Abstract
Specific fusion genes play important roles as risk factors in the pediatric B-cell acute lymphoblastic leukemia (B-ALL) population. In addition, these fusion genes are used for determination of patient treatment. However, the risk factors and long term outcomes in B-ALL patients without common fusion genes have not been well demonstrated, and thus our aim was to evaluate this patient population. We retrospectively analyzed clinical and laboratory findings, treatment responses, and outcomes in pediatric patients with B-ALL without specific fusion genes. Moreover, we analyzed whole-exome sequencing and/or RNA sequencing data from bone marrow (BM) relapsed patients. Overall, 283 patients were enrolled in the study. Traditional parameters and treatment responses at different time points (TP) were evaluated to classify risk groups and adjust treatment strategy. Statistical analysis showed that 49 (17.31%) patients relapsed, while treatment-related mortality was found in 11 (3.89%) patients. Ten-year prospective event-free survival (pEFS) was 78.2 ± 2.5%. Adverse and unreported genetic abnormalities were discovered in 25 BM relapse patients. Univariate analysis revealed that good responses of BM smears at TP1 and minimal residual disease (MRD) levels at TP2 and TP3 were strongly associated with prolonged pEFS. Moreover, multivariable analysis of outcomes and hazard ratios determined that positive MRD level was the key risk factor. The study results showed that traditional risk factors and poor prednisone response were overcome by modified chemotherapy. Next generation sequencing has proven to be a useful technique in identifying molecular risk factors in cases without common specific genetic alterations.
Highlights
Acute lymphoblastic leukemia (ALL) is the most c ommon childhood cancer, while precursor B-cell ALL (B-ALL) accounts for approximately 75-80% of newly diagnosed pediatric ALL cases [1]
A total of 305 B-ALL patients without specific fusion genes were hospitalized in the study period, two patients died before diagnosis, 15 patients refused chemotherapy, five patients were eliminated due to errors in immunophenotyping at initial diagnosis, and 283 consecutive patients were treated with the CCLG-ALL-2008 protocol and were enrolled in the study (Figure 1)
Complete remission (CR), bone marrow (BM) relapse, or extramedullary relapse were defined as standard diagnostic criteria [15,16,17], while event-free survival (EFS) was defined as the time from diagnosis to the date of last contact for EFS or to the first adverse event
Summary
Acute lymphoblastic leukemia (ALL) is the most c ommon childhood cancer, while precursor B-cell ALL (B-ALL) accounts for approximately 75-80% of newly diagnosed pediatric ALL cases [1]. Specific chromosomal translocations and their fusion genes are detectable in approximately two-thirds of pediatric B-ALL patients, and such fusion genes play important roles as risk factors in strategic treatment. B-ALL with ETV6-RUNX1 and B-ALL with MLL-AF4 were both classified as B-ALL with recurrent genetic abnormalities according to the WHO classification. The prognosis of B-ALL with ETV6-RUNX1 is better than that of B-ALL with MLL-AF4 [2,3]. Initial white blood cell (WBC) count, and abnormal chromosomal karyotypes remain the traditional risk factors for B-ALL patients without specific fusion genes, and studies have shown that early
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