Towards molecular stratification of pediatric T-cell lymphoblastic lymphomas based on Minimal Disseminated Disease and NOTCH1/FBXW7 mutational status: the French EURO-LB02 experience

While outcome for pediatric T lymphoblastic lymphoma (T-LBL) has improved with Acute Leukemia-type therapy, survival after relapse remains rare. Few prognostic markers have been identified and the value of Minimal Residual Disease (MRD) is less clear than in T-ALL. Mutations of NOTCH1 and/or FBXW7 (N/F) identify good prognosis T-LBL and both MRD and high-level Minimal Disseminated Disease (MDD) are reported to be of poor prognosis. We evaluated MDD status by 8-color flow cytometry (MFC) and/or digital droplet PCR (ddPCR) in 86 French pediatric T-LBL, of which N/F status was known for 65 (61 treated on the Euro-LB02 protocol). Both techniques gave identical results for MDD/MRD values above 0.1%, allowing compilation. While an MDD threshold of 1% had no prognostic significance, the 54% (44/82) of protocol-treated patients with MDD [&ge;]0.1% had a relatively favorable outcome (overall survival/OS; p = 0.026). MDD 0.1% status had no prognostic significance in the 68% of patients with N/F mutations, whereas low/negative MDD status (9/61) identified N/F germline patients at a high risk of relapse (5-year OS of 44.4% vs 90% for MDD [&ge;] 0.1%,p = 0.014; and a 5-year DFS of 50% vs 90.9% respectively, p = 0.041). Combining oncogenetic and MDD status allows identification of 85% of patients with an excellent outcome (5-year OS 91.9% and DFS 95%) and 15% of N/F germline/MDD< 0.1% patients who clearly require early alternative treatment (5-year OS 44.4%; p< 0.0001 and DFS 50%; p = 0.0001).