The long-term outcome and risk factors for precursor B cell acute lymphoblastic leukemia without specific fusion genes in Chinese children: experiences from multiple centers

Abstract

Specific fusion genes play important roles as risk factors for strategic treatment in pediatric B-cell acute lymphoblastic leukemia (B-ALL), and the risk factors in patients without common fusion genes have not been well demonstrated. We collected and analyzed clinical and laboratory findings, treatment responses and outcomes in B-ALL patients without specific fusion genes. Whole-exome sequencing (WES) and/or RNA sequencing (RNAseq) data from bone marrow relapsed patients were also analyzed. 283 patients were enrolled in the study. Traditional elements and treatment responses at different time points (TPs) were evaluated to classify risk groups and adjust the treatment strategy. Treatment-related mortality was found in 11 (3.89%) patients, 49 (17.31%) patients relapsed, and the ten-year prospective event-free survival (pEFS) was 78.2±2.5%. Univariate analysis revealed that significant differences were not found in the pEFS of traditional risk factors, including sex, age, WBC count or chromosome status; good responses of BM smears at TP1 and minimal residual disease (MRD) levels at TP2 and TP3 were strongly associated with prolonged pEFS. Compared with the IR or the HR group, patients in the SR group presented with longer pEFS and a lower relapse rate. Multivariable analysis of outcomes and hazard ratios revealed that a positive MRD level was a key risk factor. WES or RNAseq was performed for BM relapse patients, and adverse and unreported genetic abnormalities were discovered. Favorable outcomes were acquired in the cohort. The study results showed that traditional risk factors and poor prednisone response were overcome by modified chemotherapy, and a positive MRD level was a key risk factor in these patients. NGS is needed to discover more risk-related molecular abnormalities.

Poor treatment responses were related to poor outcomes in pediatric B cell acute lymphoblastic leukemia with KMT2A rearrangements

“…Patients who were sensitive to dexamethasone induction presented with prolonged 5 yr pEFS compared with these patients who were not. Similar results were identified in early studies for prednisone induction [ 6 , 10 ], revealing that the treatment response to glucocorticoids remains a helpful method for predicting the prognosis of pediatric B-ALL with KMT2A r.…”

“…The CR rate in our cohort was 83.33%, and the 5-year pEFS for patients who did not have TRM was 40.84 ± 9.16%. These data were far lower than those of patients with B-ALL with good indicators, ETV6-RUNX1 transcripts or hyperploid karyotypes (> 95%, > 80–90%) [ 6 , 7 , 10 ].…”

“…In our study, 4 patients died of severe infection, and the TRM was 8.33%. The data were higher than those of developed countries, partially due to the socioeconomic conditions in developing countries [ 6 , 8 – 10 , 14 ]. A total of 4 patients, including 3 of 18 infants or 1 of 30 elderly patients, died of TRM in the course of induction remission, which indicated that intensive care, antimicrobial prophylaxis and positive pressure rooms are important for neutropenic conditions.…”

“…Enrolled patients received bone marrow (BM) aspiration and/or BM biopsy at initial diagnosis. The diagnosis of B-ALL was based on FAB classification and flow cytometry (FCM); Chromosomal karyotype was evaluated according to the International System of Human Cytogenetic Nomenclature of 2009 (ISCN-2009); interphase FISH of KMT2Ar, ETV6-RUNX1, BCR-ABL1, MYC and PDGFRb were performed as delineated in a literature report [9,10]; common fusion genes, included KMT2Ar transcripts (KMT2A-AFF1, KMT2A-MLLT4, KMT2A-MLLT3, KMT2A-MLLT10, KMT2A-MLLT6, KMT2A-EPS15, KMT2A-MLLT11, KMT2A-FLNA, KMT2A-ELL, KMT2A-MLLT1 and dupKMT2A), were screened by multiplex nested RT-PCR (multiplex RT-PCR) [9][10][11]; Tumor DNA and/or total RNA samples of possible patients were obtained from BM samples at initial diagnosis, whole-exome sequencing (WES) and/or RNA sequencing (RNAseq) were performed by next-generation sequencing (NGS) as found in the literature and as we previously described [9,10]. The positive KMT2Ar transcript results obtained by multiplex RT-PCR and/or RNA-seq were confirmed by split RT-PCR or quantitative real-time RT-PCR (qRT-PCR).…”

Coexistence of ETV6-RUNX1 and MLL aberration among pediatric acute lymphoblastic leukemia: case reports and a literature review

“…The MLL dichromatic break aberration/separation aberration probe used in this study can only detect all translocation aberrations of 11q23 MLL gene, and cannot be used for detection of other aberration types such as deletion, inversion, and repetition. Conversely, RT-PCR can quickly and accurately detect multiple fusion genes, detect the fusion gene type formed by chromosome translocation in MLL gene aberration, PTD, and detect the coexistence of many fusion genes at the same time, which is a feasible method to detect MLL gene aberration ( 12 ). Thereby, we suggest that the joint detection of fusion genes by the 3 methods should be recommended.…”