Clinical Impact of NOTCH1 and/or FBXW7 Mutations, FLASH Deletion, and TCR Status in Pediatric T-Cell Lymphoblastic Lymphoma

Purpose Pediatric T-cell lymphoblastic lymphomas (T-LBL) are commonly treated on T-cell acute lymphoblastic leukemia (T-ALL) -derived protocols. Therapeutic stratification based on response to the prephase treatment and on minimal residual disease assessment is well established in T-ALL but is not easy to extrapolate to T-LBL. The identification of molecular prognostic markers at diagnosis in T-LBL could provide an alternative for early therapeutic stratification. Our study determines the frequency and prognostic value of NOTCH1/FBXW7 mutations (N/F-mut), FLASH deletion at chromosome 6q, and TCR rearrangements in a prospective cohort of pediatric T-LBL. Patients and Methods Pathologic samples were obtained at diagnosis for 54 patients treated according to the EuroLB02 protocol in France. N/F-mut were identified by direct sequencing and allelic dosage was used to detect FLASH and TCR gamma deletions, which were interpreted in conjunction with TCR gamma, TCR beta, and TCR delta rearrangements. Results N/F-mut were found in 55% of T-LBL patients, in whom they were associated with improved event-free survival (P = .01) and overall survival (P = .01). FLASH monoallelic deletions were observed in 18% of patients; they were predominantly N/F wild-type (six of nine) and tended to be of inferior prognosis (P = .09). Absence of biallelic TCR gamma deletion (ABD) was seen in 7%, all of which were N/F-mut and identified a poor prognosis group (P = .02). On multivariate analysis of N/F-mut, TCR gamma ABD, and FLASH deletion, only N/F-mut was an independent factor for good prognosis. Conclusion Mutational status of NOTCH1/FBXW7 represents a promising marker for early therapeutic stratification in pediatric T-LBL.