Targeting MCL-1 and BCL-2 with polatuzumab vedotin and venetoclax overcomes treatment resistance in R/R non-Hodgkin lymphoma: Results from preclinical models and a Phase Ib study

Lasater, EA; Amin, DN; Bannerji, R; Mali, RS; Barrett, K; Rys, RN; Oeh, J; Lin, E; Sterne-Weiler, T; Ingalla, ER; Go, M; Yu, SF; Krem, MM; Arthur, C; Hahn, U; Johnston, A; Karur, V; Khan, N; Marlton, P; Phillips, T; Gritti, G; Seymour, JF; Tani, M; Yuen, S; Martin, S; Chang, MT; Rose, CM; Pham, VC; Polson, AG; Chang, Y; Wever, C; Johnson, NA; Jiang, Y; Hirata, J; Sampath, D; Musick, L; Flowers, CR; Wertz, IE

Author(s): Lasater, EA; Amin, DN; Bannerji, R; Mali, RS; Barrett, K; Rys, RN; Oeh, J; Lin, E; Sterne-Weiler, T; Ingalla, ER; Go, M; Yu, SF; Krem, MM; Arthur, C; Hahn, U; Johnston, A; Karur, V; Khan, N; Marlton, P; Phillips, T; Gritti, G; Seymour, JF; Tani, M; Yuen, S; Martin, S; Chang, MT; Rose, CM; Pham, VC; Polson, AG; Chang, Y; Wever, C; Johnson, NA; Jiang, Y; Hirata, J; Sampath, D; Musick, L; Flowers, CR; Wertz, IE;
Details: Publication Year 2023-03,Volume 98,Issue #3,Page 449-463
Journal Title: American Journal of Hematology
Publication Type: Research article
Abstract: The treatment of patients with relapsed or refractory lymphoid neoplasms represents a significant clinical challenge. Here, we identify the pro-survival BCL-2 protein family member MCL-1 as a resistance factor for the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma (NHL) cell lines and primary NHL samples. Mechanistically, we show that the antibody-drug conjugate polatuzumab vedotin promotes MCL-1 degradation via the ubiquitin/proteasome system. This targeted MCL-1 antagonism, when combined with venetoclax and the anti-CD20 antibodies obinutuzumab or rituximab, results in tumor regressions in preclinical NHL models, which are sustained even off-treatment. In a Phase Ib clinical trial (NCT02611323) of heavily pre-treated patients with relapsed or refractory NHL, 25/33 (76%) patients with follicular lymphoma and 5/17 (29%) patients with diffuse large B-cell lymphoma achieved complete or partial responses with an acceptable safety profile when treated with the recommended Phase II dose of polatuzumab vedotin in combination with venetoclax and an anti-CD20 antibody.
Publisher: Wiley
Keywords: Humans; Myeloid Cell Leukemia Sequence 1 Protein/therapeutic use; Antineoplastic Combined Chemotherapy Protocols/adverse effects; *Lymphoma, Non-Hodgkin/drug therapy/pathology; Rituximab/therapeutic use; *Immunoconjugates/therapeutic use
Department(s): Clinical Haematology
PubMed ID: 36594167
Publisher's Version: https://doi.org/10.1002/ajh.26809
Open Access at Publisher's Site: 10.1002/ajh.26809
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-05-30 07:27:59

Last Modified: 2024-07-10 08:22:19