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Clonal “devolution” in a case of essential thrombocythemia with transformation from refractory cytopenia with multilineage dysplasia to acute myeloid leukemia

Essential thrombocythemia (ET) is a chronic myeloproliferative disorder characterized by thrombocytosis and a tendency for thrombosis and/or hemorrhage. Transformation to either myelodysplasia or acute myeloid leukemia (AML) are reported to occur in 1 – 4.5% of patients, perhaps more frequently in those treated with chemotherapy [1,2]. The commonest karyotype abnormality reported in patients of ET treated with hydroxyurea when transforming to MDS/AML has been 17p deletion [2,3]. The serial transformation of a case of essential thrombocythemia to refractory cytopenia with multilineage dysplasia (RC/MD) and subsequently to AML is a relatively rare series of events. The acquisition of new cytogenetic abnormalities at the time of transformation to AML is common. We report the case of a patient treated with hydroxyurea for essential thrombocythemia who developed RC/MD (with monosomy 7) and subsequently transformed to AML (with reversion to diploid karyotype). This is an unusual instance where karyotypic ‘‘devolution’’ to a diploid karyotype accompanied the development of increasing clinical aggressiveness of a myeloidlineage disorder. A 65 year-old male was found to have thrombocytosis of 881610/l on a routine blood examination when he was investigated for ‘‘flu-like’’ symptoms. His hemoglobin (Hb) was 12.9 g/l, and white blood cell (WBC) count was normal. No further investigations were carried out at that time and no diagnosis established. He had three episodes of transient cerebral ischemia over the next 6 months. Six months after recognition of the thrombocytosis he had a more prolonged cerebral ischemic episode and was then found to have a platelet count of 13746 10/l. Iron studies were normal and the bone marrow examination demonstrated a moderate increase in abnormal megakaryocytes with clustering and hyperlobulation consistent with the diagnosis of ET. Bone marrow reticulin was not increased. There was no evidence of the BCR-ABL fusion gene by nested PCR. Cytogenetic analysis was not performed at diagnosis. He was treated with aspirin and had no further cerebral ischemic episodes. He had no palpable hepatosplenomegaly. Hydroxyurea was used to control the platelet count, at a dose of 1 g daily for the next 31 months, and then reduced to 500 mg a day for 2 months after his Hb fell to 5 g/dl, and then reduced to 500 mg every alternate day for 1 month then ceased. He was then referred to the Peter MacCallum Cancer Centre 45 months after his initial presentation. The platelet count was 5386 10/l, Hb 6.99g/dl, and white blood cell count 1.96 10/l with a marked neutropenia of 0.76 10/l and 1% blasts. His serum LDH, vitamin B12 and red cell folate levels were normal. Serum erythropoietin level was greatly elevated at 4260 IU/ml (normal range 4.4 – 26.4), Coombs’ test negative, and absolute reticulocyte count 526 10/l (R.R. 50 – 100). The bone marrow showed decreased erythropoiesis, 4% blasts, and trilineage morphologic dysplasia. A diagnosis of RC/MD using WHO terminology was