Decitabine is an effective treatment of idiopathic myelofibrosis

Idiopathic myelofibrosis (IMF) is a progressive chronic myeloproliferative disorder. The median survival for patients with IMF is 70 months with limited treatment options (Tefferi et al, 2007a). At this time, allogeneic stem cell transplantation is the only curative treatment modality in IMF. However, it is accompanied by high transplant-related mortality. A number of potential treatment regimens have been proposed but their clinical efficacy remains suboptimal (Cervantes et al, 2007). Epigenetic modifications have been implicated in the pathogenesis of IMF, resulting in rapid cell proliferation and circulating abnormal progenitors with extramedullary haematopoiesis (Wang et al, 2002; Jones et al, 2004; Bogani et al, 2008). This suggests that hypomethylating agents can be of therapeutic value in IMF. Azacitidine had a modest efficacy in a recent Phase II trial, documenting a clinical improvement in 21% of patients (Quintas-Cardama et al, 2008). Here we report on the successful use of the hypomethylating agent Decitabine (Dacogen, SuperGen, Inc., Dublin, CA, USA) in the treatment of an elderly patient with symptomatic transfusiondependent IMF. A 65-year-old white male with history of atrial fibrillation presented in March 2004 with worsening fatigue and generalized pruritus. On physical examination, he had prominent splenomegaly and hepatomegaly. The spleen was palpable 4–6 cm below the left costal margin. The complete blood count showed: white blood cell (WBC) count, 8Æ0 · 10/l with normal differential; haemoglobin concentration (Hb), 83 g/l; haematocrit 26Æ8% with mean cell volume 109 fl; platelet count 565 · 10/l. Indirect bilirubin was elevated at 37Æ6 lmol/l, lactate dehydrogenase was 217 IU/l. A peripheral blood smear demonstrated increased numbers of target cells, numerous teardrop forms, large platelets and rare nucleated red blood cells. The bone marrow biopsy was a markedly hypercellular marrow with increased and atypical megakaryocytes, with extensive fibrosis consistent with cellular phase of IMF (Tefferi et al, 2007b). Cytogenetic studies on the bone marrow and blood were negative for t(9;22) and the JAK2 V617F mutation. The patient received a brief trial of darbepoietin for treatment of his symptomatic anemia. He responded but continued to require packed red blood cell (PRBC) transfusions, averaging two units per month, for symptomatic anaemia. Pruritus was successfully managed with low doses of prednisone. Because of the patient’s progressive symptomatic splenomegaly and thrombocytosis he was started on hydroxycarbamide. In an attempt to decrease the PRBC transfusion requirements lenalinomide was initiated at a low dose of 10 mg/d. However, the patient’s transfusion requirement increased further to 8–16 units of PRBC per month. In September 2007, he complained of increasing abdominal fullness with early satiety and weight loss. His WBC count was 4Æ9 · 10/l, Hb 75 g/l, haematocrit 22Æ8%, and platelet count 133 · 10/l. The peripheral blood smear demonstrated marked anisocytosis with macrocytes, abundant teardrop forms, nucleated red blood cells and abnormally lobulated and hypogranular neutrophils with cytoplasmic vacuoles, giant platelets and rare myelocytes and promyelocytes. A repeat bone marrow biopsy again revealed a hypercellular marrow with dysplastic myeloid and erythroid precursors. Megakaryocytes were atypical and increased in number and there was a diffuse increase in reticulofibrosis (3/ 4). Cytogenetic studies were normal. Decitabine was started at a dose of 20 mg/m for 5 d every 4 weeks. Following two cycles of decitabine, the patient’s transfusion requirement decreased to two units of PRBC per month. He gained weight and reported a substantial increase in his energy level. His spleen decreased from 10–12 cm to 2 cm below the left costal margin. He has continued on decitabine. His transfusion requirement decreased further. After six cycles, the WBC count remained 2Æ6 · 10/l, Hb 89 g/l, haematocrit 26Æ9 vol % and platelet count 274 · 10/l. He has tolerated decitabine well with a performance status of 90%. In vitro studies demonstrate that hypomethylating agents can reduce the number of circulating malignant progenitor cells in IMF (Shi et al, 2007). Treatment of peripheral blood CD34 cells from patients with IMF with decitabine followed by a histone deacetylase inhibitor, trichostatin A, result in upregulation of CXCR4 expression restoring their ability to migrate in response to stromal-derived factor-1a (Shi et al, 2007). Decitabine decreased the transfusion requirement, splenomegaly and resulted in a marked clinical improvement in our symptomatic transfusion-dependent patient with IMF. Larger studies are warranted to evaluate the efficacy of decitabine in patients with IMF.