©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 single 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 cytoreduction 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%).

Haematologica vol. 85(10):October 2000 Pipobroman in polycythemia vera 1013

Table 1. Characteristics of the patients. Efﬁcacy Pipobroman induced a complete response in Number % 153 patients (94%). The median time from the start of therapy to response was 13 weeks (range Patients 163 6-48). After response, 142 patients (93%) received continuous maintenance therapy with Male/female 98/65 60/40 PB to keep the hematocrit and hemoglobin Median follow up, months (range) 120 (7-248) within the normal ranges. In 11 patients, PB Median age, years (range) 57 (30-82) therapy could be withheld at the achievement of remission and was restored at disease expan- Mean hemoglobin value (g/dL) 19±2 sion. Six responders (4%) developed resistance Mean hematocrit value (%) 57±6 to PB after a median time of 80 months (range Mean white blood cell value (×109/L) 11±5 36-165). They received busulfan 2-4 mg/day (3 Mean platelet value (×109/L) 357±256 patients, 3 responded), or hydroxyurea 500- 1,000 mg/day (3 patients, 2 responded). In all Thrombocytosis (>400×109/L) 53 32 the 53 patients presenting with thrombocytosis Leukocytosis (>12×109/L) 53 32 the response of the hematocrit was also accom- Enlarged spleen 78 48 panied in 2-4 months by normalization of Enlarged liver 71 43 platelet counts, which were maintained subsequently in the normal range by PB therapy. Vascular accidents pre-PV 29 18 arterial 22 14 Toxicity venous 7 4 Pipobroman was well tolerated, with a good Minor neurologic disturbances 39 24 compliance. Blood counts were checked every Pruritus 35 21 4-8 weeks. No acute toxicities after PB were doc- Hypertension 28 17 umented. Grade 2 (WHO grading) leukopenia occurred in two patients and grade 4 thrombo- Thrombosis at diagnosis of PV 26 16 arterial 13 8 cytopenia in a single patient. Full hematologic venous 13 8 recovery was obtained after PB discontinuation. Hemorrhage 5 3 The main PB toxicity was gastrointestinal, with 12 patients (7%) complaining of mild gastric Myocardiopathy 3 2 pain or diarrhea. Two patients (1%) developed No symptoms 61 37 dermatologic side effects (dry skin and acne). Late complications During the course of the disease, several adverse events occurred including cardiovascular complications in 10 patients (6%), minor neurologic symptoms in 17 (10%), thrombotic The mean value of WBC and platelet counts was complications in 30 (18%), and secondary neo- 11±5×109/L and 357±256×109/L, respectively. plasms in 29 (17%). Isolated splenomegaly was present in 31 patients Cardiovascular events included hypertension (19%) and isolated hepatomegaly in 21 (12%). in 6 patients and myocardiopathy with conges- Fifty patients (31%) had liver and spleen enlarge- tive heart failure in 4. All these events occurred ment. During the two years preceding the diag- in patients over 65, and 4 had histories of car- nosis of PV, vascular episodes occurred in 29 diovascular diseases. Minor neurologic symp- patients (18%) including 10 who suffered myo- toms, mainly attributable to hyperviscosity, con- cardial infarction, 6 angina pectoris, 6 an sisted of paresthesia, headache, blurred vision ischemic stroke or transient ischemic attacks, and and tinnitus. The incidence of thrombotic com- 7 venous thrombosis. At diagnosis, the clinical plications was 18.5×105 person-years, and the features of the disease were as follows: minor cumulative risk was 6%, 11%, 16%, and 20% at neurologic disturbances such as dizziness, verti- 3, 7, 10, and 12 years of observations, respec- go, paresthesia, headache, blurred vision, tinnitus tively (Figure 1a). The median age at occurrence in 39 patients (24%), pruritus in 35 (21%), hyper- of thrombosis was 61 years (range 30-77) and tension in 28 (17%), venous thrombosis in 13 the male/female ratio 0.6. The median time (8%), myocardial infarction or angina pectoris in from the onset of PV to thrombosis was 55 8 (5%), transient ischemic attacks or cerebral months (range 4-162). Forty-nine patients expe- stroke in 5 (3%), hemorrhage in 5 (3%), and rienced thrombosis before the diagnosis of PV or myocardiopathy in 3 (2%). Sixty-one patients at diagnosis and were at high risk of vascular (37%) were asymptomatic. accidents. Seven of these 49 patients (14%)

Haematologica vol. 85(10):October 2000 1014 F. Passamonti et al.

