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©Ferrata Storti Foundation Haematologica 2000; 85:1011-1018 Hematology & Medicine original paper Efficacy of pipobroman in the treatment of polycythemia vera: long-term results in 163 patients FRANCESCO PASSAMONTI, ERCOLE BRUSAMOLINO, MARIO LAZZARINO, CLAUDIA BARATÉ, CATHERINE KLERSY,* ESTER ORLANDI, ANGELO CANEVARI, GUGLIELMO CASTELLI, SERENA MERANTE, CARLO BERNASCONI Institute of Hematology, University of Pavia; Division of Hematology, Biometry and *Clinical Epidemiology, Policlinico San Matteo IRCCS, Pavia, Italy ABSTRACT Background and Objectives. Polycythemia vera (PV) acute leukemia, late myelofibrosis, and solid tumors is a myeloproliferative disorder characterized by the is 5%, 4%, and 8%, respectively. The duration of expansion of the red cell mass. Our purpose was to pipobroman treatment did not correlate with these evaluate the efficacy of pipobroman (PB) in the long- events. term control of PV and to assess early and late ©2000, Ferrata Storti Foundation events. Design and Methods. From June 1975 to December Key words: polycythemia vera, pipobroman, thrombosis, acute 1997, 163 untreated patients with PV (median age leukemia, myelofibrosis. 57 years, range 30-82) were treated with PB in a sin- gle Institute for a median follow-up of 120 months. The diagnosis was made according to the Poly- olycythemia vera (PV) is a myeloprolifera- cythemia Vera Study Group criteria. PB was given at tive disorder characterized by expansion of the dose of 1 mg/kg/day until hematologic response the red cell mass unrelated to any pul- (hematocrit < 45% and platelets < 400×109/L) and P of 0.3-0.6 mg/kg/day as maintenance therapy. monary, cardiac, renal or neoplastic disease. Several approaches have been used to confirm Results. Hematologic remission was achieved in 94% suspected PV. The initial criteria proposed by the of patients in a median time of 13 weeks (range 6- Polycythemia Vera Study Group (PVSG) were applic- 48). Median overall survival was 215 months, with a 1 standardized mortality ratio of 1.7. The cumulative able only to patients with overt disease and risk of death was 11%, 22%, and 26% at 7, 10, and have been reconsidered in the last 10 years after 12 years, respectively. The incidence of thrombotic the introduction of more specific diagnostic events was 18.4×105 person-years and the cumula- techniques into clinical practice.2 The course of tive risk was 6%, 11%, 16%, and 20% at 3, 7, 10, PV has been well established by PVSG and GISP and 12 years respectively. Acute leukemia occurred (Gruppo Italiano Studio Policitemia) studies.3,4 A in 11 patients, myelofibrosis in 7, and solid tumors latent phase may precede the polycythemic in 11. The 10-year cumulative risk of leukemia, phase, with a known risk of thrombosis and myelofibrosis, and solid tumors was 5%, 4%, and hemorrhage. The overt polycythemic phase can 8%, respectively. In the logistic analysis age over 65 in turn develop into a spent phase. Metachro- (p = 0.0001) and thrombotic events at diagnosis (p = 0.001) were significantly correlated with a higher nous neoplasms may lead to death in about 30% risk of death. Female gender (p = 0.02) and age over of patients with PV: acute leukemia is of partic- 4 65 (p = 0.01) significantly influenced the occurrence ular prominence among such neoplasms. of thrombotic complications. Age was the only sig- Leukemia may be considered part of the natur- nificant risk factor for leukemia (p = 0.04) and for al history of the disease;3 a relation, however, solid tumors (p = 0.03), while the duration of PB with the leukemogenic risk of prior therapy treatment did not influence these risks. No signifi- could be considered.3-19 Historical data in cant risk factor was demonstrated for myelofibrosis. untreated patients with PV indicate a life- Interpretation and Conclusions. This study demon- expectancy of 18 months.20 However, in the last strates in a large series of patients, observed for a decades, the survival of these patients has dra- long period, that pipobroman is effective in the long- matically improved and has almost approached term control of PV. The risk of early thrombotic com- that of a matched population.21 Different treat- plications at 3 years is 6% and the 10-year risk of ment strategies have been utilized for patients with PV, including phlebotomy and cytoreduc- tion with either radiophosphorus or chemother- Correspondence: Francesco Passamonti, M.D., Institute of Hematology, apy.22-24 Nevertheless, there is no uniformly University of Pavia, Policlinico San Matteo IRCCS, Viale Golgi 19, 27100 accepted approach to the management of the Pavia, Italy. Phone: international +39-0382-503082 - Fax: international 25 +39-0382-502250 - E-mail: [email protected] disease. In the PVSG-01 randomized trial phle- Haematologica vol. 85(10):October 2000 1012 F. Passamonti et al. botomy was the only risk factor, in addition to to