A Phase II Investigator Initiated Study of Acalabrutinib, Lenalidomide and Rituximab (aR2) in Patients with Previously Untreated High Tumor Burden Follicular Lymphoma

Abstract

Background: The efficacy of lenalidomide and rituximab (R2) is comparable to chemoimmunotherapy in patients with previously untreated follicular lymphoma (FL). We previously reported pro-tumoral macrophage enrichment may be associated with resistance to R2. As pre-clinical studies show that BTK inhibition can mitigate the crosstalk between macrophages and FL B cells, we hypothesized that acalabrutinib, a specific BTK inhibitor, may synergize with R2 without increasing toxicity. In agreement with this, the combination of acalabrutinib and R2 (aR2) was shown to be safe and effective in patients with relapsed FL. Methods: This phase 2 single arm study (NCT04404088) was conducted between 09/2020 and 09/2021 (data cutoff 02/2023). Adult patients with previously untreated FL, grade 1 to 3A, stage 3–4, and with high tumor burden (per GELF criteria) were included. Dosing included acalabrutinib 100 mg PO twice a day in a 28-day cycle for 13 cycles, lenalidomide 20 mg PO daily on days 1–21, starting from cycle 2, and rituximab 375 mg/m2 IV weekly during cycle 2, and on day 1 of subsequent cycles. Response was assessed per Lugano 2014 criteria. The primary endpoint was best complete response (CR) rate, and an exact binomial test was used for sample size calculation (N = 24; H0 50%, HA 80%, power 80%, 2-sided alpha level 0.05). Results: Twenty-four patients were enrolled. Median age was 62 years (range, 40–82), 18 (75%) were male; median largest lymph node size was 6.2 cm (range, 1.9–15), median SUVmax was 14 (range, 6–36), and 17 (61%) patients had an intermediate-high FLIPI. Median number of cycles was 13 (range, 6–13) and 15 (62.5%) patients experienced a cycle delay, due to COVID-19 in 11 (46%) cases; 6 (25%) patients required dose reduction of lenalidomide, but none discontinued, and 2 (8%) required dose reduction of acalabrutinib and 1 discontinued. The most common (>5% of patients) grade 3–4 adverse events were neutropenia (58%), liver function test elevation (17%), infection (12.5%; 2 out of 3 related to COVID-19), anemia (8%) and skin rash (8%). Best ORR was 100% and best CR rate was 92%, as early as after 6 cycles (Figure). After a median follow-up of 22 months (95% CI: 20–24 months), 4 patients had disease progression, including 2 who transformed at 5 and 7 months, while in partial response (both with pre-treatment bulky disease and SUVmax >17), and 1 who transformed at end of treatment, after initial CR. The 2-year PFS rate was estimated at 79% (95% CI, 56%–91%). At data cutoff, 2 patients have died, 1 due to COVID-19 (while in CR, at 14 months) and 1 due to transformed lymphoma (at 10 months), both 4 months after study discontinuation. The 2-year OS rate was estimated at 92% (95% CI, 71%–98%) (Figure). Encore Abstract - previously submitted to EHA 2023 The research was funded by: Astrazeneca Keyword: Targeting the Tumor Microenvironment Conflicts of interests pertinent to the abstract. P. Strati Consultant or advisory role: PS served on advisory boards for Astrazeneca Research funding: PS received research funding from Astrazeneca for this study