Trial in Progress: A Randomized-Controlled Phase 2 Study Evaluating Venetoclax Plus Azacitidine Versus Intensive Chemotherapy in Adult Patients with Newly Diagnosed, <i>NPM1</i>-Mutated AML - the SAL/AMLCG Vincent Trial

Background &amp; significance Standard of care (SOC) in fit, NPM1-mutated, FLT3-wildtype AML patients consists of intensive induction chemotherapy (+/- gemtuzumab-ozogamicin, GO), followed by intermediate-dose cytarabine consolidation (IDAC). This treatment approach induces complete remissions (CR) in up to 85% of patients, leading to a 5-year overall survival (OS) rate of 40-50%. However, treatment-related toxicity remains high with myelosuppression leading to infectious complications and organ toxicity. Extensive supportive care and repeated episodes of hospitalization are associated with patients' discomfort and a high economic burden. Combination of venetoclax (VEN) and hypomethylating agents, e.g. azacitidine (AZA), has shown promising results in patients not eligible for intensive chemotherapy and is usually administered in an outpatient setting due to lower toxicity. Here, especially patients with NPM1-mutated disease seem to benefit, achieving CR or CRi in up to 93% and a 2-year OS rate of 72%. However, so far there is no prospective data comparing SOC to VEN/AZA in fit patients. Study design &amp; methods VINCENT is a randomized-controlled open-label, multicenter, phase 2 trial designed to evaluate efficacy and safety of VEN in combination with AZA compared to SOC intensive chemotherapy in adult patients with NPM1-mutated, newly diagnosed AML within a non-inferiority assumption (alpha 0.05, power of 0.8, non-inferiority margin of 0.15). The study (NCT05904106) is conducted within the Study Alliance Leukemia (SAL) and AML Cooperative Group (AMLCG) across Germany. Patients aged 18-70 years with newly diagnosed, NPM1-mutated AML without activating FLT3 co-mutations are eligible. Patients must be considered fit for intensive chemotherapy (ECOG score ≤2) and have adequate organ function. Patients with relapsed or refractory AML, prior cytotoxic treatment, CNS involvement or solitary extramedullary disease will be excluded. A total of 146 patients will be randomized in a 1:1 fashion to receive either VEN/AZA or SOC. In the investigational arm, patients will receive 3 cycles of VEN (400 mg PO QD, days 1-28, initial ramp-up) and AZA (75 mg/m2 SC QD, days 1-7) for induction, followed by 9 further identical consolidation cycles for patients in CR/CRi/CRh and absence of molecular failure. Patients treated within the SOC arm will receive one cycle of DA+GO for induction therapy (IT1), combining cytarabine (200 mg/m2 CIV, days 1-7), daunorubicin (60 mg/m2 IV QD, days 3-5) and GO (3 mg/m2 IV QD; days 1, 4, 7). Patients not achieving CR after IT1 will receive age-adapted HAM (cytarabine 1000-3000 mg/m2IV BID, days 1-3 plus mitoxantrone 10 mg/m2 IV QD, days 3-5) for IT2. Patients achieving CR/CRh will receive a maximum of 3 cycles of age-adapted IDAC (1000-1500 mg/m2 IV BID, days 1-3) for post-remission treatment. For the VEN/AZA arm, bone marrow (BM) assessments will be done on day 21+3 of induction cycle 1 and in each subsequent cycle on day 28-42 until cycle 6, then every 3 months until 24 months after randomization. For the SOC arm, BM assessments will be done after blood count recovery, but between day 21-28 for induction cycles and on day 28-42 of each consolidation cycle, then every 3 months until 24 months after randomization. With each BM assessment, minimal residual disease (MRD) status will be measured by NPM1 real-time qPCR and MFC. Health-related quality of life (HRQoL) will be assessed by EORTC-QLQ-C30 and EQ-5D-3L every three months until EOS. Primary endpoint is the modified event free survival (mEFS), defined as primary induction failure, hematologic relapse, molecular failure (molecular progression or molecular relapse) or death. Key secondary endpoints include safety and tolerability, CR/CRi/CRh/CRMRD- rates, MRD kinetics (molecular response and persistence), relapse-free survival and OS, early mortality, change in HRQoL and cumulative use of health care resources. Every enrolled patient will be followed up for at least 2 years from enrollment. VINCENT has been actively enrolling patients since April 2024. Currently 18 centers are active. This research is supported by a grant from AbbVie Inc.