_{Minimal Residual Disease after the 2^nd Induction Course Predicted Outcomes in Chinese Children with Acute Myeloid Leukaemia Treated According to the C-Huanan-AML 15 Protocol}

Background Minimal residual disease (MRD) detection by multicolor flow-cytometry (MFC) has been shown as a strong prognostic significance in pediatric acute myeloid leukaemia (AML). However, the published data on MFC-MRD in Chinese pediatric AML were from small cohorts of a few clinical centers. This study aimed to examine the clinical significance of MFC-MRD level in pediatric patients with newly diagnosed AML enrolled in the C-HUANAN-AML 15 trial from a large cohort of ten clinical centers in China.

Methods From January 2015 to December 2020, 584 pediatric patients (<14 years old) with de-novo AML were enrolled and treated with the C-HUANAN-AML 15 protocol from ten clinical centers in southern China. MRD monitoring was not mandatory, and as a factor for risk stratificationaccording to the protocol. MRD was assessed by MFC at the end of the 1^st and 2^nd induction course in a cohort of 456 patients.

Results The 5-year event-free survival (EFS) and overall survival (OS) of patients with MRD <0.1% at the end of the 1^st [EFS:75.6%(95%CI: 70.4%-81.2%) vs. 65.6%(95%CI: 57.9%-74.4%), P=0.032; OS: 84.4%(95%CI: 79.8%-89.2%) vs. 72.0%(95%CI: 64.3%-80.5%), P=0.0045] and 2^nd [EFS:74.7%(95%CI: 70.1%-79.6%) vs. 57.1%(95%CI: 45.2%-72.1%), P=0.00041; OS: 82.7%(95%CI: 78.6%-87.0%) vs. 60.3%(95%CI: 45.5%-79.9%), P=0.00019] induction course were significantly higher than that of children with MRD ≥0.1%. Univariate and multivariate Cox regression analysis allowing for gender, white blood count (WBC) at diagnosis, fusion gene (RUNX1-RUNX1T1, CBFB-MYH11, KMT2A-r), gene mutation (FLT3-ITD, ASXL1, NPM1, C-KIT, Biallelic mutated CEBPA) and karyotype (complex karyotype, -7 or 7q^-), MFC-MRD level showed that MRD ≥0.1% at the end of the 2^nd induction course was an independent prognostic factor for EFS and OS (HR=1.714 and 1.848, P=0.040 and 0.038, respectively). Patients with MRD ≥0.1% at the end of the 2^nd induction course receiving hematopoietic stem cell transplantation (HSCT) during the first complete remission (CR1) showed a tendential survival benefit when compared to those with consolidation chemotherapy. (5-year EFS: 74.0% (95%CI: 58.0%-94.4%) vs. 45.1% (95%CI: 30.4%-66.5%), P=0.025; 5-year OS: 72.5% (95%CI: 55.7%-94.3%) vs. 50.0% (95%CI: 29.8%-84.1%), P=0.21) .

Conclusion The MFC-MRD level after the 2^nd induction course could predict outcomes in pediatric patients with newly diagnosed AML treated with C-HUANAN-AML 15 protocol and help stratify post-remission treatment.

Keywords childhood acute myeloid leukemia; minimal residual disease by flow-cytometry; outcome

Figure 1. Event-free survival (EFS) and overall survival (OS) by minimal residual disease (MRD) status at the end of the 1^st and 2^nd induction course.Kaplan-Meier curve estimates the impact of different MRD levels at the end of the 1^st induction course on EFS (A) and OS (B); and the at the end of the 2^nd induction course on EFS (C) and OS (D).

No relevant conflicts of interest to declare.