A pre-emptive bridge-to-transplant therapy for measurable residual disease with venetoclax and azacitidine in NPM1-mutated Acute Myeloid Leukemia: Updates from the ongoing GIMEMA AML2521 phase 2 trial Free

Molecular failure (MF) after first line intensive chemotherapy (IC) in NPM1-mutated (NPM1m) acute myeloid leukemia (AML) identifies high risk patients who inevitably relapse if untreated and require allogeneic stem cell transplantation (alloSCT) to achieve prolonged survival benefit. No therapy is currently approved in the measurable residual disease (MRD) positive setting for AML patients, although increasing evidence supports the value of an early MRD-driven intervention. Bcl-2 inhibitor venetoclax (VEN) in combination with azacitidine (AZA) has shown exquisite sensitivity in newly-diagnosed unfit NPM1m AML patients, paving the way for its application in the MF fit patient setting.

Aim: To evaluate the efficacy of pre-emptive VEN-AZA in 1) preventing morphological relapse, 2) lowering MRD levels and 3) as bridge-to-transplant in adult NPM1m AML patients in MF during IC treatment or subsequent follow-up disease monitoring.

The GIMEMA AML2521 trial (NCT04867928) is a phase 2, non-randomized, interventional, open-label, multicenter trial enrolling fit-for-transplantation NPM1m adult AML patients in molecular relapse or progression, as defined by ELN2022 guidelines, after having received at least 2 cycles of IC. Inclusion criteria comprise: 1) morphological complete remission (CR); 2) centralized MRD positivity defined as NPM1m transcript/ABL1 x 100 ≥ 0.01%, evaluated with qRT-PCR. Patients receive VEN 400 mg (50 mg if concomitant posaconazole) on days 1-28 in association with azacitidine 75 mg/m² days on 1-7. Molecular negativity (MRDneg) is defined as NPM1m < 0.01% (Balsat JCO 2016); molecular reduction is defined as ≥1 log₁₀ reduction of NPM1m copies from pre-treatment levels (Jimenez-Chillon Blood Adv 2024). Overall response rate (ORR) is defined as molecular reduction plus MRDneg. AlloSCT is recommended at any time at MRDneg from cycle (C)1 onwards, or after C3 according to investigator's choice. A maximum of 6 cycles is allowed. Planned study sample size is of 35 patients.

To date, 40 NPM1m AML patients have been screened, of which 29 resulted eligible for the study. The principal cause of screening failure was overt relapsed disease in 9/11 (82%) patients, while the remaining 2 patients were in CR MRDneg at centralized screening assessment. Four patients are currently undergoing C1, thus we present data of the first 25 patients enrolled. Median patient age was 57 years (range 26-72), 15/25 (60%) were male, all patients had ECOG 0. Median hemoglobin values were 13.1 g/dL (range 10.2-15-6), median platelets 180 x 10⁹/L (range, 18-283) and median leukocytes 4.65 x 10⁹/L (range, 2.68-12.58). Disease characteristics at AML diagnosis showed concomitant FLT3-ITD mutation in 9 (36%) of patients and FLT3-TKD in 3 (12%); ELN 2022 risk was favorable, intermediate and adverse in 13 (56.5%), 9 (39.1%) and 1 (4.3%) patient, respectively. At enrolment, all patients were in confirmed CR, median NPM1m copies/ABL1 x 100 were 0.189% (range 0.016-68.15), 1 patient presented detectable FLT3 mutation.

Patients received a median of 3 cycles (range 1-6) of VEN-AZA. Median VEN duration was 28 days during C1 and C2, 18 days on C3 and 14 days on C4, C5 and C6; AZA did not require dose reductions; 44% of patients during C1 received concomitant posaconazole. Concerning study primary endpoint, 24/25 (96%) maintained CR on study treatment; 1 (4%) FLT3-ITD mutated patient relapsed. ORR was 86% and MRDneg was achieved in 20/25 (80%) of patients. Median time to MRDneg was 2.33 months (range 0.99- 6.70). So far 21/25 (84%) patients have been bridged to alloSCT in CR or better. Median time to transplant was 3.71 mo (range 2.56 – 7.39). With a median patient follow-up of 11 mo (range 3-38), all patients are alive at last evaluation and all patients who received alloSCT are in ongoing CR.

Concerning safety, the most frequent adverse events (AEs) ≥ G3 related to study drug, as expected, were of hematological nature. Overall, 22 AEs ≥ G3 were reported: 16 neutropenia, 4 thrombocytopenia; only 1 (4%) patient experienced febrile neutropenia G3.

This preliminary data shows encouraging results for AZA-VEN in preventing disease relapse, deepening molecular responses and bridging safely and effectively NPM1m AML patients in MF to alloSCT. Updated data from ongoing patients will be presented at meeting in case of abstract selection. This study has been conducted with the support of AbbVie srl.