Blood, 15 August 2000, Vol. 96, No. 4, pp. 1582-1584
BRIEF REPORT
Hydroxyurea-induced marked oscillations of platelet counts in
patients with polycythemia vera
Ayalew Tefferi,
Michelle A. Elliott,
Pai Chih Kao,
Sooyoung Yoon,
Ihab El-Hemaidi, and
Thomas C. Pearson
From the Division of Hematology and Internal Medicine
and the Division of Clinical Biochemistry and Immunology, Mayo Clinic
and Mayo Foundation, Rochester, MN, and the Department of
Haematological Medicine, St. Thomas' Hospital, London, UK.
 |
Abstract |
Two prospectively studied patients with polycythemia vera (PV)
whose platelet counts showed marked periodic fluctuation during treatment with hydroxyurea (HU) are reported. Cycle lengths in both
were approximately 28 to 30 days. In one patient, the cyclic process
was no longer evident when treatment with HU was withheld, and it
reappeared on treatment rechallenge. Circulating thrombopoietin (TPO)
levels fluctuated out of phase with the platelet count despite markedly
reduced TPO-receptor (c-Mpl) expression in bone marrow megakaryocytes.
These observations suggest that the cyclic phenomenon may be related to
both a transient state of HU-induced depletion of megakaryocytes and a
concentration-dependent mitigation by TPO of the HU effect on
megakaryocytes and their precursors. It is conceivable that the
affected patients harbor a megakaryocyte progenitor pool whose
apoptotic activity is differently modulated by either HU or high
concentrations of TPO.
(Blood. 2000;96:1582-1584)
© 2000 by The American Society of Hematology.
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Introduction |
Hydroxyurea (HU) is a nonalkylating
myelosuppressive agent that impairs DNA synthesis through the
inhibition of ribonucleotide reductase.1 The drug is often
used to supplement phlebotomy for patients with polycythemia vera (PV)
who are at high risk.2 Similarly, treatment with HU has
been shown to reduce significantly the incidence of recurrent
thrombosis in patients with essential thrombocythemia who are at high
risk.3 In addition, though the therapeutic use of HU may
be declining in patients with chronic myeloid leukemia,4
it is gaining momentum in those with sickle cell disease.5
Side effects of HU are usually limited to the integument (leg ulcers,
skin and nail hyperpigmentation, aphthous ulcers) and have been said to
occur in approximately one third of treated patients.6 In
addition, HU-induced cytopenia(s) may occur in some patients with PV if
the drug is not used judiciously but is usually transient and dose
dependent. In this report, we describe an unusual cycling of platelet
counts with marked peak-to-trough amplitude, which is associated
with HU therapy in patients with PV.
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Study design |
Patient 1
A 54-year-old woman was diagnosed with PV in 1996 when she
sought treatment for migraine headaches, aquagenic pruritus, and increased hemoglobin concentration (17.5 g/dL; baseline, 13.5 g/dL).
Hematocrit was 53%, white blood cell count was
7.4 × 109/L, and platelet count was
534 × 109/L. Additional studies revealed an increased
red cell mass, a reduced serum erythropoietin (EPO) level, and an
increased neutrophil alkaline phosphatase score. The spleen was not
palpable. The patient was initially treated with phlebotomy alone,
during which time her platelet count remained stable (Figure
1). In July 1998, HU therapy (1 g/d) was
initiated because she had a transient ischemic attack. Shortly
afterward, cyclical fluctuations of platelet count developed that were
sustained as long as the patient remained on HU treatment (Figure 1;
highest and lowest platelet counts of 1412 and
50 × 109/L, respectively). Keeping the HU dose constant
reduced the interval variations and produced a higher nadir in the
platelet count (highest and lowest platelet counts of 693 and
91 × 109/L, respectively). Withholding treatment with HU
resulted in prompt cessation of the cyclic changes, which reappeared
with the resumption of HU therapy (Figure 1; highest and lowest
platelet counts of 775 and 42 × 109/L, respectively). It
is underscored that the daily dose of HU from week 8 through week 24 (1000 mg/d) and from week 39 through week 49 (1500 mg/d) was not
altered at any point despite the marked fluctuations in the platelet
count. Serum thrombopoietin (TPO), but not EPO, levels fluctuated out
of phase with the platelet count during a therapeutic rechallenge
(Figure 1). Serum TPO was measured by "in-house"
immunochemiluminometric assay. A plastic bead-immobilized
monoclonal anti-TPO antibody was used as the capture antibody, and an
acridinium ester-labeled, immunopurified polyclonal anti-TPO antibody
was used as the detection antibody (R&D Systems, Minneapolis, MN).
Recombinant human TPO was used as a standard. The detection limit of
the assay was 10 pg/mL, with an intra-assay and an interassay
coefficient of variation of 5% and 10%, respectively.
