HOVON 181 AML: Bleximenib or Placebo in Combination with Standard Induction and Consolidation Therapy followed by Maintenance for the Treatment of Patients with Newly Diagnosed KMT2A-rearranged or NPM1-mutant Acute Myeloid Leukemia Eligible for Intensive Chemotherapy: a double-blind phase 3 study

The primary objective of this double-blind phase 3 trial is to assess whether treatment with bleximenib, compared with placebo, in combination with remission induction and consolidation chemotherapy followed by maintenance therapy, prolongs event-free survival in adult patients with newly diagnosed NPM1-mutant or KMT2A-rearranged acute myeloid leukemia who are eligible for intensive chemotherapy. This objective addresses a clinically significant need to improve outcomes in specific molecular subgroups of acute myeloid leukemia patients undergoing standard intensive treatment regimens.

This clinical trial enrolled a total of **604 participants** diagnosed with **Acute Myeloid Leukemia**. The study population included both **male and female** adults aged **18 years and older** (or the legal age of majority in the respective jurisdiction, whichever was greater). Participants were selected based on a new diagnosis of AML with either **mutated NPM1** or recurring rearrangements involving **KMT2A** according to ICC 2022 criteria, with at least 10% blasts present in bone marrow or peripheral blood. Eligible individuals were those considered suitable for **intensive chemotherapy** and had a **WHO/ECOG performance status** of 2 or less at enrollment. Additional selection criteria included adequate renal and hepatic function and a **white blood cell count** below 25 × 10⁹/L prior to randomization. No vulnerable populations were included in this trial.

This is a randomized, double-blind, placebo-controlled phase 3 clinical trial evaluating the efficacy and safety of bleximenib in combination with standard remission induction and consolidation chemotherapy, followed by maintenance therapy, in adult patients with newly diagnosed acute myeloid leukemia harboring NPM1 mutations or KMT2A rearrangements who are eligible for intensive chemotherapy. The trial utilizes bleximenib administered as film-coated tablets via the oral route, with matching placebo comparators available in 50 mg and 100 mg formulations. The study aims to assess whether the addition of bleximenib to standard-of-care intensive chemotherapy prolongs event-free survival compared to placebo in this specific patient population.

The primary endpoint is event-free survival, defined as the time from randomization to failure to achieve complete remission after remission induction, hematologic relapse after achieving complete remission, or death, whichever occurs first. The trial methodology follows a rigorous design to ensure scientific validity and participant safety throughout the treatment phases, which include induction, consolidation, and maintenance therapy. The estimated recruitment start date is December 15, 2025, with an anticipated study completion date of December 15, 2033, indicating an overall trial duration of approximately eight years.

Eligible participants must meet the following principal inclusion criteria: be at least 18 years of age (or the legal age of majority in the jurisdiction, whichever is greater) at the time of informed consent; have a new diagnosis of acute myeloid leukemia with at least 10% blasts in bone marrow or peripheral blood, with confirmed mutated NPM1 or recurring rearrangements involving KMT2A according to ICC 2022 criteria; be considered eligible for intensive chemotherapy; have a WHO/ECOG performance status of 2 or less; demonstrate adequate renal and hepatic function prior to randomization; and have a white blood cell count below 25 × 10⁹/L.

Participant involvement extends throughout the induction, consolidation, and maintenance phases of treatment, with the duration determined by treatment response, disease progression, tolerability, and protocol-specified criteria. Study visits include screening and baseline assessments to confirm eligibility, regular monitoring visits during the treatment phases to evaluate efficacy and safety parameters, and an end-of-study visit to assess final outcomes. Conditions that may lead to early termination from the study include failure to achieve complete remission, disease relapse, unacceptable toxicity, participant withdrawal of consent, investigator decision based on safety concerns, or death.

The experimental medication **JNJ-75276617** contains the active substance **bleximenib** and is manufactured by Janssen-Cilag International N.V. The investigational product is formulated as a **film-coated tablet** for **oral administration**. Two tablet strengths are utilized in this clinical trial. The chemical designation of bleximenib is N-ethyl-5-fluoro-N-isopropyl-2-[[5-(2-[(3R)-6-[(2-methoxyethyl)(methyl)amino]-2-methylhexan-3-yl]-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl]oxy]benzamide. Bleximenib is administered in combination with standard remission **induction therapy** and **consolidation chemotherapy**, followed by **maintenance therapy**. The treatment period may extend up to 999 days. The investigational medicinal product is classified as a chemical substance.

**Placebo** formulations are provided to match the active bleximenib tablets. Two placebo variants are included in the study design: placebo to match bleximenib 100 mg and placebo to match bleximenib 50 mg. The placebo products are designed to maintain blinding in this **double-blind** study. Participants randomized to the placebo arm receive matching placebo tablets in combination with the same standard induction and consolidation chemotherapy regimen, followed by placebo maintenance therapy. The placebo administration schedule mirrors that of the active treatment arm to ensure consistency in treatment protocols.

The study employs a double-blind methodology wherein neither participants nor investigators are aware of treatment assignment. Both bleximenib and placebo are administered orally according to the assigned treatment regimen. The trial evaluates the efficacy of bleximenib compared to placebo when added to standard intensive chemotherapy in adult participants with newly diagnosed **NPM1-mutant** or **KMT2A-rearranged acute myeloid leukemia**. Treatment compliance and adherence to the prescribed dosing schedule are monitored throughout the induction, consolidation, and maintenance phases of therapy.

Efficacy will be assessed using event-free survival (EFS) as the primary endpoint. EFS is defined as the time from randomization to failure to achieve complete remission after remission induction, hematologic relapse after achieving complete remission, or death, whichever occurs first. The evaluation will determine whether treatment with bleximenib, as compared with placebo, in combination with remission induction and consolidation chemotherapy followed by maintenance therapy, prolongs event-free survival in adult participants with newly diagnosed NPM1-mutant or KMT2A-rearranged acute myeloid leukemia eligible for intensive chemotherapy.