Update AML: Updated disease monitoring and treatment to enhance outcomes for pediatric AML (NCT07059975)

Abstract Background and significance: Outcomes for children with acute myeloid leukemia (AML) have not improved in decades, despite three cooperative group phase III clinical trials and a revolution in molecular characterization. Patients with intermediate risk (IR) AML have a 50% risk of relapse; patients with high risk (HR) AML have an even higher relapse risk, despite stem cell transplantation (SCT) in first remission. Moreover, after relapse outcomes are dismal. At the same time, suboptimal residual disease testing along with cardiac toxicity and poor quality of life from current therapies demand attention and intervention. As there is a current gap with no available Children's Oncology Group (COG) frontline trial for most AML patients, Texas Children's Cancer and Hematology Center (TXCH) has developed an investigator-initiated, single institution, pilot study – UPDATE AML: Updated Disease Monitoring and Treatment to Enhance Outcomes for Pediatric AML (NCT07059975). The UPDATE AML study will address three pressing needs: update AML treatment with two intensified blocks of therapy, develop individualized digital PCR (dPCR) assays to monitor residual disease, and evaluate toxicities using new biomarkers and pediatric-specific surveys. Study Design and Methods: The primary objective of UPDATE AML is to determine the tolerability of two intensive chemotherapy cycles strategically substituted for less intensive or more toxic cycles in the standard COG-based regimen for IR and HR patients. These patients will receive the common salvage regimen Idarubicin-fludarabine-cytarabine (IdaFLA) as the second cycle (Induction 2) in lieu of standard DA8 (Daunorubicin-Cytarabine) chemotherapy. We have also incorporated a block of treatment containing the BCL2 inhibitor venetoclax (combined with idarubicin-cytarabine (VIA)), which has been shown to be safe and effective in children with relapsed AML. In UPDATE AML, IR patients will receive VIA in place of MA (mitoxantrone-cytarabine) to eliminate exposure to the cardiotoxic agent mitoxantrone. HR patients will receive VIA as Intensification 1 prior to SCT, in place of the genotoxic agent etoposide and to provide venetoclax exposure prior to SCT. We will use continuous monitoring schemes for toxicity using Pocock-type boundaries with a threshold of 20% intolerability. Secondary objectives include the rate of pediatric complete remission at the end of Induction 2, 3-year event free and overall survival rates, tolerability of the overall intensified regimens for IR and HR patients, and flow-cytometric minimal residual disease (MRD) negativity rate at the end of Induction 2. Our exploratory objectives focus on developing updated approaches to MRD testing. Based on local and published data, we hypothesize that at least 80% of patients will have a clonal alteration amenable to dPCR tracking and that dPCR MRD will reveal valuable response information with higher sensitivity than current, flow cytometric-based MRD clinical tests. The TXCH Molecular Oncology team is currently developing patient-specific dPCR assays for sensitive MRD quantification. To further modernize MRD methodology, we will apply the dPCR tests to bone marrow samples and to cell-free nucleic acids (cfNA) from peripheral blood plasma which could provide future options to detect relapse without the need for bone marrow sampling. We will collect biospecimens and clinical data for correlative investigations from patients who consent to these optional studies, including generation of fully characterized patient-derived xenograft mouse models, comparing established and emerging cardiac function parameters, and collecting patient-reported outcome information with pediatric-specific tools to better understand the physical and psychosocial effects of AML treatment on the patient and family. All newly diagnosed patients at TXCH >1 month to <30 years old with non-FLT3-ITD+ AML will be eligible for enrollment after completing standard Induction 1 chemotherapy consisting of combination of daunorubicin and cytarabine +/- gemtuzumab. Patients must have adequate organ function and performance score and no underlying genetic predisposition syndromes. Over 3 years, the study is anticipated to accrue 36-40 patients and generate important feasibility data for our treatment and molecular MRD innovations. Our results will inform future cooperative group trials with respect to therapy, MRD monitoring, supportive care and correlative biology.