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 Treated with Chlorambucil to keep platelet count less than <600,000K
1999 diagnosed with AML; cytogenetics normal
Offered induction therapy with 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
If Fe deficiency is suggested trial of feso4 is required to exclude this as cause of thrombocytosis. As suggested by the Polycythemia Vera Study Group

6. Presenting Features Vasomotor symptoms: Erythromelagia
Headache, dizziness, visual disturbances
Thrombosis or bleeding
More common in women
Splenomegaly
Asymptomatic
By the age of 60 the incidence of ET is similar in men and women

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
Type
Hydroxyurea
Control
TIA 5
Digital Ischemia
stroke 1 MI
Superficial phlebitis 2
DVT
Total
2(3.6%)
14(24%)

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
Age>60 or Hx of Thrombosis
Cadiovascular risk , plt>1.5mil.
low no
intermediate
yes
High NA

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. No. at start No. of leukemias phlebotomy 134 1
chlorambucil
141 16
32 phosphorus
156 9

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
Category
No. of pts
No. with Leukemia
Pure ET 50 3
ET(?CML) 9 2
ET(?PV) 19 4
ET(?CML, ?PV) 1
ET(?MF)
totals 91 12

26. Categories of Myelosuppresive Therapy
Myelosuppressive therapy
No. of patients
No. developing acute Leukemia
none 7 1
HU only 22
AA or 32P 34 4
HU-AA&/or 32P 5
AA or 32P-HU 21
Totals 91 12
Most striking is the group treated with AA or radioactive phosphurus have such a low incidence of leukemia

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)