Survival Analysis of Gimema AML1718, a Safety Run-in and Phase 2 Open-Label Study of Venetoclax, Fludarabine, Idarubicin and Cytarabine (V-FLAI) in the Induction Therapy of Non Low-Risk Acute Myeloid Leukemia

Background: Prognosis of intermediate and high-risk acute myeloid leukemia (AML) remains poor, with a 2-year estimated overall survival of about 30-40% in the young population. AML1718 trial combined venetoclax with fludarabine, idarubicine, and cytarabine (V-FLAI) with the specific aim of improving cure rate of these AML patients. Primary end-point analysis of the AML1718 trial demonstrated remarkable efficacy in term of probability of complete remission (CR) and mesurable residual disease negativity (MRD), 79% and 64%, respectively. Hereby, we present the mature data with overall survival and disease free survival analysis of the study.

Methods: The GIMEMA AML1718 phase 1/2 multicenter trial (NCT03455504) enrolled patients from Feb 2019 to Feb 2023 and investigated safety and efficacy of V-FLAI as a first-line treatment for newly diagnosed adult patients with ELN 2017 intermediate- or high-risk AML. The study followed a modified two-stage Simon's design; safety of the combination of venetoclax 400 or 600 mg and FLAI was established in a safety run-in (6+6 patients); the two different dosages of venetoclax were randomly compared in part 1, with no significant difference (22+23 patients). Part 2 consisted in a confirmatory cohort of 67 patients treated at the lower effective dosage, as predefined (V-FLAI 400 mg). A second inductin was possible for patients without complete remission (CR/Cri/CRh). In patients responding to single induction, cytarabine-based consolidation were administered based on center guidelines. VEN administration was discontinued until recovery for patients achieving remission by day 21 and during consolidation courses; predefined dose adjustments were planned for patients receiving posaconazole. Allogeneic hematopoietic stem cell transplant (HSCT) was indicated as soon as possible. In part 2, a centralized MRD assessment was performed. Baseline characterization of patients with 91-genes panel is ongoing, and will eventually be presented at the meeting.

Results: Mature follow-up data are available for all the 124 consecutive patients who received V-FLAI in the study. As previously reported, the median age was 55 years (ranging from 18 to 66), with 70 patients (56%) being male. The vast majority of the patients were of European ancestry. All the patient had baseline ECOG performance status <2. At baseline, 67 patients (54%) were locally classified as intermediate risk and 57 patients (46%) as high-risk, mostly basing on cytogenetic analysis, NPM1 and FLT3 status; the classification will be updated basing on centralized genetic analysis. FLT3 mutation was positive in 19 patients (15.3%), NPM1 mutation in 3 patients (2.4%), while 17 patients (14%) had a seconday AML.

In our set, 95 patients received V-FLAI 400 mg and 29 patients V-FLAI 600 mg. After induction, 74 patients (59.6%) proceded to consolidation and 71 received HSCT (57.2%, of which 63, 93% in 1^st CR). With a median follow-up of 22 months (IQR 11 – 31) , 1- and 2- years overall survival were 61% (95% CI 53-71) and 48% (95% CI 38-59) while 1- and 2- years disease free survival were 60% (95% CI 50-72) and 46% (95% CI 35%-60%), respectively. After 2 years, death and relapse probability lowered, and shape of the curves seems to suggest a plateau. Central MRD proven predictive value on disease free survival, results will be detailed presented in a separate abstract.

As far as safety is of concern, we confirmed the low-incidence of treatment-related mortality, with 5 deaths recorded during induction (4.0%, no difference according VEN dose), a safety profile comparable with other intensive inductions regiments and no instances of graft failure or higher-than-expected incidence of graft-versus-host disease. No severe late effect of the combination was reported up to now.

Conclusions: V-FLAI efficacy translated in long term survival for most of the treated patients. No unexpected long term toxicity or transplant-related toxicity emerged. Predicted 2 years survival seems to favor the adoption of this combination over other alternatives in the non-low-risk, fit population; a randomized trial comparison with the standard of care is warranted.