategies in development for MDS and MPD • To discuss new agents in development for MDS and MPD

  3. Abstract 521Landscape Of Genetic Lesions In 944 Patients With Myelodysplastic Syndromes Yasunobu Nagata1,2, Vera Grossmann3, Yusuke Okuno1, Ulrike Bacher3, Genta Nagae4, Susanne Schnittger3, Yusuke Shiozawa1,2, Ayana Kon1,2, Tamara Alpermann3, Kenichi Yoshida1,2, Masashi Sanada1,2, Andreas Roller3, Niroshan Nadarajah3, Yuichi Shiraishi5, Kenichi Chiba6, Hiroko Tanaka6, H.Phillip Koeffler7,8, Hans-Ulrich Klein9, Martin Dugas9, Alexander Kohlmann3, Satoru Miyano5,6, Claudia Haferlach3, Hiroyuki Aburatani4, Wolfgang Kern3, Seishi Ogawa1,2 , Torsten Haferlach3 1Cancer Genomics Project, Gr­aduate School of Medicine, The University of Tokyo, Tokyo, Japan; 2Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan. 3MLL Munich Leukemia Laboratory, Munich, Germany; 4Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan; 5Laboratory of Sequence Data Analysis, Human Genome Center, 6Laboratory of DNA Information Analysis, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; 7Hematology/Oncology, Cedars-Sinai Medical Center; 8National University of Singapore, Cancer Science Institute of Singapore, 9Department of Medical Informatics and Biomathematics, University of Münster, Münster, Germany

  4. Landscape of gene mutations in MDS Splicing factor mutations were largely mutually exclusive The distribution of other mutations also does not seem to be random

  5. Frequency of gene mutations involved in common functional pathways The most frequent target was RNA splicing, with mutations observed in as many as 64% of cases

  6. Azacitidine and Vorinostat in MDS

  7. Conclusions from Abstract #386 • Azacitidine and vorinostat can be safely combined in patients with MDS with the following toxicities reported: • Fatigue during the first 3 cycles (8-16% per cohort) • GI toxicity including vomiting, diarrhea, and dehydration (8% of each of the cohorts) • The combination appeared well tolerated over multiple cycles without cumulative toxicity

  8. Ongoing Phase II Study

  9. Abstract 388Outcome of Patients (pts) with Low and Intermediate-1 Risk Myelodysplastic Syndrome (MDS) After Hypomethylating Agent (HMA) Failure: A Report on Behalf of the MDS Clinical Research Consortium E Jabbour, G Garcia-Manero, P Strati, NH. Al Ali, AMishra, E Padron, J Lancet, J Bryan, H Prescott, D Steensma, MA. Sekeres, GJ. Roboz, AF. List, H Kantarjian, RS. Komrokji

  10. Results with 5-aza/Dec

  11. Factors Associated with Progression into Higher-Risk Disease MDGSS= MDACC Global Scoring System; Kantrajian. Cancer 2008;113:1351-61 LRMDSS= Low Risk MDACC Scoring System; Garcia-Manero. Leukemia 2008;22:538-43

  12. Dual Inhibition of p38 and Tie2 by ARRY-614 Tie2 in MDS – Emerging Target p38 MAPK in MDS Stress/Inflammatory Stimuli (Cytokines, Hypoxia, FasL) Ang-2 Ang-1 TNF-α, IL-6, Chemokines Decreased RBC, WBC, platelets p38 Apoptosis Pleiotropic effectson Progenitors and AML blasts • Dysregulated, may be a survival factor for AML blast • Increased signaling associated with poor prognosis • Major regulator of the cellular pathways which sense stress • Over-activated, leading to inappropriate production of myelosuppressive cytokines

  13. ARRY-614 Reduces phospho-p38 in Patient Bone Marrow Representative Image Cycle 2 Screening Paired t test, P <0.05 % phospho-p38 (+) cells 15.2 % p-p38 (+) cells 2.3 % p-p38 (+) cells Aperio whole slide scanning and scoring performed by Flagship Biosciences *Screening n=30† Cycle 2 n=30† *Sample collected prior to the first dose of ARRY-614 †Number of pts for whom bone marrow samples available at screening and cycle 2

  14. ARRY-614: Responses • Overall, durable HI observed in 14 of 71 evaluable patients (20%) as of 31 Oct cut-off date. • Responses seen in each of the dose cohorts.

