Prognostic Significance of Epigenetic Modifiers Gene Mutations in Adult Acute Lymphoblastic Leukemia at Diagnosis

Abstract

Background: Epigenetic modifiers (EMs) play an important role in the occurrence and development of acute lymphoblastic leukemia(ALL). However, the prognostic significance EMs gene mutation have been poorly investigated in adult ALL. Thus, we aimed to investigate the prognostic significance of EMs gene mutation in patients with ALL. Patients and Methods: The clinical data of 205 patients with ALL diagnosed in Nanfang Hospital between July 2017 and July 2020 who received Pediatric-inspired chemotherapy were retrospectively analyzed. The patients were divided into EMs mutation(EMs-mut) group (75 case) and EMs wild type(EMs-wt) group (130 cases) base on the next generation sequencing result. Kaplan-Meier was used to analyze overall survival(OS) and event free survival(EFS) and Cox regression model was use to the univariate and multivariate analysis of OS and EFS. Results: Among 205 ALL patients,75 cases(36.6％) were positive for EMs-mut, and a total of 91 EMs mutations were detected, including 70 missense mutations(76.9％),15 frameshift mutations(16.5％) and 6 nonsense mutations(6.6％).Compared to patients with EMs-wt, the proportion of abnormal karyotype and positive for fusion gene were lower in patients with EMs-mut(χ2＝8.245,5.985;P=0.004,0.014).These patients also experienced worse early effects of induction therapy including the minimal residual disease(MRD) at the 14th day, MRD at the 28th day and MRD before consolidation therapy(P<0.001,P=0.009,P=0.007,respectively).In 205 patients with ALL,OS and EFS were significant shorter in patients with EMs-mut compared with patients with EMs-wt(median 26.6 months vs not reached, median 16.8 months vs 37.2 months; P＝0.008,0.021,respectively). Furthermore, in subgroups of 46 patients with Ph positive B-ALL,OS and EFS were also significant shorter in patients with EMs-wt compared with patients with EMs-mut(median 16.5 months vs not reached, median 12.5 months vs not reached; P=0.011,0.044,respectively).Multivariable analysis showed that harboring EMs-mut was an independent adverse factor of OS and EFS (HR＝1.853,1.647;P＝0.020,0.031,respectively) for ALL. In contrast, receiving allogeneic hematopoietic stem cell transplantation(allo-HSCT) was an independent favorable factor of OS and EFS(HR＝0.364,0.483; P<0.001,P=0.002, respectively) for ALL. Next, the 205 ALL patients were divided into 4 subgroups: EMs-mut/ chemotherapy group, EMs-mut/ HSCT group, EMs-wt/ chemotherapy group and EMs-wt/ HSCT group. We found that EMs-mut/ chemotherapy group had significantly lower OS, EFS than other subgroups. In the EMs-mut cohort, allo-HSCT significantly improved OS and EFS compared to non-allo-HSCT(not reached vs median 14.1 months, not reached vs median 7.1 months; P＝0.001,0.021,respectively). Conclusion: Mutation of EMs in adult ALL correlate with poor early effect to induction therapy. Pediatric-inspired chemotherapy was unable to completely reverse the negative effect of mutation of EMs on prognosis. Pediatric-inspired regimen therapy combined with allo-HSCT, in contrast, significantly improved the overall prognosis of EMs mutation ALL. Key words: Gene, epigenetic modifiers; Leukemia, lymphoblastic, acute; Minimal residual disease; Allogeneic hematopoietic stem cell transplantation