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

Arnaud Petit, Amélie Trinquand, Sylvie Chevret, Paola Ballerini, Jean-Michel Cayuela, Nathalie Grardel, Aurore Touzart, Benoit Brethon, Hélène Lapillonne, Claudine Schmitt, Sandrine Thouvenin, Gerard Michel, Claude Preudhomme, Jean Soulier, Judith Landman-Parker, Guy Leverger, Elizabeth Macintyre, André Baruchel and Vahid Asnafi

Key points

  • In pediatric T-Cell ALL, oncogenetic markers, minimal residual disease and WBC count are independent outcome predictors.

  • These factors should be used together for individual treatment stratification.

Abstract

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 ≥200x109/L, gHiR classifier and MRD>10-4 demonstrated a 5-year-CIR of 46%. In contrast, the 58 patients (30%) with WBC <200x109/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 ≥200x109/L, it identifies a significant subgroup of patients with low risk of relapse.

  • Submitted April 10, 2017.
  • Accepted October 12, 2017.