  15. MDS Summary • The genetic landscape described in a large cohort of MDS patients is potentially clinically relevant for diagnosis and prognosis. • For untreated MDS, clinical trials updates showed that combination of azacitidine and vorinostat may be better than azacitidine alone. • Low and intermediate risk MDS who fail hypomethylator therapy are in need of better treatments and the novel agent ARRY-614 shows signs of activity in early trial updates.

  16. MPD Overview • Two late-breaking abstracts identified CALR mutations in JAK2 wild-type patients and these results were subsequently published in the NEJM. • Long-term follow-up data was presented for the COMFORT-1 study with ruxolitinib. • In CML, the preliminary results of patients who stopped imatinib in the STIM2 study were presented.

  17. Original ArticleSomatic Mutations of Calreticulin in Myeloproliferative Neoplasms Thorsten Klampfl, Ph.D., Heinz Gisslinger, M.D., Ashot S. Harutyunyan, M.D., Ph.D., Harini Nivarthi, Ph.D., Elisa Rumi, M.D., Jelena D. Milosevic, M.Sc., Nicole C.C. Them, M.Sc., Tiina Berg, B.Sc., Bettina Gisslinger, M.Sc., Daniela Pietra, Ph.D., Doris Chen, Ph.D., Gregory I. Vladimer, Ph.D., Klaudia Bagienski, M.Sc., Chiara Milanesi, M.Sc., Ilaria Carola Casetti, M.D., Emanuela Sant'Antonio, M.D., Virginia Ferretti, Ph.D., Chiara Elena, M.D., Fiorella Schischlik, M.Sc., Ciara Cleary, M.Sc., Melanie Six, B.Sc., Martin Schalling, M.Sc., Andreas Schönegger, M.Sc., Christoph Bock, Ph.D., Luca Malcovati, M.D., Cristiana Pascutto, Ph.D., Giulio Superti-Furga, Ph.D., Mario Cazzola, M.D., and Robert Kralovics, Ph.D. N Engl J Med Volume 369(25):2379-2390 December 19, 2013

  18. Frequency of CALR Mutations in Myeloid Neoplasms. Klampfl T et al. N Engl J Med 2013;369:2379-2390

  19. Klampfl T et al. N Engl J Med 2013;369:2379-2390

  20. Clinical Features of Patients with CALR mutations Klampfl T et al. N Engl J Med 2013;369:2379-2390.

  21. Original ArticleSomatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2 J. Nangalia, C.E. Massie, E.J. Baxter, F.L. Nice, G. Gundem, D.C. Wedge, E. Avezov, J. Li, K. Kollmann, D.G. Kent, A. Aziz, A.L. Godfrey, J. Hinton, I. Martincorena, P. Van Loo, A.V. Jones, P. Guglielmelli, P. Tarpey, H.P. Harding, J.D. Fitzpatrick, C.T. Goudie, C.A. Ortmann, S.J. Loughran, K. Raine, D.R. Jones, A.P. Butler, J.W. Teague, S. O'Meara, S. McLaren, M. Bianchi, Y. Silber, D. Dimitropoulou, D. Bloxham, L. Mudie, M. Maddison, B. Robinson, C. Keohane, C. Maclean, K. Hill, K. Orchard, S. Tauro, M.-Q. Du, M. Greaves, D. Bowen, B.J.P. Huntly, C.N. Harrison, N.C.P. Cross, D. Ron, A.M. Vannucchi, E. Papaemmanuil, P.J. Campbell, and A.R. Green N Engl J Med Volume 369(25):2391-2405 December 19, 2013

  22. Landscape of 151 MPN patients • 97% of patients had a mutation in either JAK2, MPL, or CALR • These mutations were mutually exclusive • Clinically relevant for diagnosis and as a potential future treatment target Nangalia, J et al. N Engl J Med 2013;369:2391-2405.

