Managing complications secondary to Waldenström’s macroglobulinemia

ABSTRACT

Introduction: Waldenström’s macroglobulinemia (WM) is a rare lymphoma characterized by the accumulation of IgM-secreting lymphoplasmacytic cells in the bone marrow and other organs. Clinical sequelae relate to direct tissue infiltration by malignant cells but also to the physicochemical and immunological properties of the monoclonal IgM, resulting in a variety of disease-related complications.

Areas covered: This narrative review, following a thorough Pubmed search of pertinent published literature, discusses complications secondary to WM, related to direct tumor infiltration, monoclonal IgM circulation, and deposition, as well as other less common ones. The description and pathophysiology of these complications were described together with their specific management strategies and in the context of available treatment options for WM (anti-CD20 monoclonal antibody–based combinations, proteasome inhibitors, BTK inhibitors, and other emerging ones).

Expert opinion: The availability of many novel, active and less toxic regimens for the treatment of WM allows the management of the disease with strategies that depend on clinical presentation and disease-related complications, age, toxicity considerations, and presence of comorbidities.

KEYWORDS:

• Bing-Neel syndrome
• bendamustine
• bortezomib
• hyperviscosity syndrome
• ibrutinib
• monoclonal IgM
• peripheral neuropathy
• rituximab
• venetoclax
• Waldenström’s macroglobulinemia

Article highlights

• WM complications related to direct tumor infiltration may include bone marrow infiltration (causing cytopenias), hypogammaglobulinaemia, CNS infiltration (causing Bing-Neel syndrome).

• WM complications related to the circulation of monoclonal IgM may include hyperviscosity syndrome, Type I cryoglobulinaemia, cold agglutinin disease, acquired von Willebrand Syndrome.

• WM complications related to IgM deposition may include peripheral neuropathy, Type II cryoglobulinaemia, AL amyloidosis, IgM deposits in the skin, gut, lungs, and kidneys.

• Treatment should start only for symptomatic WM patients.

• Plasmapheresis is still an important treatment option for certain WM-related complications with rapid activity but only temporary results.

• Therapeutic options in WM include rituximab-based combinations (with cyclophosphamide, bendamustine, fludarabine, chlorambucil, or proteasome inhibitors such as bortezomib, carfilzomib, ixazomib), and less often rituximab monotherapy. New targeted therapies include BTK inhibitors (Ibrutinib, acalabrutinib, zanabrutinib), BCL2-targeting agents (Venetoclax) and in selected cases may also include stem cell transplantation.

• Therapeutic options available today can be chosen depending on patients’ age, presence of comorbidities, viscosity-related symptoms and necessity for rapid cytoreduction, as well as treatment-specific adverse effects.

Declaration of interest

MA Dimopoulos has received consultancy, and honoraria from advisory committees, from Amgen, Takeda BMS, Janssen, and Celgene. E Kastritis has received honoraria and consultancy from Amgen, Genesis Pharma, Janssen, Takeda, and Pfizer, and research support from Janssen and Amgen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.