What are myeloproliferative neoplasms??

Transcription

1 Welcome to Master Class for Oncologists Session 3: 2:45 PM - 3:30 PM New York, NY October 24, 2008 Myeloproliferative Neoplasms Speaker: Ayalew Tefferi, MD Professor of Medicine, Mayo Clinic, Rochester, MN, USA Disclosures for Ayalew Tefferi What are myeloproliferative neoplasms?? Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Scientific Advisory Board Celgene, TargeGen, Cytopia, BMS, Merck None None None None Bioreference Laboratories 1. Myeloproliferative disorders in which a clonal marker is not identified 2. A category of myeloid malignancies that consists of,, and CML only 3. A category of myeloid malignancies that were previously known as myeloproliferative disorders 4. Myeloid malignancies that are associated with a JAK2 Presentation includes discussion of the following off-label use of a drug or medical device. Hydroxyurea, interferon-alpha, imatinib mesylate, 2-CdA, busulfan, anagrelide, thalidomide, lenalidomide, prednisone, androgens, erythropoiesis stimulating agents, campath Clonal Origination and Evolution in myeloid malignancies Myeloid Neoplasms First Disease-causing Disease-transforming Acute myeloid leukemia Acquired * Chronic myeloid neoplasms Stem cell pool * * * * * * * * * ** * ** * Myelodysplastic syndrome (MDS) Myeloproliferative neoplasms (s) Polyclonal stem cell compartment Preclinical clonal hematopoiesis Disease 2 BM or PB blasts or t(15;17) t(8;21) Inv(16) Cytopenia Plasma cells Granulocytosis Erythrocytosis Thrombocytosis Monocytosis Eosinophilia Mastocytosis 1

2 2008 WHO classification of chronic myeloid neoplasms 2008 WHO classification of chronic myeloid neoplasms Molecularly-characterized characterized -eos FGFR-1 PDGFRA/B MDS Myeloproliferative Neoplasms MDS/ Molecularly characterized with eosinophilia MDS Cytopenia Dyserythropoiesis Dysgranulopoiesis Dysmegakaryopoiesis Granulocytosis Thrombocytosis Eosinophilia Mastocytosis Erythrocytosis No cytosis Cytosis without dysplasia Cytosis with dysplasia or monocytosis Eosinophilia and PDGFR/FGFR1 Monocytosis MDS/ 2008 WHO classification of chronic myeloid neoplasms Audience Response Question? Which one of the following statements about JAK2 s is inaccurate? Myeloproliferative Neoplasms 1. JAK2 exon 12 is the most frequent in MDS Classic Non-classic MDS/ Molecularly characterized -eos Chronic myelogenous leukemia (CML) Polycythemia vera () Essential thrombocythemia () Primary myelofibrosis () Chronic neutrophilic leukemia (CNL) Chronic eosinophilic leukemia, not otherwise specified (CEL-NOS) Hypereosinophilic syndrome (HES) Systemic mastocytosis (SM), unclassifiable (-U) 2. JAK2 exon 14 (i.e. JAK2V617F) induces like disease in mice 3. JAK2V617F is found in, and but not in secondary polycythemia or reactive thrombocytosis 4. JAK2V617F is not necessarily the initial diseasecausing in myeloproliferative neoplasms JAK2 s 97% V617F and 3% JAK2 exon 12 s 6 V617F and 4% MPL515 s 6 V617F and 8% MPL 515 s NOT FOUND IN SECONDARY POLYCYTHEMIA NOT FOUND IN REACTIVE THROMBOCYTOSIS NOT FOUND IN LYMPHOMA OR MASTATIC CANCER Levine et al. Nat Rev Cancer. 2007;7:673 JAK2V617F and JAK2 exon 12 induce a -like phenotype in mice MPLW515L induces a -like phenotype in mice Wernig et al. Blood 2006;107:4274 Pikman et al. PLoS Med. 2006;3:e270. Scott et al. N Engl J Med. 2007;356:459 2

