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Update in Myeloproliferative Neoplasms

Update in Myeloproliferative Neoplasms. January 20, 2012. November 16, 2011. FDA Indications for Ruxolitinib ( Jakafi ). Intermediate or high-risk Myelofibrosis =80-90% of MF patients JAK2V617F NOT required. Diagnostic Criteria for myelofibrosis. Post PV or ET MF. PMF.

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Update in Myeloproliferative Neoplasms

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  1. Update in Myeloproliferative Neoplasms January 20, 2012

  2. November 16, 2011

  3. FDA Indications for Ruxolitinib (Jakafi) Intermediate or high-risk Myelofibrosis =80-90% of MF patients JAK2V617F NOT required

  4. Diagnostic Criteria for myelofibrosis Post PV or ET MF PMF Must meet both major and ≥2 minor criteria Must meet all 3 major and ≥2 minor criteria

  5. JAK2V617F mutation:Not just for MPN anymore 95-97% PV >50% ET 50-60% MF 3-13% CMML 3-5% MDS (RARS & thrombocytosis) <5% AML

  6. Dynamic International Prognostic Scoring System in MF DIPSS Obtained at any time during follow-up 0 = Low 1-2 = Intermediate-1 3-4 = Intermediate-2 5-6 = High Passamonti et al, Blood 2010

  7. DIPSS-plus 3 additional factors **Constitutional symptoms constitute weight loss > 10% of baseline value in the year preceding diagnosis, unexplained fever, or excessive sweats persisting for > 1 month ***Unfavorable karyotype constitutes complex karyotype or sole or 2 abnormalities that include +8, −7/7q−, i(17q), inv(3), −5/5q− 12p−, or 11q23 rearrangement Tefferi, Blood 2011

  8. COMFORT-I * Patients randomized to placebo will be eligible to cross over to ruxolitinib • Primary endpoint • Proportion of subjects achieving >35% reduction in spleen volume from baseline to Week 24 as measured by MRI(or CTscan in applicable subjects) • Secondary endpoints • Duration of maintenance of a >35% reduction from baseline in spleen volume among subjects initially randomized to receive INCB018424 • Proportion of subjects with >50% reduction in total symptom score from baseline to Week 24 as measured by the modified MFSAF v2.0 diary

  9. Percent Change From Baseline in Spleen Volume in Individual Patients at Week 24 Verstovsek, S. Presented at ASCO 2011

  10. Primary Endpoint: % of Patients with ≥35% Decrease in Spleen Volume at Week 24 (ITT) Verstovsek, S. Presented at ASCO 2011

  11. Symptomatic Burden in MF Constitutional Symptoms Splenomegaly Myeloproliferation Functioning Percentage of patients reporting symptoms Scherber et al, Blood 2011

  12. Percent of Patients with ≥50% Decrease in Total Symptom Score at Week 24 (ITT) Verstovsek, S. Presented at ASCO 2011

  13. Proportion of Patients with ≥50% Reduction in Total Symptom Score Over Time Verstovsek, S. Presented at ASCO 2011

  14. Percent Change From Baseline in Total Symptom Score in Individual Patients at Week 24 Verstovsek, S. Presented at ASCO 2011

  15. Mean Percent Change in Individual Symptoms Verstovsek, S. Presented at ASCO 2011

  16. Symptoms Return without drug

  17. Increased serum cytokines in MPN MPN patients Mouse Model CD40 IFN-α IL-2R IL-11 VCAM-1 IL-2 IL-9 MIP-1α ICAM-1 MMP-2 MIP-1β IL-8 IL-7 MMP-10 IL-12 TNF IL-18 IL-13 IL-15 VEGF KC IL-10 IL-16 IL-1α,ß IL-6 G-CSF TIMP-1 IFN-γ Lower in MPN (Tyner et al, 2010) (Verstovsek et al, 2010 Slezak et al, 2009, Boissinot et al, 2010, Tefferi et al 2011)

  18. TNF is elevated in MPN and correlates with JAK2V617F allele burden Fleischman et al, Blood 2011

  19. Elevated IL-8 and IL-2R associated with decreased survival in PMF Intermediate-1 All patients Intermediate-2 Tefferi et al, JCO 2011

  20. Consequences of Increased Inflammation HSC exhaustion Stress hematopoiesis Constitutional Symptoms -weight loss -fatigue -fever

  21. Impact of Ruxolitinib on inflammatory cytokines Verstovsek et al, NEJM 2010

  22. Ruxolitinib decreases inflammatory cytokines Verstovsek et al, NEJM 2010

  23. JAK inhibitors: not just for MPN

  24. Hematology Laboratory Values *Patients are included at their worst on study grade regardless of whether this represents a change from their baseline • Grade 3 and 4 anemia and thrombocytopenia were more common in those with • higher baseline grade • Discontinuation of treatment because of anemia and thrombocytopenia was rare • (1 patient in each treatment group for each event Verstovsek, S. Presented at ASCO 2011

  25. Non-hematologic Adverse Events Observed in at Least 10% of Ruxolitinib-Treated Patients Verstovsek, S. Presented at ASCO 2011

  26. Mean hemoglobin and Red Blood Cell Products Over Time Verstovsek, S. Presented at ASCO 2011

  27. Red Blood Cell Transfusions Verstovsek, S. Presented at ASCO 2011

  28. JAK2V617F allele burden Percentage of JAK2V617F mutant allele can be quantitatively measured (available at OHSU), but clinical relevance is unknown

