Myeloproliferative Neoplasms 2015 - PowerPoint Presentation

1. Myeloproliferative Neoplasms 2015Robert J. Jacobson MD, FACP , FRCP(C).Florida Cancer SpecialistsAffiliate Professor of Biological SciencesCharles E. Schmidt School of MedicineFlorida Atlantic University, Boca Raton, FL1

2. Stem Cells and Hematopoietic DifferentiationHematopoietic stem cells capable ofSelf-renewalDifferentiationDifferentiation and proliferation controlled by molecular signalsContact with stromal cells in bone marrowGrowth factors2

3. Myeloproliferative Neoplasms (MPN)- Clonal Hematopoietic stem cell diseases- Overproduction of terminally differentiated cells of the myeloid lineagePh+ Chronic Myeloid Leukemia (CML)Polycythemia Vera (P. Vera)Essential Thrombocythemia (ET)Primary Myelofibrosis (PMF)3

4. CML Epidemiology and Etiology In the US, there were 4,870 cases in 2010 and an expected 5,430 cases in 2012 15% of all adult leukemiasIncidence increases significantly with age – Median age: ~ 67 years – Prevalence increasing due to current therapy – Most patients present in CP Majority of CML-related deaths due to progression to AP/BC – 50% of CML patients are asymptomatic at diagnosisRisk factors – Radiation exposure4

5. Most CML Patients Are Diagnosed in the Chronic Phase5Chronic Phase 80%Blast Phase 10%

6. CML with Philadelphia Chromosome6t (9; 22)

7. CML Pathogenesis: Philadelphia (Ph) Chromosome 7CML first cancer demonstrated to have underlying genetic abnormalityAssociated with Ph chromosomeResult of translocation between chromosomes 9 and 22Detected in approx. 95% of patients with CML

8. Clinical Presentation of Ph+ CML8

9. Treatment of CML Imatinib (Gleevec), developed by Dr. Brian Druker at Oregon Health & Sciences University and Novartis pharmaceutical company in mid-1990.Also found to be effective in other blood cancers and GIST by inhibiting different TK proteins. World-wide sales now $28 billion in the 10 years from 2001-2011.Now 4 drugs, second generation tyrosine kinase inhibitors available to treat CML.Drugs continue throughout life.9

10. Imatinib Mechanism of Action10

11. Treatment of CML4 Targeted drugs which block the action of tyrosine kinase (TKIs): Imatinib (Gleevec)Dastinib (Sprycel)Nilotinib (Tasigna)Bosutinib (Bosulif)Side EffectsSkin rashFluid retentionDiarrheaVascular thrombosisOmacetaxine (Synribo) or Homoharringtonine (alkaloid) approved use when 2 TKIs have failed11

12. Event-Free Survival and Survival Without AP/BC on First-Line Imatinib12

13. Survival Rates for Stem Cell Transplantation 13

14. ‘Inverted Iceberg’ Schematic of CML burden and reduction over time.14

15. CML Treatment Cessation of TKIsIf relapse occurs, it develops within the first 6 months after the treatment stoppedAbout 40%—50% of patients have no recurrence if their initial leukemic burden was low and they had been on treatment for a long duration (> 10 years)Ongoing studies investigating second generation TKIs e.g. nilotinib and achieving more rapid MMR > 4 – 5 logsCurrent recommendation is to continue with TKI treatment for lifePatients may not be able to tolerate TKI and alternative drug chosen15

16. Ph Negative MPNMajority of the patients have the gene mutation JAK2V617F Polycythemia veraEssential ThrombocythemiaPrimary Myelofibrosis16

17. Diagnosis of Polycythemia Vera Major CriteriaHgb level > 18.5 g/dL in men, >16.5 g/dL in womenPresence of the JAK2V617F mutation (in 95% of patients)Minor CriteriaBone marrow biopsy showing hypercellularitySerum Epo level below normal rangeEndogenous erythroid colony formation in vitro17PV is likely if:Both major criteria and at least 1 minor criterion are met, orFirst major criterion and at least 2 minor criteria are metEpo = erythropoietin; Hgb = hemoglobin; JAK = Janus-associated kinase; PV= polycythemia vera

