Review of BCL2 inhibitors for the treatment of Waldenström’s macroglobulinaemia and non-IgM lymphoplasmacytic lymphoma

Lymphoplasmacytic lymphoma (LPL) is a rare, indolent B-cell non-Hodgkin lymphoma. When associated with an IgM paraprotein, it is referred to as Waldenström’s macroglobulinemia (WM). Historically, treatment has relied on combination chemoimmunotherapy (CIT), but the emergence of targeted molecular therapies, particularly Bruton’s tyrosine kinase inhibitors (BTKi), has shifted the treatment landscape. Despite their efficacy, intolerance and refractoriness to BTKi have highlighted the need for alternative therapeutic options, especially for quadruple-refractory patients, who face a poor prognosis.

BCL2, a pro-survival, anti-apoptotic protein, supports the persistence of lymphoma cells. Targeting BCL2 with venetoclax, a first-in-class inhibitor, has already transformed the management of other hematologic malignancies such as chronic lymphocytic leukemia (CLL). Preclinical studies demonstrate that BCL2 inhibition induces apoptosis in LPL/WM cells. To date, five studies have investigated BCL2 inhibitors in WM, including oblimersen sodium, venetoclax, and sonrotoclax. Venetoclax as a fixed-duration therapy has shown high response rates; however, relapses are common after treatment cessation. Combining venetoclax with ibrutinib yielded deeper and more durable responses, but unexpected ventricular events led to the discontinuation of further exploration of this combination.

Currently, two pivotal trials are evaluating fixed-duration venetoclax in combination with either rituximab or pirtobrutinib. Additionally, a multi-arm study is assessing continuous sonrotoclax monotherapy for relapsed/refractory WM and its fixed-duration combination with zanubrutinib for treatment-naïve patients. While BCL2 inhibitors show promise as a chemotherapy-free, oral treatment option, their role in LPL/WM remains under investigation. Cost-effectiveness and toxicity profiles will be critical considerations, particularly in a condition with existing effective therapies such as CIT and covalent BTKi. Nonetheless, for quadruple-refractory patients with limited options, BCL2 inhibitors may offer a desperately needed therapeutic alternative.