New Therapies for MPNs

Transcription

1 Pomalidomide and IMIDS in Myelofibrosis New Therapies for MPNs Fourth International Workshop on CML and MPN Natchez Louisiana Ruben A. Mesa, MD Professor of Medicine Mayo Clinic College of Medicine Director of Myeloid Research Scottsdale Arizona

2 Pomalidomide and IMIDS in MF Anemia in MF IMIDs and MF Pomalidomide Next Steps

3 Myelofibrosis Cell Balance Ineffective Production Splenic Sequestration Medications Alloimmunization Bleeding Other Myeloproliferation Transfusions EPO

4 Goals with Treating MPNs Decrease Thrombosis Anemia Anemia & Spleen Improve Sx Spleen Decrease Allele Burden? How significant is anemia in MF? Cure Delay MPN-BP Does improving anemia in MF matter? Quality of Prolong life? Fatigue? Survival Impact on natural history? Delay MF Palliative Goals Disease Altering Goals

5 A New Prognostic Scoring System for Primary Myelofibrosis Based on a Study of the International Working Group for Myelofibrosis Research and Treatment Prognostic variable Hazard ratio 95 % CI p Age > 65 yrs < Const. symptoms < Hb < 10 g/dl < WBC > 25 x 10 9 /L < Blood blasts 1% < Patients with all variables available: n= 1,001 Cervantes et al. Blood 2008;112(11):a657

6 Dynamic International Prognostic Scoring System: Variables and Risk Groups (overall series) Passamonti et al., Blood 2010

7 Symptoms in 1179 MPD Patients 100% 80% ET (n=304) PV (n=405) MMM (n=456) 60% 40% 20% 0% Weight Loss Bone Pain Night Sweats Pruritus Fatigue Mesa et. al. Cancer 2007;109:68-76

8 Current Medications for MF Medicines for MF Anemia Androgens EPO IMIDs Thalidomide Lenalidomide Pomalidomide

9 Pomalidomide and IMIDS in MF Anemia in MF IMIDs and MF Pomalidomide Next Steps

10 Thalidomide Combinations Reference N Thal (Alone) Barosi/ Various + Pred Mesa/ Tefferi +Pred +ETA N Mesa/ Tefferi +Pred +EPO Bourantas Many Pred +CTX Mesa/ Tefferi Anemia 29% 62% 55% 100% 11% Platelets 38% 75% 71% 100% 10% Splenomegaly 41% 19% 33% 20% 0%

11 Responses-Lenalidomide in MF GR 3-4 Neutropenia 31% ; GR 3-4 PLTs 19% Tefferi et. al. Blood 2006;108:

12 Figure 1. Bone marrow histology (hematoxylin-eosin as well as reticulin stain) before and after treatment with lenalidomide in 2 patients with myelofibrosis with myeloid metaplasia who achieved major anemia response as well as resolution of peripheral-blood leukoerythroblastosis Tefferi, A. et al. Blood 2006;108: Copyright 2006 American Society of Hematology. Copyright restrictions may apply.

13 40 Patients with MF Len (10mg/day) 3 Month Pred Taper IWG-MRT Response in 12 (30%) (3/12 with PR) Evidence of response in JAK2 Allele burden, fibrosis Quintas-Cardama et. al. JCO 2009;;27:

14 E4903: Patient Distributions and Outcomes Enrollment (N=48) Ineligible N=6 Hemoglobin >10g/dL (N=2) Registration issues (N=2) Thrombocytopenia (N=1) Concurrent Therapy (N=1) Eligible (N=42) Premature Discontinuation <3 Months (N=7) Evaluation at 3 Months (N=35) Lenalidomide 10mg/day Plus Prednisone Taper through 3 Cycles Premature Discontinuation 3-6 Months (N=10) Evaluation at 6 Months (N=25) Lenalidomide 10mg/day Cycles 4-6 No response at 6 Months (N=15) IWG-MRT Response Overall (N=10; 24%) Anemia Alone (N=6) Spleen Alone (N=2) Both (N=2) Mesa et. al. 2010

15 Mesa et. al. 2010

16 Pomalidomide and IMIDS in MF Anemia in MF IMIDs and MF Pomalidomide Next Steps

17 Pomalidomide and IMIDS in MF Cytopenias and goals of therapy in MF Thalidomide Lenalidomide Pomalidomide Unment need for cytopenias responses in MF Next Steps

18 Thalidomide Lenalidomide Pomalidomide Additional amino group at phthaloyl ring of thalidomide makes CC-4047 Comparative IC 50 for TNF- from LPS stimulate PBMCs Thalidomide 194 m CC nM? Increased activity against other myelofibrosis cytokines VEGF, IL-6, bfgf

19 POM In MF POM (2 mg) POM (2 mg) + prednisone Eligible POM (0.5 mg) + prednisone Prednisone Tefferi et. al. JCO 2009;27:

20 Tefferi et. al. JCO 2009;27: Year update ASH 2009: Passamonti et. al. Abstract 1904 Overall 16/63 (25%) patients receiving POM responded for anemia at a median of 1.8 months 10/16 remained on POM a median of 1.8 years after beginning therapy Minimal splenomegaly response, and anemia response may persist even with spleen enlargement No major effect on fibrosis or JAK2 Allele burden

21 Tefferi et. al. 2009;27:

22 What would be the impact of dose escalation? Mesa et. al. AJH 2010;85(2): patients (9 eval) at 3.0 mg 12 on PHII 2/9 with (22%) anemia response 0/9 spleen response 3 at 2.5mg Days % Gr 3 Neutropenia Thalidomide 3 at 3.0 mg Days 1-21 Lenalidomide 3 at 3.5 mg Days 1-21 DLT 2/3 Myelosuppression Days 1-21 Pomalidomide

23 Dose Escalation Results Mesa et. al. AJH 2010;;85(2):

24 IMIDs in MF HB PLT SPLN REF THAL 29% 38% 41% Barosi 2002 THAL-PRED 62% 75% 19% Mesa 2002 LEN 22% 50% 33% Tefferi 2006 LEN-PRED 19%? 9% Mesa 2010 LEN-PRED 30%? 42% POM (0.5mg/day) 42% Quintas-Cardama 2009 >50%? <25% Mesa 2010 POM+/ +/-PRED 30-40% 40% <10% Tefferi 2008

25 Pomalidomide and IMIDS in MF Anemia in MF IMIDs and MF Pomalidomide Next Steps

26 Major Agents in Development for MF JAK2 Inhibitors Other Targets Clinical Phase of Testing

27 Improvement in Hemoglobin with Concomitant Resolution of Splenomegaly in a Patient on LBH initial visit cycle 1 cycle 2 cycle 3 cycle 4 cycle 5 cycle 6 cycle 7 cycle 8 cycle % Reduction in Spleen Size Mascarenhas et. al. ASH 2009:a308

28 Next Steps Thal still active, but neuropathy almost universal over time Subsets (del5(q) especially with Len (+/- pred) responses POM Phase III trial in MF as single agent IMID (?POM) combinations trials with other active agents in MF such as JAK2 Inhibitors

29 Mayo Clinic Generations of MPD Focus Dr. Silverstein Dr. Petit Dr. Solberg Dr. Camoriano Dr. Rivera Dr. MorenoAspitia Minnesota Dr. Hanson Dr. Li FL Arizona Dr. Slack