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Blood. 2018 Jan 18;131(3):289-300. doi: 10.1182/blood-2017-04-778829. Epub 2017 Oct 19.

Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-cell acute lymphoblastic leukemia.

Author information

1
Department of Pediatric Hematology and Oncology, Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Hôpitaux Universitaires Est Parisien (GH HUEP), Armand Trousseau Hospital, Paris, France.
2
Sorbonne Universités, UPMC Univ Paris 06, Unité Mixte de Recherche (UMR) S938, CDR Saint-Antoine, Groupe de Recherche Clinique (GRC) 07, GRC MyPAC, Paris, France.
3
Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades, INSERM U1151, Paris, France.
4
Laboratory of Onco-Hematology, AP-HP, Hôpital Necker-Enfants Malades, Paris, France.
5
INSERM UMRS 1153, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
6
Laboratory of Hematology, AP-HP, GH HUEP, Armand Trousseau Hospital, Paris, France.
7
Laboratory of Hematology, Saint-Louis Hospital, AP-HP, Paris, France.
8
Laboratory of Hematology, Centre Hospitalier Régional Universitaire de Lille, Lille, France.
9
Department of Pediatric Hematology and Immunology, Robert Debré Hospital, AP-HP, Paris, France.
10
Department of Pediatric Onco-hematology, Centre Hospitalier Universitaire (CHU) de Nancy, Nancy, France.
11
Department of Pediatric Onco-hematology, CHU de Saint-Etienne, Saint-Etienne, France.
12
Department of Pediatric Hematology and Oncology, Timone Hospital, Marseilles, France.
13
Research Unit EA 3279, Aix-Marseille University, Marseilles, France.
14
U1172, INSERM, Lille, France; and.
15
Department of Cytogenetics, Saint-Louis Hospital, AP-HP, Paris, France.

Abstract

Risk stratification in childhood T-cell acute lymphoblastic leukemia (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. Two hundred and twenty FRALLE2000T-treated patients were tested retrospectively for NOTCH1/FBXW7/RAS and PTEN alterations. Patients with NOTCH1/FBXW7 (N/F) mutations and RAS/PTEN (R/P) germ line (GL) were classified as oncogenetic low risk (gLoR; n = 111), whereas those with N/F GL and R/P GL mutations or N/F and R/P mutations were classified as high risk (gHiR; n = 109). Day 35 MRD status was available for 191 patients. Five-year cumulative incidence of relapse (CIR) and disease-free survival were 36% and 60% for gHiR patients and 11% and 89% for gLoR patients, respectively. Importantly, among the 60% of patients with MRD <10-4, 5-year CIR was 29% for gHiR patients and 4% for gLoR patients. Based on multivariable Cox models and stepwise selection, the 3 most discriminating variables were the oncogenetic classifier, MRD, and white blood cell (WBC) count. Patients harboring a WBC count ≥200 × 109/L, gHiR classifier, and MRD ≥10-4 demonstrated a 5-year CIR of 46%, whereas the 58 patients (30%) with a WBC count <200 × 109/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 N/F/R/P mutation profile is an independent predictor of relapse. When combined with MRD and a WBC count ≥200 × 109/L, it identifies a significant subgroup of patients with a low risk of relapse.

PMID:
29051182
DOI:
10.1182/blood-2017-04-778829
[Indexed for MEDLINE]
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