title: 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.
authors.affiliation: Haematology Department, Hospital del Mar, Barcelona, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Alvarez-Larrán
authors.affiliation: Haematology Department, Hospital La Paz, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Kerguelen
authors.affiliation: Haematology Department, Hospital Clínico, Valencia, Spain.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Hernández-Boluda
authors.affiliation: Haematology Department, Hospital Clínico, Santiago de Compostela, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Pérez-Encinas
authors.affiliation: Haematology Department, Hospital Morales Messeguer, Murcia, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Ferrer-Marín
authors.affiliation: Haematology Department, Hospital Nuestra Señora de Sonsoles, Avila, Spain.
authors.forename: Abelardo
authors.initials: A
authors.lastname: Bárez
authors.affiliation: Haematology Department, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Martínez-López
authors.affiliation: Haematology Department, Hospital Universitario de Burgos, Burgos, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Cuevas
authors.affiliation: Haematology Department, Hospital Costa del Sol, Marbella, Spain.
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Mata
authors.affiliation: Haematology Department, Hospital Ramón y Cajal, Madrid, Spain.
authors.forename: Valentín
authors.initials: V
authors.lastname: García-Gutiérrez
authors.affiliation: Haematology Department, Hospital de Cruces, Bilbao, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Aragües
authors.affiliation: Haematology Department, Hospital del Mar, Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Montesdeoca
authors.affiliation: Haematology Department, Hospital Príncipe de Asturias, Alcalá de Henares, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Burgaleta
authors.affiliation: Haematology Department, Hospital Miguel Servet, Zaragoza, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Caballero
authors.affiliation: Haematology Department, Hospital Universitario Infanta Leonor, Madrid, Spain.
authors.forename: J Angel
authors.initials: JA
authors.lastname: Hernández-Rivas
authors.affiliation: Hospital Son Espases, Palma de Mallorca, Spain.
authors.forename: M Antonia
authors.initials: MA
authors.lastname: Durán
authors.affiliation: Haematology Department, Hospital Dr. Negrín, Las Palmas de Gran Canarias, Spain.
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Gómez-Casares
authors.affiliation: Haematology Department, Hospital del Mar, Barcelona, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Besses
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004351:Drug Resistance; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000009:adverse effects / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D007958:Leukocyte Count; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D019384:Nucleic Acid Synthesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011087:Polycythemia Vera / Q000097:blood / Q000188:drug therapy*; D011379:Prognosis; D012042:Registries; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D019384:Nucleic Acid Synthesis Inhibitors; D006918:Hydroxyurea
keywords: hydroxycarbamide; myeloproliferative neoplasms; polycythaemia vera; resistance/intolerance; response criteria