Acalabrutinib Plus Bendamustine and Rituximab Displays Long-Term Activity in Frontline and R/R MCL

Acalabrutinib (Calquence) plus bendamustine and rituximab (Rituxan; BR) was safe and effective in patients with treatment-naive and relapsed/refractory mantle cell lymphoma (MCL), according to findings from the final analysis of the phase 1b ACE-LY-106 study (NCT02717624) published in Haematologica.1

At a median follow-up of 47.6 months (range, 0.6-72.4) in the treatment-naive cohort (n = 18), the median overall survival (OS) was not estimable (NE; 95% CI, 26.0-NE); the 12- and 36-month OS rates were 88.9% (95% CI, 62.4%-97.1%) and 74.6% (95% CI, 45.0%-89.8%). The median progression-free survival (PFS) was NE (95% CI, 16.4-NE); the 12- and 36-month PFS rates were 88.5% (95% CI, 61.4%-97.0%) and 68.1% (95% CI, 39.2%-85.4%), respectively.

In the relapsed/refractory cohort (n = 20), at a median follow-up of 20.4 months (range, 1.2-64.2), the median OS was NE (95% CI, 16.6-NE); the 12- and 36-month OS rates were 88.7% (95% CI, 61.4%-97.1%) and 69.7% (95% CI, 41.5%-86.2%), resepectively. The median PFS was 28.6 months (95% CI, 11.8-NE); the 12- and 36-month PFS rates were 73.0% (95% CI, 46.7%-87.8%) and 47.3% (95% CI, 22.6%-68.6%), respectively.

“The greater specificity of acalabrutinib was the basis of the current study hypothesis, which confirmed that adding acalabrutinib to BR could produce durable remission without new safety signals,” Tycel Phillips, MD, associate professor, Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope in Duarte, California, and his coauthors wrote in the study publication.

In January 2025, the FDA approved acalabrutinib in combination with BR for the treatment of adult patients with treatment-naive MCL who are ineligible for autologous hematopoietic stem cell transplantation (HSCT).2 The regulatory decision was supported by findings from the phase 3 ECHO trial (NCT02972840), which showed that patients who received the triplet achieved a significant PFS benefit compared with those treated with placebo plus BR (HR, 0.73; 95% CI, 0.57-0.94; P = .016). ECHO was initiated based on prior findings from ACE-LY-106.1

Baseline Patient Characteristics and Study Design

ACE-LY-106 was a multicenter, open-label study that enrolled patients with MCL harboring translocation t(11;14)(q13;q32) and/or overexpressed cyclin D1 and an ECOG performance status of 2 or less. Patients in the relapsed/refractory cohort received at least 1 prior therapy; those who received a prior BTK or BCL-2 inhibitor were excluded, as were patients with significant cardiovascular disease.

Patients received oral acalabrutinib at a dose of 100 mg twice daily from the first day of the first cycle until disease progression or intolerance. Intravenous bendamustine was administered at 90 mg/m2 over a 30-minute period on days 1 and 2 of each 28-day cycle for a maximum of 6 cycles. Rituximab 375 mg/m2 was given on day 1 of each cycle for 6 cycles. Patients in the treatment-naive cohort who experienced a response continued rituximab therapy every other cycle for up to 12 doses beginning at cycle 8.

The primary end point was safety. Secondary end points included overall response rate (ORR), duration of response (DOR), and PFS.

At baseline, the median age in the overall population (n = 38) was 65.5 years (range, 47-86). Most patients were male (63.2%), had an ECOG performance status of 1 or less (97.4%), had Ann Arbor stage IV disease (92.1%), and bone marrow involvement (63.2%). Patients had Mantle Cell Lymphoma Prognostic Index (MIPI) low- (28.9%), intermediate- (50.0%), or high-risk disease (13.2%); 7.9% of patients had missing MIPI score information. Blastoid MCL was present in 10.5% of patients.

Further Safety and Efficacy Data

The investigator-assessed ORR per Lugano criteria was 94.4% (95% CI, 72.7%-99.9%) in the treatment-naive cohort, with a complete response (CR) rate of 77.8%. These respective rates were 85.0% (95% CI, 62.1%-96.8%) and 70.0% in the relapsed/refractory cohort. The median DOR was not reached and 43.5 months, respectively.

In terms of safety, common any-grade treatment-related adverse effects (AEs) in the overall population included infections (73.7%), neutropenia (60.5%), and nausea (57.9%). Any-grade serious adverse effects (SAEs) occurred in 61.1% and 65.0% of patients in the treatment-naive and relapsed/refractory cohorts, respectively. Five patients died in the treatment-naive cohort and 6 died in the relapsed/refractory cohort.

At study completion, 26.3% of patients overall remained on acalabrutinib treatment. Reasons for study discontinuation included death (26.3%), disease progression (13.2%), withdrawal of consent (5.3%), withdrawal by investigator (5.3%), AEs/SAEs (7.9%), or other reasons (15.8%).

“The safety profile of acalabrutinib plus BR is consistent with expectations for the individual agents in the combination regimen,” the study authors wrote in their conclusion. “Acalabrutinib plus BR demonstrated high efficacy in patients with treatment-naive and relapsed/refractory MCL. Nonetheless, the limited sample size presents a constraint in fully interpreting certain observations. The study findings support the further exploration of acalabrutinib plus BR in patients with treatment-naive MCL in the ongoing, placebo-controlled phase 3 ECHO trial, which aims to confirm the safety profile and efficacy of long-term acalabrutinib plus BR.”

References

1. Phillips T, Wang M, Robak T, et al. Safety and efficacy of acalabrutinib plus bendamustine and rituximab in patients with treatment-naïve or relapsed/refractory mantle cell lymphoma: phase Ib trial. Haematologica. 2025;110(3):715-724. doi:10.3324/haematol.2023.284896
2. FDA approves acalabrutinib with bendamustine and rituximab for previously untreated mantle cell lymphoma. FDA. January 16, 2025. Accessed March 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-acalabrutinib-bendamustine-and-rituximab-previously-untreated-mantle-cell-lymphoma