Rituximab, a chimeric anti-CD20 IgG1 monoclonal antibody, is effective when given as a single agent in the treatment of relapsed or refractory indolent lymphomas and has activity in relapsed or refractory diffuse large-B-cell lymphoma.CD20 is a cell-surface protein that occurs almost exclusively on mature B cells. The chimeric antibody is a human IgG1 in which the CD20-binding region was derived by genetic engineering from a mouse monoclonal antibody. On the basis of phase 2 studies in which rituximab in combination with CHOP had a good safety profile and induced responses in over 90 percent of patients with indolent or aggressive lymphoma, the Groupe d'Etude des Lymphomes de l'Adulte (GELA) undertook a study to compare CHOP plus rituximab with CHOP alone in elderly patients with diffuse large-B-cell lymphoma.

These lymphomas, which usually arise from B lymphocytes, are the fifth most common type of cancer in the United States and are the fifth and sixth leading cause of death from cancer in men and women, respectively.Approximately 25 to 30 percent of non-Hodgkin's lymphomas have an indolent course; the remainder are aggressive tumors. For 25 years, the standard treatment for diffuse large-B-cell lymphoma, the most common of the aggressive non-Hodgkin's lymphomas, has been a regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), which cures about 30 to 40 percent of patients with this disease; in the rest, the lymphoma is fatal. A series of other regimens, whose acronyms create a seemingly endless game of chemotherapy Scrabble, have been developed to improve on CHOP. A large randomized trial failed to find that three of these regimens had an advantage over CHOP, which remains the standard treatment for diffuse large-B-cell lymphoma.

A new and unique therapeutic agent, rituximab, may have broken the stalemate. Rituximab is a chimeric monoclonal antibody against CD20, a surface antigen on both normal and neoplastic B lymphocytes. The antigen is present in virtually all cases of non-Hodgkin's lymphoma that arise from B cells. Rituximab was genetically engineered by joining the genes encoding the light-chain and heavy-chain variable regions of a murine antibody against CD20 with the genes for human IgG1 heavy-chain and kappa-chain constant regions. This chimeric antibody probably depletes B cells by mechanisms that involve antibody-dependent cellular cytotoxicity, complement-mediated cytotoxicity, and the induction of apoptosis.

A phase 1 clinical trial of rituximab began in 1993, and preliminary data suggested activity against B-cell lymphoma. A multicenter study tested rituximab in 166 patients with follicular or low-grade non-Hodgkin's lymphoma that had progressed after a median of two chemotherapy regimens. Half the patients had a response, the response lasted approximately one year, and the antibody was extremely well tolerated.On the basis of these data, on November 26, 1997, rituximab became the first monoclonal antibody to be approved by the Food and Drug Administration for the treatment of a human cancer, thereby shifting the course of lymphoma therapy in a new direction.

Since in vitro experiments suggested that rituximab sensitizes lymphoma cells to the cytotoxic effects of chemotherapeutic agents,the antibody was rapidly incorporated into numerous chemotherapy regimens, with encouraging results. The response rates with CHOP plus rituximab in patients with indolent or aggressive non-Hodgkin's lymphoma were higher than would be expected with chemotherapy or antibody alone. However, such impressive data required confirmation in a randomized trial, such as the one reported in this issue of the Journal. Coiffier et al. randomly assigned 399 patients who were 60 to 80 years of age and had diffuse large-B-cell lymphoma to receive either CHOP or CHOP plus rituximab. Patients in this age group tend to tolerate chemotherapy poorly and have a shorter survival than younger patients. The two groups were balanced according to known risk factors. The combined therapy resulted in a higher rate of complete remission (76 percent, as compared with 63 percent with CHOP alone); in addition, for the first time in the initial treatment of diffuse large-B-cell lymphoma, a statistically significant prolongation of survival was observed.

All these exciting results initiated the current trend to adopt CHOP plus rituximab as the new standard of care for patients with B-cell lymphoma. However, this approach is premature. In the study by Coiffier et al., the rate of survival was 70 percent with CHOP plus rituximab and 57 percent with CHOP at a median follow-up of two years. However, the difference between the survival curves begins to shrink at 2.5 years and will continue to shrink as older patients die from the disease, complications of therapy, and age-related conditions. In a curable disease such as diffuse large-B-cell lymphoma, prolongation of long-term survival is more important than a difference in short-term median survival. Longer follow-up times are needed to show that the advantage conferred by rituximab persists. A larger, U.S. trial, comparing CHOP with CHOP plus rituximab in patients at least 60 years of age, has been completed. If the analysis of its data confirms the results reported by Coiffier et al., it will support a shift to a new standard of therapy for diffuse large-B-cell lymphoma.

We compared high-dose therapy plus autologous stem-cell support with the standard regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in a randomized trial. The patients were 15 to 60 years of age, had untreated aggressive lymphoma, and were at low, low intermediate, or high intermediate risk of death (i.e., a maximum of two adverse prognostic factors) according to the age-adjusted International Prognostic Index. The primary outcome was event-free survival at five years.

Results Of 207 consecutive patients, 197 underwent randomization; 99 were assigned to receive CHOP, and 98 to receive high-dose chemotherapy plus stem-cell transplantation. Overall, 78 percent of the patients completed the assigned treatment; the median follow-up was four years.