Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial
Menée dans le cadre d'un essai clinique (CLL8) évaluant l'ajout de rituximab à une combinaison fludarabine-cyclophosphamide pour le traitement de première ligne d'une leucémie lymphocytaire chronique, cette étude identifie des mutations des gènes TP53 et SF3B1 en association avec la réponse thérapeutique
Mutations in TP53, NOTCH1, and SF3B1 were analyzed in the CLL8 study evaluating first-line therapy with fludarabine and cyclophosphamide (FC) or FC with rituximab (FCR). TP53, NOTCH1, and SF3B1 were mutated in 11.5%, 10.0%, and 18.4% of patients, respectively. While NOTCH1mut and SF3B1mut virtually showed mutual exclusivity (0.6% concurrence), TP53mut was frequently found in NOTCH1mut (16.1%) and in SF3B1mut (14.0%) patients. There were few significant associations with clinical and laboratory characteristics but genetic markers had strong influence on response and survival. In multivariable analyses, an independent prognostic impact was found for FCR, thymidine kinase (TK) ≥10, unmutated IGHV, 11q deletion, 17p deletion, TP53mut, and SF3B1mut on progression-free survival; and of FCR, age ≥65 years, ECOG performance status ≥0, β2-microglobulin ≥3.5, TK ≥10, unmutated IGHV, 17p deletion, and TP53mut on overall survival. Notably, predictive marker analysis identified an interaction of NOTCH1 mutational status and treatment, in that rituximab failed to improve response and survival in patients with NOTCH1mut. In conclusion, TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current standard first-line therapy. NOTCH1mut was identified as a predictive marker for decreased benefit from the addition of rituximab to FC (FCR). This study is registered at ClinicalTrials.gov, identifier: NCT00281918.
Blood , résumé, 2014