  29. Low JAK2V617F allele burden in PMF has negative impact

  30. Low V617Fallele burden associated with shorter survival in PMF Guglielmelli et al, Blood 2009

  31. Causes of Death in PMF Cervantes et al, Blood 2009.

  32. COMFORT-I Overall Survival* * COMFORT-I was not designed nor powered to demonstrate a statistically significant difference in overall survival within the timeframe of the study endpoint. Patients who remain in COMFORT-I continue to be followed. Incyte, JP Morgan Healthcare conference Jan 9,2012

  33. Ruxolitinib Dosing For plts 50-100 X 109/L: OHSU currently enrolling for clinical trial of ruxolitinib in thrombocytopenic patients with MF Jakafi prescribing information packet

  34. Dose adjustment for thrombocytopenia Hold Drug for platelets <50 X 109/L Jakafi prescribing information packet

  35. Drug Interactions: Strong CYP3A4 inhibitors will increase levels of ruxolitinib, with strong CYP3A4 inhibitors dose reduction is recommended. Patients should be closely monitored and dose titrated based on safety and efficacy. No dose adjustment is recommended when Jakafi is coadministered with a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy Jakafi prescribing insert

  36. How to prescribe Ruxolitinib http://www.jakafi.com/Files/RUX1066.pdf

  37. Comparing various JAK inhibitors

  38. Clinical trials of non-JAK2 targeted therapies for MPN

  39. Lenalidomide for MF • Mayo Clinic - Blood. 2006 Aug 15;108(4):1158-64. • 68 patients; lenalidomide at 10 mg/d (5 mg/d if baseline platelet count < 100 x 10(9)/L) for 3 to 4 months with a plan to continue treatment for either 3 or 24 additional months, in case of response. Overall response rates were 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia. • MD Anderson - J ClinOncol. 2009 Oct 1;27(28):4760-6. • 40 patients; lenalidomide 10 mg/d (5 mg/d if baseline platelet count < 100 x 10(9)/L) on days 1 through 21 of a 28-day cycle for six cycles with prednisone taper. ORR 30% for anemia and 42% splenomegaly by IWG-MRT criteria. • ECOG Phase 2 (E4903) - Blood. 2010 Nov 25;116(22):4436-8. • 48 patients; lenalidomide 10mg daily + prednisone taper; anemia improved in 19% and splenomegaly in 10% by IWG-MRT criteria.

  40. Pomalidomide +/- prednisone in treatment of anemia in MF Tefferi et al, JCO 2009

  41. Phase II trial of pomalidomide alone in MF • Low dose pomalidomide alone (0.5mg/d) in 58 MF patients with anemia • Response limited to JAK2V617F mutated patients • 24% of V617F+ patients responded in terms of anemia and 9/10 became transfusion independent • Response predicted by basophilia in first month of treatment • 58% of patients with plts ≤ 100K experienced >50% increase in plt count Begna et al, Leukemia 2011

  42. rIFN-α may reverse fibrosis in early PMF Silver et al, Blood 2011

  43. Peg-IFN-alpha2a for PV/ET • Kiladjian et al Blood 2008;112:3065: • 37 patients; 95% had hematologic CR; only 3 stopped tx at 12 months. Decreased JAK2V617F allele burden in 90%. Molecular CR in 7 patients. 90-180 mcg weekly. • Quintas-Cardama et al JCO 2009;27:5418: • 40 PV/39 ET; one prior cytoreductive treatment; 70%/76% hematologic CR; 14%/6% molecular CR. Only 10% of patients discontinued due to toxicity; no grade 4 toxicities; grade 3 were not frequent but included pain, fatigue, dyspnea, and pruritis. Tolerability of PEG-IFN-alpha-2a at 90 mcg weekly was excellent. • Phase III trials comparing Hydroxyurea vs. Pegasys are underway (upfront high risk PV or ET; HU-resistant or refractory).

  44. PEG-IFNα induces hematologic response in PV/ET Start at 90µg/week, with goal of 135µg/week Tolerable dosing Kiladjian et al, Blood 2008

  45. 90µg/wkPEG-IFNα-2a induces molecular response in PV/ET Quintas-Cardama et al, JCO 2009

  46. Toxicities Associated with PEG-IFNα-2a -PEG-IFNα-2a 90µg/week -10% of patients discontinued due to IFN related toxicity Quintas-Cardama et al, JCO 2009

  47. The curative approach: allogenic SCT Obstacles: -Donor availability -High TRM -Advanced patient age -Still ill defined morbidity -Comorbidities -Impact of cGVHD 1Guardiola et al, Blood 1999. 2Deeg et al, Blood 2003. 3Alchalby et at, Blood 2010. 4Rondelli, ASH 2011 Abst 1750.

  48. Treatment Algorithm for myelofibrosis DIPSS/DIPSS-plus Int-2/high Low, Int-1 asymptomatic symptomatic Consider SCT Yes No observation *conventional drug therapy *ruxolitinib MyA 45-50y RI 45-65 refractory Investigational drug therapy

  49. Treatment of Anemia: Conventional Approach -Prednisone -Danazol/Androgens -Erythropoietin stimulating agents (ESA) 15-20% response, Short lived -Thalidomide + Prednisone ≈ 20% response, neurotoxicity -Lenalidomide≈ 20% response, myelosuppression Best in pts with del(5q31) -Splenectomyup to 50-75% response duration≈ 1yr -RBC transfusions

  50. Treatment goals • Prevent thrombosis • Prevent hemorrhage • Alleviate constitutional symptoms • Minimize primary and iatrogenic disease progression • Improve QOL and survival

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