The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial
A partir de données portant sur 494 patients atteints d'une leucémie lymphocytaire chronique et inclus dans un essai de phase III britannique, cette étude évalue l'association entre des mutations du gène NOTCH1 ou SF3B et la réponse thérapeutique
NOTCH1 and SF3B1 mutations have been previously reported to have prognostic significance in CLL 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 III UK LRF CLL4 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 biological variables. NOTCH1 and SF3B1 mutations were found in 10 and 17% 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 74.6mths, P=0.02) and progression-free (median 22.0 vs. 26.4mths, P=0.02) survival. SF3B1 mutations were significantly associated with high CD38 expression and with shorter overall survival (median 54.3 vs. 79.0mths, P<0.001). Furthermore, multivariate analysis, including baseline clinical variables, treatment and adverse prognostic factors demonstrated that while TP53 alterations remained the most informative marker of dismal survival in this cohort, NOTCH1 (HR 1.58, P=0.03) and SF3B1 (HR 1.52, P=0.01) mutations have added independent prognostic value.
Blood , résumé, 2012