Ibrutinib and Venetoclax: Potential Combination for r/r CLL

Alexander M. Castellino, PhD

December 10, 2017

ATLANTA ― Two of the newest drugs for the treatment of chronic lymphocytic lymphoma (CLL) have been added together, and the combination is "particularly impressive" in achieving eradication of minimal residual disease (MRD), or MRD negativity (<0.01% CLL cells,) in patients with relapsed or refractory CLL (r/r CLL). At least a third of the patients achieved MRD with the two drugs taken together for 6 months.

The two drugs are ibrutinib (Imbruvica, Pharmacyclics and Jannsen) and venetoclax (Venclexta, AbbVie/Genentech/Roche). They act as inhibitors of two separate pathways implicated in the pathogenesis of CLL. Ibrutinib is an oral Bruton tyrosine kinase, which affects antigen-induced proliferation, cell adhesion, and migration. Venetoclax is an oral inhibitor of Bcl-2, which is associated with CLL cell survival.

The results for the combination come from the Bloodwise TAP CLARITY study, which was reported here at the American Society of Hematology (ASH) 2017 Annual Meeting.

All patients who were evaluated at the 8-month time point responded to therapy.

"MRD is the deepest level of response that can be achieved with no detectable disease in the bone marrow," said lead study author Peter Hillmen, MBChB, PhD, professor of experimental hematology at Leeds Institute of Cancer and Pathology in the United Kingdom.

"These initial results are particularly impressive in a patient population for whom previous therapies have failed," Dr Hillmen said in an ASH press release.

"We have shown that the two drugs can be given in combination without obvious additional toxicity, and the inability to detect disease with the most sensitive tools we have is a very good sign that the combination is proving to be an effective treatment," he added.

A lymphoma expert who was approached for comment pointed out that "MRD negativity can be achieved with a proportion of patients treated with chemoimmunotherapy.

"The overarching question being asked in novel combination studies is whether MRD negativity can be attained with the newer combinations, and, with this finding, can therapy be abbreviated," Nadia Khan, MD, of the Lymphoma and CLL Cancer Translational Research Disease Group member at the Fox Chase Cancer Center in Philadelphia, Pennsylvania, told Medscape Medical News.


Patients in the study were required to have relapsed within 3 years of treatment with FCR (fludarabine, cyclophosphamide, rituximab [Rituxan, Genentech]) or BR (bendamustine [Treanda, Teva Oncology], rituximab), or to have a 17p deletion and had failed at least one line of therapy.

After 8 weeks of ibrutinib monotherapy (420 mg/day), tumor lysis syndrome associated with venetoclax was mitigated by starting it at a weekly dose of 10 mg/day, with weekly escalations to a final dose of 400 mg/day.

Dosing with ibrutinib and venetoclax was designed such that if MRD negativity was seen after 6 or 12 months of therapy, patients received an additional 6 or 12 months of therapy, respectively, and then stopped. Ibrutinib monotherapy was to be continued if results from a 26-month bone marrow biopsy indicated MRD positivity.

Ibrutinib monotherapy was to be continued if a 26-month bone marrow biopsy shows MRD positivity.

"Truncated therapy is an important concept for clinical practice," Dr Khan said. She explained that it is important to provide therapy to patients for the minimum possible time, and MRD is the best reflection for patients who can stop therapy for a period of time, she explained.

"We anticipate that MRD negativity will correspond to a longer disease-free interval and will correlate with improvement in [progression-free survival] and may be relevant for allowing patients to be on truncated therapy," Dr Khan said.


Fifty-four patients were enrolled in the study. Efficacy data were reported for 38 patients who received 6 months of therapy and who were evaluated for MRD 2 months later ― a key secondary endpoint of the study.

A single case of tumor lysis syndrome, managed by delaying venetoclax, was seen as increasing phosphate and creatinine at a venetoclax dose of 200 mg. Dose was rapidly re-escalated with no further event.

"We have not seen an increase in the rate of [tumor lysis syndrome] with the combination regimen compared with what we would expect to see with venetoclax single-agent therapy," Dr Hillmen said.

Grade 3 and 4 neutropenia was reported in 16 and 6 patients, respectively. To keep neutrophil count above 1 × 109, the protocol was amended to provide G-CSF; seven patients received granulocyte-colony stimulating factor.

Thirty-eight patients had MRD determinations at 8 months, having received venetoclax and ibrutinib for 6 months: 84% (32/38) of patients showed no morphological evidence of CLL in marrow biopsy, and 37% (16/38) and 32% (12/38) of patients achieved MRD negativity in peripheral blood and the bone marrow, respectively.

Data were also parsed based on prior therapy patients received. For patients receiving prior FCR or BR (n = 17), 94% (16/17) showed no morphological evidence of CLL in marrow biopsy; 52% (9/17) and 41% (7/17) achieved MRD negativity in peripheral blood and the bone marrow, respectively.

Early relapse after FCR/BR is a sign of poor prognosis, Dr Khan noted. "MRD negativity in these patients with the novel combination is impressive," she said.

According to Dr Hillmen, after 6 months of combination therapy, the trial has already exceeded the expected proportion of patients achieving undetectable CLL. The assumption was made that the trial would be deemed a success if 30% of patients achieved MRD. "But already, at 6 months, 33% of patients have undetectable disease," Dr Hillmen said.

All patients showed a response (100% overall response rate), with 39% (15/38) achieving a complete response (CR) and 8% (3/38) achieving a complete remission with incomplete bone marrow recovery.

Of patients receiving prior FCR or BR, all patients showed a response (100% overall response rate), with 53% (9/17) achieving a complete response and 12% (2/17) achieving a complete remission with incomplete bone marrow recovery.

On the basis of these data, Dr Hillmen indicated that the phase 3 NCRI FLAIR trial has been modified to include the combination of ibrutinib and venetoclax in front-line CLL. Dr Hillmen is also leading the FLAIR trial, which is comparing the ibrutinib plus venetoclax combination with both ibrutinib alone and FCR in patients with previously untreated CLL.

Dr Khan told Medscape Medical News that two large phase 3 studies in the United States comparing chemoimmunotherapy with ibrutinib-continuing therapies in the front-line setting have closed and are being analyzed. The results of these studies will also inform on how ibrutinib can best move upfront in CLL.

This trial was funded by Bloodwise under the Trials Acceleration Programme; Pharmacyclics, the manufacturer of ibrutinib; and AbbVie, the manufacturer of venetoclax. Dr Hillmen has the following disclosures: consultancy, honoraria, and/or research funding from AbbVie, Gilead, Janssen, GSK, Celgene, Pharmacyclics LLC, Novartis, Roche, and Alexion Pharmaceuticals, Inc. Other disclosures are listed in the abstract.

American Society of Hematology (ASH) 2017 Annual Meeting: Abstract 428. Presented December 10, 2017.

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