Figure 1. Nelson-Aalen cumulative hazard model of thrombosis (A), leukemia (B), myelofibrosis (C) and solid tumors (D) in patients with polycythemia vera treated with pipobroman. developed thrombosis during PB treatment. lasted 7, 9, and 11 months. All 3 patients treat- Thrombotic episodes included: superficial ed with busulphan after PB developed leukemia. thrombophlebitis of the lower limb in 13 Busulphan was administered in these 3 patients patients, mesenteric thrombosis with intestinal for 9, 16 and 44 months after 165, 100 and 100 infarction in 4, deep venous thrombosis of the months of pipobroman therapy, respectively. lower limb in 3 (two of them had pulmonary The median survival from the diagnosis of AL embolism), ischemic stroke in 3, myocardial was 4 months (range 1-9). The incidence of infarction in 3, transient ischemic attacks in 2, myelofibrosis (MF) was 4.3×105 person-years, angina pectoris in 2. Seventeen of these compli- with a cumulative risk of 1%, 4%, and 6% at 7, cations were life-threatening. Secondary neo- 10, and 12 years, respectively (Figure 1c). The plasms consisted of acute leukemia (AL) in 11 median age at the occurrence of MF was 66 patients (7%), solid tumors in 11 (7%), and years (range 54-68) and the male/female ratio myelofibrosis in 7 (4%). Table 2 illustrates the 2.5. The median time from the onset of PV to characteristics of the patients who developed MF was 119 months (range 88-166). Patients subsequent neoplasms. The incidence of acute who developed MF had been given PB for a leukemia was 6.7×105 person-years and the median of 98 months (range 42-172). The medi- cumulative risk was 1%, 5%, and 6% at 7, 10, an survival from the diagnosis of MF was 18 and 12 years, respectively (Figure 1b). The medi- months (range 5-31). The incidence of meta- an age at the occurrence of AL was 72 years chronous solid tumors (ST) was 6.8×105 per- (range 61-77) and the male/female ratio 0.6. son-years, with a cumulative risk of 4%, 8%, and The median time from the onset of PV to AL was 9% at 7, 10, and 12 years, respectively (Figure 133 months (range 88-179). Acute leukemias 1d). The median age at the occurrence of ST was were classified as myeloid in 10 patients (M1 in 67 years (range 56-75) and the male/female 4, M4 in 4, M5 in one, M6 in one), and as lym- ratio 2.6. The median time from the onset of PV phoid in one. A myelodysplastic phase heralded to ST was 85 months (range 39-110). The AL in 2 patients, while in 2 patients AL devel- patients who developed ST had been given PB oped after myelofibrosis. The patients who for a median time of 70 months (range 19-100). developed AL had been given PB for a median Solid tumors were as follows: lung cancer in 5 time of 100 months (range 88-165). Of the 3 patients, gastrointestinal tract cancer in 2, patients who received PB-HU in sequence, none prostate, bladder, thyroid and skin cancer in one developed AL. The treatment with hydroxyurea patient each.

Haematologica vol. 85(10):October 2000 Pipobroman in polycythemia vera 1015

Table 3. Causes of death.

No. of patients %

Acute leukemia 11 23 Thrombosis 9 19 Cardiovascular complications 6 13 Solid tumors 5 10 Myeloﬁbrosis 4 8 Hemorrhage 3 6 Unrelated 3 6 Unknown 7 15 Total 48 –

