Frequency and prognostic value of resistance/intolerance to hydroxycarbamide in 890 patients with polycythaemia vera

Abstract

The clinical significance of resistance/intolerance to hydroxycarbamide (HC) was assessed in a series of 890 patients with polycythaemia vera (PV). Resistance/intolerance to HC was recorded in 137 patients (15·4%), consisting of: need for phlebotomies (3·3%), uncontrolled myeloproliferation (1·6%), failure to reduce massive splenomegaly (0·8%), development of cytopenia at the lowest dose of HC to achieve a response (1·7%) and extra-haematological toxicity (9%). With a median follow-up of 4·6 years, 99 patients died, resulting in a median survival of 19 years. Fulfilling any of the resistance/intolerance criteria had no impact on survival but when the different criteria were individually assessed, an increased risk of death was observed in patients developing cytopenia [Hazard ratio (HR): 3·5, 95% confidence interval (CI): 1·5-8·3, P = 0·003]. Resistance/intolerance had no impact in the rate of thrombosis or bleeding. Risk of myelofibrotic transformation was significantly higher in those patients developing cytopenia (HR: 5·1, 95% CI: 1·9-13·7, P = 0·001) and massive splenomegaly (HR: 9·1, 95% CI: 2·3-35·9, P = 0·002). Cytopenia at the lowest dose required to achieve a response was also an independent risk factor for transformation to acute leukaemia (HR: 20·3, 95% CI: 5·4-76·5, P < 0·001). In conclusion, the unified definition of resistance/intolerance to HC delineates a heterogeneous group of PV patients, with those developing cytopenia being associated with an adverse outcome.

Risk of thrombosis according to need of phlebotomies in patients with polycythemia vera treated with hydroxyurea

“…In fact, only 1.5% of patients met the Hct resistance criterion defined by ELN as reported in previous studies. 12,13 Nevertheless, a higher rate of resistance/intolerance to HU was observed in patients requiring 3 or more PHL per year mainly due to more frequent extrahematologic toxicity; this could be explained by the higher HU doses employed in the group requiring supplemental PHL. These features illustrate how difficult it is to apply ELN resistance criteria in daily clinical practice.…”

“…Alberto Alvarez-Larrán, 1 Manuel Pérez-Encinas, 2 Francisca Ferrer-Marín, 3 Juan Carlos Hernández-Boluda, 4 María José Ramírez, 5 Joaquín Martínez-López, 6 Elena Magro, 7 Yasmina Cruz, 1 María Isabel Mata, 8 Pilar Aragües, 9 María Laura Fox, 10 Beatriz Cuevas, 11 Sara Montesdeoca, 1 José Angel Hernández-Rivas, 12 Valentín García-Gutiérrez, 13 María Teresa Gómez-Casares, 14 …”

From leeches to personalized medicine: evolving concepts in the management of polycythemia vera

“…90,91 A set of consensus criteria are commonly used to identify resistant or intolerant patients. 92 The development of cytopenias at the lowest dose of hydroxyurea needed to achieve a response was retrospectively associated with an increased risk of death and transformation to PPV-MF and AL.…”

“…92 The development of cytopenias at the lowest dose of hydroxyurea needed to achieve a response was retrospectively associated with an increased risk of death and transformation to PPV-MF and AL. 90 Patients who are not adequately controlled with therapy or who develop an intolerance do not have many options. In the case of intolerance, one common practice approach is to reduce the daily dose to the best tolerated one and make more generous use of phlebotomies to maintain the target hematocrit.…”

NCCN Guidelines Insights: Myeloproliferative Neoplasms, Version 2.2018

“…48,49 The development of cytopenia (one of the European LeukemiaNet [ELN]-defined criteria for resistance or intolerance to hydroxyurea) at the lowest dose of hydroxyurea is an adverse prognostic factor associated with higher risk of death and transformation to AML. 50,51 Patients with high-risk PV or ET treated with cytoreductive therapy as initial treatment should also be monitored for intolerance or resistance to hydroxyurea (see MPN-H; page 1202). 52 The International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and ELN have published treatment response criteria for PV and ET.…”