Welcome to Master Class for Oncologists Session 3: 9:15 AM - 10:00 AM Miami, FL December 18, 2009 Myeloproliferative Neoplasms: Bringing Order to Complexity and Achieving Optimal Outcomes Speaker: Andrew Tefferi, MD Myeloproliferative Neoplasms Ayalew Tefferi Mayo Clinic, Rochester, MN 1
A patient with increased hemoglobin/hematocrit 25-year-old male Hemoglobin 19 g/dl, duration unknown All other blood counts are normal No palpable splenomegaly or symptoms What will you do next 1. Measure red cell mass and serum erythropoietin (Epo) level 2. Peripheral blood JAK2 exon 12 mutation analysis and serum Epo determination 3. Peripheral blood JAK2V617F mutation analysis and serum Epo determination 4. Bone marrow examination with JAK2 mutation analysis 5. Screen for germline mutations associated with congenital polycythemia CML PV Suspected ET PMF A patient with increased hemoglobin/hematocrit 25-year-old male Hemoglobin 19 g/dl, duration unknown All other blood counts are normal No palpable splenomegaly or symptoms Peripheral blood BCR-ABL1 screen (+) CML Peripheral blood JAK2V617F and Epo screen (+) V617F Epo PV (-) V617F Epo not (-) V617F Epo Not PV Screen for JAK2 exon 12 mutation and if negative BM biopsy Confirms MPN Rules out CML Possibilities include ET, PMF and MDS/MPN Peripheral blood JAK2V617F screen (+) (-) (+) V617F or del(13q) or trisomy 9 PMF Bone marrow exam with JAK2V617F screen and cytogenetics Otherwise Possibilities include: PMF CML Other MPN MDS MDS/MPN What will you do next 1. Measure red cell mass and serum erythropoietin Epo level 2. Peripheral blood JAK2 exon 12 mutation analysis and serum Epo determination 3. Peripheral blood JAK2V617F mutation analysis and serum Epo determination 4. Bone marrow examination with JAK2 mutation analysis 5. Screen for germline mutations associated with congenital polycythemia BM biopsy Does not rule out ET Possibilities include ET, CML, PMF and MDS/MPN 2
Figure 5 Secondary polycythemia algorithm Hypoxia-driven Cardiac or pulmonary disease High altitude habitat Smoking/CO poisoning Sleep apnea/hypoventilation Renal artery stenosis 1. PV and ET Treatment Congenital Acquired Oxygen-independent Check serum erythropoietin (Epo) Drugs (androgens, Erythropoietin) Post renal transplant Malignant tumors Other tumors (hyperparathyroidism) 2. Myelofibrosis 3. Clonal eosinophilia Epo normal or increased p50 decreased Check p50 p50 normal Epo decreased EPOR mutation 4. Mastocytosis 1. High oxygen-affinity hemoglobinopathy 2. 2,3-BPG deficiency 1. VHL mutation (Epo usually high) 2. PHD2/HIF2α mutations (Epo normal or elevated) 3. Other unknown mutations A patient with essential thrombocythemia 30-year-old female No history of thrombosis or Platelet count 1.5 million/micl Bleeding Asymptomatic Wants to have a child How would you manage her 1. Measure ristocetin co-factor activity and if > 30% treat with daily low-dose aspirin 2. Low-dose aspirin plus interferon alpha 3. Interferon alpha only 4. Low-dose aspirin plus hydroxyurea 5. Recommend participation in JAK2 inhibitor clinical trial 3
A patient with essential thrombocythemia 30-year-old female No history of thrombosis or Platelet count 1.5 million/micl Bleeding Asymptomatic Wants to have a child How would you manage her 1. Measure ristocetin co-factor activity and if > 30% treat with daily low-dose aspirin 2. Low-dose aspirin plus interferon alpha 3. Interferon alpha only 4. Low-dose aspirin plus hydroxyurea 5. Recommend participation in JAK2 inhibitor clinical trial 4
Consider transplant or Experimental therapy PMF-PS: Survival curves of prognostic groups per the new IPSS Survival by PMF-PS Consider 1.9 High-risk karyotype N=1054 or transplant or Experimental Transfusion need.8 therapy.7.6.5.4 N=224.3.2.1 N=229 N=282 N=202 0 0 24 48 72 96 120 144 168 192 216 240 264 288 Months Probability Cervantes et al. Blood 112:657 (ASH 2008 oral presentation) 95% CI 95% CI 95% CI 95% CI PMF-PS = 0 PMF-PS = 1 PMF-PS = 2 PMF-PS = 3 1. Age > 65 years 2. Hgb < 10 g/dl 3. WBC > 25 x 10(9)/L 4. Circulating blasts 1% 5. Constitutional symptoms Compound TG101348 INCB18424 XL019 CEP701 CYT387 AZD1480 SB1518 JAK2 inhibitor ATP mimetics Primary Target JAK Family Selectivity Profile (X-fold selectivity) JAK2 IC 50 (nm) JAK2 vs. JAK3 JAK2 vs. JAK1 JAK2 vs. TYK2 3nM 332x 35x 135x 4.5nM 2nM 1nM 18nM 72x 125x 3x 8.6x 0.6x 65x 0.6x 4x 170x 5
