Time-Limited Acalabrutinib/Obinutuzumab Produces Durable Responses in Treatment-Naive CLL

Time-limited treatment with the combination of acalabrutinib (Calquence) and obinutuzumab (Gazyva) led to responses in patients with treatment-naive chronic lymphocytic leukemia, according to data from a phase 2 trial (NCT04505254) presented at the 2024 EHA Congress.¹

Findings showed the overall response rate (ORR) was 100% in efficacy-evaluable patients at 8 months (n = 21), 14 months (n = 15), and 24 months (n = 12). At 24 months, 67% of patients achieved a complete response (CR). In the 12 patients who completed 24 cycles, 75% of patients remained in remission at a median follow-up of 7 months following treatment discontinuation. Three of these patients experienced disease progression, including 1 who required retreatment.

“Ongoing correlative studies and longer follow-up will define which patient characteristics are associated with long remissions after time-limited therapy with acalabrutinib plus obinutuzumab. This may help define for whom this therapy approach could become an alternative to current recommendation for continuous therapy with BTK inhibitors,” lead study author Jan A. Burger, MD, PhD, and colleagues, wrote in a poster presentation of the data.

Burger is a tenured professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston. He is also the Privatdozent lecturer in internal medicine at the Albert-Ludwigs University School of Medicine in Freiberg, Germany.

The phase 2, open-label, single-arm, single-center trial being conducted at MD Anderson enrolled patients at least 18 years of age with treatment-naive CLL or small lymphocytic lymphoma who were indicated for treatment per 2018 International Workshop on CLL Criteria. Patients were required to have an ECOG performance status of 0 to 2 and adequate renal and hepatic function.²

All enrolled patients (n = 28) received 100 mg of acalabrutinib twice per day starting on day 1 of the first 28-day cycle and continued for up to 24 cycles. Obinutuzumab was given as a once-per-month infusion starting in cycle 3 and continued for 6 cycles. Patients who achieved a CR after cycle 8 continued acalabrutinib monotherapy, and those with a partial response or stable disease received 6 additional cycles of combination therapy. Acalabrutinib was given as monotherapy after cycle 14 in all patients. All patients discontinued treatment after 24 cycles, and in patients who experienced disease progression after discontinuing therapy, retreatment was allowed.¹

The study’s primary end point was the durability of treatment-free remissions following 24 cycles of therapy. Secondary end points include evaluating the efficacy of retreatment and identifying factors associated with prolonged remission.

The median patient age of all enrolled patients was 65 years (range, 40–83), and the majority of patients were male (61%). Per the Rai staging system, 4% of patients had low-risk disease, 39% had intermediate-risk disease, and 57% had high-risk disease. Fifty-seven percent of patients harbored IGHV mutations. Other cytogenetics included 17p deletions (4%), 11q deletions (7%), trisomy 12 (25%), and 13q deletions (50%). Fourteen percent of patients had normal cytogenetics. The median beta-2 microglobulin was 3.9 mg/L (range, 2.2-9.6), and the median absolute lymphocyte count was 35.9 K/µL (range, 3.6-188.4).

At a median follow-up of 21 months, 25 patients (89%) remained on the study. One patient died from bacterial pneumonia at cycle 3, and two others withdrew due to recurrent infections. The estimated two-year progression-free survival (PFS) and overall survival (OS) rates were 95.8%.

Bone marrow infiltration by CLL cells significantly decreased from a median of 84.2% at baseline to 0.1% after 24 cycles of therapy, and 4 patients achieved undetectable minimal residual disease.

References

1. J. Burger, Kim E, Lopez W, et al. A phase II study of time-limited treatment with acalabrutinib plus obinutuzumab in patients with treatment-naïve chronic lymphocytic leukemia. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract P1841.
2. Acalabrutinib and obinutuzumab for the treatment of chronic lymphocytic leukemia. ClinicalTrials.gov. Updated April 2, 2024. Accessed July 24, 2024. https://clinicaltrials.gov/study/NCT04505254