Hydroxyurea-induced marked oscillations of platelet counts in patients with polycythemia vera

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.

Oscillatory haematopoiesis in adults with sickle cell disease treated with hydroxycarbamide

“…The population distribution of all significant periods of oscillation for platelet and leucocyte counts showed that the most prevalent periods across the cohort were 27 ± 1 d for platelets and 15 ± 1 d for leucocytes (Fig ). Less prevalent peaks were observed for platelets at 15 ± 1 d and 45 ± 1 d, and for leucocytes at 30 ± 1 d and 78 ± 1 d. Each of these periods noted within our cohort overlap with values previously described in the literature for both haematological lineages (Fortin & Mackey, ; Tefferi et al , ; Bennett & Grunwald, ; Steensma et al , ; Burthem & Chaudhry, ; Tauscher et al , ). At the cohort level, hydroxycarbamide appeared to have a consolidating effect upon the distribution of detectable periods for oscillating platelet‐ and leucocyte‐producing bone marrow populations, leading to fewer dominant periods while receiving the drug (Fig ).…”

“…Within the scope of hydroxycarbamide maintenance therapy in SCD, while the shifts between nadirs and zeniths in these patients' blood counts may appear precipitous in the short term, our data indicates that, in general, this pattern does not pose a danger of myelotoxicity to the patient, and recovery to normal ranges occurs in many cases without intervention. As noted in previous cases, it appears that stable and consistent hydroxycarbamide dosing leads to dampening of the oscillatory behaviour over time, while frequent dosage changes often lead to amplification of the oscillations and even more far ranging nadirs and zeniths (Kennedy, ; Tefferi et al , ; Bennett & Grunwald, ; Steensma et al , ; Tauscher et al , ). Importantly, our results indicate that oscillatory haematopoiesis is not a phenomenon limited to malignant or pre‐malignant haematological disorders, a finding that should prompt further investigation of its significance and prevalence in other patient populations receiving cell cycle‐specific inhibitors.…”

“…These oscillations have been observed outside of hydroxycarbamide treatment in a wide variety of patient cohorts including chronic myeloid leukaemia (CML) (Morley et al , ; Vodopick et al , ; Mehta & Agarwal, ; Malhotra & Salam, ), cyclic neutropenia (Dale et al , ), polycythaemia vera (PV) (Morley, ) and even as a feature of normal haematopoiesis (Morley et al , ; Moser et al , ). Oscillations in association with hydroxycarbamide therapy have also been reported in several retrospective case series totalling seven patients with CML (Kennedy, ; Bennett & Grunwald, ), and 20 patients with PV (Tefferi et al , ; Steensma et al , ; Burthem & Chaudhry, ; Tauscher et al , ). Though the subject of numerous case reports, it has not been until recently that a statistical method of distinguishing these oscillation patterns has been applied to blood count data (Fortin & Mackey, ; Bennett & Grunwald, ; Tauscher et al , ).…”

“…Using this methodology, it was observed in patients with CML receiving hydroxycarbamide that neutrophil, monocyte, platelet, haemoglobin, and reticulocyte counts all demonstrated oscillations in a range of periods from 30 to 80 d (Fortin & Mackey, ; Bennett & Grunwald, ). This observation was also made in patients with PV receiving hydroxycarbamide in platelet and leucocyte counts, with their oscillations exhibiting a much narrower range of periods from 28‐30 d (Tefferi et al , ; Bennett & Grunwald, ; Steensma et al , ; Burthem & Chaudhry, ; Tauscher et al , ). Oscillatory blood counts among these cohorts were noted to range far outside of normal values before reaching their absolute nadir or zenith.…”

“…Because of the previous apparent association of blood count oscillations with myeloproliferative disease states, numerous theories attributed the mechanism of these oscillations to malignant or pre‐malignant specific pathobiology. While there is some evidence that even in normal individuals there may be a continuous stable oscillation of every haematopoietic cell lineage (Morley et al , , ; Von Schulthess & Gessner, ; Moser et al , ), the myeloproliferative disease‐centric theories postulate that clonal bone marrow progenitor cells present in myeloproliferative diseases may be abnormally sensitive to lineage‐specific growth signals, hydroxycarbamide therapy, or a combination of factors (Zent et al , ; Santillán et al , ; Tefferi et al , ; Steensma et al , ). These neoplastic alterations in signalling pathways are thought to manifest as oscillations apparent in macroscopic measures, such as peripheral blood counts.…”