Novel Agents: A Brief Overview

CLL12 ( Identifier: NCT02863718)

CLL12 is a placebo-controlled, double-blind, randomized phase 3 trial evaluating the efficacy and safety of oral ibrutinib in patients with previously untreated Binet stage A CLL without an indication for therapy. Patients with intermediate-, high-, or very high-risk disease according to GCLLSG risk model were randomized to ibrutinib 420 mg daily or placebo and treatment is continued until disease progression, but no more than 60 months post-randomization. The primary endpoint was event-free survival (EFS). This is the first and largest study of novel agents in patients with asymptomatic CLL.3

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Results from the primary endpoint analysis were reported in 2019. A total of 363 patients were randomly assigned to receive ibrutinib (n = 182) or placebo (n = 181). After a median follow-up of 31 months, the median EFS was not reached in the ibrutinib group and was 47.8 months in the placebo group (hazard ratio [HR], 0.25; 95% CI, 0.14-0.43; P <.0001). In addition, progression-free survival (PFS) was not reached for ibrutinib and was 14.8 months in the placebo arm (HR, 0.18; 95%CI, 0.12-0.27). At the data cutoff, the OS results were still immature.3

With respect to safety, the frequency of any-grade adverse events (AEs) was similar in the ibrutinib arm (82.2%) and the placebo arm (84.8%). The most frequent AEs leading to treatment interruption in the ibrutinib group compared with the placebo group were arrhythmias (18 vs 0 patients), bleeding (8 vs 1 patient), diarrhea (4 vs 3 patients), and neoplasia (4 vs 3 patients). Treatment was discontinued by 34.1% of patients in the ibrutinib arm compared with 45.9% in the placebo arm. AEs (n = 53) were the main reason for discontinuation in the ibrutinib group, but disease progression (n = 45) was more common in the placebo group.3

Additional phase 2 studies are also ongoing evaluating the use BTK inhibitors alone or in combination for patients with early-stage CLL.1

Expert Perspective: Clinical Trials

“Hematologists/oncologists in the community setting are encouraged to refer newly diagnosed CLL patients to specialized centers for a thorough baseline evaluation,” commented lead author Dr. Muchtar in an email interview.

“We recommend all patients get tests performed to compute the CLL-IPI score, which can be very helpful in predicting outcomes, particularly time to first therapy, in early stage patients,” Dr. Muchtar further explained. “This referral platform can be an opportunity to recruit patients to early intervention trials, which is a growing area of CLL research.”

Disclosures: Some guideline authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


  1. Muchtar E, Kay NE, Parikh SA. Early intervention in asymptomatic chronic lymphocytic leukemia. Clin Adv Hematol Oncol. 2021;19(2):92-103.
  2. Woyach JA. Treatment-naive CLL: lessons from phase 2 and phase 3 clinical trials. Blood. 2019;134(21):1796-1801. doi:10.1182/blood.2019001321
  3. Langerbeins P, Bahlo J, Rhein C, et al. Ibrutinib versus placebo in patients with asymptomatic, treatment‐naïve early stage CLL: primary endpoint results of the phase 3 double‐blind randomized CLL12 trial [EHA abstract 007]. Hematol Oncol. 2019;37:38-40.