3 Initial clonogenic event Pardanani et al. Stem Cells 2007;25:2358 Nussenzveig et al. Exp Hematol ;35:32 Audience Response Question? Pikman et al. PLoS Med. 2006;3:e270 Pardanani et al. Blood 2006;108:3472 Other interacting s MPLW515L/K JAK2V617F Allele dose Campbell et al. Blood 2006;108:3548 Tiedt et al. Blood :3931 Germline genetic variation Pardanani et al. Blood 2008;111:2785 What are the initial tests you would order when you suspect, in the modern era? 1. Peripheral blood JAK2V617F analysis and serum erythropoietin level 2. Bone marrow JAK2V617F analysis and serum erythropoietin level 3. Red cell mass measurement and JAK2V617F analysis 4. Red cell mass measurement, JAK2V617F analysis and serum erythropoietin level Erythrocytosis MDS Thrombocytosis,, or CML Splenomegaly from extramedullary hematopoiesis 2008 WHO classification of Chronic myeloid neoplasms Molecularly characterized with eosinophilia,, or CML Leukocytosis CML,, or Clinical manifestations of myeloproliferative neoplasms /MDS Bone marrow myeloproliferation Myelofibrosis Osteosclerosis Angiogenesis, or CML Anemia or CML Thrombocytopenia Cachexia CMML JMML acml MDS/-U e.g. RARS-T BCR-ABL JAK2 V617F CML JAK2 Exon 12 MPL W515 Classic Non-classic CNL CEL/HES SM -U KIT D816V PDGFRA PDGFRB FGFR1 CML Suspected Audience Response Question? Peripheral blood BCR-ABL screen (+) CML (+) V617F Epo Peripheral blood V617F and Epo screen (-) V617F Epo not (-) V617F Epo Not Screen for JAK2 exon 12 Confirms Rules out CML Possibilities include, and MDS/ Peripheral blood V617F screen (+) (-) Bone marrow exam with V617F screen and cytogenetics (+) V617F or 13q- anomaly (-) V617F Possibilities include: CML Other MDS MDS/ 32 y/o woman with ; asymptomatic and no history of thrombosis; platelet count 1.6 million; ristocetin co-factor activity 5; wants to be pregnant. How would you manage? 1. Interferon alfa only 2. Interferon alfa plus aspirin 3. Aspirin only 4. Hydroxyurea and aspirin Does not rule out Possibilities include, CML, and MDS/ 3

4 Non-life life-threatening complications in and Life-threatening complications in and Microvascular symptoms in / include erythromelalgia, headache, e, and transient visual disturbances Aspirin 81 mg PO daily AML risk MF risk 10-yr 20-yr 10-yr <2% <8% <5% <5% <15% <1 thrombosis risk At diagnosis 22% At follow-up 36% thrombosis risk At diagnosis 23% At follow-up 29% 20-yr <2 <3 Thrombosis Blastic transformation Pruritus Paroxetine Paroxetine 20 mg/daily in in case of no response, try IFN-α 3 million units SC TIW Recurrent miscarriages Aspirin therapy may reduce risk Constitutional symptoms Cytoreductive therapy in the presence of marked splenomegaly Fibrotic transformation Risk stratification for thrombosis in and 100 Randomized study in high-risk Hydroxyurea Low-risk High-risk Age < 60 years and No history of thrombosis and Platelet count < 1 million Age 60 years or Previous thrombosis Thrombosis risk is not significantly increased compared to controls* Thrombosis risk is significantly increased Thrombosis- free survival n=56 Controls n=58 Low-risk with extreme thrombocytosis Platelet count 1 million/µl Thrombosis risk might be lower??? *Presence of cardiovascular risk factors does not appear to accentuate thrombosis risk 20 0 Finazzi et al: BJH 110:577, 2000 P= Years Carobbio et al. Blood, Jun 2008; doi: /blood Does cytoreduction reduce the risk of thrombosis or bleeding in low-risk associated with extreme thrombocytosis? A retrospective study of 99 consecutive low-risk patients with platelet count of 1000 x 10 9 /L All patients (n=99) Treated (n=75) Not treated (n=24) P value Major thrombosis 21 (21%) 18 (24%) 3 (13%) 0.23 Harrison et al. NEJM 2005;353:33 median f/u 39 months HU was better in terms of arterial thrombosis, serious hemorrhage, e, fibrotic transformation and treatment tolerance. Major bleeding Aspirin use 7 (7%) 46 (46%) 6 (8%) 33 (44%) 1 (4%) 13 (54%) Anagrelide was better in venous thrombosis. No difference in leukemic transformation Tefferi et al. Blood, Oct 2006; 108:

