NOTCH1 gene fusions in the T-cell receptor ß (TRB) were identified in some children with T-cell lymphoblastic lymphoma (T-LBL) and were associated with increased relapse risk, according to a clinical trial published in Blood. In contrast, the study found that TRB::NOTCH1 fusions were absent in children with T-cell acute lymphoblastic leukemia (T-ALL), which has similar clinical, genetic, morphologic, and immunophenotypic properties to T-LBL.
“The discovery of TRB::NOTCH1 fusions in pediatric T-LBL but not in T-ALL suggests a distinct pathogenic mechanism for T-LBL. This fusion is associated with an increased risk of relapse, which is a critical finding for clinical practice,” said corresponding author Birgit Burkhardt, MD, PhD, of the University Hospital Muenster in Germany. “Currently, standard treatment protocols do not differentiate between patients with or without this genetic fusion. Our findings suggest that screening for TRB::NOTCH1 fusions should be incorporated into standard diagnostic protocols, specifically for T-LBL. Identifying this fusion early could help stratify patients into more appropriate risk categories and potentially guide more aggressive or targeted therapeutic strategies to improve outcomes.”
Treatment is similar for the non-Hodgkin lymphoma subtypes T-LBL and T-ALL, with poor survival for patients who relapse. This study investigated the incidence and prognostic relevance of TRB::NOTCH1 fusions in 192 children and adolescents with T-LBL and 167 children with T-ALL. The researchers screened for the gene fusion using multiplex PCR and genomic capture high-throughput sequencing. They calculated event-free survival (EFS) from the diagnosis date to last follow-up or first event, including relapse, secondary malignancy, or death of any cause.
TRB::NOTCH1 fusions were detected in 12 (6.3%) patients with T-LBL (75% male, median age = 15.1 years), but in none of those with T-ALL (75% male, median age = 9.2 years; p=0.0006). Of the patients with T-LBL without the fusion, 71% were male, and their median age was 9.9 years. In patients with T-LBL, the TRB::NOTCH1 fusion was associated with a higher incidence of relapse versus those with gene fusion-negative T-LBL, at 67% versus 17%, respectively (p<0.001). The relapse rate was 15% for patients with T-ALL. EFS at six years from diagnosis ranged from 75% to 80% for patients with T-ALL and T-LBL without TRB::NOTCH1 fusions. EFS stood inferior at 25% for patients with T-LBL with TRB::NOTCH1 fusions because of the higher incidence of relapse in these patients. The gene fusion was associated with patients’ age, as it was absent in those younger than 10 years (p=0.0004).
Breakpoints within the TRB locus were most frequently located in the J2-7 segment and varied between exon 24 and 27 for NOTCH1. The researchers compared the molecular profile of the 12 patients with T-LBL with TRB::NOTCH1 fusions with that of previously reported cases and found a lower rate of NOTCH1 mutations in those whose disease had TRB::NOTCH1 fusions, at 59% versus 8% (p<0.001). The incidence of other genetic variants associated with T-LBL did not differ. For 11 patients with paired samples from initial diagnosis and first relapse, TRB::NOTCH1 fusions were identified at both time points in four patients with no newly occurring TRB::NOTCH1 fusion at relapse, supporting the potential role of the gene fusion as a “pathogenic driver rather than an acquired genetic event,” the authors explained.
“The TRB::NOTCH1 fusion leads to the expression of a truncated, constitutively active NOTCH1 protein, driven by the TRB promoter. This mechanism bypasses the usual regulatory controls of NOTCH1, contributing to the aggressive nature of the disease,” Dr. Burkhardt said. “The traditional approach of treatment might be less effective for patients with TRB::NOTCH1 fusions due to the altered functional dynamics of the NOTCH1 protein. This calls for the development of alternative therapeutic strategies to target these fusions and/or to improve outcomes for patients.”
The authors did not disclose any limitations to the study but suggested that further research would validate the fusion’s role as a prognostic marker in T-LBL.
A group of international investigators is collaborating on a project “screening retrospective cases to learn more about affected cases,” Dr. Burkhardt said. “Furthermore, it would be interesting to investigate if this translocation is also present in adult patients to get an overall picture of this genetic anomaly in T-LBL. Expanding our research to include adult patients could provide comprehensive insights and potentially reveal age-related differences in the manifestation and impact of the TRB::NOTCH1 fusion.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Te Vrugt M, Wessolowski JS, Randau G, et al. Pediatric T-cell lymphoblastic lymphoma but not leukemia harbor TRB::NOTCH1 fusions with unfavorable outcome [published online ahead of print, 2024 July 18]. Blood. doi: 10.1182/blood.2024025307.
