Blood, Vol. 92 No. 4 (August 15), 1998:
pp. 1459-1461
CORRESPONDENCE
Is Hydroxyurea Leukemogenic in Essential Thrombocythemia?
 |
LETTER |
To the Editor:
Hydroxyurea (HU) is a structurally simple antimetabolite that
interferes with DNA synthesis by inhibiting ribonucleotide reductase. Although not directly genotoxic, HU may impair the repair of damaged DNA, raising a legitimate concern regarding mutagenecity. Accordingly, Sterkers et al1 reported their experience in 357 patients
with essential thrombocythemia (ET) and concluded that treatment with HU may induce acute leukemia characterized by a particular cytogenetic abnormality (17p
). While the study provides valuable clinical information derived from an impressively large collection of patients, several points deserve commentary.
In the particular study, conventional criteria were used to diagnose
ET. However, baseline bone marrow and cytogenetic studies were not
performed in an unspecified number of patients (the investigators should provide the information). It appears that these studies were
performed only when clinical or laboratory features suggested myeloid
metaplasia, chronic myelogenous leukemia (CML), or a myelodysplastic syndrome (MDS). However, these measures are not adequate to prevent the
inadvertent inclusion of atypical cases of the latter disorders in the
study population.2 Biologic heterogeneity in ET is further exemplified by recent studies demonstrating the presence of bcr-abl transcripts3 and polyclonal hematopoiesis4 in a
significant number of patients with ET. Therefore, conclusions
regarding leukemic risk in ET are more accurate when baseline bone
marrow examinations with cytogenetic studies are available in all
patients. It might even be argued that molecular studies may be needed
in future studies to identify karyotypically occult cases of CML.
The study population included patients who are either untreated (31 patients), or received therapy with single agent pipobroman (12 patients), busulfan (35 patients), HU (201 patients), 32P
(29 patients), or HU and other agents (50 patients). The corresponding leukemic incidences were 0%, 0%, 3%, 3.5%, 7%, and 14%,
respectively. It is imperative to note that the study was not
randomized and was systematically biased into grouping patients on the
basis of treatment requirement. Furthermore, allocation to the
different treatment groups was sometimes dictated by age and/or
disease refractoriness, both of which could influence leukemic risk. In other words, the patients in the different treatment groups are not
biologically comparable. In addition, the number of events occurring in
each treatment group are too small to allow statistically valid
comparisons. Therefore, it is impossible to draw accurate conclusions
regarding drug leukemogenecity from the present study.
Because of the increasing use of HU in nonhematologic
disorders,5 any implication regarding drug leukemogenecity
should be accurate and based on sound evidence. Data from retrospective cohort studies are often misleading because of the lack of appropriate comparison groups. In general, published reports on the association of
HU and acute leukemia have been inconsistent and the strength of the
association has been relatively small. In our experience, we did not
encounter a single case of acute leukemia in either a population-based
study of 39 cases6 or a retrospective study of 74 young
women with ET observed for a median of greater than 5 years.7 In both studies, approximately half of the patients were treated with HU. The current availability of nonmutagenic platelet-lowering agents should allow examination of the issue in a
prospective randomized setting.8
Ayalew Tefferi
Division of Hematology
Mayo Clinic
Rochester,
MN
| |
REFERENCES |
1.
Sterkers Y,
Preudhomme C,
Lai JL,
Demory JL,
Caulier MT,
Wattel E,
Bordessoule D,
Bauters F,
Fenaux P:
Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemia treated with hydroxyurea: High proportion of cases with 17p deletion.
Blood
91:616,
1998[Abstract/Free Full Text]
2.
Stoll DB,
Peterson P,
Exten R,
Laszlo J,
Pisciotta AV,
Ellis JT,
White P,
Vaidya K,
Bozdech M,
Murphy S:
Clinical presentation and natural history of patients with essential thrombocythemia and the Philadelphia chromosome.
Am J Hematol
27:77,
1988[Medline]
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3.
Blickstein D,
Aviram A,
Luboshitz J,
Prokocimer M,
Stark P,
Bairey O,
Sulkes J,
Shaklai M:
Bcr-Abl transcripts in bone marrow aspirates of Philadelphia-negative essential thrombocythemia patients
Clinical presentation.
Blood
90:2768,
1997[Abstract/Free Full Text]
4.
Elkassar N,
Hetet G,
Briere J,
Grandchamp B:
Clonality analysis of hematopoiesis in essential thrombocythemiaAdvantages of studying T lymphocytes and platelets.
