Ibrutinib/Venetoclax Combo Impresses in Early CLL Data

Peter Hillmen, MBChB, PhD

The combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) elicited a complete response (CR) or CR with incomplete hematologic recovery (CRi) rate of 47% for patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to findings from the TAP CLARITY study presented at the 2017 ASH Annual Meeting.

In 38 efficacy-evaluable patients, all experienced at least a partial response to the combination of ibrutinib and venetoclax (objective response rate [ORR], 100%). Of these patients, 37% treated with the combination were negative for minimal residual disease (MRD) in the peripheral blood at 8 months. When testing the bone marrow (BM), the MRD-negative rate was 32%. Trephine was normal for 84% of patients.

"These initial results are particularly impressive in a patient population for whom previous therapies have failed," lead investigator Peter Hillmen, MBChB, PhD, of the Leeds Institute of Cancer and Pathology, said in a release. "We have shown that the 2 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."

The study enrolled 54 patients with relapsed/refractory CLL. The median age of patients was 64 years (range, 31-84), and most were males (69%). Eight percent of patients had bulky disease, defined as lymph nodes ≥5 cm. The ECOG performance status was 0 (59%), 1 (33%), 2 (6%), and not known (2%). Twenty percent of patients had 17p deletions and 25% had 11q deletions without 17p deletions.

The median number of prior therapies was 1 (range, 1-6), with the most common prior therapy for 81% of patients being FCR (fludarabine, cyclophosphamide, and rituximab) or BR (bendamustine and rituximab). Forty-four percent of patients had relapsed within 3 years of BR or FCR. Twenty percent of patients had received idelalisib.

Venetoclax was administered at 400 mg per day and ibrutinib was given at 420 mg per day. Ibrutinib was given alone for the first 2 weeks of the study followed by the addition of venetoclax at a lower dose that was escalated to the full 400 mg dose. The duration of treatment was customized based on MRD status. If the 8-month BM findings were MRD-negative, treatment was stopped at 14 months. If they were negative at 14 months, treatment was stopped at 26 months. If patients remained MRD-positive after 26 months, they continued single-agent ibrutinib. MRD was defined as fewer than 0.01% CLL cells in the BM.

The ORR with the combination of venetoclax and ibrutinib consisted of 15 CRs (39%) and 3 patients had a CRi (8%). The remaining patients had a partial response (53%).

In patients who relapsed on FCR/BR in less than 36 months, the peripheral blood and BM MRD rates were 52% and 41%, respectively. Trephine was normal for 94% of patients. The ORR for this group consisted of 9 CRs (53%), 2 CRis (12%), and 6 PRs (35%).

Seventy-one percent of those receiving prior idelalisib (n = 7) were MRD-negative in the peripheral blood and 43% tested MRD-negative in the BM. Forty-three percent (n = 3) had a CR and the remainder had a PR.

The most common adverse event (AE) of interest was bruising (n = 33), which has been associated with ibrutinib. Most of these events were grade 1 in severity. Additionally, 16 cases of grade 3 neutropenia were seen in the study, with 25 total reports of neutropenia. Other AEs of interest included sub-conjunctival hemorrhage (n = 3) and respiratory, thoracic, and mediastinal disorders (n = 1).

One patient experienced tumor lysis syndrome (TLS) at an early 200-mg dose of venetoclax. The treatment was delayed until this AE cleared up and then was rapidly re-escalated with no further TLS. There was a recommendation in the trial to co-administer granulocyte-colony stimulating factor (G-CSF), to keep neutrophil counts above 1 x 10⁹/L. Overall, 7 patients received this intervention.

"We have not seen an increase in the rate of TLS with the combination regimen compared with what we would expect to see with venetoclax single-agent therapy," Hillmen said. "Predicable side effect were almost all minor. GI or neutropenia events were most common."

The phase III FLAIR trial is currently enrolling patients to further explore the combination of ibrutinib and venetoclax in the frontline setting. The combination is being compared with ibrutinib alone or FCR.

Hillmen P, Munir T, Rawstron A, et al. Initial Results of Ibrutinib Plus Venetoclax in Relapsed, Refractory CLL (Bloodwise TAP CLARITY Study): High Rates of Overall Response, Complete Remission and MRD Eradication after 6 Months of Combination Therapy. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 428.