Current and Emerging Treatments for Waldenström Macroglobulinemia

Abstract

Waldenström macroglobulinemia (WM) is a rare lymphoplasmacytic lymphoma. The primary goal of therapy is to reduce symptoms related to direct infiltration of the bone marrow and decrease monoclonal IgM-associated complications. Active agents in the management of WM can be broadly classified as rituximab-alkylator combination therapy, proteasome inhibitor-based therapy, and Bruton’s tyrosine kinase inhibitor-based therapy. <i>MYD88</i><sup>L265P</sup> and <i>CXCR4</i> genetic status are pivotal for tailoring treatment options. Ibrutinib is a suitable treatment option for both treatment-naïve and relapsing WM patients. Recent advances in the intracellular B cell and cytokine signaling pathways have contributed to the development of novel therapeutic strategies. Current clinical trials are promising and may further advance WM-directed therapy.

Current Status of Novel Agents for the Treatment of B Cell Malignancies: What’s Coming Next?

“…Of the many BTK inhibitors developed in the last 10 years, three (ibrutinib/PCI-32765, acalabrutinib/ACP 196, and zanubrutinib/BGB 3111) are now used in the clinic to treat B cell malignancies ( Figure 2 a and Table 2 ). Ibrutinib and acalabrutinib are authorized for untreated and R/R CLL/SLL and CLL with 17p deletion [ 146 , 147 , 148 , 149 ], ibrutinib and zanubrutinib are authorized for R/R MZL patients who have received at least one line of an anti-CD20-based regimen [ 149 ], and ibrutinib, acalabrutinib and zanubrutinib are authorized for WM patients and for MCL patients who have received at least one line of treatment [ 119 , 147 , 148 , 149 , 150 ]. These three agents are orally administered alone or in combination with an anti-CD20 mAb such as rituximab ( Table 2 ).…”

“…A phase III trial (NCT02004522) of duvelisib vs. ofatumumab (an anti-CD20) in patients with R/R CLL/SLL was terminated in 2021 after the occurrence of serious adverse events, including severe infections and diarrhea/colitis [ 161 ]. Clinical evaluations of the efficacy of idelalisib as a monotherapy and of duvelisib combined with anti-CD20 (obinutuzumab) in R/R MM were recently reviewed by Grimont et al [ 119 ]. Idelalisib is associated with significant hepatotoxicity, which may limit the drug’s use in WM [ 118 ].…”

Carbon‐13 labeling of ibrutinib for human microdosing

“…Ibrutinib has been approved to treat B cell cancers like mantle cell lymphoma, 2 chronic lymphocytic leukemia, 3 marginal zone lymphoma, and Waldenström's macroglobulinemia, as well as chronic graft-versus-host disease. 4 More recently, BTK inhibitors, including ibrutinib, as well as other known drugs, were screened for potential activity against COVID-19. 5,6 Preclinical and clinical studies have shown that ibrutinib is susceptible to rapid and extensive phase I oxidative metabolism mediated by cytochrome P450 3A.…”

“…Ibrutinib is a once‐daily small molecule inhibitor that binds irreversibly to Bruton's tyrosine kinase (BTK) 1 via its covalent acrylamide warhead, which blocks malignant B cell receptor signaling, disrupts B cell adhesion and migration, and drives malignant B cells into apoptosis. Ibrutinib has been approved to treat B cell cancers like mantle cell lymphoma, 2 chronic lymphocytic leukemia, 3 marginal zone lymphoma, and Waldenström's macroglobulinemia, as well as chronic graft‐versus‐host disease 4 . More recently, BTK inhibitors, including ibrutinib, as well as other known drugs, were screened for potential activity against COVID‐19 5,6 …”

Multifaceted Immunomodulatory Effects of the BTK Inhibitors Ibrutinib and Acalabrutinib on Different Immune Cell Subsets – Beyond B Lymphocytes

“…Targeting BTK in CLL and MCL with ibrutinib results in direct inhibition of cell proliferation and homing/migration due to disruption of BCR and chemokine receptor signaling (Herman et al, 2011;de Rooij et al, 2012;Ponader et al, 2012;Hendriks et al, 2014;Pal Singh et al, 2018). Based on the clinical evidence, ibrutinib has been given the United States Food and Drug Administration (FDA) approval for the treatment of multiple B cell malignances, including CLL/small lymphocytic lymphoma (SLL), MCL, marginal zone lymphoma (MZL) and Waldenstrom macroglobulinemia (WM) (Hendriks et al, 2014;Pal Singh et al, 2018;Zi et al, 2019;Bond and Maddocks, 2020;Castillo et al, 2020b;Grimont et al, 2020;Hanna et al, 2020;Noy et al, 2020;Treon et al, 2021). Furthermore, ibrutinib, as monotherapy or in combination therapies with other targeted drugs (such as anti-CD20, anti-PD-1/PD-L1 and inhibitors of Bcl-2, PI-3Kδ or proteosome), has demonstrated efficacy in patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Richter's transformation (RT), multiple myeloma (MM), B cell pro-lymphocytic leukemia (B-PLL), acute lymphoblastic leukemia (ALL), lymphoproliferative disorders (LPD), and primary and secondary central nervous system lymphomas (PCNSL/SCNSL) in recent clinical trials (Hendriks et al, 2014;Pal Singh et al, 2018;Chari et al, 2020;Chen et al, 2020;Fowler et al, 2020;Oka et al, 2020;Schaffer et al, 2020;Graf et al, 2021;Hodkinson et al, 2021;Lewis et al, 2021).…”