Venetoclax and Azacitidine for Relapse Prevention in NPM1-Mutated Acute Myeloid Leukemia in Molecular Failure: Results from the Ongoing Gimema AML2521 Phase 2 Trial

Background: Molecular failure (MF) after first line intensive chemotherapy (IC) in NPM1-mutated (NPM1m) AML identifies higher risk patients who will inevitably relapse if untreated and who require treatment intensification with allogeneic stem cell transplantation (alloSCT). However, no therapy is currently available in the measurable residual disease (MRD) setting, although increasing evidence supports both the value of an early intervention and the efficacy of venetoclax (VEN) and azacitidine (AZA) in NPM1m AML.

Aim: To evaluate the efficacy of VEN-AZA in preventing morphological relapse as a bridge-to-transplant strategy in adult NPM1m AML patients who experience MF during IC treatment or subsequent follow-up monitoring.

Methods: This is the GIMEMA AML2521 trial (ClinicalTrials.gov NCT04867928); a phase 2, non-randomized, interventional, open-label, multicenter trial enrolling fit-for-transplantation adult NPM1m AML patients in molecular relapse or progression 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. AlloSCT is recommended at any time at MRD-negativity (MRDneg), defined as NPM1m < 0.01%, from cycle (C)1 onwards.

Results: Twenty-four NPM1m AML patients have been screened, of which 20 resulted eligible for the study. Five patients are currently undergoing C1, thus we present data of the first 15 patients enrolled. Median patient age is 55 years (range 48-62), 7 of 15 (47%) are male, all patients have ECOG=0. AML characteristics at diagnosis show concomitant FLT3-ITD mutation in 5 (33%) of patients and FLT3-TKD in 3 (20%); 1 patient presented ELN2022 adverse risk for TP53 mutation. At enrolment, all patients were in confirmed CR, median NPM1m values were 0.188 (IQR 0.087, 1.615), no patients presented detectable FLT3 mutations. Patients received a median of 3 cycles (range 1-6) of VEN-AZA. Concerning primary endpoint, no patients experienced morphological relapse while on study treatment. Overall, 9 (60%) patients achieved MRDneg during treatment and 3 (20%) a molecular response (NPM1m decrease ≥1 log), for an overall molecular response (OMR) of 80%. Median time to MRDneg is 1.64 months (IQR1.31, 3.02). So far 13 (87%) of patients have been bridged to alloSCT in CR or better. Median time to transplant is 3.45 mo (IQR 3.09, 4.24). Concerning safety, the most frequent adverse events (AEs) ≥ G3 related to study drug, as expected, were of hematological nature, involving 7 of 15 (47%) patients. Overall, 15 AEs ≥ G3 were reported: 10 neutropenia, 3 thrombocytopenia, 1 pancytopenia; only 1 (7%) patient experienced febrile neutropenia G3. With a median follow-up of 9.8 mo (IQR 6.4, 17.0), all patients are alive and in CR.

Conclusions: This preliminary data shows promising results for AZA-VEN in preventing disease relapse and in bridging safely and effectively NPM1m AML patients in MF to alloSCT. Updated data will be presented at meeting in case of abstract selection. This study has been conducted with the support of Abbvie SRL.