Ibrutinib Plus Venetoclax Shows Promise in Treatment-Naïve CLL

First-line combination therapy with ibrutinib and venetoclax was associated with higher rates of undetectable measurable residual disease (MRD), remission, and three-year progression-free survival (PFS) in patients with chronic lymphocytic leukemia (CLL). This is according to results of a new study published in JAMA Oncology, which suggest that Bruton tyrosine kinase [BTK] inhibitor ibrutinib plus BCL2 inhibitor venetoclax may be an effective oral nonchemotherapy regimen for patients with CLL.1

Previous data suggests patients with CLL given BTK inhibitor monotherapy with ibrutinib or acalabrutinib rarely enter complete remission (CR) or have undetectable MRD remission.

In contrast, venetoclax is often combined with obinutuzumab, a CD20 monoclonal antibody, for one year in treatment-naïve patients. For this combination regimen, the documented undetectable MRD rate is approximately 76% in peripheral blood and 57% in bone marrow.2

Researchers led by Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center evaluated the synergistic and complementary therapeutic activities of the ibrutinib and venetoclax combination in 80 patients with treatment-naïve CLL. Dr. Jain and colleagues focused their analysis on MRD and remission durability.

To be eligible for enrollment in the study, patients with CLL were required to meet at least one of the following criteria:

  • del(17p)
  • TP53-mutated CLL
  • del(11q)
  • unmutated immunoglobulin heavy-chain variable gene
  • age 65 or older

The treatment regimen started with ibrutinib 420 mg/day monotherapy. After three cycles of ibrutinib monotherapy, participants received venetoclax in addition to ibrutinib. Venetoclax followed a standard weekly dose ramp-up from 20 mg/day to a target of 400 mg/day. The combination regimen was administered for 24 planned 28-day cycles.
Researchers assessed MRD in bone marrow while patients were receiving combination therapy. Following completion of treatment, the investigators monitored MRD in blood samples every six months.

Best response, defined as CR and CR with incomplete count recovery, was the primary endpoint, assessed at any time during treatment for up to two months after the study. Other time-to-event outcomes, such as PFS and overall survival (OS), were also assessed.

At baseline, the median age of patients was 65 years (range = 26-83). Approximately 18% of patients had del(17p) and 14% had TP53-mutated CLL. The majority of patients were men (71%).

A total of five patients discontinued the study while on the initial ibrutinib monotherapy for reasons unrelated to disease progression. The median follow-up for all patients, including those who discontinued treatment, was 38.5 months, and ranged from 5.6 to 51.1 months.

In an intent-to-treat analysis of the overall cohort, 56% of patients (n=45) demonstrated bone marrow undetectable MRD remission at the end of 12 cycles. Approximately 66% (n=53) of patients demonstrated bone marrow undetectable MRD remission at 24 cycles. The majority of patients (75%) achieved bone marrow undetectable MRD remission as best response.

Patients with <1% bone marrow MRD at initial response assessment following the start of combination therapy had a significantly greater likelihood of achieving bone marrow undetectable MRD remission by the end of cycle 12 (77% vs. 20%; p<0.001). Additionally, those who showed a >2-log reduction in bone marrow MRD at the end of cycle three were significantly more likely to show bone marrow undetectable MRD remission at the end of cycle 12 (83% vs. 20%; p<0.001).

Three-year PFS and OS rates were 93% and 96%, respectively. In patients with del(17p)/TP53-mutated CLL, the estimated three-year PFS was 86%. None of the patients in the study had disease progression, but two patients developed diffuse large B-cell lymphoma Richter transformation.

Limitations of this study included its lack of placebo control, single-center design, small sample size, and short follow-up period.

Study authors report relationships with AbbVie, which sponsored this trial.


  1. Jain N, Keating M, Thompson P, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia: A nonrandomized phase 2 trial [published online ahead of print, 2021 Jun 10.] JAMA Oncol. doi:10.1001/jamaoncol.2021.1649.
  2. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225-2236