Resumen de Outcomes of Substituting Oral Fludarabine for Intravenous Fludarabine in Combination with Cytarabine and Filgrastim for Treatment of Primary Refractory or Relapsed Acute Leukemias

Roberta Demichelis Gómez, Erick Crespo Solís, Luis Fernando Pérez Jacobo, Ubaldo Rafael Valencia Rocha, Adriana Rosas López

• Background: Treatment of relapsed/refractory acute myeloid or lymphoid leukemia consists of salvage chemotherapy followed by allogeneic hematopoietic stem-cell transplantation. Intravenous fludarabine, cytarabine, and filgrastim is an effective regimen in this setting. In view of the lack of availability of intravenous fludarabine in Mexico from 2009-2013, we substituted an equivalent oral fludarabine dose (40 mg) for the intravenous formulation. Objective: This is a retrospective comparison of the toxicity and effectiveness of oral fludarabine, cytarabine, and filgrastim versus intravenous fludarabine, cytarabine and filgrastim. Results: A total of 44 patients with relapsed/refractory acute myeloid leukemia or acute lymphoid leukemia treated in an academic medical center from 2005-2013 with oral fludarabine, cytarabine and filgrastim (21 patients) or intravenous fludarabine, cytarabine and filgrastim (23 patients) were included in the analysis. There was a trend towards a higher complete remission rate and a longer overall survival following intravenous fludarabine, cytarabine, and filgrastim as compared with oral fludarabine, cytarabine, and filgrastim: complete remission rates 39.1 vs. 23.8% (p = 0.342) and overall survival 6.14 vs. 10.78 months (p = 0.363), respectively. A higher incidence of neutropenic fever (100 vs. 76.2%; p = 0.019) and septic shock (34.8 vs. 0%;

  p = 0.003) and a longer hospitalization (26.8 vs. 19.4 days; p = 0.046) were observed with intravenous fludarabine, cytarabine, and filgrastim. In multivariate analysis, factors associated with a shorter survival were septic shock (HR: 3.93; 95% CI: 1.67-9.25;

  p = 0.002) and a higher number of previous treatments (HR: 2.5; 95% CI: 1.26-4.99; p = 0.009). Complete remission was associated with better survival (HR: 0.18; 95% CI: 0.08-0.44; p < 0.001). Conclusions: Further studies are needed to determine the optimal dose and timing of oral fludarabine when given as part of the fludarabine, cytarabine, and filgrastim regimen for relapsed/refractory acute leukemia. Our data suggest that the dose of oral fludarabine used, 40 mg/m2 per day for five days, may be a lower bioequivalent dose to the intravenous dose in fludarabine, cytarabine, and filgrastim. (REV INVES CLIN. 2015;67:287-95)