FLT3 inhibitor lestaurtinib plus chemotherapy for newly diagnosed KMT2A-rearranged infant acute lymphoblastic leukemia: Children's Oncology Group trial AALL0631

Abstract

Infants with KMT2A-rearranged acute lymphoblastic leukemia (KMT2A-r ALL) have a poor prognosis. KMT2A-r ALL overexpresses FLT3, and the FLT3 inhibitor (FLT3i) lestaurtinib potentiates chemotherapy-induced cytotoxicity in preclinical models. Children's Oncology Group (COG) AALL0631 tested whether adding lestaurtinib to post-induction chemotherapy improved event-free survival (EFS). After chemotherapy induction, KMT2A-r infants received either chemotherapy only or chemotherapy plus lestaurtinib. Correlative assays included FLT3i plasma pharmacodynamics (PD), which categorized patients as inhibited or uninhibited, and FLT3i ex vivo sensitivity (EVS), which categorized leukemic blasts as sensitive or resistant. There was no difference in 3-year EFS between patients treated with chemotherapy plus lestaurtinib (n = 67, 36 ± 6%) vs. chemotherapy only (n = 54, 39 ± 7%, p = 0.67). However, for the lestaurtinib-treated patients, FLT3i PD and FLT3i EVS significantly correlated with EFS. For FLT3i PD, EFS for inhibited/uninhibited was 59 ± 10%/28 ± 7% (p = 0.009) and for FLTi EVS, EFS for sensitive/resistant was 52 ± 8%/5 ± 5% (p < 0.001). Seventeen patients were both inhibited and sensitive, with an EFS of 88 ± 8%. Adding lestaurtinib did not improve EFS overall, but patients achieving potent FLT3 inhibition and those whose leukemia blasts were sensitive FLT3-inhibition ex vivo did benefit from the addition of lestaurtinib. Patient selection and PD-guided dose escalation may enhance the efficacy of FLT3 inhibition for KMT2A-r infant ALL.

Fig. 1. CONSORT diagram: the flow of patients from enrollment to treatment assignment.

Risk assignment followed induction (Supplemental Table S1) for eligible patients. Post induction treatment assignment was non-random during the safety/activity (S/A) phase, including 25 patients to Arm B (19 IR, 6 HR), 11 to Arm C-DL1 (5 IR, 6 HR), and 11 to Arm C-DL2 (6 IR, 5 HR). In addition, 28 patients (22 IR, 6 HR) were non-randomly assigned to Arm C-DL2 after the amendment shown in Supplemental Fig. S1.

Fig. 2. Survival and cumulative incidence of events from study entry by risk group.

A EFS and OS for all 146 KMT2A-r patients. B EFS and OS for IR patients are superior to EFS and OS for HR patients. C Cumulative incidence of treatment failure or relapse, with death considered a competing event, was significantly higher for HR than IR patients. D Cumulative incidence of death as the first event, with treatment failure and relapse considered competing for events, was similar in HR and IR patients.

Fig. 3. Survival and cumulative incidence of events from post-induction treatment assignment by treatment arm.

There is no significant difference in EFS (A) or OS (B) for all KMT2A-r patients assigned to Arm B vs. Arm C-DL2. Similarly, there is no significant difference in EFS for IR patients (C) or HR patients (D) between those assigned to Arm B vs. Arm C-DL2. Cumulative incidences of treatment failure/relapse (E) and death as a first event (F) are also not different between Arm B and Arm C-DL2.

Fig. 4. Survival according to results of FLT3 inhibitor laboratory correlative assays for patients treated with lestaurtinib (Arm C).

A The mean PIA of five troughs was calculated for each patient, and the patient categorized based on pre-defined protocol criteria as “FLT3 inhibited” (≥85%) or “FLT3 uninhibited” (<85%). Inhibited patients demonstrated significantly higher EFS than uninhibited patients. B Median ex vivo sensitivity (EVS) in lestaurtinib cytotoxicity assays was calculated for all assayed samples on the trial, and patients’ leukemic blasts collected at study entry were categorized as “sensitive EVS” (above median) or “resistant EVS” (below median). Sensitive patients demonstrated significantly higher EFS than resistant patients. C Patients that were both FLT3 inhibited and sensitive EVS had a strikingly higher EFS than patients that were either FLT3 uninhibited or resistant EVS.