  23. Long-Term Outcomes of Ruxolitinib Therapy in Patients with Myelofibrosis: 3-Year Update From COMFORT-I Srdan Verstovsek,1Ruben A. Mesa,2 Jason Gotlib,3 Richard S. Levy,4Vikas 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,16Azra Raza,17 Kris Vaddi,4 William Sun,4 Wei Peng,4Victor Sandor,4 and Hagop Kantarjian,1 for the COMFORT-I investigators 1The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Mayo Clinic, Scottsdale, AZ, USA; 3Stanford Cancer Institute, Stanford, CA, USA; 4Incyte Corporation, Wilmington, DE, USA; 5Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada; 6Washington University School of Medicine, St. Louis, MO, USA; 7Frankston Hospital and Department of Clinical Haematology, MonashUniversity, Frankston, Australia; 8*Oregon Health and Science University, Portland, OR, USA; 9Saint Agnes Cancer Institute, Baltimore, MD, USA; 10Weill Cornell Medical Center, New York, NY, USA; 11University of Michigan, Ann Arbor, MI, USA; 12Emory University School of Medicine, Atlanta, GA, USA; 13Birmingham Hematology and Oncology, Birmingham, AL; 14Duke University Health System, Durham, NC, USA; 15Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; 16Cancer Care Centers of South Texas/US Oncology, San Antonio, TX, USA; 17Columbia 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

  24. COMFORT-I Background • 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 ruxolitinibcompared with placebo • Ruxolitinib treatment was associated with an overall survival advantage relative to placebo at a median follow-up of 51 weeks1 • 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 • Verstovsek S, et al. N Engl J Med. 2012; 366:799-807. • Verstovsek S, et al. Haematologica. 2013 Sept 13. Epub ahead of print. PMID 24038026.

  25. Durability of Spleen Volume Reduction • In patients originally randomized to ruxolitinib, 59% achieved a ≥35% reduction in spleen volume 1.0 ≥10% reduction (n=91) 0.8 ≥35% reduction (n=91) 0.6 Probability 0.4 0.2 0 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 Weeks from initial ≥ 35% spleen volume reduction Number of patients at risk ≥35% reduction 91 86 77 75 68 62 59 54 51 49 42 40 38 37 27 25 23 1 1 ≥35% reduction: Time from first 35% reduction to <35% reduction and 25% increase from nadir. ≥10% reduction: Time from first 35% reduction to <10% reduction from baseline.

  26. Improvements in EORTC QLQ-C30 Over Time Global Health Status/QoL Fatigue 10 25 20 15 20 5 15 15 10 0 Mean Change From Baseline Mean Change From Baseline 10 10 -5 Mean Change From Baseline 5 5 5 -10 0 0 12 24 36 48 60 72 84 96 108 120 132 144 0 12 24 36 48 60 72 84 96 108 120 132 144 -15 0 Weeks Weeks RUX PBO 0 -5 Arrows indicate improvement Physical Functioning Role Functioning -20 -10 -5 -25 -5 -15 -10 -30 -20 Weeks Mean Change From Baseline -10 -35 -25 -15 0 12 24 36 48 60 72 84 96 108 120 132 144 0 12 24 36 48 60 72 84 96 108 120 132 144 Weeks

  27. Overall Survival • Overall survival favored patients originally randomized to ruxolitinib compared with patients originally randomized to placebo 1.0 Randomized to Ruxolitinib 0.8 * Randomized to Placebo  Ruxolitinib 0.6 Probability HR=0.69 (95% CI: 0.46, 1.03); P=0.067 0.4 No. of deaths: Ruxolitinib=42; Placebo=54 Median follow-up: 149 weeks 0.2 Percent of at-risk placebo who crossed over or discontinued 4 13 22 35 54 73 88 97 99 100 100 100 100 100 100 100 100 100 100 100 100 100 0 Number of patients at risk 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 160 168 176 Ruxolitinib 155 155 153 148 145 143 137 131 125 124 122 115 112 111 111 108 106 101 84 45 19 1 0 Weeks Placebo 154 153 149 144 134 129 119 114 107 105 100 100 95 92 88 85 82 79 68 38 28 8 0 30 *By week 80, all patients originally randomized to placebo discontinued or crossed over to ruxolitinib therapy

