CD20 is a transmembrane B-cell differentiation antigen that plays a role in the development of B-cells into plasma cells. It is expressed in both healthy (late pre-B and mature B-cells) as well as in malignant B-cells. 

Blocking CD20 is associated with disruption of B-cell proliferation and differentiation and plays a role in the management of non-Hodgkin's lymphomas (NHL), including follicular lymphoma (FL) and marginal zone lymphoma (MZL).  

Currently, there are four antineoplastic anti–CD20 monoclonal antibodies (MAbs) available in the United States: rituximab, obinutuzumab, ofatumumab, and ibritumomab tiuxetan. A recent review examined the role that anti–CD20 therapy plays in the management of FL and MZL. (Ibritumomab tiuxetan is a radiopharmaceutical, which is only used in combination with rituximab and was not included in this review.)

Rituximab is thought to work via several mechanisms of action, which include both direct antitumor effects (i.e., induces apoptosis) and immunological effects. The direct apoptotic effects of rituximab are both caspase-mediated and caspase-independent. The immunological mechanisms involve complement-dependent cytotoxicity (CDC), Fc-γ receptor–mediated effects (antibody-dependent cell-mediated cytotoxicity [ADCC] and cell-mediated phagocytosis [ADCP]), T-cell–induced immune effects, and possibly, a “vaccinal effect” (i.e., an immune response generated by T-cells to target specific idiotypes of FL cells).

Resistance to anti–CD20 MAbs involve the effector pathways: CDC, ADCC, and ADCP. Other mechanisms may also exist, such as complement inhibition by membrane proteins like decay-accelerating factor (DAF, CD55) or membrane cofactor protein (MCP, CD46). CDC activity may be reduced by CD59. BCL-2 proteins can interfere with apoptosis. Clonal selection and trogocytosis, i.e., the elimination of rituximab-CD20 complex from the surface of the targeted cell, can lead to the survival of malignant cells. 

In an effort to reduce the risk of relapse and resistance, newer anti–CD MAbs have been developed. Ofatumumab is similar to rituximab, except that the junction of CD20 is in a different location (i.e., CD20-MAb complex binds closer to the cell membrane surface) than rituximab, which makes for a tighter and long-lasting binding. Despite its higher CDC, ofatumumab has not been found to offer any clinical advantage over rituximab. Monotherapy ofatumumab has minimal clinical benefit in FL and when combined with chemotherapy and comparable to rituximab and chemotherapy in FL. As a result of these shortcomings, the FDA has only approved ofatumumab for chronic lymphocytic leukemia. 

Obinutuzumab, another humanized MAb, has undergone glycoengineering technology, which has increased its binding affinity to the Fc-γ receptor on the immune effector cells. This structural alteration has led to different binding orientations, producing an increase in ADCC and ADCP function and higher direct cell death induction, but this has come at a cost of decreased CDC capacity for obinutuzumab compared with rituximab. Obinutuzumab in combination with bendamustine is approved for relapsed/refractory FL patients treated with a rituximab-containing regimen; it is considered frontline treatment of FL. 

Rituximab has been combined with human hyaluronidase to allow for higher concentrations of rituximab to be administered SC. It is solely indicated for SC administration. Prior to this, the only option to administer rituximab was IV. The safety and efficacy of the rituximab/hyaluronidase combination compared with IV rituximab has been proven in noninferiority studies. 

Rituximab has significantly improved the management of FL since it was first approved in 1997. In patients with advanced stage FL, clinical response has been seen in 46% to 48% of patients with relapsed disease. When combined with chemotherapy, including CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), the overall response rate is 95% with a complete response of 55% and a partial response of 40%. In addition to combining rituximab with CHOP, it has also been combined with CVP (cyclophosphamide, vincristine, and prednisone), CVPH-interferon, and bendamustine, which serve as first-line treatments of FL. 

In the management of relapsed or refractory FL, treatment options have included rituximab monotherapy, novel agents such as obinutuzumab or ofatumumab plus rituximab, rituximab plus chemotherapy such as lenalidomide or bendamustine, radioimmunotherapy, and in select cases, stem cell transplantation. Overall response rate, time to progression, and PFS were improved with lenalidomide plus rituximab, but OS was not. 

Ofatumumab had only modest activity in patients previously treated with rituximab. In patients treated with obinutuzumab and chemotherapy versus rituximab and chemotherapy, there was a lower risk of progression, relapse, and death and more adverse effects in the former group, although response rates were similar for both groups. Bendamustine combined with obinutuzumab followed by obinutuzumab monotherapy has shown benefit in OS and PFS in refractory FL.

Treatment of MZL, a rare hematological malignancy, is much less standardized than it is in FL, and data for management of MZL are often  extrapolated from the management of FL. Among the three different types of MZL, treatment varies ranging from microbial eradication to the use of chlorambucil in combination with rituximab for mucosa-associated lymphoid tissue lymphoma to watch and wait for splenic MZL and nodal MZL. 

Anti–CD20 MAbs have significantly enhanced the management of patients with NHLs. Pharmacists need to be aware of where these drugs fit into the armamentarium of therapeutic options to treat indolent malignancies, such as FL. As managers of drug formularies, pharmacist should stay current with the availability of rituximab biosimilars as these biologicals offer an opportunity for cost-savings, which can greatly benefit the pharmacy budget.

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