Flai (fludarabine, cytarabine, idarubicin) plus low-dose gemtuzumab ozogamicin as induction therapy in cd33-positive aml: Final results and long term outcome of a phase ii multicenter clinical trial

The aim of this prospective clinical trial was to evaluate the efficacy and safety of a combination of Gemtuzumab-Ozogamicin (GO) and FLAI scheme (fludarabine, cytarabine, idarubicin) as a first-line therapy in CD33 positive acute myeloid leukemia (AML). We treated 130 consecutive patients, aged <65, with a median age of 52 years (range, 18-65). FLAI-GO induction regimen included fludarabine (30 mg/sqm) and cytarabine (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 (SCT) was planned for all high-risk AML patients, after consolidation with intermediate doses of cytarabine and idarubicin (AC-IDA) and a high dose of cytarabine. CD33 expression exceeded 20% in all cases. Primary endpoints of the study included feasibility, overall response rate (ORR) and toxicity. Secondary endpoints included the evaluation of minimal residual disease (MRD) by WT1 expression; feasibility and outcome of consolidation with SCT, overall survival (OS) and disease-free survival (DFS). After induction with FLAI-GO, complete remission (CR) rate was 82% (106 of 130 patients). Four patients achieved partial remission (PR) and 12% (16 of 130 patients) were resistant (ORR 85%); there were only four cases (3%) of death during induction (DDI). The hematological and extra hematological toxicity of FLAI-GO was manageable; 45% of patients experienced transient and reversible GO infusion related adverse events (especially fever and chills), but no cases of veno-occlusive disease occurred during chemotherapy or after allogeneic SCT. In the setting of patients who achieved a cytological CR after FLAI-GO, the mean of WT1 copies dropped from 8337±9936/104ABL (at diagnosis) to 182±436 copies/104ABL after induction therapy (p = 0.0001) showing a very good disease debulking. After a median follow-up of 54 months, 67/130 (52%) patients were alive. The probability of 1, 2, and 5-year OS was 80%, 63%, and 52%, respectively. The probability of 1, 2, and 5-year DFS was 77%, 58%, and 52%, respectively. Allogeneic and autologous SCT was performed in 60 (46%) and 23 (18%) patients, respectively. In summary, the final results of this trial confirm that FLAI-GO is an active and safe treatment strategy for CD33-positive AML patients aged ≤ 65 years, allowing a high ORR, a good disease debulking, favorable safety profile, low DDI, and subsequent high SCT rate. The encouraging results of this trial, consolidated by a long follow-up, support the reintroduction of GO in clinical practice. This article is protected by copyright. All rights reserved.