Prognostic and predictive role of gene mutations in chronic lymphocytic leukemia: results from the pivotal phase III study COMPLEMENT1

Autoři	TAUSCH E BECK P SCHLENK RF JEBARAJ BMC DOLNIK A YOSIFOV DY HILLMEN P OFFNER F JANSSENS A BABU KG GROSICKI S MAYER Jiří PANAGIOTIDIS P MCKEOWN A GUPTA IV SKORUPA A PALLAUD C BULLINGER L MERTENS D DOHNER H STILGENBAUER S
Rok publikování	2020
Druh	Článek v odborném periodiku
Časopis / Zdroj	haematologica
Citace
Doi	http://dx.doi.org/10.3324/haematol.2019.229161
Popis	Next generation sequencing studies in chronic lymphocytic leukemia (CLL) have revealed novel genetic variants that have been associated with disease characteristics and outcome. The aim of this study was to evaluate the prognostic value of recurrent molecular abnormalities in patients with CLL. Therefore, we assessed their incidences and associations with other clinical and genetic markers in the prospective multicenter COMPLEMENT1 trial [treatment naive patients not eligible for intensive treatment randomized to chlorambucil (CHI.) vs. ofatumumab-CHI, (O-CHL)]. Baseline samples were available from 383 patients (85.6%) representative of the total trial cohort. Mutations were analyzed by ampliconbased targeted next generation sequencing (tNGS). In 52.2% of patients we found at least one mutation; the incidence was highest in NOTCH/ (17.0%), followed by SF3B1 (14.1%), ATM (11.7%), TP53 (10.2%), POT/ (7.0%), RP.S/5 (4.4%), FBXW7 (3.4%), MYD88 (2.6%), and BIRC3 (2.3%). While most mutations lacked prognostic significance, TP53 (HR2.02, P<0.01), SF3B1 (HR1.66, P=0.01), and NOTCH/ (HR1.39, P=0.03) were associated with inferior progression-free survival (PFS) in univariate analysis. Multivariate analysis confirmed the independent prognostic role of TP53 for PFS (HR1.71, P=0.04) and overall survival (OS) (HR2.78, P=0.02), and of SF3B1 for PFS only (HR1.52, P=0.02). Notably, NOTCH1 mutation status separates patients with a strong from those with a weak benefit from addition of ofatumumab to CHL (NOTCH1(wt): HR0.50, P<0.01; NOTCHmut: HR0.81, P=0.45). In summary, TP53 and SF3B1 were confirmed as independent prognostic factors and NOTCH/ as a predictive factor for reduced of atumumab efficacy in a randomized chemo/immunotherapy Ca trial. These results validate NGS-based mutation analysis in a multicenter trial and provide a basis for expanding molecular testing in the prognostic workup of patients with CLL.