Refining risk stratification for B-cell precursor Adult Acute Lymphoblastic Leukemia treated with a Pediatric-inspired Regimen by Combining IKZF1 deletion and Minimal Residual Disease.

Unlabelled: Minimal residual disease (MRD) is the most important prognostic factor for B-cell acute lymphoblastic leukemia (B-ALL) however nearly 20-30% of patients relapsed even when they achieved negative MRD, how to identify these patients is less addressed. In this study, we aimed to reassess the prognostic significance of MRD and IKZF1 in adult B-ALL patients receiving pediatric chemotherapy regimens. In the PDT-ALL-2016 cohort (NCT03564470), adult B-ALL patients were treated with a pediatric-inspired regimen; patients were redefined as standard (MRD-negative and IKZF1wild-type), intermediate (MRD-positive or IKZF1 deletion), and high-risk (MRD-positive and IKZF1 deletion) groups by combining IKZF1 deletion status and MRD. Furthermore, the prognostic panel of IKZF1 deletion and/or MRD-positive was confirmed in the independent cohort from the COG-P9906 dataset. In the high- and intermediate-risk groups, allogeneic hematopoietic stem cell transplantation (allo-HSCT) was strongly associated with higher 5-year overall survival (OS), higher leukemia-free survival (LFS), and lower cumulative incidence of relapse (CIR). In the standard-risk group, there was no significant advantage in the 5-year OS, LFS, and CIR of patients who received allo-HSCT versus those who received chemotherapy. Our study demonstrated that combining early MRD response and IKZF1 deletion allows for better risk stratification of patients to identify those who may benefit from allo-HSCT in the context of an intensified pediatric-inspired regimen.

Introduction: Minimal residual disease (MRD) is the most important prognostic factor for B-cell acute lymphoblastic leukemia (B-ALL) however nearly 20-30% of patients relapsed even when they achieved negative MRD, how to identify these patients is less addressed. In this study, we aimed to reassess the prognostic significance of MRD and IKZF1 in adult B-ALL patients receiving pediatric chemotherapy regimens.

Methodology: A total of 202 newly diagnosed adult patients with B-ALL treated at Nanfang Hospital between January 2016 and September 2020 were enrolled in the population-based protocol of the PDT-ALL-2016 trial (NCT03564470), a GRAALL-backbone, peg-aspargase-intensified, antimetabolite-based pediatric-inspired regimen therapy. The validation dataset COG-P9906, which includes complete gene expression profiles and clinical data for 190 samples, is accessible via the NCBI Gene Expression Omnibus (GEO) at the following link: (https://www.ncbi.nlm.nih.gov/geo/), under the accession code GSE11877.

Main Findings: B-ALL patients were redefined as standard (MRD-negative and IKZF1wild-type), intermediate (MRD-positive or IKZF1 deletion), and high-risk (MRD-positive and IKZF1 deletion) groups by combining IKZF1 deletion status and MRD. In the PDT-ALL-2016 cohort, patients in the high- and intermediate-risk groups who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) exhibited significantly improved 5-year overall survival (OS), leukemia-free survival (LFS), and lower cumulative incidence of relapse (CIR) compared to those who received chemotherapy alone. In the PDT-ALL-2016 cohort, no significant advantage was observed in the 5-year OS, LFS, and CIR of patients in the standard-risk group who received allo-HSCT compared to those who received chemotherapy.

Discussion: Traditional risk factors, incorporating clinical and cytogenetic features, have been previously evaluated to stratify risks and guide treatment decisions. However, the prognostic strength of this stratified system is limited by the pediatric-inspired protocol background, making it difficult to identify patients with a high risk of relapse. Therefore, in the era of pediatric-inspired protocols, it is imperative to reassess traditional risk factors to identify patients at high risk of recurrence and mortality. In this study, we retrospectively evaluated the combination of MRD and IKZF1 to develop an efficient risk stratification tool for adult patients with B-ALL in the pediatric-inspired chemotherapy era. Moreover, allo-HSCT had distinct efficacy at different risk levels, which means that the decision to perform allo-HSCT may be well guided by this risk classification scheme.

Conclusion: In conclusion, based on our cohort study and validation cohort, we demonstrated that the combination of MRD and IKZF1 deletion allows for better risk stratification of adults with B-ALL and that allo-HSCT mitigates the poor prognosis of MRD+ and/or IKZF1 subgroups.