P1253: MAVORIXAFOR DISRUPTS THE CROSS TALK BETWEEN WALDENSTRÖM’S MACROGLOBULINEMIA CELLS AND THE BONE MARROW MICROENVIRONMENT RESULTING IN ENHANCED SENSITIVITY TO B-CELL TARGETED THERAPIES

Abstract

Background: Waldenström’s macroglobulinemia (WM) is a rare B-cell malignancy characterized by infiltration of bone marrow (BM) and lymphoid tissues with lymphoplasmacytic cells along with hypersecretion of monoclonal immunoglobulin M (IgM) by progenitor B cells. Studies have shown that more than 90% of patients with WM have an L265P mutation in the myeloid differentiation primary response gene 88 (MYD88), and 30% to 40% of those patients show mutations in the carboxyl terminus of C-X-C receptor 4 (CXCR4). The CXCR4/C-X-C motif ligand 12 (CXCL12) axis plays an important role in the homing and retention of WM cells in the BM. The interaction of WM cells and the BM microenvironment, via cell-to-cell contacts or indirectly through secreted factors (e.g. interleukin 6 [IL-6], C-C motif ligand 5 [CCL5]), is thought to be essential for the pathogenesis of WM and to confer drug resistance. A clinical trial evaluating the efficacy of the CXCR4 antagonist, mavorixafor, in combination with the BTK inhibitor, ibrutinib in patients with MYD88L265P and CXCR4WHIM WM is currently ongoing (NCT04274738). However, the effects of mavorixafor with ibrutinib and other B-cell targeted therapies on WM cells harboring only the single mutation in MYD88L265P and without a CXCR4 mutation have not been evaluated. Aims: This study was designed to elucidate the crosstalk between WM cells and the BM stromal cell (BMSC)-based microenvironment and to explore the effect of mavorixafor in combination with different B-cell targeted therapies in a WM/BMSC co-culture model. Methods: WM cells (MWCL-1 cell line, MYD88L265PCXCR4WT) pretreated with mavorixafor and B-cell targeted therapies (BTK antagonists: ibrutinib, zanubrutinib, evobrutinib, pirtobrutinib, nemtabrutinib; or BCL2 inhibitor venetoclax) were co-cultured with established BMSCs (HS27a cells). Apoptosis, IL-6 production, and IgM release were measured after 48 or 72 hours. The effects of mavorixafor on calcium mobilization, cell migration, and adhesion to BMSCs were also measured. Results: Co-culture of WM cells with established BMSCs led to increased IgM secretion and enhanced surface expression of CXCR4 in WM cells by activation of the IL-6 receptor (IL-6R)/ Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Co-culture with established BMSCs protected WM cells from the effects of B-cell targeted therapies, reducing apoptosis of tumor cells and decreasing the IgM-reducing efficacy of the targeted therapies. Mavorixafor alone reduced IgM secretion, blocked CXCL12-induced cell migration and Ca2+ mobilization and disrupted the adhesion of WM cells to established BMSCs. Mavorixafor in combination with B-cell targeted therapies synergistically enhanced antitumor activity in WM cells, inhibited BMSC-induced IgM hypersecretion, and overcame the protective effects of BMSCs on tumor cells. Summary/Conclusion: Our studies provide preliminary evidence for the potential use of mavorixafor in disrupting the interaction of WM cells with the BMSC-based microenvironment, enhancing the efficacy of B-cell targeted therapies in the treatment of WM and potentially other lymphomas. Further studies using additional WM cell lines and/or primary patient cells are warranted to support these findings.