Essential Thrombocythemia Followed by Acute Leukemia

1. Essential Thrombocythemia Followed by Acute Leukemia Does therapy lead to leukemic transition or is it a failure of accurate diagnosis? Joel Saltzman MD Hematology/Oncology Fellow Metro Health Medical Center

2. 63 yo male admitted with Appendicitis • Diagnosed with Essential Thrombocythemia 1992. Treated with Chlorambucil to keep platelet count less than <600,000K • 1999 diagnosed with AML; cytogenetics normal • Offered induction therapy with 7+3. Pt refused. Continued on Chlorambucil. • Stable AML x 2 years

3. WS labs. • WBC: 14.0, 45% Segs, 7% Bands, 15%Blasts • Plts: 693K • PCR for BCR/ABL +

4. Objectives • Establish the diagnostic criteria for Essential Thrombocythemia (ET) • Discuss the natural history of ET • Discuss the evidence supporting the treatment of ET • Discuss acute Leukemia following ET

5. Diagnostic Criteria for ET • Platelet count >600,000 • Hematocrit,40 or normal RBC mass • Normal serum ferritin and MCV • No Philadelphia Chromosome or bcr/abl gene rearrangement • Absence of collagen Fibrosis on bone marrow • No cytogenetic or morphologic evidence for a myelodysplastic syndrome • No cause for reactive thrombocytosis

6. Presenting Features • Vasomotor symptoms: Erythromelagia • Headache, dizziness, visual disturbances • Thrombosis or bleeding • More common in women • Splenomegaly • Asymptomatic

7. Pathophysiology • Clonal disorder of a multipotent stem cell which gives rise to erythrocytic, granulocytic, and megakaryocytic series • Cytogenetic abnormalities demonstrated in <25% of patients • Trisomy 8 most common abnormality

8. Clinical Course • No change in life expectancy • Majority of patients have course complicated by thrombosis and hemorrhage. • Arterial thrombus > venous thrombus • Arterial thrombi more common with smoking, hypertension, coronary artery disease, diabetes mellitus

9. What is the evidence supporting treatment for ET? Cortelazzo et. al. New England Journal of Medicine, April 1995 • Randomized trial comparing treatment with Hydroxurea to no myelosuppression in 114 Pts with ET at high risk for thrombosis. • Platelet count kept below 600,000 in the treatment group

10. What defined the High Risk Patient? • Age > 60 years (55%) • Previous history of thrombosis (15%) • Both (30%) • Platelet Count >1,500,000(excluded from randomization because of high risk of bleeding/thrombosis)

11. Methods • 56 pts randomly assigned to hydroxyurea group. Seen every two weeks until plt count <600,000. Starting dose of hydroxyurea 15mg/kg/day. • 58 patients were the control patients and were seen every two months

12. Mean Platelet Counts

13. Incidence of Thrombosis

14. Hydroxyurea therapy • Hydroxyurea reduces the incidence of major ischemic episodes from 24% to 3.6% in this high risk patient population

15. Accepted risk stratification in ET

16. So Why Worry? • Berk et. al. New England Journal of Medicine, 1981, “Increased Incidence of Acute Leukemia in Polycythemia Vera associated with Chlorambucil therapy” • 431 patients randomized to phlebotomy alone, clorambucil, and radioactive phosphorus

17. Results: Berk et. al.

18. Experience of the PVSG with ET • Study the Clonal Myeloproliferative Diseases for the past 20 years • Polycythemia Vera • Essential Thrombocythemia • Chronic Myeloid Leukemia • Myelofibrosis

19. Modifications in the Diagnostic Criteria for ET • Used to include stainable iron in marrow • Now a normal or increased ferritin is accepted to r/o Iron Deficiency • Absence of bcr/abl gene rearrangement or Philadelphia chromosome • No cytogenetic or morphologic evidence of MDS. Absence of 5q- or ringed sideroblasts

20. Presenting Characteristics of 100 patients with original criteria • PVSG chose only patients with plts> million. (9 were excluded) • 50/91 met all the newly established criteria for ET • 41 patients patients did not meet all established criteria. • Three major problems were found in these 41 patients

21. Major difficulties with 41pts • Iron deficiency not rule out (28 pts) • Polycythemia Vera was not formally excluded (9pts) • Lack of karyotypic analysis to exclude Philadelphia chromosome

22. Lack of bone marrow karyotype adequate to rule-out PH1 • 18 patients lacked this analysis • 6 of these patients eventually had karyotypic analysis consistent with CML. Most progressed to chronic phase CML and 5/6 progressed to acute blastic leukemia • It is now recognized that some CML patients will have bcr/abl without chromosomal abnormality

23. Patients were placed in 4 prospective trials • Protocol 54:randomization between radioactive phosphorus and Melphalan • Protocol 10: same as above except increased dose of 32P • Protocol 12: Hydroxyurea • Seven patients were simply followed without treatment

24. PVSG experience with Hydroxyurea in ET • 29/91 of these initial patients were enrolled in PSVG-12 • 6/29 developed acute leukemia • No major differences were observed between the two groups were noted

25. Categories of Thrombocytosis

26. Categories of Myelosuppresive Therapy

27. Conclusions • Hydroxyurea remains the treatment of choice for patients at high risk for the thrombotic complications or at risk for them • Low incidence of acute leukemias in patients treated with HU alone, suggests the lack of a leukemogenic effect • Accurate diagnosis of ET is essential to long term management (I.E. send RT PCR for BCR/ABL)