Role of TP53 mutations and of MRD monitoring by IG/TR rearrangements in refining prognosis of KMT2A-rearranged adult B-lineage Acute Lymphoblastic Leukemia patients

Acute lymphoblastic leukemia (ALL) with KMT2A::AFF1 t(4;11)(q21;q23) fusion represents a high-risk entity with poor prognosis in both pediatric and adult populations. In adults, KMT2A rearrangements account for approximately 5–10% of BCR-ABL1-negative cases and are typically associated with higher white blood cell counts, a pro-B immunophenotype, and older age. Despite comparable rates of complete remission (CR) and minimal residual disease (MRD) negativity after induction, KMT2A::AFF1-positive patients experience significantly shorter overall survival (OS), disease-free survival (DFS), and event-free survival (EFS) than KMT2A-negative patients. Considering the current outcomes of BCP-ALL in young adults, we hypothesized that additional genomic alterations, particularly in TP53, and MRD monitoring based on IG/TR rearrangements could improve prognostic stratification in adult patients with KMT2A-rearranged ALL. To test this hypothesis, 27 KMT2A-rearranged patients were identified within a cohort of 292 adults enrolled in the LAL2317 and LAL1913 protocols for Ph-negative BCP-ALL. TP53 sequence mutations were analyzed, and MRD was assessed using a “double-target” strategy, comparing levels of the KMT2A fusion transcript with clonal IG/TR rearrangements. Results showed that TP53 mutations were present in 36% of evaluable patients (9/25), including both clonal and subclonal variants, and were strongly associated with adverse clinical outcomes: specifically, one of the two refractory cases, two relapsed patients, and the only patient who died during induction all carried a clonal TP53 mutation, and one relapsed patient carried a subclonal TP53 mutation. Furthermore, TP53-mutated patients exhibited significantly impaired MRD responses at both early (TP1) and later (TP2) timepoints, whereas over half of TP53 wild-type patients achieved MRD negativity. The second part of the study investigated the utility of the KMT2A-r fusion transcript as an MRD marker compared to IG/TR rearrangements. IG/TR-based MRD monitoring failed to 3 detect residual disease in 41% of KMT2A::AFF1-positive cases, confirming the superior prognostic accuracy of KMT2A fusion transcript-based MRD. Finally, a strong preference for VH6 gene family usage was observed in 76% of KMT2A-rearranged patients, absent in both Ph-negative and Ph-positive Pro-B controls, suggesting a potential biological biomarker specific to KMT2A-driven leukemogenesis. In conclusion, TP53 mutations identify a high-risk patient subgroup, KMT2A-based MRD assessment provides more reliable prognostic information than IG/TR monitoring, and VH6 gene usage may serve as a distinctive biomarker in this patient population. These findings support the need for early, intensive, and targeted therapeutic strategies in adults with KMT2A-rearranged ALL.