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

Abstract

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 AML. We treated 130 patients, aged <65, with a median age of 52 years. 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. SCT was planned for all high-risk AML patients, after consolidation with intermediate doses of cytarabine and idarubicin 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 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%. Four patients achieved partial remission (PR) and 12% were resistant (ORR 85%); death during induction (DDI) was 3%. The hematological and extra hematological toxicity of FLAI-GO was manageable; 45% of patients experienced transient and reversible GO infusion related adverse events. In the setting of patients who achieved a cytological CR after FLAI-GO, the mean of WT1 copies dropped from 8337±9936 copies/10 ABL (diagnosis) to 182 ± 436 copies 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.

Toward the potential cure of leukemias in the next decade

“…Overall, FLAG-IDA was associated with a reduction in the relapse rate (38% vs 55%; P < .001) and with improved relapse-free survival (45% vs 34%; P = .01). 159 We believe that significant progress in the therapy of AML will emerge through several important therapeutic leads, guided by deciphering the molecular pathophysiology of AML. 157 In a recent study by the Italian group using FLAG-IDA plus GO in 130 patients up age 65 years, the CR rate was 80%, the induction mortality was 3%, and the 5-year survival rate was 52%.…”

“…Several studies have demonstrated that the addition of high-dose cytarabine during induction, 153,154 and the introduction of adenosine nucleoside analogs (fludarabine, cladribine) into cytarabine/anthracycline regimens, improved patient outcome. [155][156][157][158][159] At our institution, the fludarabine/high-dose cytarabine/idarubicin (FAI) regimen 160 and its equivalent with cladribine (the CLIA regimen) are frontline standards of care, to which we add targeted therapies based on the molecular profile (eg, sorafenib or midostaurin in FLT3-mutated AML). The FAI regimen, also called FLAG-IDA, is used with or without GO and has demonstrated success.…”

“…These are excellent results in adult AML therapy. 159 We believe that significant progress in the therapy of AML will emerge through several important therapeutic leads, guided by deciphering the molecular pathophysiology of AML. These include: 1) FLT3 inhibitors, 2) IDH1/IDH2 inhibitors, 3) GO and novel antibodies targeting CD33 and CD123, 4) venetoclax as an important BCL2 inhibitor, and 5) the introduction of checkpoint inhibitors (CPIs) into AML theraphy.…”

Gemtuzumab ozogamicin and novel antibody-drug conjugates in clinical trials for acute myeloid leukemia

“…82% of patients achieved CR, and the 2-year OS and disease-free survival (DFS) were 63 and 54% respectively. 63.8% of patients underwent AlloSCT after the induction therapy [50]. GO was studied in the EORTC-GIMEM AML-17 trial, a randomized trial that evaluated the GO therapy followed by standard chemotherapy, MICE (mitoxantrone, cytarabine, etoposide) in older patients (age 61 to 75 years) with newly diagnosed AML [51].…”

Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia

“…(39, 40) Results of GO plus multi-agent intensive chemotherapy (other than daunorubicin and cytarabine) have resulted in impressive response rates and holds promise, particularly in reducing disease burden degree and allowing for subsequent successful alloSCT in the salvage setting. (41–43) Larger prospective confirmatory studies of GO added to targeted therapies agents are needed to more firmly establish GO in the treatment paradigm for the RR-AML population.…”