  28. Mean Platelet Count and Hemoglobin Level Over Time Platelet Count Hemoglobin 370 115 Ruxolitinib Ruxolitinib Placebo Placebo 110 320 105 270 Mean Hemoglobin (g/L) Mean Platelets (x109/L) 100 220 95 170 90 120 85 0 12 24 36 48 60 72 84 96 108 120 132 144 0 12 24 36 48 60 72 84 96 108 120 132 144 Weeks Weeks Number of patients Number of patients 155 145 143 136 124 113 110 107 104 100 94 88 RUX 155 144 143 136 124 112 110 107 104 100 94 88 79 79 151 132 113 83 37 PBO 151 128 112 82 37

  29. Incidence of New Onset Grade 3 or 4 Anemia and Thrombocytopenia Over Time Ruxolitinib Grade 3 Ruxolitinib Grade 4 Placebo* Grade 3 Placebo* Grade 4 Anemia Thrombocytopenia 18.7 3.8 0.8 0 0 • Consistent with observations at the 2-year follow-up, grade 3 or 4 anemia and thrombocytopenia typically only occurred early (≤6 months) in ruxolitinib treatment and decreased with long-term therapy *All patients receiving placebo at the primary analysis crossed over or discontinued within 3 months of the primary analysis; therefore, data for patients receiving placebo is shown for up to 6 months only

  30. 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

  31. Update on the Long-term Efficacy and Safety of Momelotinib, a JAK1 and JAK2 Inhibitor, for the Treatment of Myelofibrosis A Pardanani,1 J Gotlib,2 V Gupta,3 AW Roberts,4 M Wadleigh,5 S Sirhan,6LM Bavisotto,7 J Kawashima,8 P Lee,8 M Kowalski,8 W Deng,8 D Niforos,8 A Tefferi1 1Mayo Clinic, Rochester, MN, USA; 2Stanford University, Stanford, CA, USA; 3Princess Margaret Cancer Centre, Toronto, ON, Canada; 4Royal Melbourne Hospital, Parkville, Australia; 5Dana-Farber Cancer Institute, Boston, MA, USA; 6Jewish General Hospital, Montreal, QC, Canada; 7Porta Clinica, Seattle, WA, USA; 8Gilead Sciences, Foster City, CA, USA American Society of Hematology December 7-10, 2013 New Orleans, LA Oral No. 61758

  32. Anemia Response Transfusion dependence at baseline is defined as ≥ 2 units of RBC transfusions in the 30 days prior to C1/D1 and/or identified as transfusion dependent in medical history

  33. Duration of Anemia Response 1.0  Censored  Event 0.9 Number of events (%): 18 (30.5) Number of censored (%): 41 (69.5) Median (days) (95% CI): 1,042 (514, NE) 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 0 600 800 0 400 200 1000 Duration of anemia response (days)

  34. Symptoms Response at 3 Months 100 90 80 70 Percent 60 50 40 30 20 10 0 Abdominal discomfort Fatigue Pruritus Cough Edema Bone pain Fever Early satiety Night sweats Marked Improvement - defined as ≥ 50% improvement from baseline Complete Resolution

  35. Conclusions • Momelotinib was well tolerated overall. • Grade 3/4 thrombocytopenia (29%), neutropenia (5%), and elevated lipase (4%). • Peripheral neuropathy in 38% with all occurrences less than Grade 2 • 2 patients stopped treatment due to neuropathy • 17 patients had neuropathy at baseline • Treatment improved splenomegaly and disease-related symptoms along with decreasing transfusion needs.

