Clinical Impact of NOTCH1 and/or FBXW7 Mutations, FLASH Deletion, and TCR Status in Pediatric T-Cell Lymphoblastic Lymphoma
Menée sur 54 patients pédiatriques atteints d'un lymphome T lymphoblastique, cette étude française évalue la fréquence et la valeur pronostique de mutations des gènes NOTCH1 et FBXW7, de délétions du gène FLASH du chromosome 6q et de réarrangements sur les récepteurs des lymphocytes T
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/Fmut), 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/Fmut were identified by direct sequencing and allelic dosage was used to detect FLASH and TCRγ deletions, which were interpreted in conjunction with TCRγ, TCRβ, and TCRδ rearrangements.Results N/Fmut 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 TCRγ deletion (ABD) was seen in 7%, all of which were N/Fmut and identified a poor prognosis group (P = .02). On multivariate analysis of N/Fmut, TCRγ ABD, and FLASH deletion, only N/Fmut 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.
Journal of Clinical Oncology , résumé, 2012