Figure 2. Kaplan-Meier cumulative survival graph of patients der (HR=2.3; 95% CI: 1.08-7.91; p=0.02) and with polycythemia vera treated with pipobroman. by age over 65 years (HR= 2.89; 95% CI: 1.30- 6.42; p=0.01). The only variable influencing the risk of AL and ST was age (acute leukemia: Table 2. Clinical characteristics of patients who developed HR=1.09; 95% CI: 1.02-1.16; p=0.04; solid secondary neoplasms. tumors: HR=1.06; 95% CI: 1.01-1.12; p= 0.03). The duration of PB therapy did not significant- Acute leukemia Myelofibrosis Solid tumors ly influence the risk of AL or ST. The shift from PB to busulphan seemed to influence the risk of No. of patients 11 7 11 AL, without reaching statistical significance Male/female ratio 0.6 2.5 2.6 (HR=3.0; 95% CI: 0.8-11.5; p=0.1). No significant risk factor was demonstrated for MF. The Median age, years (range) 72 (61-77) 66 (54-68) 67 (56-75) risk of death correlated with age over 65 Median time from PV diagnosis, (HR=1.06; 95% CI: 1.03-1.09; p=0.0001) and months, (range) 133 (88-179) 119 (88-166) 85 (39-110) with the presence of thrombotic events at diag- Median duration of PB therapy nosis (HR=2.9; 95% CI: 1.6-5.2; p=0.001). months, (range) 100 (88-165) 98 (42-172) 70 (19-100) Discussion Incidence (×105 person-years) 6.7 4.3 6.8 In this study, pipobroman proved to be an Cumulative risk at 7, 10, 12 years, % 1, 5, 6 1, 4, 6 4, 8, 9 effective treatment for patients with PV. This piperazine derivative induced a complete Significant risk factors Age – Age response in 94% of patients, with very mild toxicity and good compliance, allowing a median survival of 215 months. The 10-year cumulative Survival and causes of death risk of thrombosis was 16%, that of leukemia At the time of this analysis, 115 patients (71%) 5%, of myelofibrosis 4%, and of solid tumors 8%. are alive. The median overall survival was 215 These results, obtained in a cohort of patients months; the actuarial overall survival was 89%, treated for a median of 10 years, indicate that 78%, and 74% at 7, 10, and 12 years, respec- PB is effective in the long-term control of PV with tively (Figure 2). The different causes of death a relatively low risk of thrombosis, myelofibrosis are illustrated in Table 3 and include: AL in 11 and subsequent neoplasms. The notion of the patients (23%), thrombosis in 9 (19%), cardio- effectiveness of PB in PV goes back to the vascular diseases in 6 (13%), ST in 5 (10%), MF 1980s.9–10 Accordingly, this drug has been used in 4 (8%), and hemorrhage in 3 (6%). In 3 in large prospective studies.15,19 Table 4 illus- patients (6%) the cause of death was unrelated trates the results of PB in this study and in the to PV, and in 7 (15%) it was unknown. two largest series of patients with PV treated with this agent. In one study of 199 PV patients The age-and sex-standardized mortality ratio 19 (SMR) was 1.7. This parameter showed a great followed for a median of 7.6 years, all evalu- variability between different age and sex groups, able patients responded to PB. The median sur- ranging from 4.6 for males aged 50-60 years to vival was 191 months from diagnosis and 37% 0.3 for males over 70. of the patients developed disease-related complications including thrombosis, leukemia, Analysis of risk factors myelofibrosis, and solid tumors. In particular, In a logistic analysis, the relative risk of throm- the 10-year cumulative risk of AL and of MF was bosis was significantly influenced by female gen- 6% and 9%, respectively. The French Polycythemia

Haematologica vol. 85(10):October 2000 1016 F. Passamonti et al.