  36. Phase 3 Study Design (GS-US-352-0101) Screening (≤ 35 days) Long-term Follow-up Open-label Phase Double-blind Treatment Phase Momelotinib + placebo Momelotinib Momelotinib QD N=420 1:1 randomization Ruxolitinib + placebo Momelotinib Week 24 Day 1 Within 5 days of randomization Week 192 Year 4 Year 5

  37. Preliminary Report Of The STIM2 Study:  A Multicenter Stop Imatinib Trial For Chronic Phase Chronic Myeloid Leukemia De Novo Patients On Imatinib Francois-Xavier Mahon, Franck E. Nicolini, Marie-Pierre Noël, Martine Escoffre, Aude Charbonnier, Delphine Rea, Viviane Dubruille, Bruno Varet, Laurence Legros, Agnès Guerci, Gabriel Etienne, Francois Guilhot, Stéphanie Dulucq, Philippe Rousselot, and Joelle Guilhot on behalf of the Intergroupe Français des Leucémies Myéloïdes Chroniques

  38. INTRODUCTION A pilot and STIM1 demonstrated that Imatinib could be safely discontinued in patients with a sustained DMR with undetectable BCR-ABL transcripts for at least 2 years 1,2. - Results since confirmed by the Australian TWISTER study3 . - In both studies, 50% of the patients were previously treated with IFN leading to a non- homogeneous cohort of patients. 1.Rousselot et al. Blood 2007;109:58–602. Mahon et al. Lancet oncology, 2010;11: 1029-1035 3. Ross et al. Blood, 2013; 122:515-22).

  39. STIM2 study: A multicenter Stop Imatinib trial for CML de novo only treated with imatinib • Main inclusion criteria • CMR for at least 2 years under treatment with imatinib   • Molecular monitoring according to international recommendations • Main exclusion criteria • < 18 years old   • Interfering treatment (corticosteroids, immunosuppressors, chemotherapy, radiotherapy) N=200

  40. Characteristics of patients N=127 • Number of patients included between 04/2011-09/2013: 131* • From 23 different French centers • Mean age at diagnosis: 54 years • Mean age at the inclusion: 61 years • Gender distribution: 63 males, 64 females • Median duration of CMR before stopping :35 months (24-97) • Sokal Score Low, intermediate, High, unk : 55, 52, 15, 5 • Median Follow up: 16 months (range 0-27) * Four patients previously treated by IFN incorrectly included were excluded

  41. STIM study design Q- RT-PCR from peripheral blood every month in the first year and every 2 months thereafter STOP Start Imatinib Sustained CMR for ≥ 2 years CMR Molecular recurrence: positivity of BCR–ABL transcript in Q-RT-PCR confirmed by a second analysis point indicating the increase of one log in relation to the first analysis point, at two successive assessments, or loss of MMR at one point. Five BCR–ABL analyses by Q- RT-PCR during these 2 years Sixth datapoint checked in centralized laboratory Mahon FX et al. The Lancet Oncology, 2010;11(11): 1029-1035.

  42. STIM2 study: Preliminary results Molecular relapse N = 52

  43. Fluctuation of BCR-ABL detection after discontinuation STOP UMRD: undetectable minimumal residual disease at least in MR4.5 With > 50 000 copies of ABL gene

  44. STIM2 study : Preliminary results undetectable transcript N = 35 Follow-up*: 15.7 mos (0.9-26.7) undetectabletranscript N = 127 Fluctuation PCR, non relapsing N = 40 Time to fluctuation*: 2.3 mos (0.9-7.5) Molecular relapse N = 52 Time to relapse*: 2.0 mos (0 -8.0) * Median (range) from Imatinib discontinuation

  45. SURVIVAL WITHOUT CML TREATMENT STIM2 Event = treatment re-challenge

  46. Conclusions • Imatinib can be safely and prospectively discontinued in pts with DMR of at least 2 years duration in patients treatedwith imatinib. • Positive fluctuation PCR results do not lead to CML relapse or progression thereforecompleteeradication of residualleukemic stem cellsmay not benecessary. • Theseresultsconfirmed the findings of the earlierstudies (STIM1). • The investigators plan to perform statistical analysis in the 3 different groups of patients. • The study recommended proposing discontinuation only in a clinical trial with close molecular monitoring.

  47. Summary • Genomic studies this year provided insights into the mutational status of MDS patients and identified CALR mutations in a large percentage JAK2 wild-type MPD patients. • Clinical trials are currently investigating the benefit of adding an additional agent to the standard of care of azacitidine in MDS. • New agents are in development and being evaluated in clinical trials for MDS and MPD. • CML trials are investigating stopping TKI therapy after a sustained and deep molecular response.

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