Decrease in Palpable Spleen Size by Cycle 520-800 mg/day* TG101348 (N = 12) Pardanani et al. EHA 2009 Effect of TG101348 in Patients With Leukocytosis (WBC >11 x10 9 /L) Percentage of Subjects 100 90 80 70 60 50 40 30 20 10 0 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 (n = 12) (n = 12) (n = 11) (n = 7) (n = 5) (n = 5) >/=25% >/=50% 100% WBC Count (x10^9/l) 110 100 90 80 70 60 50 40 30 20 10 0 Baseline Follow-Up N = 18. Median treatment duration 30 weeks (range 10-64 weeks). Doses at follow-up 240-680 mg/day. 102-001 102-003 102-004 101-005 105-007 104-008 106-009 101-014 104-015 106-016 105-018 101-020 103-022 102-023 106-024 105-026 104-027 106-028 *Starting dose. Doses (mg/day) Cycle 1, 680-800; Cycles 2-5, 520-680; Cycle 6, 680. JAK2V617F allele burden (N=24) Intent to treat population that are mutation-positive 50% of treated patients achieved more than 30% reduction in allele burden ASH 2008 update with median follow-up of over one year 100 90 80 70 60 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 Baseline Last reading Side effects: Grade ½ nausea/vomiting/diarrhea (mostly transient) Myelosuppression Grade ½ increase in transaminases/lipase/amylase (transient) Grade 1 increase in serum creatinine (transient) No effect on V617F burden No effect on fibrosis No effect on anemia Toxicity included thrombocytopenia Diagnostic Algorithm for Primary Eosinophilia 1st step Peripheral blood screening for FIP1L1-PDGFRA PDGFRA using FISH or RT-PCR Mutation present FIP1L1-PDGFRA PDGFRA associated clonal eosinophilia 2nd step Bone marrow biopsy with cytogenetics 5q33 translocation present 8p11 translocation present Other abnormalities or excess blasts PDGFRB rearranged clonal eosinophilia FGFR1 rearranged clonal eosinophilia present CEL-NOS 3rd step Peripheral blood lymphocyte phenotyping and TCR gene rearrangement studies Abnormal or clonal lymphocytes present lymphocytic variant hypereosinophilia All the above negative Idiopathic eosinophilia including HES 6
Treatment algorithm in HES or clonal eosinophilia FISH for CHIC2 and cytogenetic studies for 5q33 translocations CHIC2+ or 5q33+ Imatinib-insensitive insensitive eosinophilic disorder Imatinib 100 mg/day CEL or other myeloid malignancy HES T clone-positive PDGFRA-rearranged MPN PDGFRB-rearranged MPN Is treatment necessary Chronic therapy Prednisone for acute therapy Low-dose prednisone Hydroxyurea Interferon alpha Imatinib Mepolizumab Alemtuzumab Practical classification of mast cell disease 1 Cutaneous mastocytosis (skin-only disease) Both can manifest mast cell mediator release symptoms 2 Systemic mastocytosis (SM) i Indolent SM ii Aggressive SM (cytopenia,, bone disease, organomegaly,, etc.) 1. SM without associated 2 nd myeloid/lymphoid neoplasm 2. SM with associated 2 nd myeloid/lymphoid neoplasm 3. Mast cell leukemia Survival for 342 systemic mastocytosis patients classified by disease type compared with the expected age and gender matched US Population s survival Treatment for Systemic Mastocytosis Survival 0 20 40 60 80 100 ISM, (n=159) ASM, (n=41) AHD, (n=138) MCL, (n=4) Expected US Survival Indolent H1 and H2 blockers Cromolyn Phototherapy Topical steroids Aggressive Cladribine or IFN-α Associated with MDS or CMML Mast cell leukemia Lim et al. Blood 2009;113:5727. 0 10 20 30 Years from Dx 01Oct08 If this fails, OK to try IFN-α or cladribine If this fails, don t count on either dasatinib or midostaurin Treat as MDS or CMML Treat as AML or with cladribine then transplant 7
Questions & Answers Thank you for attending Master Class for Oncologists 44 8