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Advances in LPL/WM Research Could Inform New Treatment Avenues


Investigators say it may soon be possible to design therapies better at staving off resistance among patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM), which is an incurable disease.

Lymphoplasmacytic lymphoma/Waldenström Macroglobulinemia (LPL/WM) remains an incurable disease, but new research suggests strides are being made to better understand the mechanisms of drug resistance among patients with the condition.

The paper, published in Frontiers in Oncology, also offers potential strategies to stave off resistance.

The authors begin by explaining the condition. The LPL portion of the condition is a rare form of B-cell–derived non-Hodgkin lymphoma marked by the abnormal growth of transformed clonal lymphoplasmacytes and plasma cells.

“This tumor almost always displays the capability of secreting large amounts of monoclonal immunoglobulins (Ig) of the M class (WM),” the authors explained.

Although some patients exhibit no symptoms, others present with lymphoma-type disease, and others with symptoms related to IgM paraprotein.

They said next-generation sequencing has in recent years led to new understandings of some of the common mutations present in the disease, which has also opened the door to potential predictive biomarkers. For instance, the myeloid differentiation factor 88 (MYD88) L265P molecular lesion appears to be present in more than 90% of cases. Further, in about one-third of cases, C-X-C Motif Chemokine Receptor 4 (CXCR4) mutations are involved.

The authors next outlined some of the potential treatment options for these patients. In what they described as the most common scenario, a patient with MYD88 mutations and wild-type CXCR4 disease, treatment with Bruton’s tyrosine kinase (BTK) inhibitors plus rituximab (Rituxan) or chemoimmunotherapy with the association of rituximab and an alkylating agent is fitting in cases where there is no need for rapid debulking.

“When a rapid debulking is required to alleviate symptoms caused by hyperviscosity or to avoid an incipient kidney damage, chemoimmunotherapy or proteasome inhibitors (ie, bortezomib [Velcade] are advised,” they wrote. However, they also noted that clinicians should expect relapses, so the goal of treatment should be to elicit the longest and deepest response possible.

The investigators also discussed mechanisms of drug resistance to various potential therapies, beginning with chemotherapy, immunotherapy, proteasome inhibitors, and BTK inhibitors, saying better knowledge of the mechanisms of drug resistance is helping investigators to begin to craft better treatment strategies. They said kinase inhibitors (KIs) are becoming a particularly important part of the treatment armamentarium for the disease.

“Mutations of the KIs’ target, coexistence of genetic alterations, overactivation of compensatory signaling pathways, and other mechanisms have been now recognized as central in the development of neoplastic clones able to escape the cytotoxic effects of KIs,” they explained.

They said a deeper understanding of drug resistance should make it possible to develop more effective combination therapies, and they added that it may also be possible to use particular sequencing of available drugs in order to better fend off relapses.

“However, a clear answer to this issue is still awaited,” they said.

The investigators concluded that if definite complete responses could be attainable for LPL/WM, “it is likely that the future achievements of novel therapies will consist chiefly in prolonging at most the progression-free and treatment-free survival without affecting the quality of life of the patients.”


Piazza F, Di Paolo V, Scapinello G, Manni S, Trentin L, Quintieri L. Determinants of drug resistance in b-cell non-hodgkin lymphomas: the case of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Front Oncol. Published online January 11, 2022. doi:10.3389/fonc.2021.801124

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