Abstract
For newly diagnosed acute myeloid leukemia (ND-AML), the traditional “3+7” induction is still the foundation of intensive chemotherapy. For certain subgroups, the combination of targeted drug can improve response rate and long-term survival. As previous reported in RJ-AML 2014 and 2016 trial [Am J Hematol. 2022;97(1):43-51; 65th ASH Annual Meeting and Exposition, San Diego, CA], day 5 peripheral blast clearance rate (D5-PBCR) can be used as an indicator of early treatment response. For patients in the D5-PBCR (+) group, addition of homoharringtonine can benefit favorable and intermediate risk groups. While for adverse-risk and FLT3-ITD mutated cases, other interventions were needed.
IA+X 2024 is a multicenter, non-randomized, phase II clinical trial, conducted to evaluate the efficacy of targeted drug (drug “X”) in combination with “3+7” regimen for ND-AML (ClinicalTrials.gov NCT06652685). Patients receive IA-10 regimen (idarubicin 10mg/m2 on days 1–3 and cytarabine 100mg/m2 on days 1–7) as the initial induction. On day five of induction, D5-PBCR will be tested. Patients will be assigned to different arms according to the results of molecular tests and D5-PBCR. For CBF-AML patients, no interventions are needed. For FLT3-ITD mutated patients, a combination of gilteritinib is recommended (induction and consolidation: 80mg/d on days 8-21). All other D5-PRCR (+) patients will receive Venetoclax (VEN) addition (induction: 100mg on day 6, 200mg on day 7, and 400mg on days 8–13; consolidation: 400mg/d on days 8-14).
The primary end point is composite complete remission (CRc) rate. We hypothesized that the CRc rate may increase by 15% (from 67% to 82%) with the addition of drug “X”. As designed using the single-arm, Simon two-stage model, twenty-nine patients were accrued in the first stage of analysis and if more than 20 CRc were observed, 31 additional patients will be included. The secondary end points include total CRc rate, overall survival (OS) and event-free survival (EFS). Consolidation therapy will be assigned according to the patients' ELN 2022 risk stratification. Here, we report the interim analysis.
Between August 2024 and April 2025, a total of 115 patients underwent screening, 97 were included in the intention-to-treat (ITT) population and received IA-10 induction from 5 sites in China. Twenty-seven patients were classified as CBF-AML (14 cases with RUNX1::RUNX1T1 fusion, 13 with CBFβ::MYH11 fusion). The analysis of CBF-AML subgroup showed 100% CR rate after one cycle of induction with 50% and 100% MRD negativity by flow cytometry (<0.01%) in RUNX1::RUNX1T1 and CBFβ::MYH11 fusion groups, respectively.
D5-PBCR were analyzed in 70 patients and 42 (60%) had D5-PBCR (+). Baseline characteristics, including age, sex, WBC, bone marrow blast counts, and cytogenetic parameters were similar between two groups. Patients with NPM1 mutation were more sensitive to IA-10, while TP53 mutation was more common in D5-PBCR (+) group. Of the 42 D5-PBCR (+) patients, 3 cases discontinued IA and 6 were unfit for drug “X” additional. Of the 28 D5-PBCR (-) patients, 2 patients discontinued IA and 2 were unfit for gilteritinib combination.
The overall composite CR rate after one course of induction was 76.2% in the ITT cohort, and 87.7% in the Per-Protocol (PP) cohort. In PP population, CR rates were 95.8% and 81.8% for D5-PBCR (-) and D5-PBCR (+) groups, respectively. No early death events occurred within 60 days of induction. All patients in the 2022 ELN favorable-risk group obtained CR. FLT3-ITD mutated patients (15 in ITT and 12 in PP) showed high response with IA+gilteritinib, which is also observed in patients with NUP98 fusion. However, there is a certain degree of prolongation in the duration of bone marrow suppression. While subgroup analysis showed that only one patient with TP53 mutation achieved CR after one cycle of IA+VEN induction. Even after receiving the second course of induction, only 2 patients achieved remission, with the remaining 5 patients in non-remission.
The IA+X 2024 protocol has currently met the requirements for the interim analysis as designed, and enrollment is planned to continue. All patients in the favorable-risk group achieved CR after one course of induction. And for patients with TP53 mutation, a new re-induction regimen needs to be designed.
