3 years ago

Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-Cell Acute Lymphoblastic Leukemia.

Arnaud Petit, André Baruchel, Elizabeth Macintyre, Judith Landman-Parker, Hélène Lapillonne, Jean-Michel Cayuela, Amélie Trinquand, Jean Soulier, Gerard Michel, Vahid Asnafi, Guy Leverger, Claudine Schmitt, Paola Ballerini, Aurore Touzart, Nathalie Grardel, Sylvie Chevret, Claude Preudhomme, Benoit Brethon, Sandrine Thouvenin
Risk stratification in childhood T-ALL is mainly based on minimal residual disease (MRD) quantification. Whether oncogenetic mutation profiles can improve the discrimination of MRD-defined risk categories was unknown. 220 FRALLE2000T treated patients were tested retrospectively for NOTCH1/FBXW7/RAS and PTEN alterations. Patients with N/F mutation and R/P germline (GL) were defined as oncogenetic low risk (gLoR), while N/F GL and R/P GL or mutation and N/F mutation and R/P mutation were defined as high risk (gHiR). MRD (Immunoglobulin and T-Cell Receptor markers) tested at complete remission (day 35) was available for 191 patients. R/P alteration negatively impacted outcome in N/F mutated patients. 111 patients were classified as gLoR and 109 as gHiR. Five-year-cumulative incidence of relapse (CIR) and disease free survival (DFS) were respectively 36% and 60% for gHiR versus 11% and 87% for gLoR patients. Importantly, among the 60% of patients with MRD<10-4, 5-year-CIR was 29% for gHiR versus 4% for gLoR patients. Based on multivariable Cox models and stepwise selection, the three most discriminating variables were the oncogenetic classifier, MRD and WBC count. Patients harboring WBC ≥200x10(9)/L, gHiR classifier and MRD>10(-4) demonstrated a 5-year-CIR of 46%. In contrast, the 58 patients (30%) with WBC <200x10(9)/L, gLoR classifier and MRD<10(-4) had a very low risk of relapse, with a 5-year-CIR of only 2%. In childhood T-ALL, the NOTCH/FBXW7/RAS/PTEN mutation profile is an independent predictor of relapse. When combined with MRD and WBC count ≥200x10(9)/L, it identifies a significant subgroup of patients with low risk of relapse.

Publisher URL: http://doi.org/10.1182/blood-2017-04-778829

DOI: 10.1182/blood-2017-04-778829

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