A phase 2 study of zanubrutinib in combination with rituximab and lenalidomide in de novo diffuse large B-cell lymphoma
Mené sur 40 patients âgés de plus de 75 ans et atteints d'un lymphome diffus à grandes cellules B de novo, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse complète, et la toxicité d'un traitement combinant zanubrutinib, rituximab et lénalidomide
Older patients with diffuse large B cell lymphoma (DLBCL) present unfavorable genetic and microenvironmental alterations. In this phase 2 trial, we assessed the efficacy and safety of zanubrutinib in combination with rituximab and lenalidomide (ZR2) in patients with de novo DLBCL aged ≥75 years (NCT04460248). Forty patients were enrolled, and the primary endpoint was complete response rate, which was 65.0% (95% confidence interval [CI]: 48.3-78.9) at the end of induction treatment. The 2-year progression-free and overall survival rates were 67.1% (95% CI: 50.1-79.4) and 82.4% (95% CI: 66.5-91.2). The most common grades 3 and 4 hematologic adverse event (AE) was neutropenia (n = 14; 35.0%). The most common grades 3 and 4 non-hematologic AEs were increased alanine transaminase (n = 5; 12.5%) and aspartate transaminase level (n = 5; 12.5%), and pulmonary infection (n = 5; 12.5%). No events of atrial fibrillation were observed. Importantly, the efficacy of ZR2 was more dependent on tumor microenvironmental than genetic alterations, in association with up-regulation of Class I and II human leukocyte antigen, increased number and function of conventional type 1 dendritic cells. Pre-existing expansion of intra-tumoral CD8+T cells and treatment-induced clonal T-cell receptor (TCR) repertoire contributed to better clinical outcome. TCR sequencing of the peripheral blood mononuclear cell samples from patients with durable remission detected the expanded T cell clones 3 years post-treatment. These findings thus provided better understanding of T-cell immunological memory effect on immunotherapy as ZR2, and a paradigm shift in the era of mechanism-based targeted therapy of aggressive lymphoma.
Blood , résumé, 2025