FLAG with Oral Fludarabine for Primary Refractory or Relapsed Acute Lymphoid or Myeloid Leukemia
Authors: Demichelis Roberta , Crespo Erick , Pérez Fernando , Valencia Ubaldo , Guzman Patricia 
Published: October 2019

Abstract
Primary refractory or relapsed acute myeloid or lymphoid leukemia are characterized by unsatisfactory response to current therapy and short survival. The therapeutic approach consists on salvage chemotherapy treatment followed by allogenic hematopoietic stem-cell transplantation (HSCT). FLAG (Fludarabine, Cytarabine and G-CSF) is an effective salvage therapy in this setting. The regimen is designed with intravenous (IV) Fludarabine. In a period of time there was no IV Fludarabine available in our Country, only an oral presentation. There are some bioequivalence studies of oral and IV Fludarabine, mostly in chronic lymphocytic leukemia/low grade lymphomas. Based of these studies we treated patients with FLAG with the equivalent dose of oral Fludarabine (dose 40 mg/m2 day).
This is a comparative retrospective study of efficacy and toxicity of FLAG with oral and IV Fludarabine.
Forty-four patients with relapsed or refractory acute leukemia were treated with FLAG between 2005 and 2013. The diagnoses were: Pre-B ALL (63.3%), AML (31.8%), APL (2.3%) and T-ALL (2.3%). The median age was 26.7 years and 63.6% were early relapses, 20.5% primary refractory and 15.9% late relapses. In 59.1% of the cases FLAG was the second line of treatment and in 40.9% it was the third or forth line. Twenty-one patients (47.7%) were treated with oral Fludarabine and 23 patients (52.3%) with IV Fludarabine. There were no differences between both groups.
Results: Complete remission (CR) rate was 31.8% (33.3% for AML and 31% for ALL), 23.8% with oral Fludarabine and 39.1% with IV Fludarabine (P=0.342). Median overall survival (OS) was 8.07 months: 6.14 months with oral Fludarabine and 10.78 months with IV Fludarabine (P=0.363). There was a higher incidence of neutropenic fever with IV Fludarabine than with oral Fludarabine (100% vs. 76.2%, P= 0.019) as well as higher incidence of septic shock (34.8% vs. 0%, P=0.003) and a longer hospitalization (26.8 vs. 19.4 days, P=0.046).
On univariate analysis, the factors associated with shorter overall survival were: number of lines of treatment (more than 1 previous to FLAG) (HR: 2.03, CI 95% 1.09-3.78; P=0.03) and septic shock (HR: 2.8, CI 95% 1.24-6.36; P=0.023). Factors associated with a higher survival were: CR with FLAG (HR: 0.26, CI 95% 0.12-0.58; P<0.001) and HSCT (HR: 0.15, CI 95% 0.02-1; P= 0.009). On multivariate analysis, factors that remained significant were number of lines of treatment (HR: 2.5, CI 95% 1.26-4.99; P= 0.009), septic shock (HR: 3.93, CI 95% 1.67-9.25; P=0.002) and CR with FLAG (HR: 0.18, CI 95% 0.08-0.44; P<0.001).
There is a non significant tendency of better CR rates and OS with IV Fludarabine. There is a significative difference in toxicity with higher rates of neutropenic fever, septic shock and a longer hospitalization.
Oral Fludarabine is effective for salvage treatment of primary refractory or relapsed acute lymphoid or myeloid leukemia. As far as we know there are no previous reports of oral fludarabine-containing FLAG in acute leukemia patients. The optimal dose needs to be determined. The prognosis is this group of patients is very poor and the responses are only transitory. Salvage chemotherapy should be used only as a bridge for HSCT.

Disclosures
No relevant conflicts of interest to declare.