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Myelofibros 2013 – nya data med tonvikt på JAK2 inhibition

Myelofibros 2013 – nya data med tonvikt på JAK2 inhibition. Jan Samuelsson. Disclosures. Consultancy ; Swedish Orphan Biovitrum Novartis Shire. Take home messages. Never forget allogeneic SCT in suitable PMF pts

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Myelofibros 2013 – nya data med tonvikt på JAK2 inhibition

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  1. Myelofibros 2013 – nya data med tonvikt på JAK2 inhibition Jan Samuelsson

  2. Disclosures Consultancy; Swedish OrphanBiovitrum Novartis Shire

  3. Take home messages Neverforgetallogeneic SCT in suitable PMF pts JAK2 inhibitors conferveryvaluableclinicalresponses - - splenomegaly,constitu-tional symptoms, survival and regression of fibrosis No ”homeruns” yet with new drugs - probablyrationale for combination trials in PMF

  4. New therapy guidelines • NMPN guidelines for all MPN updated 2012-2013 • On-line at www.nmpn.org

  5. Cure of PMF via stem cell transplantation (SCT) • SCT should be considered in all PMF patients at diagnosis. • It is recommended in transplantable patients with INT-2 or HR at diagnosis, and during follow-up of low/INT-1 patients that progress to a higher risk score.

  6. Abelsson et al Bone Marrow Transpl 2012; 47, 380

  7. Abnormally Increased IL-8 and IL2R Plasma Levels Are Prognostically Detrimental Int-1 (n=27) All (n=127) Int-2 (n=70) Treatment naive (n=90) Tefferi A et al. JCO 2011;29:1356-1363

  8. Elevated C-reactive protein is associated with shortened leukemia-free survival in patients with myelofibrosis.Barbui et al Leukemia 2013

  9. Gene Clusters • Inflammation • Immune system • Platelet alpha granule • Apoptosis

  10. Figure 1. Fold changes for the 5 genes in ET, PV, and PMF compared to control subjects. Patient groups and genes are shown on the x-axis and fold changes on the Y-axis. NS: non-significant; S: significant

  11. Figure 2. Hierarchical cluster analysis with euclidean distance of ET, PV and PMF patients. Rows in the heat map represent the five genes DEFA4, ELA2, CTSG, OLFM4, and AZU1, and columns represent patients. The color key ranges from green to red representing standardized expression values of -3.0 to 3.0. Greenindicates low expression, black intermediate expression, and red high expression. Five major clusters can be identified. Cluster 1 (green, low expression), Cluster 2 (green-black, low-intermediate expression), Cluster 3 (black-red, intermediate expression), Cluster 4 (red-black, intermediate-high expression), and Cluster 5 (red, high expression).T The dendogram shows the degree of similarity between patients.

  12. Mutation Complexity in PMF • 382 (79.1%) of patients presented at least one somatic mutation • 154 pts (32.5%) had >2 mutations • 31 pts (6.4%) had >3 mutations Vannucchi AM et al, ASH2012

  13. Mutations Associated with Reduced Overall Survival in Multivariate Analysis EZH2 ASXL1 WT WT Mut Mut P= 0.0008 P< 0.0001 SRSF2 WT Mut P< 0.0001

  14. Mutations Associated with Leukemia in Multivariate Analysis EZH2 ASXL1 WT Mut Mut WT P=.003 HR=1.98 (95%CI: 0.88-4.46) P<.0001 HR=2.5 (95%CI: 1.51-4.13) SRSF2 IDH1/2 Mut Mut WT WT P=.007 HR= 2.73 (95%CI: 1.34-5.55) P<.0001 HR= 2.66(95%CI: 1.10-6.47) * Competitive Risk Analysis

  15. A "Molecularly High-Risk" Status Associates with Reduced Overall Survival P<0.0001 • EZH2 • ASXL1 • SRSF2 • IDH1/2 Low Risk High Risk HR= 2.29 (95%CI: 1.65-3.19) • In the “molecularly high-risk” category, overall survival was 81 months (range: 61.9-99.5) compared with 148 months (range: 52.5-243.2) in the “molecularly low-risk” category (P<0.0001). Mutivariate analysis. Vannucchi AM et al, ASH2012

  16. The "Molecularly High-Risk" Status Contributes to Refined IPSS Categorization IPSS (LOW-INT1) IPSS (INT2-HIGH) P= 0.017 P= 0.002 Low Risk Low Risk High Risk High Risk