response. Phlebotomy was utilized during the advanced age and history of prior thrombosis, first months of treatment when hematocrit at associated with a significant risk of early throm- diagnosis exceeded 55%. In 26 patients (16%) botic accidents.3 In addition, about 90% of phle- phlebotomy was added occasionally during the botomized patients tend to discontinue this course of the disease prior to PB dose escala- treatment over time.13 Cytoreduction, obtained tion. Although no fixed criteria for administra- with different agents such as chlorambucil,3,6 tion of antiaggregating agents were adopted, 56 radiophosphorus,3,5,7,18,26 busulfan,7,8 pipobro- patients (34%) received antiaggregating therapy man,9,10,15,19 and hydroxyurea,11,14-18 is effective in at diagnosis with aspirin, dipyridamole, or ticlo- reducing early thrombotic events but could pidine. increase the risk of cancer.3,4 Anagrelide27 and α- 28 Statistical methods interferon are promising agents still requiring Data are presented as mean and standard long-term evaluation. The role of aspirin in the deviation for continuous variables, or median if prevention of thrombotic complications is being skewed, and as absolute and relative frequen- evaluated by the European Collaboration on Low- 29 cies for categorical variables. The following end- Dose Aspirin (ECLAP) study. Pipobroman (PB) is points were considered for the analysis: a) time a piperazine derivative with a chemical formula to thrombosis occurrence, b) time to leukemia related to alkylants. It acts as a metabolic com- development, c) time to myelofibrosis d) time petitor of pyrimidine bases and is of established 9,10,15,19 to solid tumors e) time to death. Kaplan Meier effectiveness in the control of PV. This estimation was used to calculate and plot the paper illustrates the long-term results in 163 cumulative probabilities of survival and event- patients with PV homogeneously treated with free survival; the cumulative hazard was also PB, expanding and updating our original find- 10 plotted. A Cox proportional hazard model was ings with particular emphasis on late events. fitted to assess the univariate prognostic value of Design and Methods a series of candidate risk factors including: age, sex, hemoglobin, hematocrit, platelet count, This study was conducted at the Institute of white blood cell count, red cell mass, serum ery- Hematology of the University of Pavia between thropoietin level, spleen and liver enlargement, June 1975 and December 1997 and included plethora at diagnosis, thrombotic events prior to 163 patients with PV treated with PB for more or at diagnosis, duration of PB therapy, phle- than 6 months. As of December 1998, the medi- botomy. Hazard ratios (HR) with 95% confi- an follow-up was 120 months (range 12-248). dence intervals (95% CI) were computed to mea- Patients lost to follow-up (4%) were censored at sure the relative risk of the event in one catego- the date of their last visit. ry of the tested variable in respect of the refer- Diagnostic criteria ence category. For the same variables the inci- The diagnosis of PV was made according to dence rate (expressed in number of events x per- the PVSG criteria.1 Culture studies (BFU-E and son-months of observation) with 95% CI was CFU-E) and the dosage of serum erythropoietin also calculated. The standardized mortality ratio were introduced to diagnose PV in 1987 and (SMR) with 95% CI was calculated in order to 1990, respectively. Response to therapy was allow comparison of the observed mortality with defined as a decrease of hematocrit to less than the expected one, based on the probability of 45% and a decrease of platelets to less than death in an age-and-sex-matched Italian popu- 400×109/L. The diagnoses of acute leukemia lation. The Stata 6.0 program (StataCorp Col- (AL) and myelodysplasia were based on the lege Station, TX, USA) was used for computa- French-American-British criteria.30,31 Myelo- tions. fibrosis (MF) was defined by the association of the following findings: leuko-erythroblastosis, Results anemia with tear-drop shaped red cells, spleno- Patients megaly, thrombocytopenia or thrombocytosis, extensive bone marrow fibrosis, systemic symp- The clinical characteristics of the 163 patients toms (fever, weight loss, bone pain). The diag- of this study are illustrated in Table 1. The nosis of solid cancer was based on a biopsy of male/female ratio was 1.5 and the median age of the suspected lesion. the patients was 57 years (range 30-82) with 17 of them under 40 years (10%). At diagnosis the Treatment mean value of hemoglobin and hematocrit was The induction dose of PB was 1 mg/kg/day 19±2 g/dL and 57±6%, respectively. Leukocytosis orally until response. The maintenance dose var- (WBC >12×109/L) and thrombocytosis (platelets ied between 0.3 and 0.6 mg/kg/day, according >400×109/L) were present in 53 patients (32%).
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