Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol

Abstract

Purpose: Notch pathway activation by mutations in either NOTCH1 and/or FBXW7 is one of the most common molecular events in T-cell acute lymphoblastic leukemia (T-ALL) and, in pediatric disease, predicts for favorable outcome. Their prognostic significance in adult T-ALL is unclear. We sought to evaluate the outcome according to mutation status of patients with adult T-ALL treated on the United Kingdom Acute Lymphoblastic Leukaemia XII (UKALLXII)/Eastern Cooperative Oncology Group (ECOG) E2993 protocol.

Methods: NOTCH1 and FBXW7 were screened by a combination of denaturing high-performance liquid chromatography and sequencing in 88 adult patients with T-ALL treated on the UKALLXII/ECOG E2993 protocol and compared with clinical characteristics and outcome.

Results: NOTCH1 and FBXW7 mutations were common (60% and 18%, respectively) and were not associated with age or WBC count. NOTCH1 heterodimerization domain mutations were associated with FBXW7 mutations (P = .02), and NOTCH1 proline, glutamic acid, serine, threonine (PEST) rich domain and FBXW7 mutations were mutually exclusive. There were an equal number of high- and standard-risk patients in the NOTCH1 and FBXW7 mutated (MUT) groups. Patients wild type (WT) for both markers trended toward poorer event-free survival (EFS; MUT v WT, 51% v 27%, P = .10; hazard ratio, 0.6). Analysis by each marker individually was not significantly predictive of outcome (NOTCH1 MUT v WT, EFS 49% v 34%, P = .20; FBXW7 MUT v WT, EFS 53% v 41%, P.72).

Conclusion: NOTCH1 and FBXW7 mutant-positive patients do not fare sufficiently well to warrant an individualized treatment approach in future studies.

Trial registration: ClinicalTrials.gov NCT00002514.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

A simplified algorithm of the United Kingdom Acute Lymphoblastic Leukaemia XII/Eastern Cooperative Oncology Group E2993 treatment protocol. HD-MTX, high-dose methotrexate.

Fig 2.

Outcome of adult patients with T-cell acute lymphoblastic leukemia treated on United Kingdom Acute Lymphoblastic Leukaemia XII/Eastern Cooperative Oncology Group E2993 protocol stratified by NOTCH1 and FBXW7 mutational status. (A) Event-free survival (EFS) by NOTCH1 and/or FBXW7 mutation. (B) Overall survival (OS) by NOTCH1 and/or FBXW7 mutation. (C) EFS by NOTCH1 mutation. (D) OS by NOTCH1 mutation. (E) EFS by FBXW7 mutation. (F) OS by FBXW7 mutation. MUT, mutated; WT, wild type.