[Rituximab resistance in B-cell lymphoma and its elimination]

Rituximab is commonly incorporated into CD20-positive B-cell lymphoma therapy to improve response and prognosis. With increasing use, resistance to rituximab is a continuing concern, but CD20 mutation as a cause of resistance has not previously been reported. Freshly collected lymphoma cells from 50 patients with previously untreated or relapsed/resistant non-Hodgkin's B-cell lymphomas(diffuse large B cell, n=22; follicular, n=7; mucosa associated lymphoid tissue, n=16; chronic lymphocytic leukemia, n=2; small lymphocytic lymphoma, n=1; lymphoplasmacytic, n =1; mantle cell lymphoma, n=1)were assessed for CD20 expression by flow cytometry, and CD20 gene sequencing was performed on extracted DNA. CD20 mutations were found in 11 of 50 patients(22.0%), and could be grouped as: C-terminal deletion(8.0%), early termination(10.0%), and extracellular domain(2.0%)or transmembrane domain (2.0%)mutations. The mean fluorescence intensity of CD20 on fresh lymphoma cells was significantly lower for the Cterminal deletion mutation(3.26; 95% CI: 0.09-6.89)compared with wild type(30.8; 95% CI: 22.4-39.2)(p<0.05). In contrast, early termination mutations did not show significant differences in CD20 expression compared with wild type (19.5; 95% CI: 10.7-28.4)(p>0.05). It is possible that C-terminal deletion mutations of CD20 may be related to relapse/resistance after rituximab therapy. These mutations should be examined in patients showing progression of disease after partial remission. Other mechanisms are also discussed.