The clinical outcomes and genomic landscapes of acute lymphoblastic leukemia patients with E2A‐PBX1: A 10‐year retrospective study

Abstract

The clinical outcomes and genomic features of E2A‐PBX1 (TCF3‐PBX1)‐positive B‐cell acute lymphoblastic leukemia (B‐ALL) patients remain unclear. A total of 137 patients carrying E2A‐PBX1 among 3164 B‐ALL patients between 2009 and 2019 were retrospectively analyzed. The 5‐year overall survival (OS) and disease‐free survival (DFS) rates of the whole cohort were 68.6% and 61.0%, respectively. Age [DFS, p = 0.037; cumulative incidence of relapse (CIR), p = 0.005] and the level of minimal residual disease (MRD) after induction chemotherapy (OS, p = 0.020; DFS, p = 0.002; CIR, p = 0.006) were independent risk factors. In adolescents/adults, allogeneic hematopoietic stem cell transplantation (allo‐HSCT) at first complete remission (CR1) significantly improved the 5‐year prognosis (OS, p < 0.001; DFS, p < 0.001; CIR, p < 0.001). Haploidentical HSCT decreased the CIR compared with human leukocyte antigen‐matched HSCT in adolescents/adults (p = 0.017). Mutations in PBX1, PAX5, CTCF and SETD2, amplification of AKT3, and deletion of CDKN2A/B were common in the total cohort, while transcriptome differences were found in the cell cycle, nerve growth factor (NGF) signaling pathway and transcriptional regulation by TP53 between adolescents/adults and children. Patients with multiple subclones at diagnosis tended to have unfavorable 3‐year prognoses (DFS, p = 0.010; CIR, p = 0.021). Leukemia clones with DNA repair gene mutations showed aggressive and treatment‐refractory phenotypes in this subtype of ALL. Our study indicated that age, the level of MRD and DNA repair gene mutations were associated with E2A‐PBX1‐positive B‐ALL outcomes. Allo‐HSCT, especially haploidentical HSCT, could improve the prognosis of adolescent/adult patients.

Prognostic factors of childhood acute lymphoblastic leukemia with TCF3::PBX1 in CCCG‐ALL‐2015: A multicenter study

“…reported that RB1 deletion and mutations in PAX5 and PHF6 were associated with pediatric TCF3::PBX1 ALL. Zhou et al 32 . suggested that multiple subclones existed at diagnosis tended to be associated with unfavorable prognosis, and leukemia clones with mutations in DNA repair genes showed aggressive and treatment‐refractory phenotypes in this subtype of ALL.…”

“…reported that RB1 deletion and mutations in PAX5 and PHF6 were associated with pediatric TCF3::PBX1 ALL. Zhou et al32 suggested that multiple subclones existed at diagnosis tended to be associated with unfavorable prognosis, and leukemia clones with mutations in DNA repair genes showed aggressive and treatment-refractory phenotypes in this subtype of ALL. To better understand the molecular mechanisms underlying disease pathogenesis and progression, we are now conducting transcriptome sequencing analyses in our current CCCG-ALL-2020 protocol.In summary, our results suggest that conventional intensive chemotherapy is insufficient for patients with TCF3::PBX1 ALL who have positive MRD after remission induction, and especially for male patients presenting with testicular leukemia at diagnosis.…”

Prognostic significance of steroid response in pediatric acute lymphoblastic leukemia: The CCCG-ALL-2015 study

“…Previous studies have reported that patients positive for MLL gene rearrangements have high WBC counts, CNS involvement, relative resistance to glucocorticoids and L-ASP, and early recurrence ( 24 ) and that the MLL gene is not associated with dexamethasone response ( 23 ). Most TCF3/PBX1 -positive patients have been shown to have adverse prognostic factors, such as high WBC count and older age ( 25 , 26 ). In the NPCLC-ALL-2008 trial, the complete response, prednisone response, and recurrence rates were not significantly different between TCF3/PBX1 -positive and TCF3/PBX1 -negative patients ( 27 ).…”

Clinical features and outcomes of fusion gene defined adult Ph-negative B-cell precursor acute lymphoblastic leukemia patients: a single institutional report

“…But remarkably, several previous studies, along with ours, showed that patients with TCF3-PBX1 had significantly lower RFS rates than TCF3-PBX1 -negative patients [ 13 , 37–39 ]. Furthermore, previous studies showed remarkable efficacy of allo-HSCT in TCF3-PBX1 patients [ 36 , 38 , 40 ]. In our current study, in patients under chemotherapy, TCF3-PBX1 showed a quite low 3-year OS rate even lower than KMT2A rearrangement, but this low OS rate ceased to exist when this comparison with KMT2A rearrangement was performed in the whole cohort, which confirmed that allo-HSCT was a potential treatment for patients with TCF3-PBX1 .…”