Imatinib Mesylate in Polycythemia Vera. A Heterogeneous Response Pattern but a Consistent Reduction in Phlebotomy Requirements.

Background. Imatinib targets the ATP-binding sites of the protein tyrosine kinase domains associated with Bcr-abl, platelet-derived growth factor receptors (PDGFR) and c-kit. Most recently imatinib has been to inhibit autonomous erythropoiesis in vitro in polycythemia vera (PV)(1). Several clinical studies have indicated that imatinib may reduce phlebotomy requirements (2,3), but only a few patients have been followed for longer periods on imatinib monotherapy (2,3).

Aim of the study. To evaluate the safety and efficacy of long term monotherapy with imatinib in PV.

Patients.Eight patients (median age 60 years, range 39–68) have been treated. Five of the patients were enrolled in a phase II treatment protocol and three patients have been treated off protocol. None of the patients in the protocol had received cytotoxic treatment whereas the three patients treated off protocol had been treated with hydroxyurea (HU) and PEG-Intron. Imatinib was given at an initial dose of 400 mg/day in all patients.

Methods. The diagnosis of PV was made according to conventional criteria, including an increased red cell blood volume and a low plasma erythropoietin. All patients were negative for the Bcr-abl transcript. A complete response (CR) was defined as phlebotomy-free within the first year of treatment, lasting at least 6 mo together with a platelet count less than 600 x 10^9/l and absence of splenomegaly. A partial response (PR) was defined by phlebotomy-free within the first year of treatment, lasting at least 6 mo together with a platelet count more than 600 x 10⁹/l and a palpable spleen but less than 50 % of the original size (2). A minor response (MR) was defined as a reduction in the need of phlebotomies of at least 50 % but no change in the platelet counts.

Results. Four patients have been followed for 12 mo on a dose of 400 mg daily apart from short periods, when the dose had to be decreased to 100 mg/day and 300mg/day, respectively, due to temporary side effects. Responses were seen in all evaluable patients (7/7) (CR=1; PR=6). The PR’s in two of the patients were obtained when HU (n=1) or PEG-Intron (n=1) were added. A definite decline in the Ht within the first month (< 0.45) and a reduction in the need of phlebotomies were recorded in all evaluable patients whereas the leucocyte and platelet counts displayed a highly heterogeneous response pattern with unchanged and even rising platelet counts in 3 patients. The one patient with a CR displayed a reduction of spleen size and a decrease in the degree of bone marrow fibrosis after being treated for 12 mo. Almost complete alleviation of severe pruritus was noticed in one patient a few weeks after starting imatinib. One patient had to discontinue treatment after 1 week due to severe musculoskeletal pain. Otherwise the side effects were moderate and often transient. One of the patients noticed no side effects at all.

Conclusions. Imatinib in PV is followed by a decrease in the Ht but highly heterogeneous leucocyte-and platelet responses in some patients when using 400 mg/day.Combinational therapy with HU or PEG-Intron seems safe and effective.