Efficacy and Toxicity of FLAI vs ICE for Induction Treatment of Newly Diagnosed AML Patients, Younger Than 60 Years.

Acute myeloid leukaemias (AMLs) are a heterogeneous family of hemopoietic malignancies that share a high frequency and a high degree of Pgp-mediated multidrug resistance (MDR), one of the major causes of treatment failure. Induction treatment (FLAI), including 5 days administration of Idarubicin (IDA- 10mg/sqm/day), in combination with high-dose Arabinosyl Cytosine (HDAC-2g/sqm/day) and Fludarabine (FLUDA-25mg/sqm/day) was adopted as induction treatment of newly diagnosed patients with AML, except acute promyelocytic leukemia (APL). In our previous experience (Russo et al. Leuk. Lymphoma, 2001), FLAI regimen showed to be highly effective (CR rate 72%), also in AML MDR-pos patients, with a low extra-hematological toxicity. In this prospective randomized trial, FLAI was compared with ICE (IDA 10mg/sqm/day x 3 days + AC p.c 100mg/sqm/day x 10 days + VP16 100mg/sqm/day x 5 days) for induction of remission. Post-induction treatment program included: HDAC (3g/sqm/12h x 6 days), MEC (Mitoxantrone 12 mg/sqm/day x 4 days, Etoposide 100 mg/sqm/day x 4 days, Cytarabine 1 gr/sqm/day x 4 days) and allogeneic or autologous BMT. Over a period of 2 years, 118 patients were randomly assigned to FLAI (67) or ICE (51). The clinical and hematological characteristics of the two patient population were not different. In the FLAI group, the complete remission (CR) rate was 72% after the first course and 76% after HDAC; in the ICE group, the CR rate was 53% and 69%, respectively (P <0,02). Interestingly, the CR rate of MDR-pos. and MDR-neg. patients treated with FLAI was similar (68% vs 67%), while the CR rate of MDR-pos. and MDR-neg. patients treated with ICE showed a significant trend in favour of MDR negative patients (20% vs 55%). The median time to recovery of neutrophils > 1.0 x 10⁹/L and platelets > 50 x 10⁹/L was significantly better in FLAI arm than in ICE arm. In both groups, it was seen an approximately equal rate of FUO, Gram negative/Gram positive bacteremias and systemic fungal infections. Infections and haemorrhages caused death during induction (DDI) in 3% of patients treated with FLAI and in 10% of patients treated with ICE. Non-hematological toxicity of FLAI was mild and significantly lower than ICE. In particular, in the FLAI arm, only 3/67 pts developed a grade 3 or 4 gastro-intestinal toxicity, whereas in ICE arm 16/51 patients experienced this toxicity (p=0.0001). Other grade 3 or 4 toxicity (ipertransaminasemia, cutaneus toxicity, renal or cardiac failure) were seen in 1/67 pts in FLAI arm versus 7/51 pts in ICE arm (p=0.02). In conclusion, these preliminary results strongly suggest that FLAI, as single induction course, is an highly effective regimen with a limited non-haematologic toxicity. Furthermore, FLAI seems to be more effective than ICE to overcome Pgp-mediated multidrug resistance.