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.
Download ReportTranscript 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.
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 PMF Must meet all 3 major and ≥2 minor criteria Post PV or ET MF Must meet both major and ≥2 minor criteria 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 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 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 COMFORT-I Primary endpoint * Patients randomized to placebo will be eligible to cross over to ruxolitinib • 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 Percent Change From Baseline in Spleen Volume in Individual Patients at Week 24 Verstovsek, S. Presented at ASCO 2011 Primary Endpoint: % of Patients with ≥35% Decrease in Spleen Volume at Week 24 (ITT) Verstovsek, S. Presented at ASCO 2011 Symptomatic Burden in MF Night Sweats Weight Loss Fever 62% Constitutional Symptoms 48% 29% Early Satiety Abdominal Discomfort Cough 75% 72% Splenomegaly 55% Bone Pain Itching 55% 54% Fatigue Inactivity insomnia Myeloproliferation 99% 76% Functioning 74% 0% 20% 40% 60% 80% 100% Percentage of patients reporting symptoms Scherber et al, Blood 2011 Percent of Patients with ≥50% Decrease in Total Symptom Score at Week 24 (ITT) Verstovsek, S. Presented at ASCO 2011 Proportion of Patients with ≥50% Reduction in Total Symptom Score Over Time Verstovsek, S. Presented at ASCO 2011 Percent Change From Baseline in Total Symptom Score in Individual Patients at Week 24 Verstovsek, S. Presented at ASCO 2011 Mean Percent Change in Individual Symptoms Verstovsek, S. Presented at ASCO 2011 Symptoms Return without drug Increased serum cytokines in MPN MPN patients Mouse Model CD40 IL-2R IL-2 IL-9 MIP-1α MIP-1β IL-7 TNF KC MMP-2 ICAM-1 MMP-10 IL-8 IL-13 IL-15 IL-18 VEGF IL-6 (Tyner et al, 2010) IFN-α IL-11 VCAM-1 IL-16 IL-1α,ß TIMP-1 G-CSF IL-12 IL-10 IFN-γ Lower in MPN (Verstovsek et al, 2010 Slezak et al, 2009, Boissinot et al, 2010, Tefferi et al 2011) TNF is elevated in MPN and correlates with JAK2V617F allele burden Fleischman et al, Blood 2011 Elevated IL-8 and IL-2R associated with decreased survival in PMF Intermediate-1 All patients Intermediate-2 Tefferi et al, JCO 2011 Consequences of Increased Inflammation HSC exhaustion Stress hematopoiesis Constitutional Symptoms -weight loss -fatigue -fever Impact of Ruxolitinib on inflammatory cytokines Verstovsek et al, NEJM 2010 Ruxolitinib decreases inflammatory cytokines Verstovsek et al, NEJM 2010 JAK inhibitors: not just for MPN 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 Non-hematologic Adverse Events Observed in at Least 10% of Ruxolitinib-Treated Patients Verstovsek, S. Presented at ASCO 2011 Mean hemoglobin and Red Blood Cell Products Over Time Verstovsek, S. Presented at ASCO 2011 Red Blood Cell Transfusions Verstovsek, S. Presented at ASCO 2011 JAK2V617F allele burden Percentage of JAK2V617F mutant allele can be quantitatively measured (available at OHSU), but clinical relevance is unknown Low JAK2V617F allele burden in PMF has negative impact Low V617Fallele burden associated with shorter survival in PMF Guglielmelli et al, Blood 2009 Causes of Death in PMF 31% Leukemia 19% Progression without leukemia 14% Thrombosis 10% Infection 5% Bleeding Portal Hypertension 4% Secondary Neoplasm 4% 13% Other 0% 5% 10% 15% 20% 25% 30% 35% Cervantes et al, Blood 2009. 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 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 Dose adjustment for thrombocytopenia Hold Drug for platelets <50 X 109/L Jakafi prescribing information packet 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 How to prescribe Ruxolitinib http://www.jakafi.com/Files/RUX1066.pdf Comparing various JAK inhibitors Drug Target Phase Disease Efficacy Toxicity INCB18424 JAK2, JAK1 Approved III MF PV/ET Splenomegaly, symptoms Anemia, thrombocytopenia TG101348, (SAR302503) JAK2, FLT3 II MF Splenomegaly, symptoms Anemia, thrombocytopenia, gastrointestinal SB1518 JAK2, FLT3 II MF Splenomegaly, symptoms Gastrointestinal CEP701 JAK2, FLT3 II MF, PV/ET Splenomegaly, symptoms Gastrointestinal, anemia, thrombocytopenia CYT387 JAK1, JAK2 I MF Splenomegaly, symptoms, anemia First dose effect, cytopenias LY2784544 JAK2 I MF, ET/PV NPR NPR AZD1480 JAK2, JAK3 I/II MF NPR NPR NS018 JAK2 I MF NPR NPR Clinical trials of non-JAK2 targeted therapies for MPN Drug RAD001 Target Phase mTOR Pomalidomide IMiD PEG-IFNa-2a LBH589 Disease Efficacy Toxicity II MF Splenomegaly, symptoms Minimal III MF Biological III HDAC II PV/ET Anemia Erythrocytosis, thrombocytosis, symptoms MF Splenomegaly, anemia Minimal Myelosuppression, depression Anemia, thrombocytopenia, gastrointestinal 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 Clin Oncol. 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):44368. – 48 patients; lenalidomide 10mg daily + prednisone taper; anemia improved in 19% and splenomegaly in 10% by IWGMRT criteria. Pomalidomide +/- prednisone in treatment of anemia in MF Tefferi et al, JCO 2009 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 rIFN-α may reverse fibrosis in early PMF Silver et al, Blood 2011 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). PEG-IFNα induces hematologic response in PV/ET Start at 90µg/week, with goal of 135µg/week Tolerable dosing Kiladjian et al, Blood 2008 90µg/wk PEG-IFNα-2a induces molecular response in PV/ET Quintas-Cardama et al, JCO 2009 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 The curative approach: allogenic SCT Conditioning Myeloablative Reduced-Intensity N Study Donor 551 Retr 42 562 Retr 43 RD=36 URD=20 RD=40 URD=9 1033 Prosp FluBu+AT G 55 RD=33 URD=70 66 Prosp FluMel+/ATG Obstacles: -Donor availability -Advanced patient age -Comorbidities 1Guardiola Median Age 55 RD=32 URD=34 TRM (%) OS 27 47% (5-y) 58% (3-y) 16 67% (5-y) RD=16 URD=33 RD=78% (2-y) URD=44% (1y) -High TRM -Still ill defined morbidity -Impact of cGVHD et al, Blood 1999. 2Deeg et al, Blood 2003. 3Alchalby et at, Blood 2010. 4Rondelli, ASH 2011 Abst 1750. Treatment Algorithm for myelofibrosis DIPSS/DIPSS-plus Int-2/high Low, Int-1 asymptomatic symptomatic Consider SCT Yes No observation *conventional drug therapy *ruxolitinib refractory Investigational drug therapy MyA 45-50y RI 45-65 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 Treatment goals • • • • Prevent thrombosis Prevent hemorrhage Alleviate constitutional symptoms Minimize primary and iatrogenic disease progression • Improve QOL and survival