  17. A "Molecularly High-Risk" Status Associates With Leukemia Transformation High Risk • EZH2 • ASXL1 • SRSF2 • IDH1/2 Low Risk P<0.0001 HR 2.96 (95%CI:1.85-4.76) • In the “molecularly high-risk” category, leukemia-free survival was 129 months (range: 90-168) compared with 323 months (range: 194-452) in the “molecularly low-risk” category (P<0.0001) – Competitive risk analysis Vannucchi AM et al, ASH2012

  18. The "Molecularly High-Risk" Status Predicts for Leukemia Risk within IPSS Categories IPSS (LOW-INT1) IPSS (INT2-HIGH) P= 0.001 P= 0.01 High Risk’ High Risk Low Risk Low Risk

  19. Figure 5

  20. PEG- IFN in PMFIanotto et al BHJ 2013 • Retrospectivestudy of pegylated-interferon a-2a (Peg-IFNa-2a) therapy in 62 PMF/post-PV/ET MF pts • Mean follow-up was 26 months. Therapy stopped in only 28 pts • 16/25 anaemic pts (64%) achieved a response and transfusion-independence was obtained in 5/13 pts

  21. Efficacy and safety of pegylated‐interferon α‐2a in myelofibrosis: a study by the FIM and GEM French cooperative groups British Journal of Haematology13 JUL 2013 DOI: 10.1111/bjh.12459http://onlinelibrary.wiley.com/doi/10.1111/bjh.12459/full#bjh12459-fig-0001

  22. PEG- IFN in PMFIanotto et al BHJ 2013 • Constitutional symptoms resolved in 82% of patients • 5 leucopenic patients normalized their leucocyte counts • A normal platelet count was obtained in 5/8 thrombocytopenic patients • Splenomegaly was reduced in 46% of patients.

  23. PEG- IFN in PMFIanotto et al BHJ 2013 • Complete resolution of thrombocytosis in 83 %, and of leucocytosis in 69 % of pts • Side effects (mostly haematological) were mainly of grade 1–2. • The only factor independently associated with treatment failure was a spleen enlargement of more than 6 cm below the costal margin

  24. JAK2 - inhibitors

  25. Utveckling av JAK2 hämmarewww.clinicaltrials.gov • 41 studier med ruxolitinib • PV fas III vs HU, klar jan 2014 • Akut leukemi, KML, myelom, DLBCL, HD, perifert T, MDS • Psoriasis och RA • Solida tumörer; prostata, bröst, pancreas

  26. Utveckling av JAK2 hämmare • SAR302503 • 11 studier, fas III avslutad • Förutom PMF även PV/ET och solida tumörer • Pacritinib (tidigare SB1518) • Fas III vs best availabletherapy pågår • Momelotinib • Start FAS III vs ruxolitinib start vilken dag som helst

  27. Studier vid myelofibros –tämligen uniforma patientgrupper • INT-2 eller HR • Tidigare behandlade patienter • PMF eller post-PV/ET fibros • Mjälte 5 cm under arcus • TPK > 100 (ruxo), > 50 (övriga) • Perifera blaster < 10 %

  28. A Phase II randomized dose-ranging study of the JAK2-selective inhibitor SAR302503 in patients with intermediate-2 or high-risk primary myelofibrosis (MF), post-polycythemia vera MF, or post-essential thrombocythemia MF Moshe Talpaz, MD, Catriona Jamieson, MD, PhD, Nashat Y Gabrail, MD, Claudia Lebedinsky, MD, Frank Neumann, MD, Guozhi Gao, PhD, Feng Liu, PhD, Ayalew Tefferi, MD and Animesh Pardanani, MBBS, PhD Presented at the 54th Annual American Society of Hematology Meeting and Exposition December 8-11, 2012, Atlanta, GA

  29. ARD11936 Study design

  30. Change in spleen volume at end of cycle 3 by MRI • The mean percent reduction from baseline in spleen volume at the end of cycle 3 ranged from 30.1% in the 300 mg group to 41.8% in the 500 mg group. • Spleen response (≥ 35% reduction in volume) in the highest dose cohort (500 mg) was 63.6%.

  31. The proportion of patients who achieved ≥50% reduction in MPN-SAF score was similar in all dose groups. In all dose groups, patients with constitutional symptoms at baseline reported improvements in symptoms. Of the systemic symptoms, night sweats and itching showed the greatest improvement. Symptom reduction at the end of cycle 3 by the MPN-SAF in patients with symptoms present at baselinea

  32. The most common nonhematological AEs were gastrointestinal (diarrhea, nausea, vomiting). Most common non-hematologic adverse eventsa

  33. Gastrointestinal adverse events by treatment cycle • Rates of gastrointestinal adverse events decreased over time and at the time of this analysis had not lead to permanent treatment discontinuation. A similar trend was observed for nausea.