Blood
89:128,
1997[Abstract/Free Full Text]
5.
Charache S,
Terrin ML,
Moore RD,
Dover GJ,
Barton FB,
Eckert SV,
McMahon RP,
Bonds DR:
Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia [see comments].
N Engl J Med
332:1317,
1995[Abstract/Free Full Text]
6. (abstr, suppl 1)
Mesa RA,
Tefferi A,
Jacobsen SJ,
Wollan PC,
Silverstein MN:
The incidence and epidemiology of essential thrombocythemia and agnogenic myeloid metaplasia: An Olmstead County study.
Blood
90:347a,
1997
7. (abstr)
Fonseca R,
Tefferi A:
Essential thrombocytosis in young women.
Proc Am Soc Clin Oncol
16:6a,
1997
8.
Anagrelide Study Group:
Anagrelide, a therapy for thrombocythemic states: Experience in 577 patients.
Am J Med
92:69,
1992[Medline]
[Order article via Infotrieve]
| |
RESPONSE |
To the Editor:
We agree with Dr Tefferi that one should be very cautious before
drawing conclusions about leukemogenicity of HU from a retrospective analysis in which treatment was not randomized. A major objective of
our work1 was to try to understand the relatively high
number of cases of progression to MDS and AML with the 17p deletion we had recently observed at our institution in ET and also (unpublished results) in polycythemia vera (PV). These cases appeared
to be more frequent after HU or pipobroman than after classical
alkylating agents such as busulfan, although the causality between the
former drugs and MDS and AML with this 17p
syndrome
cannot be determined.
In this study, we also found that 4.5% of all ET patients, including
3.5% of the 201 treated with HU alone progressed to MDS or AML. Only
195 of the patients had been karyotyped at diagnosis, and bone marrow
core biopsy is not a usual procedure at our institution when ET is
suspected and no clinical or biological features suggesting agnogenic
myeloid metaphase (AMM) are present. However, it is improbable that the
17 patients who progressed to MDS or AML, especially the 7 who had
received HU alone, initially had another disorder than ET. Indeed, had
those cases been CML with thrombocythemic onset, t(9;22) would have
been present at leukemic progression. Furthermore, none of the
progressions was preceded by a phase of prominent myeloid metaplasia,
which would have been observed had the initial disease been incipient
AMM. Also of note is that MDS with thrombocythemia mainly include
acquired sideroblastic anemia and the 5q syndrome,
which, in our experience, are always complicated by anemia long before
a possible (and rare) progression to AML is observed and cannot be
mistaken for ET for a long period of time.3
In addition, the incidence of AML and MDS we observed after HU alone
(3.5% of 201 cases) was almost similar to that observed in the
literature (3.4% of 293 cases).2 Although it is true that
treatment was not randomized in our study, patients who received HU
alone did not seem to represent a population with particularly active
disease, which could have been associated with a higher risk of
evolution to AML. Indeed, our practice has been to treat most ET
(<10% remained untreated in the present series) and, over the last
12 years, first-line treatment has almost always been HU. Only patients
who did not achieve permanent normalization of platelet counts with HU
(ie, presumably patients with more active disease) received additional
drugs.
We believe that our findings confirm other reports that treatment with
HU alone is associated with a certain risk of leukemic progression in
ET and PV. The absence of progression reported by Tefferi with HU alone
in two series rests on a relatively small number of cases and
relatively small follow-up. The association between HU and leukemic
progression in ET, especially with 17p deletion, does not prove that HU
is directly a causative agent. Progression to AML, particularly with
17p deletion, is part of the natural evolution of another
myeloproliferative disorder, ie, CML. Therefore, HU may not be
leukemogenic in diseases other than MPD. On the other hand, caution
over its use and close follow-up of patients treated for
nonneoplastic disorders will certainly be required.
Pierre Fenaux
Claude Preudhomme
Jean-Luc Laï
Yvon Sterkers
Department of Hematology
CHU Lille
Lille,
France
| |
REFERENCES |
1.
Sterkers Y,
Preudhomme C,
Laï JL,
Demory JL,
Caulier MT,
Wattel E,
Bordessoule D,
Bauters F,
Fenaux P:
Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemai treated with hydroxyurea: High proportion of cases with 17p deletion.
Blood
91:616,
1998
2.
Fenaux P:
Myelodysplastic syndromes.
Hematol Cell Ther
38:363,
1996[Medline]
[Order article via Infotrieve]
