Acalabrutinib Triplet Demonstrates High Response and Manageable Safety in Frontline Follicular Lymphoma

The addition of acalabrutinib (Calquence) to lenalidomide (Revlimid) and rituximab (Rituxan), a regimen known as aR², was a safe and effective frontline nonchemotherapy regimen for patients with follicular lymphoma (FL), according to Paolo Strati and colleagues, who reported findings in Nature Communications.¹ The combination yielded a best objective response rate (ORR) of 100% and a best complete response (CR) rate of 92%.¹

The phase 2 single arm study (NCT04404088) evaluated 31 patients with previously untreated FL. Twenty-four patients were enrolled in the trial. After a median follow-up of 43 months (95% CI, 41–47), 8 patients relapsed or progressed. At follow-up, median progression-free survival (PFS) was not reached, the 2-year PFS rate was 79% (95% CI, 65%–97%), and the 3-year PFS rate was 62% (95% CI, 45%–85%).

All patients received 100 mg of acalabrutinib twice a day, 20 mg of lenalidomide daily on days 1 to 21, and 375 mg/m² of rituximab weekly. Treatment was repeated every 28 days for 13 cycles in the absence of disease progression or unacceptable toxicity. The primary end point was best CR rate measured by PET-CT, including CR achieved during treatment; CT-based responses were also prospectively collected. Secondary end points included safety, tolerability, and ORR.

Although the combination of lenalidomide and rituximab (R²) is recommended by the National Comprehensive Cancer Network guidelines, it lacks FDA approval in the frontline setting because of a lack of evidence of superiority over chemoimmunotherapy. The investigators hypothesized that adding the more selective BTK inhibitor acalabrutinib could enhance efficacy by modulating the tumor microenvironment and providing direct anti-lymphoma activity, without the off-target toxicity that has hampered other BTK inhibitors in combination with R².

The regimen induced rapid and deep responses. The CR rate increased from 62.5% after 3 cycles to 92% after 6 cycles, leading to the best ORR of 100%. After a median follow-up of 43 months, the median progression-free survival (PFS) was not reached. The 2-year PFS rate was 79%, and the 3-year PFS rate was 62%. The rate of progression of disease within 24 months (POD24) was 17%.

An exploratory analysis using the highly sensitive PhasED-seq assay for minimal residual disease (MRD) revealed that 73% of patients achieved MRD eradication in the blood after 6 cycles of therapy. MRD status was strongly prognostic: 83% of patients with detectable MRD at 6 cycles relapsed, compared with only 19% of those who achieved MRD eradication. Landmark analysis showed that patients with undetectable MRD had a significantly longer relapse-free survival.

At most recent follow-up, 5 (83%) of 6 patients with detectable minimal residual disease (MRD) after 6 cycles have relapsed or progressed, whereas 1 patient with detectable MRD after 6 cycles remains in CR after 32 months. Thirteen (81%) of 16 patients without detectable MRD after 6 cycles remain in CR, and 3 have relapsed after 12, 28, and 29 months (P =.01).

At baseline, patients were a median age was 62 years (range, 40–82 years), 75% were male, and 92% were White. The median largest lymph node size at baseline was 6.3 cm (range, 1.9–15 cm), 71% of patients had an intermediate or high FL International Prognostic Index (FLIPI) score, and the median standardized uptake volume was 14 (range, 6.3–35.9). Most patients (92%) had FL grade 1 to 2 and half of the patients had bone marrow involvement.

Regarding safety, the most commonly reported adverse events (AE) of any grade were neutropenia (91%), anemia (83%), fatigue (79%), thrombocytopenia (67%) and headache (58%). Most were grade 2 or less with the exception of neutropenia. Grade 3 or greater neutropenia was observed in 58% of patients and 58% of patients required growth factor support. No patient experienced neutropenic fever.

The second most frequent grade 3 or greater AEs were elevated liver function levels for alanine aminotransferase (17%) and aspartate aminotransferase (12.5%).

The investigators concluded that the high response rates, early MRD eradication, and manageable safety profile of frontline aR² justify its further exploration in larger, randomized trials, potentially challenging the current paradigm of frontline therapy for high-risk FL.

REFERENCES:

1. Strati P, Feng L, Westin JR, et al. Frontline acalabrutinib, lenalidomide and rituximab for advanced stage follicular lymphoma with high tumor burden: phase II trial. Nat Commun. 2025;16(1):7300. Published 2025 Aug 7. doi:10.1038/s41467-025-62509-z

2. Strati, P. et al. Pre-treatment maximum standardized uptake value predicts outcome after frontline therapy in patients with advanced stage follicular lymphoma. Haematologica 105, 1907–1913 (2020).