Continuous Infusion of FLAG and Idarubicin for Patients Younger Than 60 Years with Resistant Acute Myeloid Leukemia; a Prospective, Multicenter Phase II Study.

Continuous infusion (CI) of cytarabine and fludarabine can accentuate drug activities. We studied the feasibility and the efficacy of fludarabine and cytarabin as a continuous infusion plus idarubicin for resistant AML under 60 years old. Inclusion criteria were AML except for acute promyelocytic leukemia, patients with resistant acute myeloid leukemia (failure to achieve CR after initial induction chemotherapy including standard dose cytarabine; early relapse, occurring after a first CR lasting less than 12 months; relapse after allogeneic HSCT; relapses more than 2 times). Induction chemotherapy consists of idarubicin 12 mg/m2 iv infusion over 30 min (day 1–3), fludarabine 30 mg/m2/d and cytarabine 1000 mg/m2/d (day 1–5) as a 24-hour CI. G-CSF was added on day 1–5. Three more cycles of induction chemotherapy except for idarubicin were followed for consolidation. All 29 patients were enrolled. Median age was 40 (18–57). Disease status were primary refractory in 8 (27.6%), early relapse in 19 (65.5%), multiple relapse in 1 (3.4%), and relapse after SCT in 1 (3.4%). Translocation (8;21) and variants (8, 27.6%), and 2 or 3 abnormalities (7, 24.1%) were most common chromosomal abnormalities. Two patients (6.9%) could not complete induction. Twenty three patients had the early evaluation on median day 15 (14–42); median PB blast 0 (0–9.7) % and median bone marrow blast 0 (0–64) %. Median days for hematological recoveries in CR patients were follows: ANC > 500/mm3 (29 days); ANC >1000/mm3 (32 days); platelet >20K/mm3 (31.5 days); platelet>100K/ mm3 (43 days). Response for induction were CR in 8 (27.6%), CRp in 2 (6.9%), and treatment failure in 19 (65.5%, aplasia in 14, indeterminate course in 3, resistant in 2). Median days required for CR was 45 (37–63) days. Consolidation stopped in 9/11: 7 patients underwent SCT; 1 patient died during consolidation; 1 patient stopped due to toxicity; 1 patient due to other cause. Seven patients are alive and two were lost to follow-up. Nineteen patients died of infection (14 patients), toxicity during consolidation (1 patient), relapse after SCT (3 patients) and persistent disease (2 patients). Autolous SCT performed in 2 and allogeneic SCT in 5. Median overall survival in all and CR patients were 2.47 (95% CI 0.83–4.10) and 11.38 (95% CI 1.32–21.44) months, respectively. Relapse occurred after autologous SCT in 2/2 and after allogeneic SCT in 2/5. CI infusion of FLAG plus idarubicin was effective for eradicating blasts with expense of high toxic death. Reduced doses are recommended for CI of FLAG plus idarubicin.