Dr. Vose has provided an excellent overview of the immunotherapeutic options currently available, or that will soon be available, for the clinical management of patients with non-Hodgkin’s lymphoma (NHL). These new options present the clinical oncologist with a dilemma as to which is most efficacious in a given clinical situation, and in what order they should be administered over a patient’s clinical course. Among these options are the use of unlabeled monoclonal antibodies, radiolabeled antibodies, and tumor-specific idiotype vaccination.
I believe it is important to validate each of these new treatments on their individual ability to cause disease regression. However, it is also likely that ultimately they will have the greatest impact when combined with or administered following conventional therapies. We need to continue to move from single-agent clinical trials to trials of rational combinations or sequences that may provide a survival advantage, but as Dr. Vose points out, this will require results from prospective randomized phase III trials.
The explosive use of the chimeric anti-CD20 antibody rituximab(Drug information on rituximab) (Rituxan) in clinical oncology is instructive of this process. Phase I/II trials demonstrated that the antibody was safe and caused tumor regression in patients with a variety of B-cell histologies.[1-3] Response rates to single-agent therapy were generally higher in patients with follicular NHL and in patients who had received less prior therapy. However, responses were also seen when rituximab was administered as a single agent in patients with relapsed aggressive NHL.
While responding patients have obviously benefited, there have not been any single-agent trials that demonstrate changes in survival. Nevertheless, the lack of serious side effects allowed combination trials with chemotherapy, and several small studies have demonstrated that rituximab may be given with or following standard CHOP chemotherapy (cyclophosphamide [Cytoxan, Neosar]/doxorubicin HCl/vincristine [Oncovin], prednisone(Drug information on prednisone)), without compromising the chemotherapy dose or altering the toxicity.[5,6]
Data from these trials suggest a high response rate and a promising length of remission but do not demonstrate that rituximab plus CHOP is better than CHOP alone. The results of an interim analysis presented at the 2000 meeting of the American Society of Hematology by Dr. Bertrand Coiffier on behalf of the Groupe d’Etude des Lymphomes de l’Adulte (GELA) provided the first glimpse of evidence that the combination of CHOP and rituximab is superior to CHOP alone in elderly patients with aggressive NHL. The combination was superior in terms of remission induction rates as well as 1-year disease-free and overall survival.
The early and preliminary results of this trial are exciting but threaten to halt the progression of critical ongoing trials that are evaluating rituximab in other combinations and clinical situations. It is important that the confirmatory trials are properly evaluated and that data from these trials mature and are published. Hopefully, these trials will confirm the findings from GELA.
Ongoing trials in other histologies, such as low-grade NHL, should be completed to determine the effects of combined therapy in diseases that are associated with a continuous pattern of relapse.
Several new agents that utilize either iodine-131 or yttrium-90 to provide targeted radiation to B-cell tumors expressing the CD20 antigen are in the late stages of clinical trials. These agents appear to have greater antitumor effects as single agents than as unlabeled anti-CD20 antibodies, although with increased toxicity.[8,9]
It is important to note that all radiolabeled antibodies have significant dose-limiting toxicity, and that that toxicity may be dependent on the patient’s tumor burden. In most cases, this involves bone marrow suppression, making combination studies with these agents and standard chemotherapy difficult. Sequential administration or the use of stem cell support may alleviate this complication.
The induction of an antitumor immune response in a patient may foster more selective antitumor activity. Data from several small phase I/II trials evaluating this approach in follicular NHL patients following chemotherapy suggest that immune responses may be generated, and that successfully immunized patients who are in remission have a low relapse rate.[10,11] Ongoing phase III trials are necessary to validate these findings. Also, it remains to be determined if recent technological advances make a customized treatment approach feasible.
The availability of these new agents and the lack of clear clinical trial results to guide proper combinations or sequences will present challenges for the management of lymphoma patients. For example, the induction of an idiotype-specific immune response may be difficult in patients who have been recently treated with anti-CD20 antibodies, because of the transient depletion of B cells. Likewise, the induction of a human antimouse antibody response to a murine antibody may preclude subsequent treatment with another murine antibody later in the course of a patient’s disease.
Studies should continue to compare these promising approaches directly in prospective clinical trials. It is gratifying to see immunotherapy emerge into the clinical arena for lymphoma therapy. Hopefully, these advances will improve long-term cure rates and decrease treatment toxicities for lymphoma patients as well as for those with other malignancies.