Treatment of Polycythemia Vera: Use of 32P Alone or in Combination With Maintenance Therapy Using Hydroxyurea in 461 Patients Greater Than 65 Years of Age

Abstract

Despite myelosuppression, polycythemic (PV) patients greater than 65 years of age have a high risk of vascular complications, and the leukemic risk exceeds 15% after 12 years. Is the addition of low-dose maintenance treatment with hydroxyurea (HU) after radiophosphorus (32P) myelosuppression able to decrease these complications? Since the end of 1979, 461 patients were randomized to receive (or not) low-dose HU (5 to 10 mg/kg/d), after the first 32P-induced remission, and were observed until death or June 1996. Maintenance treatment very significantly prolonged the duration of 32P-induced remissions and reduced the annual mean dose received to one-third. However, despite this maintenance, 25% of the patients had an excessive platelet count and the rate of serious vascular complications was not decreased, except in the most severe cases with short-term relapse of polycythemia. Furthermore, the leukemia rate was significantly increased beyond 8 years and a significant excess of carcinomas was also observed. The continuous use of HU did not decrease the risk of progression to myelofibrosis (incidence of 20% after 15 years). Life expectancy was shorter (a median of 9.3 years v 10.9 years with 32P alone), except in the most severe cases (initial 32P-induced remission lasting <2 years) in which maintenance treatment moderately prolonged the survival by reducing the vascular risk. In most cases of PV, in which the duration of the first 32P-induced remission exceeded 2 years, the introduction of HU maintenance did not reduce the vascular risk. Although it considerably decreased the mean dose of 32P received, HU maintenance therapy significantly increased the leukemia and cancer risks and reduced the mean life expectancy by 15%. However, in cases with more rapid recurrence, the introduction of maintenance treatment reduced the vascular risks and moderately prolonged survival. The use of HU as a maintenance therapy is therefore only justified in this situation.

Second malignancies in patients with essential thrombocythaemia treated with busulphan and hydroxyurea: long‐term follow‐up of a randomized clinical trial

“…Six cases of AML (21%) out of 28 ET patients treated with HU plus alkylating agents or 32 P were observed by Murphy et al (1997). A large study in PV patients randomized to receive maintenance with HU or no maintenance after a first course of 32 P (Najean & Rain, 1997b) found a higher incidence of AML and carcinomas in the group maintained with HU.…”

Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk‐stratification and management

“…The difference in survival was attributed to an increased incidence of acute myeloid leukemia (AML) in patients treated with chlorambucil or radiophosphorus compared with those treated with phlebotomy alone (13.2% vs 9.6% vs1.5% over a period of 13-19 years). 54 Other randomized studies in PV have compared hydroxyurea against pipobroman (the first report showed a significant difference favoring pipobroman in the incidence of transformation into postPV MF but no difference in survival, incidence of thrombosis, or the rate of leukemic conversion; however, a longer-term follow-up revealed a shorter survival, an increased risk of leukemic transformation, and a lower risk of postPV MF, associated with pipobroman therapy), 56,57 radiophosphorus alone or with HU (no difference in survival, incidence of thrombosis, or risk of transformation into postPV MF but radiophosphorus alone was associated with significantly less incidences of both acute leukemia and other cancers), 58 and radiophosphorus plus phlebotomy against phlebotomy plus high-dose aspirin (900 mg/d) in combination with dipyridamole (225 mg/d) (the addition of antiplatelet agents provided no benefit in terms of thrombosis prevention but increased the risk of gastrointestinal bleeding). 59 Ruxolitinib, a JAK1/2 inhibitor, was also compared with hydroxyurea, in a phase 3 study in PV patients intolerant or not-responding to hydroxyurea 60 ; the study showed hematocrit control of 60% for ruxolitinib vs 20% for standard therapy; in addition, as expected, spleen and symptom control was better with ruxolitinib.…”

Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis

“…The French Polycythaemia Study Group (FPSG) published two randomised trials in 1997. The first was a two-arm comparison of 32 P alone against 32 P with maintenance hydroxycarbamide (formerly known as hydroxyurea) in patients over the age of 65 years (Najean & Rain, 1997a). Significant numbers of patients crossed between the two treatment arms.…”

“…In a series of reports on the use of hydroxycarbamide the incidence of acute leukaemia varied from 0% to 12% in patients treated with hydroxycarbamide alone (Weinfeld et al, 1994;Tatarsky & Sharon, 1997). The FPSG trial reported that patients aged over 65 years had an actuarial incidence of leukaemia of 12% in the hydroxycarbamide alone arm (Najean & Rain, 1997a). However, the FPSG randomized trial in patients below 65 years showed that pipobroman had a lower rate of progression to leukaemia and other cancers compared with the combination of 32 P and hydroxycarbamide.…”