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Ref Type Journal Article
PMID (31919090)
Authors Tausch E, Beck P, Schlenk RF, Jebaraj BJ, Dolnik A, Yosifov DY, Hillmen P, Offner F, Janssens A, Babu KG, Grosicki S, Mayer J, Panagiotidis P, McKeown A, Gupta IV, Skorupa A, Pallaud C, Bullinger L, Mertens D, Döhner H, Stilgenbauer S
Title Prognostic and predictive role of gene mutations in chronic lymphocytic leukemia: results from the pivotal phase III study COMPLEMENT1.
Journal Haematologica
Vol
Issue
Date 2020 Jan 09
URL
Abstract Text 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 and 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 PFS in univariate analysis. Multivariate analysis confirmed the independent prognostic role of TP53 for PFS (HR1.71,p=0.04) and 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 and a weak benefit from ofatumumab addition to CHL (NOTCH1wt:HR0.50,p<0.01, NOTCH1mut:HR0.81,p=0.45). In summary, TP53 and SF3B1 were confirmed as independent prognostic and NOTCH1 as a predictive factor for reduced ofatumumab efficacy in a randomized chemo (immune)therapy 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. ClinicalTrials.gov registration number: NCT00748189.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ATM D2720N missense unknown ATM D2720N lies within the PI3K/PI4K domain of the Atm protein (UniProt.org). D2720N has been identified in sequencing studies (PMID: 27147599, PMID: 31919090), but has not been biochemically characterized and therefore, its effect on Atm protein function is unknown (PubMed, Aug 2020).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NOTCH1 mutant chronic lymphocytic leukemia decreased response Chlorambucil + Ofatumumab Phase III Actionable In a Phase III trial (COMPLEMENT1), the addition of Arzerra (ofatumumab) to Chlorambucil treatment in patients with chronic lymphocytic leukemia was associated with increased benefit to median progression-free survival (mPFS) in patients with wild-type NOTCH1 (mPFS 23.8 mo with ofatumumab vs.13.3 mo without, HR 0.50, CI 95% 0.39-0.63, p<0.01), but did not result in significant mPFS benefit in patients with mutant NOTCH1 (17.2 vs.13.1 mo, HR 0.81, CI 95% 0.50-1.31, p=0.45) (PMID: 31919090; NCT00748189). 31919090