Table 4. Results of pipobroman therapy in polycythemia busulphan (3.5%).7 The first findings of the vera. PVSG-08 study with HU indicated an incidence of AL as low as 3.9%.11 Subsequent studies,14,17 Results This study Najean, Rain15 Petti et al.19 however, and the updated PVSG-08 trial,16 (FPSG) reported figures of risk of about 10% at 10 years Complete response, % 94 98 100 of observation. The FPSG randomized trial on Median survival, months 215 NR 191 HU and PB reported that the risk of AL in PV 10-yr risk of thrombosis, % 16 16 NE using HU or PB therapy was essentially identi- 10-yr risk of leukemia, % 5 4 6 cal.15 Patients with PV may develop AL as part of 10-yr risk of myelofibrosis, % 4 0 9 10-yr risk of solid tumors, % 8 8 NE the natural history of their disease. According to the findings of the PVSG-01 study, the esti- NR: not reached; NE: not evaluated. mated risk of AL in patients treated with phlebotomy alone is 1.5%.3 Myelosuppressive therapy may increase the risk of cancers to 6.7% as Study Group (FPSG) randomized 292 patients 4 15 documented by the GISP study. A significant under 65 years old to receive PB or HU. A good correlation has been demonstrated in PV control of red cells and platelets was obtained in between the cumulative dose of 32P and the risk 90% and 78% of patients receiving PB and in of leukemia,5 while only a trend towards this cor- 82% and 55% of those given HU. In the first 8 relation was observed for the cumulative dose of years of therapy, the cumulative risk of throm- chlorambucil.6 A recent FPSG study randomiz- bosis was higher in the HU group than in the PB ing 461 patients to receive 32P alone or in asso- group, but the difference did not reach statisti- ciation with HU, found a significantly higher risk cal significance. At 10 years, the risk of AL or ST of AL or ST in the combined therapy group, was comparable in the two arms (4% and 8% despite the reduction of the cumulative dose of for PB and 5% and 4% for HU, respectively), radiophosphorus in the latter group.18 This while the risk of MF was significantly higher in observation would support the concept that the HU arm (17%) than in the PB arm (0%). The drug combination is more harmful in terms of 15-year cumulative survival was about 70% in risk of leukemia than the cumulative dose of a both arms. The cumulative risk of thrombotic single agent per se.12 In this study, the risk of sub- complications in our study was 6% at 3 years, sequent leukemia was not influenced by the 11% at 7 years, and 16% at 10 years, as in the duration of PB therapy, while the use of two FPSG study.15 The problem of early thrombosis alkylators in sequence, such as PB-BU, seemed is of particular prominence in the management to influence the risk of AL, without reaching sta- of PV patients. The PVSG-01 randomized study tistical significance. reported at 3 years a higher incidence of throm- A direct leukemogenic effect of myelosuppres- botic events in the phlebotomy arm than in the sive chemotherapy in PV is suggested by the pres- 32P or the chlorambucil arms (thrombosis-free ence in leukemia cells of cytogenetic abnormali- survival 75% versus 94%, respectively).3 This ties usually associated with mutagenic exposure study demonstrated that phlebotomy and phle- such as chromosome 5 and/or 7 deletions10,14 botomy rate were significant risk factors for and by the deletion of the short arm of chromo- thrombosis in addition to advanced age and his- some 17 (17p-).32 This abnormality has recently tory of prior thrombotic events.3 The FPSG ran- been described in leukemias developing after domized trial on HU vs PB reported a slight essential thrombocythemia treated with HU33 excess of thrombotic complications from the 2nd and in other neoplasms treated with non-alky- to the 8th year of observation in the HU arm lating agents.32 Molecular studies in PV demon- compared with the PB arm (from 3% to 12% for strated an imbalance in the BCL-2 family.34,35 PB, and from 5% to 16% for HU).15 Data con- These abnormalities may contribute to the cerning early thrombotic complications with pathogenesis of the disease, causing an accu- interferon-α28 or anagrelide27 cannot be consid- mulation of erythroid cells through the inhibi- ered conclusive and require larger studies. The tion of apoptosis.35 Leukemia in PV may eventu- impact of aspirin as an antiaggregating agent in ally result from additional genetic abnormalities. the management of thrombotic complications The risk of myelofibrosis in PV is significantly in PV is under evaluation in prospective ran- lower in patients treated with chemotherapy than domized studies.29 The 10-year cumulative risk of in those treated with phlebotomy alone. At 15 leukemia after PB is between 4% and 6% (Table years of observation patients receiving phleboto- 4). Our results regarding the incidence of AL in my had a 75% risk of developing MF.26 When PV are better than those reported after chlo- phlebotomized patients subsequently received rambucil (13%)3 or after radiophosphorus myelosuppression, the risk of progression to MF (10%),3 and comparable to those observed after became similar to that observed in patients treat-