Immunohistochemical staining of the bone marrow revealed reduced
megakaryocyte expression of TPO receptor (c-Mpl). The patient did not
respond to subsequent treatment with either anagrelide (up to 4 mg/d
for 10 weeks) or 
-interferon (5 million U subcutaneously 3 times/wk
for 6 weeks [Figure 1]).
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| Figure 1.
Hydroxyurea-induced cyclic variations of platelet count
and serum thrombopoietin concentration (TPO) in a patient with
polycythemia vera.
The reference range for TPO is 11 to 70 pg/mL, and for serum EPO
concentration it is 4 to 24 pg/mL. No remarkable variations were noted
in hematocrit (Hct), white blood cell count (WBC), or EPO
concentration. Alpha INF, -interferon.
|
|
Patient 2
A 59-year-old man was diagnosed with PV in 1995 when he
sought treatment for a spontaneous left groin hematoma. Hemoglobin concentration was 21.0 g/dL, hematocrit was 64%, and platelet count
was 636 × 109/L. Additional studies revealed an
increased red cell mass, a reduced serum EPO level, an endogenous
erythroid colony growth, and a normal spleen. Initial treatment
consisted of phlebotomy supplemented by HU 1 g/d. In the following 3 weeks, the platelet count normalized and HU was withheld. After another
2 weeks, the patient was admitted to the hospital because of a syncopal
episode; the platelet count at the time was 936 × 109/L.
Treatment with HU was restarted. During the first 5 months the platelet
count fluctuated from a 28- to 30-day cycle, with doses of HU ranging
between 0.0 and 3.0 g/d (Figure 2;
highest and lowest platelet counts of 1400 and
35 × 109/L, respectively). Subsequently, the HU dose was
kept steady at 500 mg/d and the platelet cycle persisted, albeit with a
higher nadir count and a lower peak value (Figure 2; highest and lowest platelet counts of 810 and 179 × 109/L,
respectively).
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| Figure 2.
Hydroxyurea-associated cyclic variations in the platelet
count of a patient with polycythemia vera.
Use of constant drug dosage resulted in a higher nadir of the platelet
count and a smaller interval variation. Hematocrit (Hct) and white
blood cell count (WBC) did not show similar periodic
fluctuations.
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Results and discussion |
Unprovoked periodic oscillations of the platelet count have been
reported in both the absence7 and the presence of chronic myeloid disorders, including PV.8,9 The periods of cycling in these patients varied from 27 to 66 days. To our knowledge, the
current study is the first to report a well-documented case of
drug-induced cyclic variations in the platelet count of a patient with
PV (patient 1). A similar phenomenon was demonstrated in our second
patient with PV, but the causal role of HU could not be confirmed
because serial platelet counts in the absence of treatment with HU were
not documented. Use of HU has previously been associated with cyclic
variations of granulocyte count in patients with chronic myeloid
leukemia (cycle length, 30 to 50 days).10 However, it is
unclear whether the reported cases were observed with patients off
therapy to confirm the pathogenic role of HU in inducing the cycling
process. Nevertheless, periodic oscillations of the granulocyte
count have also been associated with the use of myeloid growth
factors11 and melphalan-based intermittent
chemotherapy.12
The induction of oscillatory changes in hematopoiesis may require the
presence of a destabilized stem cell pool and a cytokine-mediated feedback control that feeds into a compulsory delay in mitotic response.13 In the currently described patients, the
former situation may have been created by HU, whereas the out-of-phase variation in serum TPO level suggests retention of an autoregulatory response despite the demonstrated, and expected,14
reduction in megakaryocyte c-Mpl expression.15,16 It is
conceivable that the affected patients harbor a megakaryocyte
progenitor pool that either is unusually sensitive to HU or displays a
different apoptotic response to high concentrations of
TPO.17,18 Inhibition of either endogenous or drug-induced
apoptosis by markedly elevated levels of TPO may allow megakaryocyte
survival and platelet production despite continuous exposure to the
drug. Accordingly, the cycle is completed when drug sensitivity is
reestablished by the subsequent reduction in TPO level. The possibility
of an unusual drug-megakaryocyte interaction was further suggested by
the lack of response to subsequent treatment with either anagrelide or
-interferon.19,20
The currently described phenomenon may account for some, at
least, of the difficulty in adjusting the doses of HU in certain patients with PV or related disorders. In such instances, our experience suggests that frequent adjustments in the HU dose may produce a "bouncing ball" effect with marked peak-to-trough
amplitudes. Keeping the HU dose steady, on the other hand, may reduce
the severity of both the platelet nadir and the interval variation. Conversely, an alternative platelet-lowering agent, though not successful in one of our patients, may be tried.19,20
| |
Footnotes |
Submitted December 13, 1999; accepted March 31, 2000.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Ayalew Tefferi, Division of Hematology and
Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN
55905.
| |
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Abstract
Introduction