5 vwf Multimer Analysis Treatment Algorithm in Risk Phlebotomy Aspirin Cytoreduction Low Yes Yes No Acquired VWS High Yes Yes Yes** Type 2 M,N or patients with platelet counts over 1 million might display acquired VWS Low with extreme thrombocytosis Yes Yes* No *After ruling out clinically significant VWS (ristocetin co-factor activity < 3) **At present, my drug of choice is hydroxyurea except in case or childbearing women where I prefer IFN-alpha Low-risk: no history of thrombosis and age < 60 years and Plt. ct. < 1 million High-risk: history of thrombosis or age 60 years Low-risk with extreme thrombocytosis: Neither low- nor high-risk CP Treatment Algorithm in Risk Phlebotomy Aspirin Cytoreduction Thrombosis risk (%) 1yr 2 yr 11 yr Phlebotomy HU Low Yes Yes No High Yes Yes Yes** Low with extreme thrombocytosis Yes Yes* No *After ruling out clinically significant VWS (ristocetin co-factor activity < 3) **At present, my drug of choice is hydroxyurea except in case or childbearing women where I prefer IFN-alpha Low-risk: no history of thrombosis and age < 60 years and Plt. ct. < 1 million High-risk: history of thrombosis or age 60 years Low-risk with extreme thrombocytosis: Neither low- nor high-risk CP Cumulative survival Phlebotomy Chlorambucil P-32 Total Breslow X 2 = P= Logrank X 2 = P= Weeks Berk, PD. Et al. In: Wasserman LR. Et al. Polycythemia Vera and., WB Saunders, 1995, pp166 Events Efficacy and Safety of Low Dose Aspirin In Landolfi et al. Multicenter European study. NEJM 2004;350: patients mean f/u 3 years more smokers in the ASA arm ASA 100 mg enteric-coated coated Overall mortality not different NS reduction in major thrombosis Major bleeding episodes not different Non-fatal arterial thrombosis and cardiovascular deaths p=0.08 Non-fatal arterial and venous thrombosis and cardiovascular deaths p=0.02 Percent Mayo Clinic series of 322 patients followed for a median of years Number at Risk Observed Expected Survival Median survival 18.9 years Older age and leukocytosis predicted poor survival Thrombosis history predicted recurrent thrombosis Leukemia risk not influenced by hydroxyurea JAK2V617F status was prognostically irrelevant Wolanskyj et al. Mayo Clin Proc. 2006;81:159 Years from date of diagnosis 5

6 Modern Natural History of 396 patients followed for a median of 9.5 years Passamonti et al. Am J Med 2004;117:755 So what is the role of IFN-α or JAK2 inhibitor treatment for or? Low-risk patients without leukocytosis or anemia have a near-normal life expectancy with indolent clinical course and very low risk of thrombosis. I do not recommend that such patients be considered for either IFN-α or JAK2 inhibitor clinical trials. Median survival 20 years Survival is inferior to controls 15-year leukemia risk = 7% 15-year myelofibrosis risk = 6% 15-year thrombosis risk = 27% Leukemia risk not influenced by hydroxyurea High-risk patients are currently well managed with hydroxyurea and aspirin. A major phase III trial is needed to show new drug advantage over this inexpensive and relatively well tolerated drug. I do not recommend that such patients be considered for JAK2 inhibitor clinical trials. One has to first demonstrate long-term safety as well as potential for inducing molecular remission. High-risk patients who do not tolerate hydroxyurea or are refractory to it. OK to use IFN here but equally OK to use pipobroman (in Europe) or busulfan. Kiladjian et al. Pegylated Interferon-alfa-2a induces complete hematological and molecular responses with low toxicity in Polycythemia Vera Blood First Edition Paper, prepublished online July 23, 2008; DOI /blood Audience Response System? Clinical course in based on 311 consecutive patients from Mayo followed for a median of 27 months; range (Tefferi Tefferi et al. Unpublished) 71% required some form of treatment 42 y/o man with ; asymptomatic; spleen is palpable 10 cm below the costal margin; counts are normal. How would you manage? 41% have died 1. Observe only 2. Take the spleen out 3. Consider experimental therapy with JAK2 inhibitor 4. Consider RIC transplant 18% were splenectomized 9% developed AML 2 10-year risk Management of Myelofibrosis Transplant options Myeloablative Reduced-intensity Non-transplant options Treatment for anemia Erythropoietin Corticosteroids Androgen + Prednisone Danazol Thalidomide + Prednisone Lenalidomide Treatment for splenomegaly Hydroxyurea Splenectomy Treatment for extramedullary hematopoiesis Low-dose irradiation Supportive care ASH 2007 Abstract # 683 Dose-Reduced Conditioning Followed by Allogeneic Stem Cell Transplantation in Patients with Myelofibrosis. Results from a Multicenter Prospective Trial of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) Nicolaus Kroeger et al. Prospective multicenter trial; 104 pts; med. age 55 (32-68); unrelated 71 Busulfan (10 mg/kg orally or 8mg/kg i.v), fludarabine (180 mg/m2) and ATG (30 60 mg/kg) Low risk with constitutional symptoms (18%) or intermediate risk (n= 58%) and high risk (n=19%) Everybody but one engrafted in approximately 20 days Treatment mortality at 1 year 19%; 27% if exclude low-risk; GVHD 32% Relapse at 3 years 29%; 3-year OS 7; EFS 55% 6