  34. Anemia was the most common hematologic toxicity. Grade 3/4 thrombocytopenia was minimal. aData available for 9 patients in the 300 mg group Laboratoryabnormalities

  35. JAKARTA study outline

  36. Phase III Registration Trials COMFORT I Primary Endpoint Number of subjects achieving ≥ 35% reduction in spleen volume from baseline to week 24* COMFORT II Primary Endpoint Number of subjects achieving ≥ 35% reduction in spleen volume from baseline to week 48* COMFORT I INC424 (oral) 15 mg BID or 20 mg BID Patients with MF (N = 309) Randomized 1:1 Placebo (oral) BID USA, Canada, Australia COMFORT II INC424 (oral) 15 mg BID or 20 mg BID Patients with MF (N = 219) Randomized 2:1 Best available therapy EUROPE: Austria, Belgium, France, Germany, Italy, Netherlands, Spain, Sweden, UK Both trials published NEJM March 1 2012 * As measured by MRI (or CT scan in applicable subjects).

  37. Original ArticleA Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis Srdan Verstovsek, M.D., Ph.D., Ruben A. Mesa, M.D., Jason Gotlib, M.D., Richard S. Levy, M.D., Vikas Gupta, M.D., John F. DiPersio, M.D., Ph.D., John V. Catalano, M.D., Michael Deininger, M.D., Ph.D., Carole Miller, M.D., Richard T. Silver, M.D., Moshe Talpaz, M.D., Elliott F. Winton, M.D., Jimmie H. Harvey, Jr., M.D., Murat O. Arcasoy, M.D., Elizabeth Hexner, M.D., Roger M. Lyons, M.D., Ronald Paquette, M.D., Azra Raza, M.D., Kris Vaddi, Ph.D., Susan Erickson-Viitanen, Ph.D., Iphigenia L. Koumenis, M.S., William Sun, Ph.D., Victor Sandor, M.D., and Hagop M. Kantarjian, M.D. N Engl J Med Volume 366(9):799-807 March 1, 2012

  38. Comfort I Primary Endpoint Response>35% Spleen Reduction by MRI P < 0.0001 Odds ratio (95% CI) 134.4 (17.97, 1005) Ruxolitinib (n = 155) Placebo (n = 153) • Patients who discontinued prior to week 24 or crossed over prior to week 24 were counted as non-responders 39 Verstovsek et. al. EHA 2011 (a505) Presidential Symposium Saturday

  39. Patient Global Impression of Change at Week 24  Ruxolitinib  Placebo n=48 n=45 n=32 n=22 n=28 n=20 n=15 n=10 n=6 n=7 n=6 n=4 n=2 n=1

  40. Comfort I Symptom ResponseIndividual Symptom Scores • For all individual symptoms above, comparisons between ruxolitinib- and placebo-treated groups were highly statistically significant (P < 0.01) 41 Mesa et. al. EHA 2011 (a912) Poster Saturday

  41. Long-Term Outcome of Ruxolitinib Treatment in Patients With Myelofibrosis: Durable Reductions in Spleen Volume, Improvements in Quality of Life, and Overall Survival Advantage in COMFORT-I Srdan Verstovsek1, Ruben A. Mesa2, Jason Gotlib3, Richard S. Levy, Vikas Gupta5, John F. DiPersio6, John V. Catalano7, Michael W.N. Deininger8*, Carole B. Miller9, Richard T. Silver10, Moshe Talpaz11, Elliott F. Winton12, Jimmie H. Harvey Jr.13, Murat O. Arcasoy14, Elizabeth O. Hexner15, Roger M. Lyons16, Ronald Paquette17, Azra Raza18, Kris Vaddi4, Susan Erickson-Viitanen4, William Sun4, Victor Sandor4 and Hagop M. Kantarjian11University of Texas MD Anderson Cancer Center, Houston, TX; 2Mayo Clinic, Scottsdale, AZ; 3Stanford Cancer Institute, Stanford, CA; 4Incyte Corporation, Wilmington, DE; 5Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada; 6Washington University School of Medicine, St. Louis, MO; 7Frankston Hospital and Department of Clinical Haematology, Monash University, Frankston, Australia; 8Oregon Health & Science University, Portland, OR; 9Saint Agnes Cancer Institute, Baltimore, MD; 10Weill Cornell Medical Center, New York, NY; 11University of Michigan, Comprehensive Cancer Center, Ann Arbor, MI;12Emory University School of Medicine, Atlanta, GA; 13Birmingham Hematology and Oncology, Birmingham, AL; 14Duke University Health System, Durham, NC; 15Abramson Cancer Center at The University of Pennsylvania, Philadelphia, PA; 16Cancer Care Centers of South Texas/US Oncology, San Antonio, TX; 17UCLA Division of Hematology/Oncology, Los Angeles, CA; 18Columbia Presbyterian Medical Center, New York, NY*Currently at Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT

