Clinical Status and Optimal Use of Rituximab for B-Cell Lymphomas

Monoclonal antibodies (MoAbs) for cancer have been the subject of intense clinical investigation for nearly 2 decades. [1] Although the concept of MoAb therapy is simple, a host of unforeseen difficulties hindered the realization of clinical benefit from this therapeutic approach. The review by McLaughlin and colleagues of rituximab (Rituxan), the first MoAb approved for the treatment of cancer, describes one of the success stories in this field. Many other candidate antibodies have appeared to be equally promising during preclinical testing, only to fail during subsequent clinical trials. The lessons learned from these failures (eg, anti-B4-blocked ricin) and the successes, like rituximab, highlight the challenges involved in the development of an effective MoAb for cancer therapy. Obstacles to the Development of Effective MoAbs One challenge has been the selection of appropriate target antigens. Although hematologic malignancies are relatively unique in their expression of cell surface antigens not present on other tissues, not every antigen has proven to be an optimal target. Studies with antibodies targeting CD5,[2,3] CD19, and CD22[4] demonstrated that these antigens internalize upon antibody binding, making them poor targets for serotherapy with unconjugated antibodies. Furthermore, the tumor must persistently express antigen despite intense negative selection imposed by the antibody; otherwise, the tumor could escape therapy. Rituximab recognizes CD20, which remains stable in the face of antibody binding, making it a nearly ideal target antigen. Optimal dosing and adequate tissue penetration represent further stumbling blocks to effective serotherapy. Unlike studies with conventional cytotoxic agents, initial phase I studies with rituximab never reached a maximum tolerated dose. Some published studies have used larger doses than the currently approved 375 mg/m2 weekly × 4 regimen, For example, Coiffier et al used doses up to 500 mg/m2 in a weekly × 8 regimen in patients with intermediateor high-grade lymphoma. [5] Thus, the best dose and schedule of rituximab remain to be established. [6,7] Moreover, even when serum levels that correspond to effective in vitro cytotoxicity can be achieved, tissue levels may still be subtherapeutic, particularly within poorly vascularized lymphomatous nodes. Studies of the Campath-1H MoAb (anti-CD52) demonstrate effec-tive penetration into bone marrow and spleen but not into lymph nodes and extranodal tissue sites. [8] In contrast, rituximab has shown efficacy even in bulky tumors. Whether its activity is augmented in the minimal disease setting requires further investigation. As with all therapies, the potential toxicities of MoAbs must always be considered. Although acute reactions to all MoAbs are common, particularly during initial infusions, few patients require discontinuation of the agent. Subacute toxicities may vary considerably, depending on the particular antibody. Campath-1H induces significant Tand B-cell depletion, since it targets a cell surface antigen common to both lymphocyte lineages. The resulting profound lymphopenia significantly increases the risk of opportunistic infections. To date, no major toxicity has been seen with rituximab, despite prolonged B-cell depletion following therapy. This minimal side effects profile therefore makes rituximab an attractive agent for combination therapies and as salvage therapy for patients who may have impaired marrow reserve and reduced tolerance for toxicity. Rituximab Combined With Chemotherapy In vitro data suggesting synergy of rituximab with conventional chemotherapy represent the most exciting potential for this agent. [9,10] A phase II trial of rituximab in combination with CHOP