Background. We previously reported pro-tumoral macrophages may be associated with resistance to lenalidomide and rituximab (R 2) treatment in follicular lymphoma (FL) ( Marques-Piubelli, Blood Adv 2022). As pre-clinical studies suggest that BTK inhibition can mitigate the crosstalk between monocyte/macrophages and FL B cells, we hypothesized that acalabrutinib, a specific BTK inhibitor, may synergize with R 2 without increasing toxicity. In agreement with this, the combination of acalabrutinib and R 2 (aR 2) was shown to be safe and effective in patients with relapsed FL ( Strati P et al, ASH 2022). Here, we investigated the safety and efficacy of aR 2 in previously untreated FL patients and analyzed the biological effects of this combination on peripheral blood immune cells.

Methods. This phase 2 single arm study (NCT04404088) was conducted between 09/2020 and 09/2021 (data cutoff 06/2023). Adult patients with previously untreated FL, grades 1 to 3A, stage 3-4, and meeting indication for treatment per GELF criteria were included. Treatment consisted of acalabrutinib lead-in at 100 mg PO twice a day for one 28-day cycle and continued for total of 13 cycles, lenalidomide 20 mg PO daily on days 1-21, during cycle 2-13, and rituximab 375 mg/m 2 IV weekly during cycle 2, and on day 1 of cycle 3-13. The primary endpoint was best complete response (CR) rate per Lugano 2014 criteria. Bulk RNA sequencing with deconvolution to characterize circulating immune cells was performed on peripheral blood collected at baseline, and on day 1 of cycles 2 and 6.

Results. We enrolled and treated 24 patients. Baseline characteristics are shown in the Table. Median number of cycles was 13 (range, 6-13) and 15 (62.5%) patients experienced a cycle delay, due to COVID19 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 COVID19), anemia (8%) and skin rash (8%).

Best ORR was 100%, best CR rate was 92%, and median time to CR was 3 months ( Figure). After a median follow-up of 26.8 months (95% CI 24.6-29.6 months), 6 (25%) patients had disease progression, including 2 who transformed at 5 and 7 months. The 2-year PFS rate was 79.2% (95% CI, 64.5-97.2%). At data cutoff, 2 patients have died, 1 due to COVID19 (while in CR, at 14 months) and 1 due to transformed lymphoma (at 10 months). The 2-year OS rate was 91.7% (95% CI, 81.3-100%).

While the frequency of circulating immune cells were unchanged after single agent acalabrutinib, its use associated with a significant decrease in the expression of VMO1 (FDR 0.001), a gene encoding for a protein expressed on extra-cellular exosomes derived from non-classical monocytes, and a significant increase in gene signatures of monocyte proliferation (p=0.01), TNF response (p=0.01), anti-viral (p=0.006) and anti-tumoral activity (p=0.009), consistent with the expected effect of BTK inhibition in monocytes. After 5 cycles of aR 2, we observed a decrease in the frequency of circulating B cells (p=0.003) and regulatory NK cells (p=0.01), and an increase in the frequency of circulating naive T cells (p=0.004), CD4+ T cells (p=0.005) and classical monocytes (p=0.003).

Conclusion. Our results indicate that the addition of acalabrutinib to R 2 is a safe and effective frontline non-chemotherapy regimen for FL patients, resulting in high CR rates, and induces favorable biological changes in multiple circulating immune cells. Since CRs occurred early, the study has been amended to include 26 additional patients who will be treated with only 6 cycles of aR2.

Strati:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astrazeneca Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hutchinson MedoPharma: Consultancy; Kite Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Genentech: Consultancy. Westin:Calithera: Research Funding; Nurix: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; SeaGen: Consultancy; Abbvie: Consultancy; ADC Therapeutics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Kite/Gilead: Consultancy, Research Funding; Morphosys/Incyte: Consultancy, Research Funding; Kymera: Research Funding; MonteRosa: Consultancy. Turova:Bostongene: Current Employment. Zaitsev:Illumina: Current equity holder in publicly-traded company; Adaptive Biotechnology: Current equity holder in publicly-traded company; BostonGene: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Patents & Royalties: Patents. Wang:Bostongene: Current Employment. Flowers:Burroghs Wellcome Fund: Research Funding; Ziopharm: Research Funding; Xencor: Research Funding; TG Therapeutics: Research Funding; Takeda: Research Funding; Sanofi: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Nektar: Research Funding; Morphosys: Research Funding; Kite: Research Funding; Jannsen Pharmaceuticals: Research Funding; Iovance: Research Funding; Guardant: Research Funding; Cellectis: Research Funding; Amgen: Research Funding; Allogene: Research Funding; Adaptimmune: Research Funding; Acerta: Research Funding; 4D: Research Funding; Spectrum: Consultancy; SeaGen: Consultancy; Pharmacyclics Jansen: Consultancy; N-Power Medicine: Consultancy, Current holder of stock options in a privately-held company; Karyopharm: Consultancy; Gilead: Consultancy, Research Funding; Genmab: Consultancy; Genentech Roche: Consultancy, Research Funding; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Denovo Biopharma: Consultancy; Celgene: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Beigene: Consultancy; Abbvie: Consultancy, Research Funding; CPRIT Scholar in Cancer Research: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding. Nastoupil:Gilead Sciences/Kite Pharma: Honoraria, Research Funding; AstraZeneca: Honoraria; Regeneron: Honoraria; Genentech, Inc., Genmab, Gilead/Kite, Janssen, Merck, Novartis, Takeda: Honoraria, Research Funding; AbbVie: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; DeNovo: Honoraria; Caribou Biosciences: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; ADC Therapeutics: Honoraria. Neelapu:Precision Biosciences: Research Funding; Takeda: Consultancy, Other: Advisory board member; Carsgen: Consultancy; Orna Therapeutics: Consultancy, Other: Advisory board member; Janssen: Consultancy, Other: Advisory board member; Immunoadoptive Cell Therapy Private Limited: Consultancy, Other: Scientific Advisory Board; Chimagen: Consultancy, Other: Advisory board member; Kite, A Gilead Company: Consultancy, Other: Advisory Board Member, Research Funding; Allogene: Consultancy, Other: Advisory board member, Research Funding; Incyte: Consultancy, Other: Advisory board member; Athenex: Consultancy, Other: Advisory board member; Astellas Pharma: Consultancy, Other: Advisory board member; Sellas Life Sciences: Consultancy, Other: Advisory board member; Morphosys: Consultancy, Other: Advisory board member; Merck: Consultancy, Other: Advisory Board Member; Adicet Bio: Consultancy, Other: Advisory board member, Research Funding; Caribou: Consultancy, Other: Advisory board member; Bristol Myers Squibb: Consultancy, Other: Advisory Board Member, Research Funding; Fosun Kite: Consultancy, Other: Advisory board member; Sana Biotechnology: Consultancy, Other: Advisory board member, Research Funding; Longbow Immunotherapy: Current holder of stock options in a privately-held company; Bluebird Bio: Consultancy, Other: Advisory board member; Synthekine: Consultancy, Other: Advisory board member; N/A: Patents & Royalties: Related to cell therapy and the safety switch described (intellectual property).

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2023
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