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

Eugen Tausch, Philipp Beck, Richard F Schlenk, Billy J Jebaraj, Anna Dolnik, Deyan Y Yosifov, Peter Hillmen, Fritz Offner, Ann Janssens, Govind K Babu, Sebastian Grosicki, Jiri Mayer, Panagiotis Panagiotidis, Astrid McKeown, Ira V Gupta, Alexandra Skorupa, Celine Pallaud, Lars Bullinger, Daniel Mertens, Hartmut Döhner, Stephan Stilgenbauer, Eugen Tausch, Philipp Beck, Richard F Schlenk, Billy J Jebaraj, Anna Dolnik, Deyan Y Yosifov, Peter Hillmen, Fritz Offner, Ann Janssens, Govind K Babu, Sebastian Grosicki, Jiri Mayer, Panagiotis Panagiotidis, Astrid McKeown, Ira V Gupta, Alexandra Skorupa, Celine Pallaud, Lars Bullinger, Daniel Mertens, Hartmut Döhner, Stephan Stilgenbauer

Abstract

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.

Figures

Figure 1.
Figure 1.
Incidence and distribution of genetic parameters (gene mutations, genomic aberrations and IGHV status). (A) Cluster diagram of patients (columns) with data for all genetic parameters (rows) (right) and overall incidence (left). Distribution of markers is ordered by rows. (B) Circos plots of the co-occurrence of gene mutations with each other (left) and pairwise with chromosomal aberrations (right). Lengths of arcs correspond to total incidences of respective markers while the width of each ribbon corresponds to the proportion of co-occurrence with a respective second marker. (C) Distribution of gene mutations in the IGHV mutation status subgroups.
Figure 2.
Figure 2.
Visualization of co-occurrence of gene mutations and genomic aberrations based on pairwise Fisher exact test. Line length corresponds to √(1/odds ratio). Therefore, lines with a length >1 show mutual exclusivity (red) and lines with a length <1 co-occurrence (blue). Line width corresponds to stated P-value of pairwise comparison; when P>0.1, no line is depicted. Font size characterizes incidence of mutation/aberration; green indicates association with mutated IGHV, and yellow indicates association with unmutated IGHV (P<0.1 each). FBXW7 is depicted twice.
Figure 3.
Figure 3.
Kaplan-Meier estimates of progression-free survival (PFS) (left) and overall survival (OS) (right) according to the status of selected gene mutations for the total patient cohort. Red lines: mutated (mut) subgroups; blue lines: wild-type (wt). Denoted P-values were calculated by log-rank test (mut vs. unmutated subgroup).
Figure 4.
Figure 4.
Kaplan-Meier estimates of progression-free survival (PFS) in the chlorambucil + ofatumumab (left) and chlorambucil alone (right) treatment arms according to NOTCH1 mutation status. Mutated subgroups are depicted by red lines, wild type by blue lines. Denoted P-values were calculated by log-rank test (mutated vs. unmutated subgroup).
Graphical Abstract
Graphical Abstract

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