Phase 2 Study of FLAGM (Fludarabine+High-Dose Ara-C +G-CSF+Mitoxantrone) for Relapsed or Refractory Acute Myeloid Leukemia (AML): A Report From the Japan Adult Leukemia Study Group (JALSG).

Abstract 1058

Poster Board I-80

High-dose ara-C is a basic regimen for the treatment of either relapsed or refractory AML. To improve the outcome of salvage therapy, various combinations of high-dose ara-C have being studied. We herein report the outcome of a phase 2 study of FLAGM. Between 2004 and 2008, JALSG conducted a phase 2 study of FLAGM for relapsed or refractory AML to evaluate its efficacy and toxicity. We thereafter further attempted to predict the response to FLAGM by determining the capability of blast cells to yield the intracellular active metabolite of ara-C: ara-C triphosphate (ara-CTP) in vitro before the start of treatment. JALSG FLAGM enrolled 41 relapsed or refractory AML patients (pts) aged 15-64 yrs (median 52 yrs). The patients were treated with fludarabine 15 mg/m2 twice daily (bid)(d1-4), as well as with ara-C 2g/m2, bid (d1-4), G-CSF 300 μg/m2 (d1-4), and mitoxantrone 10 mg/m2 (d3-5). Six pts showed primary refractory AML. 21 pts relapsed within 12 months after the 1st complete remission (CR), whereas 11 pts suffered their 1st relapse later than 12 months thereafter. Only 1 pt with a 2nd relapse was enrolled. Two pts showed refractory AML after relapse. The diagnoses according to the FAB criteria were as follows: M0 - 3 pts, M1 - 7 pts, M2 – 21 pts, M4 - 8 pts, M5 - 2 pts. Performance status: ECOG 0, 1 and 2 in 76%, 22% and 2% of the pts, respectively. Eight pts had good-risk cytogenetics, 26 pts had intermediate-risk cytogenetics, 2 pts poor-risk cytogenetics, no metaphases were obtained and no cytogenetics were performed in 5 pts. Twenty-one blast samples were evaluated for the production of ara-CTP. The blasts were incubated in vitro either with or without 10 μM fludarabine nucleoside (F-ara-A) for 3 h, followed by washing in fresh media and then subsequent incubation with 10 μM ara-C for 3 h. The nucleotide pool was extracted from each sample and applied to HPLC to measure the ara-CTP production. Following FLAGM, 28 pts (68%) achieved a CR and 1 pt (2%) a CR with an incomplete platelet count recovery (CRp), thus resulting in an overall response rate of 70%. The CR rate of pts in primary refractory and that of pts in 1st relapse were 50% and 79%, respectively. 83% of the pts with a late relapse (duration of 1st CR >=12 months) and 77% of the pts with an early relapse (duration of 1st CR <12 months) achieved a CR (P=0.7). The CR rate of the pts previously treated with high-dose ara-C and that of the pts not treated with high-dose ara-C were 79% and 69% (P=0.5). In addition, the age, sex, PS, and cytogenetic risk did not significantly influence the CR rate. Only one pt suffered an early death due to pneumonia and pulmonary bleeding. Twenty-seven pts underwent stem cell transplantation after CR and 8 of them have demonstrated a long-term survival. The most frequently reported adverse events (grade 2-4) were: infection (73%), nausea/vomiting (33%), stomatitis (20%), diarrhea (20%), pyrexia (15%); all pts had leucopenia andthrombocytopenia. The mean concentration of ara-CTP in the blast cells after incubation with F-ara-A and ara-C of CR pts was comparable with that of non-CR pts (588 vs 747 pmol/1×107cells P=0.47). There was no difference in the increment of concentration of ara-CTP between CR pts and non-CR pts (1.19vs1.18 P=0.6). In conclusion, this study confirms that FLAGM yielded a 70% response rate in either relapsed or refractory AML pts. Although randomized studies are still needed, FLAGM appears to be a good option for the treatment of either relapsed or refractory AML pts, whatever the duration of the 1st CR or previous treatment. However, this study failed to demonstrate that the fludarabine-mediated augmentation of ara-CTP production in vitro is a predictor of the response to FLAGM.