Association of combined IKZF1plus genotype and ABL1 mutations with outcomes in adult BCR::ABL1-positive acute lymphoblastic leukemia

Abstract

Abstract Background Combining IKZF1plus genotyping and minimal residual disease status at three months of treatment helps refining risk stratification for adult BCR::ABL1–positive acute lymphoblastic leukemia (BCR::ABL1+ ALL) in our previous study. (Wang C, et al. Blood Cancer J. 2024 Apr 24;14(1):71). In parallel, ABL1 kinase domain mutations persist as a major therapeutic challenge. In spite of prognostic significance of the two factors individually, studies on the association of IKZF1plus genotype and ABL1 mutations remain limited. Aim To establish the prognostic profile and investigate underlying biological features of concomitant IKZF1plus genotype and ABL1 mutations in adult BCR::ABL1+ ALL. Methods Fron June 2014 to December 2024, newly diagnosed adult BCR::ABL1+ ALL patients (aged ≥18) treated in our institute were included. The patients received a TKI-based [imatinib or flumatinib (a second-generation TKI)] standardized VIP regimen (Vincristine/Idarubicin/Prednisone), and eligible patients were recommended to undergo allo-HSCT. At diagnosis, fresh bone marrow or blood samples were collected from patients with written informed consent. Multiplex ligation-dependent probe amplification (MLPA) was used for IKZF1plus genotyping at diagnosis, polymerase chain reaction was employed to routinely monitor MRD and ABL1 mutation status, and bulk RNA sequencing was utilized to characterize biological features. (Clinical Trial Registration Number: ChiCTRONRC-14004968, ChiCTR2100042248 and ChiCRT2100044308). Results According to MLPA results, 246 newly diagnosed BCR::ABL1+ ALL patients were classified into IKZF1plus (n = 98), and non-IKZF1plus genotype (n = 148), respectively. And based on ABL1 mutation analysis, the patients were categorized into three groups: T315I mutation (n = 62), mutations other than T315I (non-T315I, n = 34), and no mutation (n = 150), respectively. Compared to no mutation group, T315I mutation group exhibited a notably higher proportion of IKZF1plus genotype (P = 0.02), adults aged older than 65 years (P = 0.01), higher white blood cell counts (P = 0.02), MRD positivity at 3 months of treatment (P < 0.001), relapse (P < 0.001) and death (P < 0.001). Similarly, relative to non-T315I mutation group, T315I mutation group also demonstrated a significantly greater frequency of IKZF1plus genotype (P = 0.01) and relapse (P = 0.004). Till July 31, 2025, the overall median follow-up period was 31.8 months (range, 6.4-122.4). The 3-year overall survival (OS) of T315I mutation group was the worst [34.4% (95% CI: 19.8%-49.1%)], lower than non-T315I mutations group [61.7% (95% CI: 41.8%-81.7%), P = 0.07] or no mutation group [91.2% (95% CI: 85.8%-96.5%), P < 0.001]. Then focusing on IKZF1plus genotype, patients were stratified into three subgroups based on ABL1 mutation analysis:IKZF1plus/T315I (n = 34), IKZF1plus/non-T315I (n = 9), and IKZF1plus/no mutation (n = 55). IKZF1plus/T315I subgroup exhibited the lowest 3-year OS rate [21.2% (95% CI: 3.0%-39.4%)], and allo-HSCT markedly improved their 3-year OS [allo-HSCT: 47.6% (95% CI: 18.8%-100.0%) vs non-HSCT: 8.4% (95% CI: 1.3%-53.7%), P = 0.001]. In comparison, IKZF1plus/non-T315I subgroup showed a moderately better 3-year OS rate [42.9% (95% CI: 6.2%-79.5%), P = 0.17], with allo-HSCT associated with a trend toward improved prognosis. Lastly, IKZF1plus/no mutation subgroup demonstrated the highest 3-year OS rate [88.3% (95% CI: 78.5%-98.1%), P < 0.001], whose outcomes were similar in patients undergoing allo-HSCT or not. Additionally, transcriptomic profiling via RNA sequencing revealed that compared to IKZF1plus/no mutation subgroup,IKZF1plus/T315I subgroup was characterized by significant down-regulation of p53 signaling pathways (P = 0.03), indicating a potential molecular basis for their poor prognosis. Conclusion Integrating IKZF1plus genotyping and ABL1 mutation status, our findings firstly refine risk stratification and delineate distinct prognostic subgroups in high-risk adult BCR::ABL1+ ALL with IKZF1plusgenotype. Notably, IKZF1plus patients harboring T315I mutation constitute a subgroup with dismal survival, likely associated with the down-regulation of p53 pathways, and they would benefit from allo-HSCT. Conversely, IKZF1plus cases without ABL1 mutations exhibit a markedly favorable prognosis.