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

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

HIF-1α: a potential treatment target in chronic lymphocytic leukemia

“…Even though treatment options for CLL have improved tremendously within the last decade, dysfunctional TP53 is still associated with inferior patient outcome. 18 The development of novel treatment strategies is, therefore, extremely important for this patient group, as well as in the light of overcoming or avoiding therapy resistance to novel targeted therapies due to clonal evolution and/or selection of clones with aggressive phenotype, including disrupted TP53 status.…”

A step ahead toward precision medicine for chronic lymphocytic leukemia

“…In this issue of Haematologica , Tausch et al have analyzed the prognostic and, more importantly, the predictive role of a panel of gene mutations in the randomized, phase III COMPLEMENT1 trial comparing chlorambucil with ofatumumab-chlorambucil in treatment-naïve CLL patients not eligible for intensive therapy because of age or comorbidities. 5 The COMPLEMENT 1 trial had documented that addition of the type 1 anti-CD20 mAb ofatumumab to chlorambucil leads to clinically significant improvement in progression-free survival (PFS) (22.4 months in the arm treated with ofatumumab chlorambucil vs . 13.1 months in the arm treated with single agent chlorambucil), with a manageable side effect profile.…”

“…Remarkably, in the genetic analysis performed by Tausch et al , mutations of NOTCH1 were seen to predict weak benefit from the addition of ofatumumab to the chlorambucil backbone. 5 The NOTCH1 signaling pathway is a key feature in CLL growth and survival, and is deregulated by mutations in a sizable fraction of CLL 7 ( Figure 1 ). NOTCH1 mutations in CLL may target either the autoregulatory PEST domain, or the non-coding 3’- untranslated region (3’-UTR) sequence.…”

“… 7 In the context of the COMPLEMENT1 trial, the addition of ofatumumab to chlorambucil provided a significant benefit in PFS to NOTCH1 wild-type patients, whereas no statistically significant benefit was achieved in NOTCH1 mutated cases, including patients whose mutations disrupted the NOTCH1 PEST autoregulatory domain as well as patients with NOTCH1 mutations affecting the 3’-UTR of the gene. 5 …”

“… 8 The fact that NOTCH1 mutations behave as a predictor of reduced benefit from type 1 anti-CD20 mAb in two prospective, randomized trials with different anti-CD20 antibodies (ofatumumab in COMPLENT1; rituximab in CLL8), different chemotherapy backbones (chlorambucil in COMPLEMENT1; fludarabinecyclophosmide in CLL8), and different target CLL populations (patients not eligible to intensive therapy in COMPLEMENT1; patients eligible to fludarabine-containing regimens in CLL8) contributes further to the robustness of the predictive significance of NOTCH1 mutations in CLL treated with chemo-immunotherapy containing anti-CD20 type 1 mAb. 5 , 8 …”