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Update in Myeloproliferative Neoplasms January 20, 2012.

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Presentation on theme: "Update in Myeloproliferative Neoplasms January 20, 2012."— Presentation transcript:

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 PMF Post PV or ET MF Must meet all 3 major and ≥2 minor criteria Must meet both 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 DIPSS 1-2 = Intermediate = Intermediate = High 0 = Low Passamonti et al, Blood 2010 Dynamic International Prognostic Scoring System in MF Obtained at any time during follow-up

7 DIPSS-plus 3 additional factors Tefferi, Blood 2011 **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

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

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 Percentage of patients reporting symptoms Scherber et al, Blood 2011 Splenomegaly Constitutional Symptoms Myeloproliferation Functioning

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 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) KC CD40 IL-2 IL-7 IL-9 IL-6 VEGF TNF MIP-1β MIP-1α TIMP-1 G-CSF IL-1α,ß IL-18 IL-16 ICAM-1 MMP-10 MMP-2 VCAM-1 IFN-α IL-11 IL-8 Mouse Model MPN patients Increased serum cytokines in MPN IL-10 IL-12 IL-2R IL-13IL-15

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 All patients Intermediate-1 Intermediate-2 Tefferi et al, JCO 2011

20 Consequences of Increased Inflammation Stress hematopoiesis HSC exhaustion 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 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 COMFORT-I Overall Survival*

33 Ruxolitinib Dosing For plts X 10 9 /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 10 9 /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. Jakafi prescribing insert 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

36 How to prescribe Ruxolitinib

37 Comparing various JAK inhibitors DrugTargetPhaseDiseaseEfficacyToxicity INCB18424 JAK2, JAK1 Approved III MF PV/ET Splenomegaly, symptoms Anemia, thrombocytopenia TG101348, (SAR302503) JAK2, FLT3IIMF Splenomegaly, symptoms Anemia, thrombocytopenia, gastrointestinal SB1518 JAK2, FLT3IIMF Splenomegaly, symptoms Gastrointestinal CEP701 JAK2, FLT3IIMF, PV/ET Splenomegaly, symptoms Gastrointestinal, anemia, thrombocytopenia CYT387 JAK1, JAK2IMF Splenomegaly, symptoms, anemia First dose effect, cytopenias LY JAK2IMF, ET/PVNPR AZD1480 JAK2, JAK3I/IIMFNPR NS018 JAK2IMFNPR

38 DrugTargetPhaseDiseaseEfficacyToxicity RAD001mTORIIMF Splenomegaly, symptomsMinimal PomalidomideIMiDIIIMFAnemiaMinimal PEG-IFNa-2aBiologicalIIIPV/ET Erythrocytosis, thrombocytosis, symptoms Myelosuppression, depression LBH589HDACIIMF Splenomegaly, anemia Anemia, thrombocytopenia, gastrointestinal Clinical trials of non-JAK2 targeted therapies for MPN

39 Lenalidomide for MF Mayo Clinic - Blood Aug 15;108(4): –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 Clin Oncol Oct 1;27(28): –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 Nov 25;116(22): –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 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 Kiladjian et al, Blood 2008 Tolerable dosing

45 Quintas-Cardama et al, JCO µg/wk PEG-IFNα-2a induces molecular response in PV/ET

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

47 The curative approach: allogenic SCT ConditioningNStudy Median AgeDonor TRM (%)OS Myeloablative55 1 Retr42 RD=36 URD=202747% (5-y) 56 2 Retr43 RD=40 URD=958% (3-y) Reduced-Intensity103 3 Prosp FluBu+AT G55 RD=33 URD=701667% (5-y) 66 Prosp FluMel+/- ATG55 RD=32 URD=34 RD=16 URD=33 RD=78% (2-y) URD=44% (1y) Obstacles: -Donor availability -High TRM -Advanced patient age -Still ill defined morbidity -Comorbidities -Impact of cGVHD 1 Guardiola et al, Blood Deeg et al, Blood Alchalby et at, Blood Rondelli, ASH 2011 Abst 1750.

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

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) -Splenectomy up 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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