Randomized Phase 3 Trial of Venetoclax Added to Fludarabine, High‑Dose Cytarabine, and Gemtuzumab Ozogamicin in Children with Relapsed Acute Myeloid Leukemia

The primary objective is to assess whether the addition of venetoclax to fludarabine, high‑dose cytarabine and gemtuzumab ozogamicin improves overall survival in children with relapsed acute myeloid leukemia compared with the chemotherapy regimen without venetoclax. Demonstrating a survival advantage would substantiate the therapeutic benefit of incorporating venetoclax into salvage treatment for this high‑risk population.

The trial enrolled 48 participants, comprising both male and female children, adolescents, and young adults with a diagnosis of acute myeloid leukemia who experienced a relapse and lacked a documented FLT3/ITD mutation. Eligible ages spanned the pediatric to young adult spectrum, corresponding to the study’s age‑range codes for children and adolescents. All enrollees were required to have recovered sufficiently from prior anticancer therapy, demonstrate a performance status of ECOG 0–2 (or ≥50 % Lansky/Karnofsky), and possess adequate renal, hepatic, and cardiac function as defined by protocol‑specified laboratory thresholds. Selection criteria also mandated cessation of graft‑versus‑host‑disease or organ‑rejection prophylaxis for at least 14 days, a minimum interval since any cellular therapy, stem‑cell transplant, or recent chemotherapy, and the ability to provide informed consent (or assent with guardian consent). General health requirements excluded active graft‑versus‑host disease, recent intensive chemotherapy, or recent exposure to antibody‑drug conjugates, cytokines, or radiation beyond defined wash‑out periods. No specific dietary or physical‑activity restrictions were imposed beyond standard clinical care for this vulnerable population.

The study is a randomized phase III parallel‑group trial comparing fludarabine, high‑dose cytarabine, and gemtuzumab ozogamicin (FLA + GO) with or without the addition of venetoclax in patients with acute myeloid leukemia who have experienced a relapse. Eligible participants undergo a screening visit to confirm inclusion criteria, after which they are randomized to one of the two treatment arms. The experimental arm receives oral venetoclax 600 mg daily in combination with standard FLA + GO dosing (fludarabine 30 mg/m² IV, cytarabine 2 g/m² IV, gemtuzumab ozogamicin 3 mg/m² IV), while the control arm receives FLA + GO alone. Treatment cycles are administered according to the protocol schedule, followed by regular follow‑up visits for safety monitoring, response assessment, and collection of survival data. The primary efficacy endpoint is overall survival, defined as the time from randomization to death from any cause. Participants remain in the trial from the screening visit through the final follow‑up and end‑of‑study visit, which occurs after the last scheduled assessment. Early termination may occur if a participant experiences unacceptable toxicity, disease progression, organ dysfunction, withdrawal of consent, or any major protocol deviation. Recruitment began on 1 June 2022 and the study is planned to conclude on 16 July 2031.

The experimental agent venetoclax is provided as an oral suspension and as a film‑coated tablet, each delivering a dose of 600 mg per administration. The product is taken by oral use; dosing is intended to be once daily throughout the treatment cycle as specified in the study protocol.

Azacitidine is supplied as a subcutaneous formulation (PHF00202MIG) and administered at a dose of 75 mg/m² per injection. The route of administration is subcutaneous use, with the schedule defined by the protocol.

Cytarabine is provided for intravenous infusion (PHF00230MIG) at a dose of 2 g/m². The route is intravenous use, and the infusion schedule follows the protocol‑specified timing.

Gemtuzumab ozogamicin is delivered as an intravenous preparation (PHF00230MIG) at a dose of 3 mg/m². Administration is by intravenous use according to the investigational schedule.

The comparator regimen consists of fludarabine combined with high‑dose cytarabine and gemtuzumab ozogamicin (FLA+GO). Fludarabine is administered intravenously per standard practice for relapsed acute myeloid leukemia, while cytarabine and gemtuzumab ozogamicin are given at the doses described above.

Drug administration is performed under direct clinical supervision. Oral medication compliance is monitored by pill count and patient diaries, whereas intravenous infusions are recorded in infusion logs. All dosing and schedule adherence are documented in the case report forms to ensure protocol compliance.

The efficacy of the treatment arms will be assessed using the primary endpoint of overall survival (OS), defined as the time from randomization until death from any cause.