Photo Credit: Ponchai Soda
The following is a summary of “Addition of Acalabrutinib to Lenalidomide and Rituximab Induces High Complete Response Rates in Patients with Previously Untreated Follicular Lymphoma: Results of a Phase II Study,” published in the December 2023 issue of Hematology by Strati et al.
Follicular lymphoma (FL) patients who respond poorly to lenalidomide and rituximab (R 2) treatment may have increased pro-tumoral macrophages. Acalabrutinib, a specific BTK inhibitor, has been shown to mitigate the interaction between macrophages and FL B cells, suggesting a potential synergy with the combination of acalabrutinib and R 2 (aR 2).
Researchers initiated a retrospective study to assess the safety and efficacy of aR2 in previously untreated FL patients and evaluate its biological effects on peripheral blood immune cells.
They conducted a Phase 2 study (NCT04404088) from September 2020 to September 2021, with a data cutoff in June 2023. Adults with previously untreated FL, grades 1 to 3A, stages 3-4, meeting GELF criteria were included. Patients received acalabrutinib at a dose of 100 mg orally twice daily for 14 cycles. Lenalidomide was administered at 20 mg orally daily on days 1-21 of cycles 2-14. R2 was administered at 375 mg/m2 intravenously weekly during cycles 2 and 3. The primary endpoint assessed the best CR rate per Lugano 2014 criteria. Blood samples were collected at the beginning of the study and on day 1 of cycles 2 and 6 to analyze immune cells.
The results showed 24 patients with baseline characteristics. Median cycles were 13 (range, 6-13), and 62.5% experienced cycle delays, primarily due to COVID-19 in 46% of cases. Lenalidomide dose reduction was needed for 25%, while none was discontinued. Acalabrutinib dose reduction occurred in 8%, with one patient discontinuing. Grade 3-4 adverse events (>5% of patients) included neutropenia (58%), liver function test elevation (17%), infection (12.5%; 2 of 3 related to COVID-19), anemia (8%), and skin rash (8%). The treatment showed high efficacy with a complete response rate of 92%, a median time to complete response of 3 months, and a 2-year progression-free survival rate of 79.2%. The 2-year overall survival rate was 91.7%.
Acalabrutinib + R2 treatment resulted in a significant decrease in VMO1 expression (FDR 0.001). VMO1 is a gene that encodes a protein on extracellular exosomes from non-classical monocytes. Additionally, there was a significant rise in gene signatures related to monocyte proliferation (P=0.01), TNF response (P=0.01), anti-viral (P=0.006), and anti-tumoral activity (P=0.009), aligning with the expected effects of BTK inhibition in monocytes. After 5 cycles of aR2, a drop in the frequency of circulating B cells (P=0.003) and regulatory NK cells (P=0.01) occurred, alongside 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).
They concluded that acalabrutinib combined with R2 achieved high CR rates in FL patients and triggered favorable immune changes, prompting a study amendment for shorter treatment.
Source: ash.confex.com/ash/2023/webprogram/Paper180762.html
