Fludarabine-based salvage therapy for refractory/relapsed acute leukemias: A single center experience

Abstract

First line regimens for the treatment of adult acute leukemias are highly effective in achieving initial remission, however, relapse is seen in about half of cases [1]. Around 20–30% of these cases are refractory to conventional treatment, becoming a challenging domain for the heme-oncologists [2, 3]. The primary strategy for these cases is reinduction chemotherapy followed by allogenic stem cell transplantation [4, 5]. Fludarabine, a purine nucleotide analog, has recently become the focus of treatment for acute leukemias and myelodysplastic syndromes (MDS). Its active metabolite, Fludarabine triphosphate, inhibits ribonucleotide reductase with subsequent accumulation of intracellular cytosine arabinoside (AraC) triphosphate [6, 7]. The toxicity profile of Fludarabine has been shown to be acceptable [8], but it is often combined with additional agents to improve efficacy and limit untoward toxicity [9-11]. The combination of Fludarabine with Ara-C increases the intracellular Ara-C content by twoto seven-fold in leukemic cells, which has shown a positive correlation with remission rates [12]. Idarubicin (IDA), an anthracycline, is also added because of its less susceptibility to multidrug resistance compared to other anthracyclines in human leukemia cell lines; and have lesser cardiotoxicity making them favorable for heavily pretreated patients [13, 14]. Granulocyte colony stimulating factor (G-CSF) prior to Fludarabine increases the fraction of cells in cycle when they are most vulnerable to AraC, and enhances the incorporation of AraC into DNA [15, 16]. The synergistic action of Fludarabine, AraC and IDA with or without G-CSF (abbreviated as FLAG-IDA and FLA-IDA respectively) have found widespread use as salvage chemotherapy for refractory/relapsed Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL) with complete remission rates ranging from 40–60% with variable 30day mortalities ranging from 4% to 9% [4, 5, 17, 18]. Additionally, a recent retrospective trial by Farooq et al. [19] compared outcomes in 76 patients treated for FLAG-IDA and FLAG; and found a significant improvement in survival in patients treated for Fludarabine-based regimen without IDA [19]. However, a small single-center study from Pakistan by Hashmi et al. [20] found a much higher 30-day mortality rate of 25% (3/12 patients) with FLAG-IDA and similar complete remission rates (66%). Hence, the purpose of our study is to identify the 30-day mortality rate in a larger cohort of patients with ALL/AML being treated with Fludarabine-based regimens in a single tertiary care center in Pakistan. Additionally, we aim to compare outcomes in adult patients with ALL/AML being treated with Fludarabine-based regimens with and without G-CSF, since this comparison has previously been performed without the addition of IDA in treatment regimens [9]. We hypothesize the 30-day mortality rate with Fludarabine-based regimens will be lower than the previously published 25% and there will be a significant difference in post-treatment outcomes between patients being treated with FLA-IDA and FLAG-IDA.