Ibrutinib and Venetoclax Combo 'Impressive' in Front-Line CLL

Alexander M. Castellino, PhD

May 29, 2019

The combination of two targeted therapies — ibrutinib (Imbruvika, Pharmacyclics/Janssen) and venetoclax (Venclexta, AbbVie) – has shown impressive results in the front-line treatment of chronic lymphocytic leukemia (CLL).

This combination avoids the use of chemotherapy, and the treatment may not need to be continued indefinitely, say researchers.

After 24 cycles of combination therapy, 88% of patients had complete remission (CR) or complete remission with incomplete count recovery, and 61% of patients had remission with undetectable minimal residual disease (MRD).

These data from an investigator-initiated phase 2 study were published online today in the New England Journal of Medicine, authored by Nitin Jain, MD, associate professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, and colleagues.

"The results are impressive…[and] every patient had a response, almost all had a complete response, and in most [patients] no residual disease was detected," writes Adrian Wiestner, MD, PhD, of the National Heart, Lung, and Blood Institute, Bethesda, Maryland, in an invited editorial.

Wiestner was particularly surprised not to see a Kaplan-Meier curve. "Here, the assessment of minimal residual disease (MRD) has replaced the progression-free survival [PFS] curve of old," he writes. This may usher an era where one sees a "shift in focus away from traditional clinical trial endpoints to more stringent measures of clinical efficacy that may be central to regulatory decisions," he suggests.

Study Details

The idea to evaluate the combination of ibrutinib and venetoclax stemmed from "the clinically complementary activity, preclinical synergism, and nonoverlapping toxic effects" seen with the combination, the authors write.

The study enrolled 80 patients with treatment-naïve CLL with at least one high-risk genetic feature; median age was 65 years. Unmutated IGHV was the major high-risk genetic feature (83%).

Ibrutinib monotherapy (420 mg once daily) was given for the first three cycles, each of 28 days; venetoclax was initiated at cycle 4. Combined ibrutinib and venetoclax was administered for a total of 24 cycles. Patients with positive MRD at the end of combination therapy were permitted to remain on ibrutinib monotherapy until disease progression.

Median follow up was 14.8 months. After the first three cycles of ibrutinib monotherapy, partial remission was seen in 96% of patients and no patient showed MRD (defined as less than 1 CLL cell in 10,000 leukocytes). This window of therapy was associated with downgrading risk for tumor lysis syndrome with venetoclax in 80% of high-risk and 48% of medium-risk patients.

After the addition of venetoclax, complete remission rates with or without incomplete count recovery kept improving over time, as did the absence of MRD. After 18 cycles of combination therapy, all patients showed complete or partial remission, with 96% of patients showing complete remission with or without normal blood count recovery and 69% having undetectable MRD in the bone marrow.

Responses were reported across all high-risk subgroups and were independent on the genetic lesions — del(17p), del(11q), unmutated IVHG, or mutated TP53.

The investigators note that CLL typically occurs in patients older than 65 years of age, a group that typically shows a lower rate of complete remission and undetectable MRD. Not so in this study: this combination showed a remarkably high efficacy, with 94% of patients achieving complete remission with or without incomplete count recovery and 76% showing undetectable MRD in the bone marrow after 12 cycles of the combination. 

The estimated 1-year PFS was 98% and overall survival (OS) was 99%.

No new safety concerns were noted with the combination, and the toxicity profile of the combination was similar for what has been observed with the two agents in the monotherapy studies. Grade 3 or higher adverse events were reported for 60% of patients, with neutropenia occurring in 48% of patients. Atrial fibrillation, attributed to ibrutinib, was reported in 15% of patients. The risk for neutropenic fever was 5%, similar to the rate seen with venetoclax in a previous study.

"A longer follow-up is needed to adequately assess the long-term safety of this combination," Jain and colleagues note.

Time-Limited Treatment Strategy in CLL

Two time-limited combinations have already been approved for use in CLL.

The combination of venetoclax and rituximab (Rituxan, Genentech) has been approved for relapsed/refractory CLL, with venetoclax administered for 2 years and rituximab given over six standard cycles.

Two weeks ago the US Food and Drug Administration approved the combination of venetoclax and obinutuzumab (Gazyva, Genentech) for the front-line treatment of CLL for a 12-month duration based on CLL14 (NCT02242942), where the combination showed significantly better PFS compared with the combination of obinutuzumab and chlorambucil.

Currently, ibrutinib and venetoclax given as single agents are approved for the front-line treatment of CLL until disease progression.

The ibrutinib plus venetoclax combination offers several advances over current treatment approaches, Jain and colleagues suggest.

"In the present trial, the combined treatment will stop after 24 cycles [approximately 2 years]" the authors write, noting that it has several advantages over an indefinite treatment strategy.

Increased depth of remission seen with the combination may lead to prolonged PFS and OS and are likely to eliminate aggressive clones, thus avoiding resistance, Jain and colleagues suggest. It also reduces the long-term toxicity seen with indefinite treatment and may be associated with lower cost.

However, ibrutinib monotherapy until disease progression is still an option for patients with detectable MRD. "On the basis of experience with single-agent ibrutinib in first-line therapy, patients who continue ibrutinib can be expected to do well," Wiestner suggests.

The appropriate duration of treatment remains uncertain, Jain and colleagues comment. This and several other ongoing studies are exploring the question.

In the editorial, Wiestner poses several questions that still need to be addressed and that impact clinical practice: "Can treatment ever be safely stopped? Are there subgroups with a poor prognosis that require additional therapy? What is the nature and mechanism of ibrutinib and venetoclax resistance? And does substituting another BTK [Bruton's tyrosine kinase] inhibitor in place of ibrutinib preserve activity with a lower risk of toxic effects?"

The study was supported by AbbVie, the manufacturer of venetoclax. AbbVie also owns Pharmacyclics, the manufacturer of ibrutinib . Several authors report relationships with industry, including AbbVie, as detailed in the article. Wiestner reports grants from Merck, Pharmacyclics, and Acerta Pharma (member of the AstraZeneca group), outside of the submitted work.

N Engl J Med. Published online May 30, 2019. Abstract, Editorial

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