Haematologica vol. 85(10):October 2000 Pipobroman in polycythemia vera 1017 ed with 32P.26 Besides, myelosuppression seems Potential implications for clinical practice 26 to avoid or to delay this evolution. In this study ♦ with PB the 4% 10-year risk of MF is comparable Pipobroman is a useful drug in front-line treatment of polycythemia vera and a definite alter- with that found in other series of patients treat- native to hydroxyurea.37 ed with this agent (0-8%)15,19 and lower than that observed with HU (15%)15 or radiophosphorus (12%).18 Moreover, in the French study, hydroxyurea given after 32P did not protect patients from References progression to MF.18 The authors supposed that the lack of control of the platelet count during the 1. Berlin N. Diagnosis and classification of the poly- cythemias. Semin Hematol 1975; 12:339-51. follow up (57% of patients developing MF had 2. Barbui T, Finazzi G. Treatment of polycythemia vera. platelets > 400×109/L) had influenced the pro- Haematologica 1998; 83:143-9. gression to MF.18 In our experience pipobroman 3. Berk PD, Goldbergh JD, Donovan PB, Fruchtman SM, was effective in the long-term control of platelet Berlin NI, Wasserman LR. Therapeutic recommenda- tions in polycythemia vera based on Polycythemia Vera counts. The advantage of pipobroman may Study Group. Semin Hematol 1986; 23:132-43. derive from its activity on the megakaryocytic 4. Polycythemia vera: the natural history of 1213 patients line15 probably resulting in more efficient inhibi- followed for 20 years. Gruppo Italiano Studio Polici- tion of the release of fibrogenic cytokines. In the temia. Ann Intern Med 1995; 123:656-64. present study the risk of solid tumor increased 5. Modan B, Liliefeld AM. Polycythemia vera and leukemia: the role of radiation treatment. Medicine constantly over time, in accordance with the 1965; 44:305-44. reports on other PV series.3,4,7-19 The patient’s age 6. Berk PD, Goldberg JD, Silverstein MN, et al. Increased at diagnosis was the only variable significantly risk of acute leukemia in polycythemia vera associat- associated with the risk of subsequent solid ed with chlorambucil therapy. N Engl J Med 1981; 304:441-7. tumors, while the duration of PB therapy did not 7. Treatment of polycythemia vera by radiophosphorus influence this risk. Our study could not confirm or busulfan: a randomized trial. “Leukemia and Rozman’s statement that the overall survival in Hematosarcoma” Cooperative Group, European PV is comparable with that of the normal popu- Organization for Research on Treatment of Cancer 21 (E.O.R.T.C.). Br J Cancer 1981; 44:75-80. lation. Indeed, the standardized mortality ratio 8. Messinezy M, Pearson TC, Prochazka A, Wetherley- in our study was 1.7, in accordance with that of Mein G. Treatment of primary proliferative poly- the Italian Cooperative4 and French studies.15 cythaemia by venesection and low dose busulphan: In conclusion, this report demonstrates, in a retrospective study from one centre. Br J Haematol 1985; 61:657-66. large series of patients homogeneously treated 9. Najman A, Stachowiak J, Parlier Y, Gorin NC, and observed for a long period, that pipobro- Duhamel G. Pipobroman therapy of polycythemia man is an effective and well tolerated agent for vera. Blood 1982; 59:890-4. the control of PV, with a relatively low risk of 10. Brusamolino E, Salvaneschi L, Canevari A, Bernasconi early thrombotic complications (6% at 3 years). C. Efficacy trial of pipobroman in polycythemia vera and incidence of acute leukemia. J Clin Oncol 1984; The 10-year risk of acute leukemia, late myelofi- 2:558-61. brosis, and solid tumors is 5%, 4%, and 8%, 11. Kaplan ME, Mack K, Goldberg JD, Donovan PB, Berk respectively. The duration of PB treatment does PD, Wasserman LR. Long term management of poly- not correlate with these events. cythemia vera with hydroxyurea: a progress report. Semin Hematol 1986; 23:167-71. Contributions and Acknowledgments 12. Nand S, Messmore H, Fisher SG, Bird ML, Schulz W, FP designed the study and wrote the paper. EB and Fisher RI. Leukemic transformation in polycythemia vera: analysis of risk factors. Am J Hematol 1990; 34: ML helped to evaluate and interpret the data. FP, ClB 32-6. and CK were responsible for the statistical analysis. FP, 13. Najean Y, Dresch C, Rain JD. The very-long-term EB, ML, ClB, EO, AC, GC, SM, CB were involved in course of polycythaemia: a complement to the previ- the recruitment of the patients. All the authors gave ously published data of the Polycythaemia Vera Study Group. Br J Haematol 1994; 86:233-5. their critical contribution to the manuscript. ML and 14. Weinfeld A, Swolin B, Westin J. Acute leukemia after CaB revised the paper and gave final approval for its hydroxyurea therapy in polycythaemia vera and allied submission. disorders: prospective study of efficacy and leukae- mogenicity with therapeutic implications. Eur J Disclosures Haematol 1994; 52:134-9. Conflict if interest: none. 15. Najean Y, Rain JD. Treatment of polycythemia vera: Rebundant publication: no substantial overlapping the use of hydroxyurea and pipobroman in 292 patients under the age of 65 years. Blood 1997; 90: with previous papers. 3370-7. Manuscript processing 16. Fruchtman SM, Mack K, Kaplan ME, Peterson P, Berk PD, Wasserman LR. From efficacy to safety: a Poly- Manuscript received June 21, 2000; accepted Sep- cythemia Vera Study group report on hydroxyurea in tember 2, 2000. patients with polycythemia vera. Semin Hematol

Haematologica vol. 85(10):October 2000 1018 F. Passamonti et al.