  42. Patient Disposition at Current Analysis • All patients receiving placebo at the primary analysis crossed over or discontinued within 3 months of the primary analysis • Median time to crossover: 41.1 weeks

  43. Durability of Spleen Volume Reduction 1.0 ≥10% reduction (n=90) 0.8 0.6 Probability ≥35% reduction 0.4 0.2 0 0 8 16 24 32 40 48 72 80 88 104 112 64 96 56 Weeks from Onset No. at risk 90 84 75 72 63 57 52 47 43 41 35 4 4 4 • 90/155 (58%) had a 35% reduction at any time point during the study • 64% maintained a ≥35% reduction for at least 2 years ≥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.

  44. Overall Survival: ITT Population 1.0 0.8 Ruxolitinib Placebo 0.6 HR=0.58 (95% CI: 0.36, 0.95); P=0.028 Survival Probability No. of deaths: Ruxolitinib=27; Placebo=41 0.4 Median follow up: 102 weeks 0.2 Age adjusted HR*=0.61 (95% CI: 0.37, 0.99); P=0.040 0 0 12 24 36 48 60 72 84 96 108 120 132 Weeks No. at risk Ruxolitinib 155 154 148 145 136 125 121 113 96 44 6 Placebo 154 148 142 133 117 111 102 95 74 32 7 Note: For this unplanned analysis, P-values are descriptive and nominally significant. *Age was the only baseline characteristic that differed significantly between treatment groups as reported in Verstovsek S, et al. N Engl J Med 2012;366:799-807 (median age: ruxolitinib, 66 years; placebo, 70 years; P<0.05).

  45. Overall Survival by JAK2V617F Mutation Status JAK2V617F-Positive JAK2V617F-Negative 1.0 1.0 0.8 0.6 Survival Probability 0.8 HR=0.65 (95% CI: 0.26, 1.63) 0.4 0.2 Ruxolitinib (n=40) 0.6 Placebo (n=27) 0 0 12 24 36 48 60 72 108 120 132 96 84 Survival Probability Weeks HR=0.54 (95% CI: 0.30, 0.98) 0.4 0.2 Ruxolitinib (n=113) Placebo (n=123) 0 0 12 24 36 48 60 72 108 120 132 96 84 Weeks

  46. Non-hematologic Adverse Events Observed in at Least 10% of Ruxolitinib-Treated Patients

  47. Original ArticleJAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis Claire Harrison, D.M., Jean-Jacques Kiladjian, M.D., Ph.D., Haifa Kathrin Al-Ali, M.D., Heinz Gisslinger, M.D., Roger Waltzman, M.D., M.B.A., Viktoriya Stalbovskaya, Ph.D., Mari McQuitty, R.N., M.P.H., Deborah S. Hunter, Ph.D., Richard Levy, M.D., Laurent Knoops, M.D., Ph.D., Francisco Cervantes, M.D., Ph.D., Alessandro M. Vannucchi, M.D., Tiziano Barbui, M.D., and Giovanni Barosi, M.D. N Engl J Med Volume 366(9):787-798 March 1, 2012

  48. Patient Treatments on BAT Arm 49 (67%) patients received one or more BAT medications 24 (33%) patients received no medication

  49. COMFORT-II Efficacy Results (ITT) Primary Endpoint Key Secondary Endpoint Ruxolitinib 95% CI: 24.4, 40.2 P < .0001 Ruxolitinib 95% CI: 21.3, 36.6 P < .0001 28.5% n = 41 31.9% n = 46 % With ≥ 35% spleen volume reduction % With ≥ 35% spleen volume reduction BAT 95% CI: 0.0, 5.0 BAT 95% CI: 0.0, 5.0 0 0 Ruxolitinib BAT Ruxolitinib BAT • Median time to response, 12.29 weeks • Of the 69 patients who achieved ≥ 35% reduction in spleen volume at any time during the study, 44 (64%) did so at the first assessment (at 12 weeks) Week 48 Week 24

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