Therapy of B-cell lymphoma with anti-CD20 antibodies can result in the loss of CD20 antigen expression

Rituximab is a chimeric antibody with human gamma-1 and kappa constant regi ons and murine variable regions. It recognizes the CD20 antigen, a pan B-ce ll marker. Therapeutic trials in patients with B-cell non-Hodgkin's lymphom a (NHL) have shown significant efficacy with a primary response rate of 50% , and a secondary response rate of 44% after repeat treatments in prior res ponders. The selection for proliferating tumor cells that no longer express CD20 may compromise repeated treatment. We have identified a patient who d eveloped a transformed NHL that lost CD20 protein expression after two cour ses of therapy with rituximab, In a pretreatment lymph node biopsy, 83% of B cells (as defined by CD19 and surface immunoglobulin) expressed surface C D20. A biopsy from the recurrent tumor after two courses of rituximab revea led a diffuse large cell NHL where 0% of B cells expressed CD20 with no evi dence of bound rituximab. Cytoplasmic staining showed no CD20 protein. Sequ encing of immunoglobulin heavy chain cDNA identified identical variable seq uences in the initial and recurrent lymphomas, confirming the association b etween the two tumors. Literature and database review suggests that approxi mately 98% of diffuse large cell lymphomas express CD20, which suggests tha t these tumors rarely survive without CD20. This is the first identified ca se of loss of CD20 expression in a lymphoma that has relapsed after rituxim ab therapy, although several other cases have since been identified. Consid ering the significant number of patients treated with anti-CD20 antibodies, this may occur only rarely and is unlikely to preclude recurrent therapy w ith anti-CD20 antibodies in the majority of patients. However, because many patients have relapsed after anti-CD20 antibody therapy and have not been biopsied to identify clones with down-regulated CD20 antigen, we do not cur rently know the true frequency of this phenomenon. When possible, patients should undergo evaluation for CD20 expression before repeated courses of an ti-CD20 therapy.