Long-Term Incidence of Hematological Evolution in Three French Prospective Studies of Hydroxyurea and Pipobroman in Polycythemia Vera and Essential Thrombocythemia

Abstract

Despite recent discoveries made in myeloproliferative disorders other than chronic myelogenous leukemia, which it is hoped will result in earlier diagnosis, and better evaluation and management of patients, hematological evolution to myelofibrosis, acute leukemia, and myelodysplastic syndromes (AL/MDS) remain major causes of long-term mortality in polycythemia vera (PV) and essential thrombocythemia (ET) patients. Evaluation of long-term leukemogenic risk of currently available drugs, therefore, is crucial. We report updated results of three French prospective trials of hydroxyurea and pipobroman in PV and ET patients with a median follow-up longer than 10 years. The results show that the incidence of AL/MDS is higher than previously reported with no evidence of a plateau (with approximately 40% of AL/MDS cases occurring after the 12th year of follow-up). Although hydroxyurea currently remains the first choice in the treatment of high-risk PV and ET patients, the use of nonleukemogenic drugs, such as interferon alpha (IFN-alpha) or anagrelide, should be assessed more widely in randomized trials using accurate diagnostic criteria and taking into account the presence of the JAK2 mutation, given that they may have an impact on disease evolution.

Interferon-α therapy in bcr-abl-negative myeloproliferative neoplasms

“…Recent results, however, suggest that indications of treatment with IFN-a should be larger. First, the possibly higher incidence of progression to MDS and AL in the very long term in PV and ET than assessed earlier 80 suggests that non leukemogenic drugs such as IFNa may be more largely used in those disorders by comparison with chemotherapeutic agents. An additional advantage of IFN-a may be its ability to specifically reduce the MPN clone in a large proportion of PV patients, and even to induce complete molecular remissions (assessed by disappearance of the JAK2 mutation).…”

“…79 Still, very long-term results of prospective studies in HU-treated MPN patients with more than 10 years of follow-up showed a cumulative incidence of AL/MDS of more than 10% beyond 12 years of follow-up, suggesting that the risk of leukemic evolution could be higher than reported earlier in studies with shorter follow-up. 80 The relative contribution of HU and of a natural, very long-term evolution of the disease in the pathogenesis of those late AL/MDS remains unclear. Those findings have however led published guidelines in ET and PV to recommend the use of clearly non-leukemogenic drugs such as IFN-a in younger patients requiring cytoreductive therapy.…”

Life expectancy and prognostic factors in the classic BCR/ABL-negative myeloproliferative disorders

“…87 In some studies, patient's age influenced the risk of leukaemia in PV, 65,87 whereas leukocyte count did in both ET and PV. 17,88 No clear association has been demonstrated between leukaemia and a specific drug exposure history, 18,87,89 with the exception of 32 P and chlorambucil, 67 whereas the use of more than one cytoreductive therapy clearly increased the risk of leukaemia. 18,67 In PV, the ECLAP study failed to show significant differences in terms of leukaemic evolution between patients treated with hydroxyurea and those managed with phlebotomy only.…”

Long-term management of thrombocytosis in essential thrombocythaemia

“…Interestingly, the bone marrow of hydroxycarbamide-treated patients shows a dysplastic appearance, including left-shifting of myelopoiesis, macrocytosis of red cells and dysplasia of megakaryocytes, which is not seen with non-cytostatic drugs [41]. In clinical studies with more than 96 months median follow-up, transformation to AML/MDS occurred in 0-22% of patients with ET/PV treated with hydroxycarbamide as the sole therapeutic agent [33,37,[42][43][44][45][46]. The only long-term study designed to investigate this endpoint shows that transformation to AML in hydroxycarbamide-or pipobroman-treated patients generally occurs after 10 or more years' therapy, with the incidence reaching 10-12% after 12 years [45].…”

“…In clinical studies with more than 96 months median follow-up, transformation to AML/MDS occurred in 0-22% of patients with ET/PV treated with hydroxycarbamide as the sole therapeutic agent [33,37,[42][43][44][45][46]. The only long-term study designed to investigate this endpoint shows that transformation to AML in hydroxycarbamide-or pipobroman-treated patients generally occurs after 10 or more years' therapy, with the incidence reaching 10-12% after 12 years [45]. In conclusion, the leukaemogenicity of hydroxycarbamide remains a concern that has not been diminished by recent data.…”