7 Prognosis in Primary Myelofibrosis N=319 MF conventional treatment survival Hgb 10 g/dl or above Plt 100k or above WBC < 30k and > 4k Monocytes < 1k Mayo Low-risk (n=152) Median survival 134 months Intermediate-risk (n=96) Median survival 50 months High-risk (n=71) Anemia Lenalidomide 10 mg/day is 5q- present Thalidomide 50 mg/day Fluoxymesterone 10 mg po bid Prednisone 0.5 mg/kg/day Symptomatic splenomegaly Hydroxyurea 500 mg po tid Splenectomy Involved field irradiation Other chemotherapy months Median survival 29 months Low-risk vs. High-risk P< Hazard ratio 0.15 (CI ) Intermediate-risk vs. High-risk P= Hazard ratio 0.43 (CI ) Danazol 400 mg po bid * Erythropoietin 40,000 U SC weekly* Tefferi et al. Cancer 109:2083-8, 8, 2007 MF treatment algorithm Audience Response Question? Yes Lenalidomide Observation Asymptomatic Is 5q- present? No What is the prognostic score? Favorable Symptomatic Experimental therapy Vs. Anemia thal/pred Splenomegaly HU Unfavorable 45 < 45 RIC Myeloablative transplant So what is new in the treatment of? 1. JAK2 inhibitors and nothing else 2. Imatinib mesylate 3. Hypomethylating agents 4. All of the above 5. None of the above Janus Kinases (JAK1, JAK2, JAK3, TYK2) are among over 90 tyrosine kinases in humans Anti-JAK2 drug therapy ATP Binding Pocket Levine et al. Nat Rev Cancer. 2007;7:673 V617F Mutation 7

8 Compound Anti-JAK2 ATP mimetics Primary Target JAK2 IC 50 (nm) JAK Family Selectivity Profile (X-fold selectivity) JAK2 vs. JAK3 JAK2 vs. JAK1 JAK2 vs. TYK2 ASCO 2008 Abstract No: 7004 Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 7004) A phase I/II study of INCB018424, an oral, selective JAK inhibitor, in patients with primary myelofibrosis () and post polycythemia vera/essential thrombocythemia myelofibrosis (Post-/ MF) Verstovsek et al. 1Leukemia Department, M.D. Anderson Cancer Center, Houston, TX, 2Mayo Clinic, Rochester, MN 3Incyte Corporation, Wilmington, DE TG nM 332x 35x 135x INCB BID Dosing INCB Once Daily Dosing XL019 2nM 125x 65x 170x INCB nM 72x 0.6x 4x 10 mg BID 25 mg BID 50 mg BID 25 mg QD 50 mg QD 100 mg QD N=6 N=22 N=6 200 mg QD N=3 CEP-701 1nM 3x?x?x N=12 N=27 Maintenance Expansion Switch N=5 N=7 N=5 Over 100 patients enrolled as of today Data presented on 39 patients on the 10 or 25 mg BID doses 44 Improvement in Constitutional Symptoms-1 25 mg BID 10 mg BID Responder Analysis-Spleen or Liver Size MFSAF Score (Maximum = 10) Baseline N=14 1 Mo 3 Mo Baseline N=10 1 Mo 3 Mo Baseline N=7 1 Mo 3 Mo N=11 N=8 N=8 10 baseline 10 1 mo Baseline 1 Mo Baseline 1 Mo Fatigue Night Sweats Pruritis Proportion of Subjects mg BID 10 mg BID N=24 N=12 % Reduction in Spleen or Liver 0-25% >25-49% 5 or More Includes only patients with assessment for all time points INCB Treatment (25 mg BID) : Other Aspects of Myelofibrosis Bone Marrow No significant changes in fibrosis or cellularity No significant change in blasts Aberrant cytokine production Acquired stem cell (s) Clonal myeloproliferation Stromal reaction and tissue injury Altered bone marrow microenvironment Peripheral Blood No significant change in LDH No significant change in CD34+ cells No significant change in leukoerythroblastosis 47 Immunologic response Ineffective hematopoiesis Extramedullary hematopoiesis Cachexia 8

