Low dose melphalan in the treatment of myelofibrosis: A single centre experience

Myelofibrosis with myeloid metaplasia (MMM) is defined as a clonal myeloproliferative disorder arising from a somatic mutation of a multi-potent hemopoietic progenitor cell. This results in chronic myeloproliferation and atypical megakaryocytic hyperplasia leading to cytokine-driven polyclonal fibroblastic proliferation causing bone marrow fibrosis. The clinical phenotype is characterized by progressive anemia, massive splenomegaly, extramedullary hematopoiesis and a leukoerythroblastic blood film; however, clinical features and symptoms at presentation are highly variable. Treatment of MMM is generally instituted when the disease becomes symptomatic as most conventional treatment does not affect overall survival. Allogeneic stem cell transplantation offers the only potential for cure but is only available to a minority of patients due to the high median age at diagnosis. The most common chemotherapeutic agents used have been busulfan and hydroxyurea to reduce massive splenomegaly and/or severe leuko-thrombocytosis [1,2]. However, the leukemogenic potential of these drugs and the lack of efficacy in improvement of overall survival [3,4] have led to other treatment modalities being tried. Petti et al. [5] evaluated the use of low dose melphalan (2.5 mg three times a week, with progressive increase up to a maximum of 2.5 mg daily) in 99 evaluable patients with MMM after being pretreated for at least 2 months with danazol or prednisone. The response rate (RR) was 66.7% with 26 patients achieving a complete response (CR) (normalization of clinical and hematological parameters). Median duration of CR was 28.4 months and of partial responses (PR) (improvement of 50% in at least one clinical and hematological parameter) was 26 months. Of note, this study conferred a survival advantage to responders with the median survival of CR and PR patients being 71.2 months compared to 36.5 months in non-responders (NR). Based on these results, we started administering low dose melphalan to a cohort of patients with myelofibrosis. The diagnosis of myelofibrosis was made in our patients with a leukoerythroblastic blood film, tear drop poikilocytes, splenomegaly, dry bone marrow aspiration, bone marrow biopsy showing an increase in reticulin fibres with abnormal proliferation and nuclear lobulation of megakaryocytes. The Philadelphia chromosome was not routinely tested in this cohort of patients. Bone marrow histology was defined according to the WHO criteria as pre-fibrotic (cellular) or fibrotic stages. Melphalan was administered orally at a dose of 2 mg daily three times a week. This dosage was increased to a maximum of 2 mg daily five times a week in non-responders or patients who had relapsed. CHR (complete hematological response) was defined as normalization of peripheral blood counts and CCR (complete clinical response) was defined as resolution of splenomegaly as determined by clinical evaluation. PR was defined as an improvement of 50% in spleen size, a decrease in transfusional requirements or an achievement of Hb 100 g L. Patients who did not fulfil the criteria of CHR/CCR or PR were deemed to be non-responders (NR). Disease relapse was defined as a new worsening in any clinical or hematological parameter after an improvement of 3 months.