title: NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951.
abstract: Risk-adjusted treatment stratification in T-cell acute lymphoblastic leukemias (T-ALLs) is currently based only on early response to chemotherapy. We investigated the prognostic implication of hyperactivation of NOTCH pathway resulting from mutations of NOTCH1 or FBXW7 in children with T-ALL enrolled in EORTC-CLG trials. Overall, 80 out of 134 (60%) patients were NOTCH+ (NOTCH1 and/or FBXW7 mutated). Although clinical presentations were not significantly associated with NOTCH status, NOTCH+ patients showed a better early response to chemotherapy as compared with NOTCH- patients, according to the rate of poor pre-phase 'responders' (25% versus 44%; P=0.02) and the incidence of high minimal residual disease (MRD) levels (11% (7/62) versus 32% (10/31); P=0.01) at completion of induction. However, the outcome of NOTCH+ patients was similar to that of NOTCH- patients, with a 5-year event-free survival (EFS) of 73% and 70% (P=0.82), and 5-year overall survival of 82% and 79% (P=0.62), respectively. In patients with high MRD levels, the 5-year EFS rate was 0% (NOTCH+) versus 42% (NOTCH-), whereas in those with low MRD levels, the outcome was similar: 76% (NOTCH+) versus 78% (NOTCH-). The incidence of isolated central nervous system (CNS) relapses was relatively high in NOTCH1+ patients (8.3%), which could be related to a higher propensity of NOTCH+ leukemic blasts to target the CNS.
authors.affiliation: Département de Génétique, APHP, Hôpital Robert Debré, Université Paris 7-Denis Diderot, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Clappier
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authors.initials: S
authors.lastname: Collette
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authors.initials: N
authors.lastname: Grardel
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authors.lastname: Girard
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authors.lastname: Suarez
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authors.initials: G
authors.lastname: Brunie
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authors.lastname: Kaltenbach
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authors.lastname: Yakouben
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authors.initials: F
authors.lastname: Mazingue
authors.forename: A
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authors.lastname: Robert
authors.forename: P
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authors.lastname: Boutard
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authors.lastname: Plantaz
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authors.lastname: Rohrlich
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authors.lastname: van Vlierberghe
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authors.lastname: Preudhomme
authors.forename: J
authors.initials: J
authors.lastname: Otten
authors.forename: F
authors.initials: F
authors.lastname: Speleman
authors.forename: N
authors.initials: N
authors.lastname: Dastugue
authors.forename: S
authors.initials: S
authors.lastname: Suciu
authors.forename: Y
authors.initials: Y
authors.lastname: Benoit
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authors.initials: H
authors.lastname: Cavé
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D018572:Disease-Free Survival; D044783:F-Box Proteins / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D006801:Humans; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D011446:Prospective Studies; D051881:Receptor, Notch1 / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D044767:Ubiquitin-Protein Ligases