Azacitidine as epigenetic priming for chemotherapy is safe and well-tolerated in infants with newly diagnosed KMT2A-rearranged acute lymphoblastic leukemia: Children's Oncology Group trial AALL15P1

Abstract

Infants less than 1 year old diagnosed with KMT2A-rearranged (KMT2A-r) acute lymphoblastic leukemia (ALL) are at high risk of failure to achieve remission, relapse, and death due to leukemia, despite intensive therapies. Infant KMT2A-r ALL blasts are characterized by DNA hypermethylation. Epigenetic priming with DNA methyltransferase inhibitors increases the cytotoxicity of chemotherapy in preclinical studies. The Children's Oncology Group trial AALL15P1 tested the safety and tolerability of 5 days of azacitidine treatment immediately prior to the start of chemotherapy on day 6, in four post-induction chemotherapy courses for infants with newly diagnosed KMT2A-r ALL. The treatment was well-tolerated, with only two of 31 evaluable patients (6.5%) experiencing dose-limiting toxicity. Whole genome bisulfite sequencing of peripheral blood mononuclear cells demonstrated decreased DNA methylation in 87% of samples tested following 5 days of azacitidine treatment. Event-free survival was similar to that in prior studies of newly diagnosed infant ALL. Azacitidine is safe and results in decreased DNA methylation of peripheral blood mononuclear cells in infants with KMT2A-r ALL, but the incorporation of azacitidine to enhance cytotoxicity did not impact survival. Clinicaltrials.gov identifier: NCT02828358.

Figure 1.

Treatment schema. Patients with KMT2A-r received four azacitidine (EPI) courses, each immediately prior to a chemotherapy course. The dose-limiting toxicity evaluation period extended from the start of EPI1 to the completion of Delayed Intensification Part 1 until the patient met parameters to begin EPI4.

Figure 2.

CONSORT (CONsolidated Standards of Reporting Trials) diagram. KMT2A-r: KMT2A rearranged; FISH: fluorescence in situ hybridization; EPI: azacitidine.

Figure 3.

Whole genome bisulfite sequencing data. (A, B) Percentage of CpG sites methylated, measured by whole genome bisulfite sequencing, for EPI1 (A) and EPI2 (B). Twenty-three infants had samples submitted for both days 1 and 5 of both EPI1 and EPI2. Each line indicates an individual infant. Red indicates patients who experienced an event (treatment failure, relapse, second malignant neoplasm, or death) and blue indicates patients who did not experience an event. EPI1: first course of azacitidine treatment; EPI2: second course of azacitidine treatment.

Figure 4.

Outcomes for all patients and patients stratified by minimal residual disease status at the end of induction. (A, B) Event-free survival (A) and overall survival (B) for all eligible patients, stratified by KMT2A-rearrangement receiving azacitidine (Positive + Aza) and KMT2A-germline (Negative) status. (C, D) Event-free survival (C) but not overall survival (D) was significantly better for KMT2A-rearranged patients with negative minimal residual disease at the end of induction. Aza: azacitidine.