FLAG-IM (Fludarabine, Ara-C, G-CSF, Idarubicin, Mylotarg) Is an Effective Salvage Regimen Producing High Rates of Remission (CR+CRi) in Relapsed/Refractory AML.

Despite advances in post-remission therapy, the outcome of patients (pts) with relapsed or refractory AML remains poor. In particular, pts who relapse with an initial remission duration of < 1 year, fail a previous salvage regimen, or relapse after allogeneic transplant have dismal outcomes with CR rates ranging from 0–20%. Between April 2004 and June 2007, we treated 41 pts with a novel salvage regimen, FLAG-IM, for relapsed or refractory AML. Treatment consisted of fludarabine 25mg/m2/d on d1-5, cytarabine 2000 mg/m2/d on d1-5, idarubicin 12mg/m2/d on d1-5, and gemtuzumab ozogamicin (Mylotarg) 9 mg/m2 on d8 with G-CSF 5 mcg/kg on d1 until neutrophil recovery. CD33 expression in ≥ 30% of the blast population by flow cytometry was required for treatment. Pt population consisted of 20:21(M:F) with median age of 47 years (range 16–68), and included pts with secondary AML (n=6, 15%), intermediate risk (22, 54%) and poor risk (16, 39%) cytogenetics. Treatment indication included primary refractory disease in 7 (17%), 1st relapse, 1st salvage with initial remission duration of < 1 yr in 16 (39%), and 2nd or higher salvage regimen in 14 (34%). 17 (41%) received FLAG-IM for relapse post-allogeneic transplant. Of the 41 pts treated, 38 are evaluable for response. By IWG criteria, a CR was achieved in 12/38 (32%) and CRi in 10/38 (26%) for an overall response rate of 58%. Eight (21%) had persistent disease while 8 (21%) died with aplasia. With a median follow up of 397 days (range 23–1136), the median overall survival (OS) for the entire cohort was 147 days with 1 yr KM estimate of OS is 28.7% (95%CI, 13.4–43.9). Median event-free survival was 108 days with 1 yr KM estimate of 18.9% (95%CI, 6.1–31.6). For pts who achieved a CR or CRi, neutrophil recovery (ANC>500/mm3) occurred at a median of 28 days (range 21–50). The principal nonhematologic toxicity was grade 3-4 hepatotoxicity which occurred in 13 (32%) pts which was generally transient but fulfilled criteria for VOD in 3 (7%) pts. Of the 16 pts (39%) who underwent subsequent allogeneic transplant post FLAG-IM, median OS was 1089 days vs 94 days for no transplant, p=0.0002, with 1 yr KM estimate of 52.4% (95%CI 26.4–78.2). We conclude that FLAG-IM is an effective salvage regimen for AML with high rates of remission observed in a historically refractory patient population. The high response rates have allowed subsequent allogeneic transplantation in a significant fraction of patients resulting in long term survivors.