ACUTE MYELOID-LEUKEMIA AND MYELODYSPLASTIC SYNDROMES FOLLOWING ESSENTIAL THROMBOCYTHEMIA TREATED WITH HYDROXYUREA - HIGH PROPORTION OF CASES WITH 17P DELETION

Treatment with alkylating agents or radiophosphorous (P-32) has been s hown to carry a certain leukemogenic risk in myeloproliferative disord ers (MPDs), including essential thrombocytemia (ET). The leukemogenic risk associated to treatment with hydroxyurea in ET, on the other hand , is generally considered to be relatively low. Between 1970 and 1991, we diagnosed ET in 357 patients, who were monitored until 1996. One o r several therapeutic agents had been admistered to 326 patients, incl uding hydroxyurea (HU) in 251 (as only treatment in 201), pipobroman i n 43, busulfan in 41, and P-32 in 40. With a median follow-up duration of 98 months, 17 patients (4.5%) had progressed to acute myeloid leuk emia (AML; six cases) or myelodysplastic syndrome (MDS; 11 cases). Fou rteen of these patients had received HU, as sole treatment in seven ca ses, and preceded or followed by other treatment in seven cases, mainl y pipobroman (five cases). The remaining three leukemic progressions o ccurred in patients treated with P-32 (two cases) and busulfan (one ca se). The incidence of AML and MDS after treatment, using P-32 alone an d P-32 with other agents, busulfan alone and with other agents, HU alo ne and with others agents, and pipobroman alone and with other agents was 7% and 9%, 3% and 17%, 3.5% and 14%, and 0% and 16%, respectively. Thirteen of 17 patients who progressed to AML or MDS had successful c ytogenetic analysis. Seven of them had rearrangements of chromosome 17 (unbalanced translocation, partial or complete deletion, isochromosom e 17q) that resulted in 17p deletion. They also had a typical form of dysgranulopoiesis combining pseudo Pelger Huet hypolobulation and vacu oles in neutrophils, and p53 mutation, as previously described in AML and MDS with 17p deletion. Those seven patients had all received HU, a s the only therapeutic agent in three, and followed by pipobroman in t hree. The three patients who had received no HU and progressed to AML or MDS had no 17p deletion. A review of the literature found cytogenet ic analysis in 35 cases of AML and MDS occurring after ET, 11 of whom had been treated with HU alone. Five of 35 patients had rearrangements that resulted in 17p deletion. Four of them had been treated with HU alone. These results show that treatment with HU alone is associated w ith a leukemic risk of approximately 3.5%. A high proportion of AML an d MDS occurring in ET treated with HU (alone or possibly followed by p ipobroman) have morphologic, cytogenetic. and molecular characteristic s of the 17p(-) syndrome. These findings suggest that widespread and p rolonged use of HU in ET may have to be reconsidered in some situation s, such as asymptomatic ET. (C) 1998 by The American Society of Hemato logy.