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Blood, 1 May 2003, Vol. 101, No. 9, pp. 3749-3749
CORRESPONDENCE
To the editor:
Efficacy and safety of long-term use of hydroxyurea in young
patients with essential thrombocythemia and a high risk of thrombosis
The optimal treatment of young patients with essential
thrombocythemia (ET) at high risk of thrombohemorrhagic complications is uncertain. Storen and Tefferi1 recently reported on the long-term use of anagrelide, a platelet-lowering agent without myelosuppressive activity. In a population of 35 young ET patients (median age, 38 years; range, 17-48 years) followed for a median of
10.8 years (range, 7-15 years), rates of 20% for thrombosis, 20% for
major bleeding, and 24% for anemia were observed. Hydroxyurea (HU) may
be a more effective agent, because a significant reduction in the
incidence of thrombotic complications was demonstrated in a randomized
clinical trial including ET patients of all ages.2 However, long-term exposure to this agent may increase the rate of
leukemic transformation, and it is presently unknown how this benefit-risk ratio applies to younger patients. To address this issue, we examined a consecutive cohort of 25 ET
patients aged younger than 50 years (median age, 42 years; range, 18-49 years) who started on HU therapy before January 1, 1997, and were previously untreated. Hydroxyurea was given for platelet count
persistently higher than 1 500 × 109/L (12 cases; 48%) or the occurrence of a major vascular event, such as
ischemic stroke (5 cases), myocardial infarction (3 cases), portal vein
thrombosis (2 cases), peripheral arterial thrombosis (2 cases), or
pulmonary embolism (1 case). Patients with thrombosis were given
standard antithrombotic prophylaxis with aspirin (100 mg/d) if
arterial, or warfarin to a target international normalized ratio of 2.5 if venous. No cytoreductive drugs other than HU were used. The median
platelet count at the start of HU was
933 × 109/L (range,
426-3 200 × 109/L). The aim of therapy was to maintain
platelet count less than 600 × 109/L, or less than
400 × 109/L in those patients who had thrombosis with
platelet count between 400 and 600 × 109/L. Patients
were checked every 3 months, or more frequently if indicated, and, at
the last control, the target range of platelet counts was achieved in
20 patients (80%) (median, 450 × 109/L;
range, 312-698 × 109/L). After 8 years median follow-up
(range, 5-14 years), no patient had to withdraw the drug for
intolerance or adverse effects. One case (4%) of transient ischemic
attack but no major thrombosis or severe bleeding was recorded. Most
important, no case of leukemic or neoplastic transformation or
death occurred. This indirect comparison of long-term cohort studies suggests that HU
is more effective than anagrelide in preventing thrombosis in the
young, apparently without an increase in leukemic risk. There are
theoretic reasons to support the superiority of HU as an antithrombotic
drug, besides its platelet-lowering effect. As a general
myelosuppressive agent, HU also affects polymorphonuclear leukocytes
(PMNs) and red blood cells counts, and there is growing evidence in the
literature that these cells play a major role in the pathogenesis of
thrombosis, also in ET patients.3 Further data come from
the widespread use of HU in children with sickle cell disease to reduce
the frequency of vaso-occlusive events. Recent works indicate that the
clinical efficacy of the drug in this setting is related to the
correction of abnormal interactions between PMNs and vascular
endothelium, thus preventing reduced blood flow, microvascular
occlusion, and vascular damage.4 Interestingly, after more
than 10 years of use, no leukemia has been related to HU treatment in
these children. Randomized clinical trials are needed to accurately compare the
efficacy and toxicity of platelet-lowering agents in ET. However, it is
foreseen that these studies will give reliable information mainly on
short-term clinical end points, such as drug toxicity and early
vascular complications. Long-term outcomes, such as leukemogenesis, can
hardly be evaluated in randomized trials and remain to be investigated
in appropriate cohort studies such as those reported herein. To date,
our long-term results support the use of HU also for younger patients
with ET, if they carry a high risk of life-threatening
thrombohemorrhagic complications due to a previous thrombotic history
or persistent very high platelet count.
Guido Finazzi, Marco Ruggeri, Francesco Rodeghiero, and Tiziano Barbui
Correspondence: Dr Guido Finazzi, Divisione di Ematologia,
Ospedali Riuniti, Largo Barozzi 1, 24128 Bergamo, Italy; e-mail:
gfinazzi{at}ospedaliriuniti.bergamo.it
References
1.
Storen EC, Tefferi A.
Long-term use of anagrelide in young patients with essential thrombocythemia.
Blood.
2001;97:863-866[Abstract/Free Full Text].
2.
Cortelazzo S, Finazzi G, Ruggeri M, et al.
Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis.
N Engl J Med.
1995;332:1132-1136[Abstract/Free Full Text].
3.
Falanga A, Marchetti M, Evangelista V, et al.
Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera.
Blood.
2000;96:4261-4266[Abstract/Free Full Text].
4.
Benkerrou M, Delarche C, Brahimi L, et al.
Hydroxyurea corrects the dysregulated L-selectin expression and increased H2O2 production of polymorphonuclear neutrophils from patients with sickle cell anemia.
Blood.
2002;99:2297-2303[Abstract/Free Full Text].
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