CLONAL SELECTION OF CD20‐NEGATIVE NON‐HODGKIN'S LYMPHOMA CELLS AFTER TREATMENT WITH ANTI‐CD20 ANTIBODY RITUXIMAB (1999)

Treatment of relapsed low-grade or aggressive non- Hodgkin's lymphoma (NHL) with the chimaeric anti-CD20 monoclonal antibody IDEC-C2B8 (rituximab) has shown promising results with response rates of 50% and 33% and a median time to progression of 10 and 8 months, respectively (Maloney et al, 1997; Coiffier et al, 1998). It was suggested that retreatment with rituximab might be possible and reasonable in follicular lymphomas; however, only limited clinical information has been available to date. Here we describe a 54-year-old woman with a follicular t(14;18)+ NHL which was diagnosed in 1982. She was initially treated with combination chemotherapy and achieved complete remission until 1990. Upon multiple relapses, she received different chemotherapy regimens including anthracyclines and alkylating agents, and also local irradiation. In September 1997 she had evidence of further progression with multiple abdominal and paravertebral lymphomas and peripheral blood pancytopenia. Her bone marrow biopsy showed a markedly reduced cellularity with diffuse infiltration of a CD20+ follicular lymphoma. At this time she was treated with rituximab in four weekly doses of 375 mg/m2. After the first application a significant decrease of the lymphomas was observed, and after 4 weeks of treatment a 40% regression was demonstrated by computed tomography. Six months later she further progressed at multiple sites. Because an objective response had been achieved previously, rituximab treatment was started again. After two applications of 375 mg/m2 per week without evidence of clinical response, a biopsy of the inguinal lymphe node was performed. Surprisingly, histological and flow cytometrical examination revealed transformation of the follicular lymphoma into a high-grade diffuse large cell lymphoma with 85–95% of the lymphoma cells being negative for CD20, but positive for CD10, CD19 as well as the proliferation-associated marker Ki 67. At the same time, all of the peripheral blood B lymphocytes expressed normal levels of CD20 by flow cytometry. Although transformation of follicular low-grade lymphomas into high-grade B-cell lymphomas often present as diffuse large cell lymphomas, the finding of a CD20-negative lymphoma was unexpected, since the vast majority of aggressive lymphomas consistently express CD20. The lack of CD20 expression on the lymphoma cells in this particular case might represent a clonal selection of CD20-negative cells following prior treatment with rituximab. Though it is known that binding of the anti-CD20 antibody on lymphoma cells can be demonstrated up to 2 weeks after application (Maloney et al, 1994), it is unlikely that this phenomenon could result in complete CD20 negativity in both flow cytometrical and immunohistological analyse (using different antibodies), since at the same time normal CD20+ peripheral blood B cells could be detected. Moreover, a clinical response of the lymphoma — which was impressive at the time of previous administrations — was clearly absent. Although we cannot totally exclude that the lymphoma in this patient represents one of the rare examples of a CD20-negative transformed aggressive lymphoma, we conclude that a clonal selection of CD20-negative cells might emerge after prior treatment with rituximab. This observation stresses the importance of confirmation of CD20 expression on B-cell lymphomas prior to the initiation of rituximab treatment.