Impact of NOTCH1/FBXW7 mutations on outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on the MRC UKALL 2003 trial.

Abstract

Activating mutations in the NOTCH1 pathway are frequent in pediatric T-cell acute lymphoblastic leukemia (T-ALL) but their role in refining risk stratification is unclear. We screened 162 pediatric T-ALL patients treated on the MRC UKALL2003 trial for NOTCH1/FBXW7 gene mutations and related genotype to response to therapy and long-term outcome. Overall, 35% were wild-type (WT) for both genes (NOTCH1(WT)FBXW7(WT)), 38% single NOTCH1 mutant (NOTCH1(Single)FBXW7(WT)), 3% just FBXW7 mutant (NOTCH1(WT)FBXW7(MUT)) and 24% either double NOTCH1 mutant (NOTCH1(Double)FBXW7(WT)) or mutant in both genes (NOTCH1(MUT)FBXW7(MUT)), hereafter called as NOTCH1±FBXW7(Double). There was no difference between groups in early response to therapy, but NOTCH1±FBXW7(Double) patients were more likely to be associated with negative minimal residual disease (MRD) post-induction than NOTCH1(WT)FBXW7(WT) patients (71% versus 40%, P=0.004). Outcome improved according to the number of mutations, overall survival at 5 years 82%, 88% and 100% for NOTCH1(WT)FBXW7(WT), NOTCH1(Single)FBXW7(WT) and NOTCH1±FBXW7(Double) patients, respectively (log-rank P for trend=0.005). Although 14 NOTCH1±FBXW7(Double) patients were classified as high risk (slow response and/or MRD positive), only two had disease progression and all remain alive. Patients with double NOTCH1 and/or FBXW7 mutations have a very good outcome and should not be considered for more intensive therapy in first remission, even if slow early responders or MRD positive after induction therapy.

• Authors: S Jenkinson, K Koo, M R Mansour, N Goulden, A Vora, C Mitchell, R Wade, S Richards, J Hancock, A V Moorman, D C Linch, R E Gale
• Journal: Leukemia (Leukemia) Vol. 27 Issue 1 Pg. 41-7 (Jan 2013) ISSN: 1476-5551 [Electronic] England
• PMID: 22814294 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• DNA, Neoplasm
• F-Box Proteins
• F-Box-WD Repeat-Containing Protein 7
• FBXW7 protein, human
• Receptor, Notch1
• Vincristine
• Dexamethasone
• Ubiquitin-Protein Ligases
• Asparaginase
• Daunorubicin

Topics

• Adolescent
• Adult
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Asparaginase (administration & dosage)
• Cell Cycle Proteins (genetics)
• Child
• Child, Preschool
• Cohort Studies
• DNA, Neoplasm (genetics)
• Daunorubicin (administration & dosage)
• Dexamethasone (administration & dosage)
• F-Box Proteins (genetics)
• F-Box-WD Repeat-Containing Protein 7
• Female
• Genotype
• Humans
• Infant
• Male
• Mutation (genetics)
• Polymerase Chain Reaction
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, mortality)
• Prognosis
• Receptor, Notch1 (genetics)
• Remission Induction
• Survival Rate
• Ubiquitin-Protein Ligases (genetics)
• Vincristine (administration & dosage)
• Young Adult