Effective Management of Patients with Leukemic Transformation of Myelofibrosis.

Myelofibrosis (MF) is a clonal stem cell Philadelphia chromosome negative myeloproliferative neoplasm (MPN) characterized by progressive cytopenias, massive splenomegaly, early satiety, and a hypercatabolic state manifested by fevers, fatigue, and weight loss. Approximately 10-20% of MF patients will transform to acute myeloid leukemia (AML) over a 10-year period with a median overall survival at time of transformation of 2.6 months (Mesa 2005). In a multivariate analysis, peripheral blood blast count > 3% and/or a platelet count < 100 × 10⁹/L at time of diagnosis of MF were independent risk factors for leukemic transformation (LT) (Huang 2008). Standard induction chemotherapy improved survival to 3.9-5 months (Mesa 2005, Tam 2008). Survival was decreased due to a high relapse rate and treatment-related mortality. Patients who received an allogeneic stem cell transplant early in the disease course had superior survival. We describe the outcome of ten consecutive patients with MF-LT at our institution.

A retrospective chart review was performed to evaluate patients with MF-LT, including clinical characteristics, therapies administered, and survival outcomes. Between the years of 2007 and 2009, ten MF-LT patients were identified in our institution. The median age was 66 (range 45-77) with 60 percent male and 40 percent female patients. Thirty percent (3/10) of patients were JAK2 V617F positive. Seven patients were cytogenetically abnormal and three had a normal karyotype. Chromosomal abnormalities included +1q (2 pts), +8 (2 pts), -7 (2 pts), inv 3 (1 pt), and t(6;9) (1 pt). Fifty percent of patients had a post-essential thrombocythemia related MF, while 30 percent had an MDS/MF overlap syndrome. Time to LT ranged from 3 months to 12 years with a median of 12 months. In three cases, there was discordance between bone marrow blasts by immunohistochemical staining and peripheral blood manual count. Six patients were treated with decitabine at 20 mg/m² for 5 days (for two to ten cycles), and four received reduced intensity conditioning allogeneic stem cell transplantation (RIC-ASCT). Patients were eligible for RIC-ASCT if they were under 70 years of age, had no significant comorbidities, and had either an HLA compatible sibling or an unrelated donor with at most one mismatched allele.

The median survival from diagnosis of LT with the use of decitabine has not yet been reached but exceeds 7.5 months in this patient population. Two out of six patients treated with decitabine died 6 and 8 months after LT. The remaining four patients are still alive at 6, 7, 9, and 36 months after LT and are actively receiving therapy. Four out of six patients who received decitabine had subjective improvement in fatigue as well as decrease in splenomegaly. Three out of six patients had a decrease in transfusion requirements. The four patients who underwent RIC-ASCT are all alive after a median follow-up of 16.5 months with no evidence of leukemia in the bone marrow.

These results demonstrate that single-agent decitabine for those who are not eligible for transplant or RIC-ASCT for eligible patients, leads to a significant improvement in overall survival. Further investigation using these therapeutic modalities is warranted given the aggressive nature of this disease. Furthermore, the noted discordance between bone marrow and peripheral blood blast percentage most likely reflects leukemic cell production originating at sites of extramedullary hematopoiesis.

No relevant conflicts of interest to declare.