Venetoclax in Children With Relapsed Acute Myeloid Leukemia (AML)

Relapse of AML is driven by chemotherapy resistant stem cells. One mechanism of chemotherapeutic resistance in AML is the overexpression of the protein B-cell lymphoma 2 (BCL-2), an anti-apoptotic protein which sequesters intracellular activators of apoptosis. Venetoclax is a selective, potent, orally bioavailable, small molecule inhibitor of BCL-2 that restores programmed cell death in cancer cells. This is a trial for children, adolescents and young adults with 2nd relapsed AML or 1st relapsed AML unable to receive additional anthracycline. This is randomized trial of venetoclax in combination with intensive chemotherapy (fludarabine/cytarabine/gemtuzumab ozogamicin) for the first two cycles (42-day-cycles) that would inform and evaluate if this agent is an effective option for this population to improve its poor prognosis. Participants can receive up to two cycles of induction chemotherapy before hematopoietic stem cell transplantation (HSCT). If participants who have perceived clinical benefit cannot be transplanted after the 2 cycles, maintenance treatment may be given at the discretion of the investigator. In Arm B (experimental arm), participants can continue venetoclax if they have perceived clinical benefit, and maintenance therapy will combine venetoclax with azacitidine for a maximum of 24 cycles. In Arm A (control arm), participants will receive azacitidine in monotherapy. Maintenance is continued until clinical progression or unacceptable toxicity with a maximum of 24 cycles.