1. Myeloid Blastic Transformation of Myeloproliferative Neoplasms A Review of 112 Cases Presenter: Syed Jawad Noor, PGY3 Mentor: Meir Wetzler June 09, 2010

2. Our Team Syed J. Noor Wei Tan Gregory E. Wilding Laurie A. Ford Maurice Barcos Sheila N.J. Sait Annemarie W. Block James E. Thompson Eunice S. Wang Meir Wetzler

3. Myeloproliferative Neoplasms (MPNs) Clonal hematologic diseases Excess production of ≥1 lineages of mature blood cells Predisposition to bleeding and thrombotic complications Extramedullary hemotopoiesis A variable progression to leukemia

4. MPN Types Polycythemia Vera (PV) Essential Thrombocythemia (ET) Myelofibrosis (MF) Primary MF (PMF) Secondary MF (SMF)

5. Polycythemia Vera (PV) An expansion in red blood cell production Essential Thrombocytosis (ET) An isolated elevation in platelet count

6. Myelofibrosis (MF) A fibrotic bone marrow and peripheral cytopenia Higher risk of leukemic transformation Primary or secondary (post-PV or post-ET)

7. JAK2 mutation in MPN JAK2 Signaling PP L 95% in PV; 50-60% in ET and MF

8. Myeloid Blastic Transformation of Myeloproliferative Neoplasms MPNs are known to transform into acute leukemia in approximately 4-6% of the patients ~50% of acute leukemia cases following JAK2- positive MPN continue to carry the mutation Pathogenesis of the blastic transformation in MPN remains unclear

9. Known risk factors for Blastic Transformation Alkylating agents Radiation DNA damaging chemotherapy drugs

10. Research Study Objectives To gain more insight into the evolution & risk factors playing role in blastic transformation Treatment outcome of patients developing blastic transformation from classic MPN

11. Methods

12. Patients 89 cases from literature 23 cases from RPCI PV, ET, MF, SMF or MPN-U Blast phase defined as persistent ≥20% marrow or peripheral blood blasts

13. Contd… Therapy anthracycline (daunorubicin at 60 mg/m2) + cytosine arabinoside (100 mg/m2) chemotherapy in a “7+3” fashion

14. Contd… 3 pt had SCT in addition to chemotherapy All other pts received supportive care only Response was CR or CRi

15. Statistical Analyses Fisher’s exact test. Wilcoxon rank sum test. Kaplan-Meier method. log-rank test. SAS (version 9.1)

16. Results Both RPCI and literature pt. populations did not differ in Age at diagnosis of MPN or blastic transformation, Gender Prior use of interferon Karyotype aberrations Overall survival of the two cohorts was similar and poor

17. Comparison between RPCI dataset and other three datasets

18. Diagnosis Differences Percent

19. Time from MPN diagnosis to Blast phase Percent

20. Less than 3 Therapies Percent

21. Prior Hydroxyurea Therapy Percent

22. Prior Alkylating Agents Percent

23. Prior Erythropoietin Percent

24. Normal Karyotype Percent

25. Insignificant Variables of both Cohorts Age @ MPN diagnosis Age @ AML diagnosis Gender Prior use of Interferon Karyotype aberrations

26. Overall Survival

27. Survival analysis for RPCI + other three data sets

28. Months Survival By Diagnosis

29. Age at MPN Diagnosis P=0.0493 Age @ MPN ≥60 <60

30. Less than 3 Therapies P=0.0242 <3 Therapies N Y

31. Complex Karyotype P=0.0104 Complex Karyotype Y N

32. Non-significant variables Time from MPN diagnosis to Blast phase Age @ AML diagnosis Gender Prior Hydroxyurea Prior Alkylating Agents Prior Erythropoietin Prior Interferon Karyotype abnormalities other than Complex Kryotype

33. Survival analysis for RPCI dataset

34. Median Survival in Months P <0.0001 P 0.0031 P 0.0119 P 0.0009

35. Discussion Reasons for the heterogeneity -- Differing criteria for MPN diagnosis --Variety in the yield of karyotype analysis Whether blastic transformation is a sequel of therapy, natural progression or a combination of the two continues

36. Contd…. Superior survival with allogeneic SCT SCT should be considered before the disease progresses to the blastic phase

37. Contd…. Selective JAK1 and JAK2 inhibitor, INCB018424, has demonstrated some single agent activity in relapsed/refractory patients with leukemic transformation of Myelofibrosis

38. Conclusion Patients with <3 prior therapies & Lack of complex karyotype have longer survival Attempts for early identification of patients at risk for disease progression Allogeneic SCT for the eligible patient Searching for novel therapeutic agents, alone or in combination