Abstract 6093: Mavorixafor enhances efficacy of Bruton tyrosine kinase inhibitors by overcoming the protective effect of bone marrow stroma on tumor cells in Waldenström’s macroglobulinemia
Authors: Nguyen Chi , Monticelli Halenya , Kruitwagen Tom , Tardelli Matteo , Maierhofer Barbara , Rebelo Thalia Martins , Maier-Munsa Sabine , Zmajkovicova Katarina , Dillinger Lukas , Badarau Adriana , Taveras Arthur G. 
Published: June 2022

Abstract
Waldenström’s macroglobulinemia (WM) is a rare B-cell malignancy characterized by monoclonal immunoglobulin M (IgM) hypersecretion and invasion of B cells in the bone marrow (BM) and lymphoid tissues. &gt;90% of WM cases show mutations in MYD88 and 30-40% show mutations in the carboxyl terminus of CXCR4.The CXCR4/CXCL12 axis is crucial for the homing/retention of WM cells in the BM. Emerging clinical trial data (NCT04274738; ongoing) suggest that mavorixafor, a CXCR4 antagonist, in combination with ibrutinib results in clinically meaningful changes in levels of IgM and hemoglobin in patients with MYD88L265P CXCR4WHIM WM. However, the effects of mavorixafor with ibrutinib and other Bruton tyrosine kinase (BTK) inhibitors on WM cells harboring only the single mutation (MYD88L265P without CXCR4 mutation) have not been evaluated. This study was designed to test the ability of mavorixafor to sensitize WM cells carrying MYD88L265P CXCR4WT to BTK inhibitors in a WM/BM stromal cell (BMSC) co-culture model. The effects of mavorixafor on Ca2+ mobilization, cell migration, and adhesion to BMSC were also measured. WM cells (MWCL-1 cell line, MYD88L265PCXCR4WT) pretreated with mavorixafor and BTK inhibitors (ibrutinib, zanubrutinib, evobrutinib, LOXO-305, ARQ 531) were co-cultured with established BMSCs (HS27a cells). Cell viability, apoptosis, and IgM release were measured after 72 hours. BTK inhibitors, but not mavorixafor, decreased tumor cell viability and increased apoptosis of WM cells in the absence of BMSCs. Co-culture with BMSCs enhanced CXCR4 expression and protected WM cells from the effects of BTK inhibitors. BMSCs also significantly increased IgM secretion 2- to 5-fold compared with WM cells grown in the absence of BMSCs. Mavorixafor alone inhibited CXCL12-stimulated Ca2+ mobilization and migration of WM cells and disrupted the adhesion of WM cells to BMSCs. Combination of mavorixafor with BTK inhibitors overcame the protective effect of BMSCs on tumor cells, decreasing cell viability and/or increasing apoptosis compared with BTK inhibitors alone. Mavorixafor also reduced IgM secretion, which was further decreased when combined with BTK inhibitors.This study is the first to show in vitro that the protection of WM cells against BTK inhibitors conferred by BMSCs can be overcome by inhibition of the CXCR4/CXCL12 axis. The observations and responses to mavorixafor suggest a contribution of CXCR4WT to the pathogenicity of WM cells carrying only the MYD88L265P mutation. Mavorixafor addition enhanced the efficacy of not only ibrutinib but the other BTK inhibitors tested, supporting the greater potential of this combination therapeutic strategy in WM patients with or without CXCR4WHIM mutations. Further studies using additional WM cell lines and/or primary patient cells are warranted to support these findings.
Citation Format: Chi Nguyen, Halenya Monticelli, Tom Kruitwagen, Matteo Tardelli, Barbara Maierhofer, Thalia Martins Rebelo, Sabine Maier-Munsa, Katarina Zmajkovicova, Lukas Dillinger, Adriana Badarau, Arthur G. Taveras. Mavorixafor enhances efficacy of Bruton tyrosine kinase inhibitors by overcoming the protective effect of bone marrow stroma on tumor cells in Waldenström’s macroglobulinemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6093.