Combination Ibrutinib/Venetoclax Shows Early Promise in Previously Treated CLL

About one-third of patients with previously treated chronic lymphocytic leukemia (CLL) were minimal residual disease (MRD) negative after 6 months of treatment with the combination of targeted agents ibrutinib and venetoclax, according to the results of the TAP CLARITY study (abstract 428) presented at the 59th American Society of Hematology Annual Meeting and Exposition, held December 9–12 in Atlanta.

“The last few years have shown a rapid development of understanding of the disease,” said Peter Hillmen, MBChB, PhD, professor of experimental hematology at Leeds Institute of Cancer and Pathology, United Kingdom.

During that time research has shown that antigen-mediated proliferation and Bcl-2–mediated survival are key to CLL pathogenesis. Ibrutinib works by blocking signals that stimulate cancer cells to proliferate, and venetoclax promotes cancer cell apoptosis by blocking a protein that helps cells survive.

In the CLARITY study, Hillmen and colleagues enrolled 50 patients with relapsed or refractory CLL. The primary endpoint was MRD eradication in the marrow after 12 months of ibrutinib and venetoclax, with the possibility of stopping therapies rather than having indefinite treatment, Hillmen explained. A key secondary endpoint was MRD eradication in the marrow at 6 months and 24 months.

Patients were treated with 2 months ibrutinib monotherapy. At 2 months, venetoclax was added to therapy with weekly dose escalations. All patients were given prophylactic uric acid reducing agents beginning at least 72 hours prior to starting venetoclax.

The treatment schedule had bone marrow examinations performed at 6 months, 12 months, and 24 months. If patients were MRD negative in blood and marrow at 6 months, they stop therapy at 12 months, and if they were MRD negative at 12 months, they stop therapy at 24 months.

The median age of patients was 64. The majority of patients (81%) had prior chemotherapy, including 20% who had prior idelalisib.

Thirty-eight patients reached at least month 8 having received 6 months or more of combination therapy. At 8 months, 37% of patients were MRD negative in the peripheral blood and 32% were MRD negative in the bone marrow. These rates were 52% and 41% for patients with prior chemotherapy treatment, respectively, and 71% and 43% among patients with prior idelalisib, respectively.

“Our assumption was that the trial would be a success if 30% of patients achieved the deepest level of remission after 12 months of combination therapy,” Hillmen said. “But already, at 6 months, 33% of patients have undetectable disease.”

The overall response rate was 100%, with 39% of patients achieving complete remission and 8% achieving complete remission with incomplete blood count recovery.

There was only a single case of tumor lysis syndrome, which was managed by delaying venetoclax. According to Hillmen, the patient was rapidly re-escalated with no further tumor lysis syndrome. Other adverse events included 33 patients with bruising, the majority of which was grade 1, and 25 patients with grade 3/4 neutropenia.

According to Hillmen, no patients stopped treatment and only 7 patients had any interruption of treatment.

A key limitation of the study is that it lacked a control group. On the basis of the CLARITY results, Hillmen is leading a randomized controlled phase III trial, the FLAIR trial, to compare the ibrutinib plus venetoclax combination with both ibrutinib alone and a combined regimen of three chemotherapy drugs in patients with previously untreated CLL.