1997; 34:17-23. RC, Schacter LP. Anagrelide: a new drug for treating 17. Tatarsky I, Sharon R. Management of polycythemia thrombocytosis. N Engl J Med 1988; 318:1292-4. vera with hydroxyurea. Semin Hematol 1997; 34:24- 28. Elliott MA, Tefferi A. Interferon-alpha in polycythemia 8. vera and essential thrombocythemia. Semin Thromb 18. Najean Y, Rain JD. Treatment of polycythemia vera: Hemost 1997; 23:463-72. use of 32P alone or in combination with maintenance 29. Landolﬁ R, Marchioli R. European Collaboration on therapy using hydroxyurea in 461 patients greater than Low-dose Aspirin in Polycythemia Vera (ECLAP): a 65 years of age. The French Polycythemia Study randomized trial. Semin Thromb Hemost 1997; 23: Group. Blood 1997; 89:2319-27. 473-8. 19. Petti MC, Spadea A, Avvisati G, et al. Polycythemia 30. Bennet JM, Catowsky D, Daniel MT, et al. Proposals vera treated with pipobroman as single agent: low for the classification of the myelodysplastic syn- incidence of secondary leukemia in a cohort of dromes. Br J Haematol 1982; 51:189-99. patients observed during 20 years (1971-1991). 31. Bennet JM, Catowsky D, Daniel MT, et al. Proposed Leukemia 1998; 12:869-74. revised criteria for the classiﬁcation of acute myeloid 20. Chievitz E, Thiede T. Complications and causes of leukemia: a report of the French-American-British death in polycythemia vera. Acta Med Scand 1962; cooperative group. Ann Intern Med 1985; 103:626- 172:513-23. 31. 21. Rozman C, Giralt M, Feliu E, Rubio D, Cortes MT. 32. Merlat A, Lai JL, Demory JL, Bauters F, Preudhomme Life expectancy of patients with chronic myeloprolif- C, Fenaux P. Therapy-related myelodysplastic syn- erative disorders. Cancer 1991; 67:2658-63. 22. Wasserman LR. Polycythemia Vera Study Group: a his- drome and acute myeloid leukemia with 17p deletion. torical perspective. Semin Hematol 1986; 23:183-7. A report of 25 cases. Leukemia 1999; 13:250-7. 23. Barbui T, Finazzi G. Treatment of polycythemia vera. 33. Sterkers Y, Preudhomme C, Lai JL, et al. Acute myeloid Haematologica 1998; 83:143-9. leukemia and myelodysplastic syndromes following 24. Gilbert HS. Historical perspective on the treatment of essential thrombocythemia treated with hydroxyurea: essential thrombocythemia and polycythemia vera. high proportion of cases with 17p deletion. Blood Semin Hematol 1999; 36:19-22. 1998; 91:616-23. 25. Streiff MB, Spivak JL The diagnosis and management 34. Silva M, Richard C, Benito A, Sanz C, Olalla I, Fer- of polycythemia vera (PV) in the post-Polycythemia nandez-Luna JL. Expression of Bcl-x in erythroid pre- Vera Study Group (PVSG) era: a survey of American cursors from patients with polycythemia vera. N Engl Society of Hematology (ASH) members practice pat- J Med 1998; 338:564-71. terns [Abstract]. 41th Annnual Meeting of the Amer- 35. Fernandez-Luna JL, Silva M, Richard C, Sanz C, Beni- ican Society of Hematology, New Orleans, 1999:500. to A. Pathogenesis of polycythemia vera. Haemato- 26. Najean Y, Rain JD. The very long-term evolution of logica 1998; 83:150-8. polycythemia vera: an analysis of 318 patients initial- 36. Schwartz RS. Polycythemia vera - chance, death, and ly treated by phlebotomy or 32P between 1969 and mutability. N Engl J Med 1998; 338:613-5. 1981. Semin Hematol 1997; 34:6-16. 37. Editorial. How safe is hydroxyurea in the treatment of 27. Silverstein M, Petitt R, Solberg L, Fleming JS, Knight polycythemia vera? Haematologica 1999; 84:673-4.

Haematologica vol. 85(10):October 2000