18. Clinical Features of P. Vera18Fever, weight lossPruritisPlethoric faciesCyanosed digitsSplenomegaly Thrombotic eventsTransformation to leukemiaMyelofibrosis

19. JAK2V617F and STAT Pathways19

20. Treatment of Polycythemia Vera (PV)Control and maintain Hct levels <45%Manage disease-related complications of PVPhlebotomy to maintain Hct levels <45% Low-dose aspirin in appropriate patientsHydroxyurea or IFNα as first-line cytoreductive therapy at any agePatients with inadequate response to or intolerance of HU use Ruxolitinib (Jakifi) JAK2 inhibitor20Hct = hematocrit; HU = hydroxyurea; IFNα = interferon- α

21. Essential ThrombocythemiaElevated platelet count often in excess of 1 million/dL, RBC and WBC normalJAK2V617F mutation in 50% of patientsThrombosis/hemorrhagic complicationsSplenomegaly can develop, especially if transformation to Myelofibrosis (MF)Low dose aspirin, anegrelide, hydroxyurea usedClinical trials underway with JAK2 inhibitorsPatients can live >10 years21

22. JAK2 and Other Mutations in MPN22

23. Myelofibrosis with Myeloid MetaplasiaJAK2 mutation in 60% of patientsMyelofibrosis is a clonal hematologic malignancy with reactive marrow fibrosis 23Primary myelofibrosis, or PMF, entered the scientific discourse in 1879 with varied nomenclature –Agnogenic myeloid metaplasia –Myeloid metaplasia with myelofibrosis –Chronic idiopathic myelofibrosisPatients with an antecedent diagnosis of PV or ET are diagnosed with PPV-MF or PET-MF

24. 24Red blood cells, tear-drop shapeA leukoerythroblastic blood smearPeripheral Blood and Bone Marrow in MyelofibrosisBone marrow fibrosisReticulin stain of marrow

25. Understanding MyelofibrosisMyelofibrosis can be risk stratified by: low risk intermediate risk 1 & 2  high risk –Bone marrow fibrosis –Symptom burden –Splenomegaly –Cytopenias Although the exact cause of myelofibrosis is unknown, multiple mechanisms are key features of the disease –Genetic mutations: JAK2, CALR and MPL –Excessive production of cytokines –Increased JAK1 signaling 25

26. Cytokines Play a Key Role in Myelofibrosis26

27. Overactive JAK-STAT Signaling is Present in all Patients with Myelofibrosis27

28. Clinical Relevance of the Progressive Pathology of Myelofibrosis28

29. Diagnosing primary Myelofibrosis: All major criteria plus ≥2 minor WHO criteria are required for diagnosis29

30. Risk Stratification in Myelofibrosis 30

31. Burden of Disease: Symptoms of Myelofibrosis 31

32. Examining the causes of mortality in PMF 32

33. Diagnosing PPV-MF or PET-MF33

34. 34Geyer and Mesa, ASH 2014

35.   MyelofibrosisPolycythemia VeraStatusAgent↓Spleen↓Const.Sympt.↑HB↑SURV↓Phleb↓Const.Sympt.↓VascEventsApproved (MF)Phase III (PV)Ruxolintinib(INCB18424)++++++-++++++++UnkPhase III (MF)Pacritnib-(SB1518)++++++-Unk   Phase III (MF)Phase II (PV/ET)Momelotinib(CYT387)++++++-UnkUnkUnkUnk35

36. Summary & ConclusionsMyeloproliferative neoplasms are characterized by distinct and specific genetic findings and clinical presentationsThe translocation t(9:22) and mutation JAK2V617F are responsible for the abnormal clonal production of cells derived from the myeloid lineageTherapies are now available directed against the specific tyrosine kinases (BCR-ABL) or genetic pathways (JAK-STAT) that cause the uncontrolled marrow cellular growth36