The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial.

Abstract:

:NOTCH1 and SF3B1 mutations have been previously reported to have prognostic significance in chronic lymphocytic leukemia but to date they have not been validated in a prospective, controlled clinical trial. We have assessed the impact of these mutations in a cohort of 494 patients treated within the randomized phase 3 United Kingdom Leukaemia Research Fund Chronic Lymphocytic Leukemia 4 (UK LRF CCL4) trial that compared chlorambucil and fludarabine with and without cyclophosphamide in previously untreated patients. We investigated the relationship of mutations in NOTCH1 (exon 34) and SF3B1 (exon 14-16) to treatment response, survival and a panel of established biologic variables. NOTCH1 and SF3B1 mutations were found in 10% and17% of patients, respectively. NOTCH1 mutations correlated with unmutated IGHV genes, trisomy 12, high CD38/ ZAP-70 expression and were associated with reduced overall (median 54.8 vs 74.6 months, P = .02) and progression-free (median 22.0 vs 26.4 months, P = .02) survival. SF3B1 mutations were significantly associated with high CD38 expression and with shorter overall survival (median 54.3 vs 79.0 months, P < .001). Furthermore, multivariate analysis, including baseline clinical variables, treatment, and adverse prognostic factors demonstrated that although TP53 alterations remained the most informative marker of dismal survival in this cohort, NOTCH1 (HR 1.58, P = .03) and SF3B1 (HR 1.52, P = .01) mutations have added independent prognostic value.

journal_name

Blood

journal_title

Blood

authors

Oscier DG,Rose-Zerilli MJ,Winkelmann N,Gonzalez de Castro D,Gomez B,Forster J,Parker H,Parker A,Gardiner A,Collins A,Else M,Cross NC,Catovsky D,Strefford JC

doi

10.1182/blood-2012-05-429282

subject

Has Abstract

pub_date

2013-01-17 00:00:00

pages

468-75

issue

3

eissn

0006-4971

issn

1528-0020

pii

blood-2012-05-429282

journal_volume

121

pub_type

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