Prognostic and predictive role of gene mutations in chronic lymphocytic leukemia: Results complement1 from the pivotal phase III study

Επιστημονική δημοσίευση - Άρθρο Περιοδικού uoadl:3103839 28 Αναγνώσεις

Μονάδα:
Ερευνητικό υλικό ΕΚΠΑ
Τίτλος:
Prognostic and predictive role of gene mutations in chronic lymphocytic leukemia: Results complement1 from the pivotal phase III study
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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 (CHL) vs. ofatumumab-CHL (O-CHL)]. Baseline samples were available from 383 patients (85.6%) representative of the total trial cohort. Mutations were analyzed by amplicon-based targeted next generation sequencing (tNGS). In 52.2% of patients we found at least one mutation; the incidence was highest in NOTCH1 (17.0%), followed by SF3B1 (14.1%), ATM (11.7%), TP53 (10.2%), POT1 (7.0%), RPS15 (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 NOTCH1 (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 (NOTCH1wt: HR0.50, P<0.01; NOTCH1mut: HR0.81, P=0.45). In summary, TP53 and SF3B1 were confirmed as independent prognostic factors and NOTCH1 as a predictive factor for reduced ofatumumab efficacy in a randomized chemo/immunotherapy CLL 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. © 2020 Ferrata Storti Foundation
Έτος δημοσίευσης:
2020
Συγγραφείς:
Tausch, E.
Beck, P.
Schlenk, R.F.
Jebaraj, B.M.C.
Dolnik, A.
Yosifov, D.Y.
Hillmen, P.
Offner, F.
Janssens, A.
Govind Babu, K.
Grosicki, S.
Mayer, J.
Panagiotidis, P.
McKeown, A.
Gupta, I.V.
Skorupa, A.
Pallaud, C.
Bullinger, L.
Mertens, D.
Döhner, H.
Stilgenbauer, S.
Περιοδικό:
Haematologica-the hematology journal
Εκδότης:
Ferrata Storti Foundation
Τόμος:
105
Αριθμός / τεύχος:
10
Σελίδες:
2440-2447
Λέξεις-κλειδιά:
ATM protein; baculoviral IAP repeat containing protein 3; biological marker; CD19 antigen; CD20 antigen; CD5 antigen; chlorambucil; F box/WD repeat containing protein 7; ficoll; fludarabine; myeloid differentiation factor 88; Notch1 receptor; ofatumumab; POT1 protein; protein p53; rituximab; RPS15 protein; SF3B1 protein; unclassified drug; Notch1 receptor; phosphoprotein; RNA splicing factor, 3' untranslated region; adult; amplicon; Article; base pairing; chromosome 11q; chromosome 12q; chromosome aberration; chronic lymphatic leukemia; cluster analysis; cohort analysis; comparative study; complement dependent cytotoxicity; COMPLEMENT1 trial; controlled study; cytogenetics; density gradient centrifugation; evaluation and follow up; female; flow cytometry; gene deletion; gene mutation; genetic association; genetic variability; high throughput sequencing; human; Illumina TruSeq Custom Amplicon; intention to treat analysis; major clinical study; male; missense mutation; multicenter study; nonsense mutation; overall survival; peripheral blood mononuclear cell; phase 3 clinical trial; predictive value; prognostic assessment; progression free survival; protein interaction; randomized controlled trial; RNA splice site; Sanger sequencing; single nucleotide polymorphism; stop codon; tumor associated leukocyte; variant allelic fraction; chronic lymphatic leukemia; clinical trial; genetics; mutation; prognosis; prospective study, Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Phosphoproteins; Prognosis; Prospective Studies; Receptor, Notch1; RNA Splicing Factors
Επίσημο URL (Εκδότης):
DOI:
10.3324/haematol.2019.229161
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