Combination Ibrutinib plus Venetoclax for Relapsed/Refractory CLL: Long-Term Follow-Up Data

The phase 2 CLARITY trial evaluates combination treatment with ibrutinib plus venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) to eradicate detectable disease. Following confirmation of complete remission, treatment is discontinued. Investigators reported treatment responses at the 38-month time point.

In the CLARITY study, 50 patients with relapsed or refractory CLL were treated with ibrutinib for 2 months, after which venetoclax was added.¹ Paired peripheral blood and bone marrow samples were assessed at 8, 14, and 26 months, and longitudinal peripheral blood samples were taken at multiple time points. Between May 2016 and November 2017, 54 patients were recruited. Of these, 20% had 17p deletion, 25% had 11q deletion, and 75% had unmutated IGHV. Treatment was discontinued in 4 patients due to ibrutinib-related adverse events occurring prior to adding venetoclax.

In total, 50 patients received combination ibrutinib and venetoclax treatment. Interruption of therapy was indicated following confirmation of complete remission according to iwCLL2008 criteria and minimal residual disease (MRD) of less than 10^-4 CLL cells in peripheral blood and bone marrow (MRD4). Treatment cessation was indicated if MRD4 was present upon assessment at month 8, 14, or 26. If MRD was detectable at month 26, only venetoclax was stopped and ibrutinib was continued until progression or toxicity. The protocol was amended in January 2019 to allow patients who had not achieved MRD4 at month 26 to receive 12 months of venetoclax in addition to ibrutinib.

Of the 50 patients who received the combination of ibrutinib and venetoclax, 27 stopped treatment at or before 38 months. Of these, 17 achieved MRD4. As of the 38-month assessment, 23 of the 50 enrolled patients were still receiving at least 1 trial treatment, with response data still pending for 11 patients. Of the 23 evaluable patients remaining on treatment at month 38, the overall response rate was 85%, compared with 94% among the 32 patients receiving at least 1 trial treatment at month 26.

After the first year of combination treatment, MRD responses continued to improve. Almost half of patients (24/50) had achieved MRD4 in the bone marrow at month 26, compared with 40% (20/50) at month 14. After 4 months of combination treatment, the median log CLL depletion was 2.9 for patients who were MRD-negative at month 26, compared with 1.4 for patients who were MRD-positive at month 26.

Neutropenia was the most common side effect among study participants. Of 37 cases of neutropenia reported, 3 were grade 2 and 34 were grade 3/4. A total of 44 serious adverse events and 1153 adverse events were reported. Two unexpected serious adverse reactions were reported. One case of biochemical tumor lysis syndrome occurred among participants. Two cases of COVID-19 were reported and both patients are in stable condition and have been discharged from the hospital.

After 38 months, the response to combination therapy with ibrutinib and venetoclax is sustained, despite planned discontinuation of therapy in patients who are MRD-negative. Researchers note that the initial rate of disease depletion during the first 2 months of combination treatment is highly predictive of longer-term response in patients with relapsed or refractory CLL.

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Reference

1. Munir T, Boucher RH, Webster N, et al. Continued Long Term Responses to Ibrutinib + Venetoclax Treatment for Relapsed/Refractory CLL in the Blood Cancer UK TAP Clarity Trial. American Society of Hematology 62nd Annual Meeting and Exposition. Abstract 124.