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Acute Myeloid Leukemia and Myelodysplastic Syndromes Following
Essential Thrombocythemia Treated With Hydroxyurea: High Proportion
of Cases With 17p Deletion
Yvon Sterkers,
Claude Preudhomme,
Jean-Luc Laï,
Jean-Loup Demory,
Marie-Thérèse Caulier,
Eric Wattel,
Dominique Bordessoule,
Francis Bauters, and
Pierre Fenaux
From the Service des Maladies du Sang, Laboratoire
d'Hématologie, and Service de Cytogénétique, CHU
Lille; the Service d'Hématologie, Hôpital Saint Vincent,
Lille; and the Service d'Hématologie CHU Dupuytren, Limoges,
France.
Treatment with alkylating agents or radiophosphorous
(32P) has been shown to carry a certain leukemogenic risk
in myeloproliferative disorders (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 or several therapeutic agents had been admistered to 326 patients, including hydroxyurea (HU) in 251 (as
only treatment in 201), pipobroman in 43, busulfan in 41, and
32P in 40. With a median follow-up duration of 98 months,
17 patients (4.5%) had progressed to acute myeloid leukemia (AML; six
cases) or myelodysplastic syndrome (MDS; 11 cases). Fourteen of these patients had received HU, as sole treatment in seven cases, and preceded or followed by other treatment in seven cases, mainly pipobroman (five cases). The remaining three leukemic progressions occurred in patients treated with 32P (two cases) and
busulfan (one case). The incidence of AML and MDS after treatment,
using 32P alone and 32P with other agents,
busulfan alone and with other agents, HU alone 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 cytogenetic
analysis. Seven of them had rearrangements of chromosome 17 (unbalanced
translocation, partial or complete deletion, isochromosome 17q) that
resulted in 17p deletion. They also had a typical form of
dysgranulopoiesis combining pseudo Pelger Hüet hypolobulation and
vacuoles in neutrophils, and p53 mutation, as previously described in
AML and MDS with 17p deletion. Those seven patients had all received
HU, as the only therapeutic agent in three, and followed by pipobroman
in three. The three patients who had received no HU and progressed to
AML or MDS had no 17p deletion. A review of the literature found
cytogenetic 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 with a leukemic risk of approximately 3.5%. A high
proportion of AML and MDS occurring in ET treated with HU (alone or
possibly followed by pipobroman) have morphologic, cytogenetic, and
molecular characteristics of the 17p syndrome. These
findings suggest that widespread and prolonged use of HU in ET may have
to be reconsidered in some situations, such as asymptomatic ET.
Blood, Vol. 91 No. 2 (January 15), 1998:
pp. 616-622
© 1998 by The American Society of Hematology.
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