9 JAK2 inhibition Acquired stem cell (s) Thalidomide Lenalidomide JAK2 and/or JAK1 inhibition Aberrant cytokine production Clonal myeloproliferation Altered bone marrow microenvironment Elliott et al. BJH 2002;117:288 Tefferi et al. Blood 2006;108:1158 Pomalidomide Stromal reaction and tissue injury Tefferi et al. International randomized study Currently ongoing Immunologic response Ineffective hematopoiesis Extramedullary hematopoiesis Cachexia Anemia-2 Splenomegaly-8% Thrombocytopenia-8 Neuropathy Anemia-22% Splenomegaly-33% Thrombocytopenia-5 Myelosuppression Still blinded but I am betting that anemia response and toxicity profile will be superior Current diagnostic algorithm for primary eosinophilia Current diagnostic and treatment algorithm in HES or clonal eosinophilia Peripheral blood screening for FIP1L1-PDGFRA PDGFRA Currently done by FISH or RT-PCR FISH for CHIC2 and cytogenetic studies for 5q33 translocations Present Absent CHIC2+ or 5q33+ Imatinib-insensitive insensitive eosinophilic disorder PDGFRA-rearranged with eosinophilia Treat with low-dose imatinib Bone marrow examination with cytogenetic studies 5q31 translocations 8p11 translocations Other cytogenetic abnormalities Normal cytogenetics Imatinib 100 mg/day PDGFRA-rearranged PDGFRB-rearranged CEL or other myeloid malignancy Is treatment necessary? HES Pre-HES T clone-positive Chronic therapy PDGFRB Rearranged FGFR1 Rearranged CEL HES or Pre-HES/L HES/L-IE Prednisone for acute therapy Low-dose prednisone Hydroxyurea Interferon alpha Imatinib Mepolizumab Alemtuzumab Systemic Mastocytosis (SM) Indolent SM Aggressive SM Mediator Release symptoms Urticaria Pigmentosa Topical corticosteroids 0.05% betamethasone Blood eosinophilia No blood eosinophilia PUVA H-2 blockers Cimetidine 300 mg QID Ranitidine 150 mg BID H-1 blockers Hydroxyzine 25 mg TID Cyproheptadine 4 mg TID Chlorpheniramine 4 mg QID Azelastin 4 mg BID Check for FIP1L1-PDGFRA Positive Negative Interferon-α 1-5 MU TIW Thank you for attending Master Class for Oncologists Inhibitor of mast cell degranulation Cromolyn sodium 400 mg QID Anaphylaxis-prone patients Must were medical alert bracelets Imatinib 100 mg/day Or Cladribine Standard hairy cell leukemia dose Tefferi & Pardanani Current Hematology Reports,,

10 What are myeloproliferative neoplasms?? Questions & Answers? 1. Myeloproliferative disorders in which a clonal marker is not identified 2. A category of myeloid malignancies that consists of,, and CML only 3. A category of myeloid malignancies that were previously known as myeloproliferative disorders 4. Myeloid malignancies that are associated with a JAK2 10 Which one of the following statements about JAK2 s is inaccurate?? 32 y/o woman with ; asymptomatic and no history of thrombosis;? platelet count 1.6 million; ristocetin co-factor activity 5; wants to be pregnant. How would you manage? 1. JAK2 exon 12 is the most frequent in 1. Interferon alfa only 2. JAK2 exon 14 (i.e. JAK2V617F) induces like disease in mice 3. JAK2V617F is found in, and but not in secondary polycythemia or reactive thrombocytosis 4. JAK2V617F is not necessarily the initial diseasecausing in myeloproliferative neoplasms 2. Interferon alfa plus aspirin 3. Aspirin only 4. Hydroxyurea and aspirin y/o man with ; asymptomatic; spleen is palpable 10 cm? below the costal margin; counts are normal. How would you manage? 1. Observe only 2. Take the spleen out 3. Consider experimental therapy with JAK2 inhibitor 4. Consider RIC transplant 10 10