Ibrutinib Plus Venetoclax Appears Safe and Effective in CLL for High-Risk, Older Patients

Combined treatment with ibrutinib and venetoclax was shown to be a safe and effective first-line oral regimen for high-risk and older patients with chronic lymphocytic leukemia, according to findings from an open-label phase II trial published recently in the<em> New England Journal of Medicine</em>.<br /> &nbsp;

Nitin Jain, MD

Combined treatment with ibrutinib (Imbruvica) and venetoclax (Venclexta) was shown to be a safe and effective first-line oral regimen for high-risk and older patients with chronic lymphocytic leukemia (CLL), according to findings from an open-label phase II trial published recently in theNew England Journal of Medicine.

The authors, led by Nitin Jain, MD, of The University of Texas MD Anderson Cancer Center, noted that they observed no new toxic effects from the combination that were not previously reported for the individual agents.

“As expected, the majority of patients had a partial response after 3 cycles of ibrutinib monotherapy,” they wrote. “With the addition of venetoclax, we noted a rapid conversion of partial responses into complete responses (with or without normal count recovery) and a steady increase in the proportion of patients with undetectable minimal residual disease in bone marrow.”

Of the 80 patients enrolled, nearly three-fourths (n = 59, 74%; 95% CI, 63%-83%) achieved complete remission (CR) or CR with incomplete count recovery (CRi). After 6 cycles of the combined regimen, 51 of 70 patients (73%; 95% CI, 61%-83%) attained CR or CRi. An additional 28 patients (40%; 95% CI, 28%-52%) had remission with undetectable minimal residual disease (MRD) in their bone marrow.

All of the trial patients were treated at MD Anderson. Their median age was 65 (range, 26-83) and nearly one-third were ≥70 years old. Patients were eligible if they had an ECOG performance status of 0, 1, or 2 and adequate hepatic and renal function. They also needed a platelet count of ≥20,000/mm3.

Tumor DNA from pretreatment samples underwent targeted sequencing of 29 genes, includingTP53, SF3B1, NOTCH1,andBIRC3. Importantly, all patients had at least 1 high-risk genetic feature. A total of 83% of the patients had unmutatedIGHV,while 25% had del(11q), 21% had trisomy 12, 18% had del(17p), and 14% had mutatedTP53.

The trial protocol called for 3 initial 28-day cycles of ibrutinib monotherapy (420 mg once daily) in the hopes of reducing the risk of venetoclax-associated tumor lysis syndrome. Venetoclax was added at the start of cycle 4. The venetoclax dose was escalated each week to reach a target daily dose of 400 mg. Patients received the combined regimen for 24 cycles if tolerated. Patients whose bone marrow had MRD at the end of combined treatment could continue ibrutinib monotherapy until disease progression or unacceptable toxicity. All patients received antiviral prophylaxis with valacyclovir or acyclovir, but prophylaxis for pneumocystis pneumonia was not required.

The trial’s primary endpoint was best response (CR/CRi) at any time during treatment and up to 2 months after completing the combined regimen.

Five patients withdrew from the study during the ibrutinib monotherapy phase. The median follow-up of patients who completed the trial was 14.8 months.

Following 12 cycles of combined therapy, 29 of 33 patients (88%; 95% CI, 72%-97%) were in CR/CRi. Twenty patients (61%; 95% CI, 42%-77%) had remission with undetectable MRD in their bone marrow.

For patients who completed 18 cycles of the combination, the results were even better: 25 of 26 patients (96%; 95% CI, 80%-100%) were in CR/CRi, while 18 of 26 (69%; 95% CI, 48%-86%) were in remission with undetectable MRD in their bone marrow. Of the 3 patients who completed 24 cycles of combined therapy, all were in CR/CRi, with undetectable MRD in bone marrow.

At 1 year, the estimated progression-free survival rate was 98% (95% CI, 94%-100%) and the estimated overall survival rate was 99% (95% CI, 96%-100%).

“These efficacy results are substantially better than what has been reported with ibrutinib or venetoclax monotherapy for patients with CLL; with monotherapy, the majority of responses have been partial, and remissions with undetectable minimal residual disease in bone marrow have been rare, especially with ibrutinib,” Jain et al wrote.

Responses with combined ibrutinib and venetoclax were seen across all genetic subgroups, including the high-risk subgroups, such as patients with del(17p), del(11q), unmutatedIGHV, or mutatedTP53.

Regarding patient age, the investigators noted that patients of 65-plus years often had lower remission rates than younger patients without any unexpected toxicities. After 12 treatment cycles among patients 65 and older, the rate of CR/CRi was 94%. Three-quarters of the older patients (76%) had undetectable MRD following 12 treatment cycles.

No new safety concerns were noted with combination therapy, since the toxicity profile of the combined regimen was similar to what has been seen with ibrutinib or venetoclax monotherapy. “It is notable that the incidence of grade 3 or 4 neutropenia was similar among patients 65 years of age or older (47%) and those younger than 65 years of age (49%),” they wrote.

As of the data cutoff, progression of CLL has not been seen in any of the patients and only 1 has developed Richter’s transformation.

This trial had 2 treatment groups; data on the combined regimen in patients with relapsed or refractory CLL have not yet been reported.


Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL.N Engl J Med.2019;380(22):2095-2103. doi: 10.1056/NEJMoa1900574.