TOPLINE

Ibrutinib improved event-free survival (EFS) in patients with early-stage chronic lymphocytic leukemia (CLL) who had unmutated immunoglobulin heavy variable chain (IGHV), del(11q), trisomy 12, or mutations in NOTCH1, ATM, and NFKBIE, but provided no overall survival (OS) benefit in any genetic subgroup. 

METHODOLOGY

• Watch-and-wait has been the standard approach for asymptomatic early-stage CLL.  The CLL12 trial previously showed that ibrutinib improved EFS versus placebo in early-stage CLL without an overall survival benefit, but it remained unclear whether specific genetic subgroups might benefit from earlier treatment.
• Researchers analyzed 515 patients with Binet stage A CLL from the double-blind, placebo-controlled CLL12 trial. 
• Patients were stratified into a watch-and-wait cohort (n=152, low risk) or a treatment cohort (n=363, intermediate to very high risk), randomized 1:1 to ibrutinib (n=182) or placebo (n=181).
• Investigators used central fluorescence in situ hybridization (all patients), IGHV sequencing (99.0%), and a customized Illumina AmpliSeq panel covering 12 genes (100%) to assess mutation and cytogenetic status.
• The primary outcome was EFS. OS was also evaluated.

TAKEAWAY

• Overall, 53.7% of patients had no detectable mutation; the most common mutations were NOTCH1 (7.6%), SF3B1 (7.4%), TP53 (6.8%), BIRC3 (5.2%), and ATM (5.0%). During a median follow-up of 69.3 months, 166 EFS events and 32 OS events were recorded.
• With placebo, unmutated IGHV (HR, 4.44; P < .001), del(11q) (HR, 4.39; P < .001), del(17p) (HR, 2.89; P = .026), trisomy 12 (HR, 1.78; P = .048), NRAS/KRAS/BRAF (HR, 5.38; P = .001), NOTCH1 (HR, 2.26; P = .002), ATM (HR, 2.81; P = .001), and NFKBIE (HR, 4.12; P < .001) mutations were associated with shorter EFS. With ibrutinib treatment, only del(17p) (HR, 5.07; P = .004), TP53 mutations (HR, 2.88; P = .009), and NFKBIE (HR, 2.45; P = .043) were associated with shorter EFS.
• Ibrutinib treatment was associated with lower EFS events vs placebo in subgroups with unmutated IGHV (HR, 0.52; P = .02), del(11q) (HR, 0.10; P < .001), trisomy 12 (HR, 0.33; P = .031), NOTCH1 mutation (HR, 0.19; P = .003), ATM mutation (HR, 0.12; P = .001), and NFKBIE mutation (HR, 0.15; P = .003).
• Ibrutinib treatment was independently associated with favorable EFS (HR, 0.24; P < .001), while unmutated IGHV (HR, 2.82; P < .001), del(17p) (HR, 3.55; P < .001), POT1 (HR, 2.31; P = .048), NFKBIE (HR, 2.19; P = .010), and NRAS/KRAS/BRAF (HR, 2.90; P = .024) mutations were adverse prognostic factors.
• Ibrutinib treatment showed no significant OS benefit compared with placebo, either in the overall group or within subgroups with adverse genetic markers including unmutated IGHV, mutated TP53, and del(17p).

IN PRACTICE

"Our findings in this unique trial of patients with early-stage CLL treated with placebo vs ibrutinib clearly demonstrate wait and watch as standard of care in absence of International Workshop on CLL treatment indication criteria regardless of genetic risk category and especially in the presence of high-risk factors such as unmutated IGHV and del(17p)/ TP53 mutation," the authors wrote.

SOURCE

The study was led by Armin Riecke, Division of Chronic Lymphocytic Leukemia, Department of Internal Medicine III, Ulm University, Ulm, Germany. It was published online on August 27 in Blood.

LIMITATIONS

Limited follow-up period was not sufficient to detect OS differences in all subgroups. Also, the analysis was limited by low number of mutations.

DISCLOSURES

The study was supported by University of Cologne and Johnson and Johnson. Several authors reported consulting fees, honoraria, research funding, or advisory board roles with pharmaceutical companies including Janssen, AbbVie, Roche, and others. 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.