Gemtuzumab-Ozogamicin in Combination with Fludarabine, Cytarabine, Idarubicin (FLAI-GO) as Induction Therapy in CD33-Positive AML patients Younger Than 65 Years. Report of a Multicentric Trial

INTRODUCTION. The addition of Gemtuzumab-ozogamicin (GO) to an induction regimen including synergistic drugs, such as intermediate dose of cytarabine (Ara-C), idarubicin and fludarabine (FLAI), could reduce treatment failure in AML patients. Nevertheless, the role and safety of this antibody target-therapy in first-line chemotherapy in patients younger than 65 years has not yet been defined.

PATIENTS and METHODS. The primary goal of this multicenter prospective trial (EUDRACT Number 2007-005248-26) was to evaluate the efficacy and the safety profile of FLAI plus GO as induction regimen. Sixty-eight consecutive AML patients were included from five Italian hematological centres. All patients were younger than 65 with a median age of 48 years and CD33 expression exceeded 20% in all cases. The M/F ratio was 37/31, and 54/68 (79%) of patients were poor-risk at diagnosis. The induction regimen (FLAI-GO) included fludarabine (30 mg/sqm) and Ara-C (2 g/sqm) on days 1–5, idarubicin (10 mg/sqm) on days 1, 3, and 5 and GO (3 mg/sqm) on day 6. Hematopoietic stem cell transplant (HSCT) was planned for all high risk AML patients in first complete remission (CR) after consolidation with intermediate doses of Ara-C and idarubicin (IDAC-IDA). Cytogenetic, multidrug-resistance phenotype, FLT3 mutation status, and WT1 quantitative expression analyses were performed at diagnosis in all patients. WT1 expression and cytogenetic (in positive cases) analyses were performed after induction to detect and follow Minimal Residual Disease.

RESULTS. Patients were evaluated for response rate, treatment-related adverse events, overall survival and relapse free survival. After induction with FLAI-GO, CR rate was 86% (54 of 63 evaluable pts); one patient achieved partial remission and eight were resistant. There were only two cases of death during induction (DDI). After FLAI-GO, the mean value of WT1 dropped from 4540±2342 copies/10⁴ABL to 180±277 copies/10⁴ABL. The toxicity of FLAI-GO was acceptable; 58% of patients experienced transient and reversible GO infusion-related adverse events (especially fever and chills), but no cases of veno-occlusive disease occurred during CHT or after HSCT. After a median follow-up of 9 months (range 1–32), 60/68 (88%) patients are alive (57/60 in CR). The probability of 12 and 18 mths OS a was 91% and 78%, respectively. The probability of 12 and 18 mths RFS was 87 % and 78%, respectively. Allogeneic and autologus HSCT was performed in 30 (44%) and 8 (12%) patients.

CONCLUSIONS. The preliminary results of this multicentric trial confirm that FLAI-GO is an effective and well tolerated induction regimen for CD33 positive AML patients younger than 65 years, with a high complete response rate, favourable safety profile and low DDI.