Determinants of Drug Resistance in B-Cell Non-Hodgkin Lymphomas: The Case of Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia

Lymphoplasmacytic lymphoma (LPL) is a rare subtype of B cell-derived non-Hodgkin lymphoma characterized 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 (Waldenström Macroglobulinemia, WM). The clinical manifestations of WM/LPL may range from an asymptomatic condition to a lymphoma-type disease or may be dominated by IgM paraprotein-related symptoms. Despite the substantial progresses achieved over the last years in the therapy of LPL/WM, this lymphoma is still almost invariably incurable and exhibits a propensity towards development of refractoriness to therapy. Patients who have progressive disease are often of difficult clinical management and novel effective treatments are eagerly awaited. In this review, we will describe the essential clinical and pathobiological features of LPL/WM. We will also analyze some key aspects about the current knowledge on the mechanisms of drug resistance in this disease, by concisely focusing on conventional drugs, monoclonal antibodies and novel agents, chiefly Bruton’s Tyrosine Kinase (BTK) inhibitors. The implications of molecular lesions as predictors of response or as a warning for the development of therapy resistance will be highlighted.

Predictors of response and survival in a large cohort of 319 Waldenström macroglobulinemia patients treated with ibrutinib monotherapy

Bruton tyrosine kinase (BTK) inhibitors are the only FDA-approved treatments for Waldenström macroglobulinemia (WM). Factors prognostic of survival and predictive of response to BTK inhibitors remained to be clarified. We evaluated 319 patients with WM to identify predictive and prognostic factors on ibrutinib monotherapy. Logistic and Cox proportional-hazard regression models were fitted for response and survival. Multiple imputation analyses were used to address bias associated with missing data. Major (partial response or better) and deep responses (very good partial response or better) were attained in 78% and 28% of patients. CXCR4 mutations were associated with lower odds of major (OR 0.2, 95% CI 0.1-0.5; p<0.001) and deep response (OR 0.3, 95% CI 0.2-0.6; p=0.001). CXCR4 mutations (HR 2.0, 95% CI 1.2-3.4; p=0.01) and platelet count 100 K/uL or less (HR 2.5, 95% CI 1.3-4.9; p=0.007) were associated with worse progression-free survival (PFS). We proposed a scoring system using these two factors. The median PFS for patients with zero, one and two risk factors were not reached, 5 years and 3 years (p<0.001). Patients with two risk factors had HR 2.2 (95% CI 1.3-3.8; p=0.004) compared with one factor, and patients with one factor had HR 2.3 (95% CI 1.1-5.1; p=0.03) compared with zero factors. Age 65 years or older was the only factor associated with overall survival (HR 3.2, 95% CI 1.4-7.0; p=0.005). Multiple imputation analyses did not alter our results. Our study confirms the predictive and prognostic value of CXCR4 mutations in patients with WM treated with ibrutinib monotherapy.

Multimodal Imaging of Waldenstrom Macroglobulinemia-Associated Hyperviscosity-Related Retinopathy Treated with Plasmapheresis

While plasmapheresis is well known to significantly improve both retinal findings and systemic manifestations associated with Waldenstrom macroglobulinemia, few reports exist documenting changes in optical coherence tomography angiography (OCT-A). The authors present a case of a patient with Waldenstrom macroglobulinemia who had resolution of white-centered peripheral retinal lesions and parafoveal outer nuclear layer hyperreflective material following plasmapheresis. Applying image analysis software to before and after OCT-A images, the authors were able to show an objective decrease in retinal capillary and large vessel density following plasmapheresis. This technique can be used to guide treatment and surveillance for patients with hyperviscosity-related retinopathy.