patient care perspectives

Resistance or Intolerance to Hydroxyurea in Patients With Polycythemia Vera

by Ruben A. Mesa, MD, FACP


Many patients with polycythemia vera (PV) benefit from hydroxyurea therapy, but some develop resistance or intolerance, as manifested by the persistence of elevated blood cell counts and the continuation of disease-related signs and symptoms. As newer second-line options for cytoreduction are being pursued, the need for tolerability over the long-term is recognized.  

Expert Commentary

Ruben A. Mesa, MD, FACP

Director, Mays Cancer Center at UT Health San Antonio MD Anderson
Mays Family Foundation Distinguished University Presidential Chair
San Antonio, TX

“Recognizing resistance or intolerance to hydroxyurea is important for making appropriate decisions about when to offer patients a second-line therapy.”

Ruben A. Mesa, MD, FACP

The discussions that I have with my patients with PV usually include a review of the goals of cytoreductive therapy, which are to improve disease-related symptoms, prevent the incidence or recurrence of thrombosis, and, ideally, delay or prevent progression to myelofibrosis or transformation to acute myeloid leukemia. The next step is to determine whether these goals have been met—not only the goals of symptom improvement and count reduction, but also, for those patients affected, of reduction of splenomegaly so that it becomes nonpalpable. Then, even if these goals are met, we need to consider: At what cost? Will the tolerability be acceptable to the patient on a day-to-day basis? Approximately 10% of individuals with PV treated with hydroxyurea will have to reduce the dose or stop treatment altogether due to peripheral blood cytopenias, mucositis, leg ulcers, skin cancers, dermatitis, or fever. Patients with leg ulcers tend to be older and they may already have vascular issues, but those ulcers are not going to heal with a dose reduction; hydroxyurea must be discontinued in such individuals. Moreover, patients who fail hydroxyurea therapy have a 5.6-fold increased risk of mortality and a 6.8-fold increased risk of transformation to myelofibrosis or acute myeloid leukemia.

Recognizing resistance or intolerance to hydroxyurea is important for making appropriate decisions about when to offer patients a second-line therapy. For individuals with PV who are on a daily dose of at least 2 g of hydroxyurea for at least 3 months, resistance/intolerance criteria are considered to be met when they require a continued need for phlebotomy to keep their hematocrit levels under 45% or when they have thrombocytosis, leukocytosis, or no improvement in splenomegaly related symptoms. The next step is choosing the least-toxic therapy for those who are refractory or resistant to hydroxyurea. Ruxolitinib, an inhibitor of Janus kinase 1 (JAK1) and 2 (JAK2), has proven to be superior to standard therapy in controlling the hematocrit, reducing the spleen volume, and improving symptoms associated with PV in patients with hydroxyurea resistance or intolerance. Ruxolitinib also induces normalization of leukocytosis and thrombocytosis. Much of the data on alternative cytoreductive therapies in this patient group come from retrospective analyses or clinical studies originating from a single or few academic centers, with relatively small numbers of patients and short follow-up times. Agents such as interferon-α are being studied in PV and have shown significant success in achieving hematologic responses and decreasing the JAK2 V617F mutation allele burden; however, Nazha and Gerds reported in their review that approximately 25% to 40% of patients who were treated with interferon-α in PV trials discontinued therapy due to side effects, the majority of which occurred in the first year of treatment.


Alvarez-Larrán A, Pereira A, Cervantes F, et al. Assessment and prognostic value of the European LeukemiaNet criteria for clinicohematologic response, resistance, and intolerance to hydroxyurea in polycythemia vera. Blood. 2012;119(6):1363-1369.

Alvarez-Larrán A, Pérez-Encinas M, Ferrer-Marín F, et al; Grupo Español de Neoplasias Mieloproliferativas Filadelfia Negativas. Risk of thrombosis according to need of phlebotomies in patients with polycythemia vera treated with hydroxyurea. Haematologica. 2017;102(1):103-109.

Barosi G, Birgegard G, Finazzi G, et al. A unified definition of clinical resistance and intolerance to hydroxycarbamide in polycythaemia vera and primary myelofibrosis: results of a European LeukemiaNet (ELN) consensus process. Br J Haematol. 2010;148(6):961-963.

Crittenden SC, Gilbert JE, Callen JP. Hydroxyurea-induced leg ulceration in a patient with a homozygous MTHFR polymorphism misdiagnosed as pyoderma gangrenosum. JAMA Dermatol. 2014;150(7):780-781.

Demuynck T, Verhoef G, Delforge M, Vandenberghe P, Devos T. Polycythemia vera and hydroxyurea resistance/intolerance: a monocentric retrospective analysis. Ann Hematol. 2019;98(6):1421-1426.

Nazha A, Gerds AT. Where to turn for second-line cytoreduction after hydroxyurea in polycythemia vera? Oncologist. 2016;21(4):475-480.

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