Ibrutinib/Venetoclax Combination Achieves High Rate of MRD Negativity in Relapsed/Refractory CLL

Peter Hillmen, MD, PhD

The combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) is well tolerated and eradicates minimal residual disease (MRD) in the marrow after 12 months in 39% of patients with relapsed/refractory chronic lymphocytic leukemia (CLL).

In a presentation at the 2018 American Society of Hematology meeting, Peter Hillmen, MD, professor of experimental hematology and honorary consultant hematologist at Leeds Teaching Hospitals NHS Trust, United Kingdom, reported that >90% of patients in the phase II CLARITY study achieved objective response. After 12 months of treatment with ibrutinib/venetoclax, 54% of patients are in complete remission (CR) or CR with incomplete marrow recovery (CRi), he added.

“The results of CLARITY are certainly very encouraging with deep remissions in relapsed/refractory patients, and the early signs are that we can stop treatment in patients who achieve MRD eradication,” he said.

As single agents, ibrutinib and venetoclax both significantly improve survival in CLL, but rarely lead to eradication of MRD. CLARITY (NCT02267590) is a feasibility study designed to investigate the safety and efficacy of ibrutinib combined with venetoclax in patients with relapsed or refractory CLL. The primary endpoint was MRD eradication (<0.01% CLL cells) in the marrow after 12 months of treatment.

“We believe in the UK Group that we should be designing trials guided by MRD eradication, so stopping treatment as appropriate,” he said.

Patients received 8 weeks of ibrutinib monotherapy, 420 mg/day, after which venetoclax was added at a dose of 10 mg/day with weekly escalations to 20 mg, 50 mg, 100 mg, 200 mg, and a final dose of 400 mg/day. No TLS was observed for the first 3 patients starting venetoclax at 10 mg/day, so subsequent patients began at 20 mg/day.

Both agents were stopped at month 14 if the patient was MRD-negative at month 8. If the patient was MRD-positive at month 8, treatment was stopped at month 26 with MRD negativity achieved at month 14 or month 26. If patients were MRD positive at month 26, ibrutinib monotherapy was continued.

The study enrolled 54 patients, 4 of whom stopped ibrutinib before adding venetoclax due to toxicity. The median patient age was 64 years (range, 31-83). Ten (20%) patients had 17p del, 13 (25%) had 11q del but not 17p. IGHV genes were unmuated in 40 (74%) patients.

The median number of previous therapies was 1 (range, 1-6). Twenty two (50%) of 44 patients relapsed within 3 years of refractory to fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR), and 11 (20%) received prior idelalisib (Zydelig).

Results were reported at the data lock on November 5, 2018. A total of 49 of the 50 patients passed through the venetoclax escalation phase and reached at least month 14. Of the 49 patients, 28 (57%) achieved undetectable MRD in peripheral blood and 19 (39%) were MRD negative in the bone marrow after 12 months of combined ibrutinib and venetoclax. Nine of 25 (36%) patients achieved MRD with CLL cells <0.001% in the marrow after 24 months of ibrutinib plus venetoclax. Thirty-nine (81%) patients had no morphologic evidence of CLL in the bone marrow biopsy.

Of the 20 patients who were refractory to FCR or BR, 14 (70%) had undetectable MRD in peripheral blood and 9 (45%) achieved MRD negativity in bone marrow. Of the 9 patients treated previously with idelalisib, MRD negativity in peripheral blood was achieved in 6 (67%) and undetectable MRD in bone marrow was achieved in 5 (56%).

Most toxicities were grade 1/2, with gastrointestinal disorders, musculoskeletal/connective tissue disorders, and skin and subcutaneous tissue disorders being most common. Adverse events (AEs) of special interest included bruising/hematoma in 40 patients, 39 of which were grade 1/2, and neutropenia in 37 patients, 24 grade 3 and 10 grade 4.

There was a single case of laboratory tumor lysis syndrome at the 200-mg dose level of venetoclax that resolved following dose delay. Ibrutinib was delayed in 2 patients and interrupted in 31, with dose reductions due to toxicity or serious AEs necessary for 4 patients. Venetoclax was interrupted in 37 patients, 14 due to neutropenia and 6 due to diarrhea, and was delayed in 5 others. Eighteen patients required venetoclax dose reduction.

Hillman P, Rawstron A, Brock K, et al. Ibrutinib plus venetoclax in relapsed/refractory CLL: results of the Bloodwise TAP Clarity Study. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego, CA. Abstract 182.

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