Commentary on Abstracts #1712, #1710, and #1715

Rituximab is a chimeric human-mouse anti-CD20 monoclonal antibody that has been studied most widely in patients with follicular non-Hodgkin’s lymphomas (NHLs). This antibody has induced responses in about half of these cases, including a 6% complete remission rate, with responses lasting a median of 11.6 months (McLaughlin et al: J Clin Oncol 16:2825-2833, 1998). Rituximab has only entered widespread clinical use over the past year. As a result, data are just beginning to emerge on the long-term results with this agent.

McLaughlin et al (abstract #1712) described additional follow-up of the initial 166 patients with relapsed or refractory follicular low-grade NHL treated with rituximab in the pivotal study that led to FDA approval of this agent. The median time to progression, which had been 13.0 months, remained at 13.2 months as of this report, although the median duration of follow-up was not provided. Of the 80 responders, 20 (25%) were in ongoing remission after 19.3+ to 36.7+ months. These results suggest that responses to rituximab may be relatively durable. Unfortunately, all patients with low-grade NHL treated with rituximab relapse and may require additional therapy. Many of these patients have poor bone marrow reserves from prior cytotoxic therapy. Therefore, treatment options may be limited.

Davis et al (abstract #1710) evaluated the outcome of patients retreated with rituximab following disease progression. Patients eligible for this study had responded to rituximab after the failure of multiple prior chemotherapy regimens. After these patients’ disease progressed (median of 14.2 months after their previous therapy), they were treated with the standard rituximab schedule of 375 mg/m² weekly for 4 weeks.

The complete response rate was 12.5% and partial response rate was 28.6% (overall response rate of 41%), with a median time to progression not reached at 16.7+ months. These response rates and duration are consistent with the results seen the first time that the drug was administered. Rituximab therapy was well tolerated, with no human antichimeric antibody (HACA) reactions reported.

Therefore, retreatment with rituximab may be successful and may provide a suitable alternative to cytotoxic chemotherapy in patients whose disease has not responded to prior chemotherapy and has progressed after a previous response to the antibody. Anecdotes suggest that some patients can respond several times to this agent, but a formal trial has not been reported.

An issue of major interest in clinical trials and general practice is where the monoclonal antibodies fit into the treatment algorithm for patients with indolent NHL. Drugs such as fludarabine (Fludara) are now widely used for alkylator-refractory indolent NHL and are being increasingly administered as initial therapy for these patients. Responses can be induced in about half of patients who have not responded to alkylators, with complete remissions in 12% to 15%.

McLaughlin and coworkers (abstract #1712) suggested that their results compare favorably with published data using fludarabine and cladribine (2-chlorodeoxyadenosine, CdA [Leustatin]) in relatively similar populations.

In a separate analysis performed in the United Kingdom, rituximab appeared to have a lower overall cost than either CHOP (cyclophosphamide, doxorubicin, Oncovin, and prednisone) or fludarabine, primarily because of lower treatment-related toxicity with similar activity (Sweetenham et al, abstract #1715). However, conclusions based on such historical controls require prospective confirmation. Moreover, the relative role of the various therapeutic options in these patients can be defined only by randomized trials.

Nevertheless, it is clear that combination approaches are more likely to result in more effective treatment than single-agent therapies. Of particular interest are results reported with fludarabine in combination with such drugs as mitoxantrone and dexamethasone (FND regimen)(McLaughlin et al: J Clin Oncol 14:1262-8, 1996). Future directions of clinical trials include a focus on combining rituximab with chemotherapy to develop more effective strategies.

Czuczman et al (J Clin Oncol 17:268-276, 1999) recently described 40 patients with low-grade or follicular NHL who were treated with rituximab in combination with CHOP chemotherapy. Their results were impressive, with an overall response rate of 95%, including a 55% complete remission rate. The median duration of response and time to progression were not reached as of the time of publication.

These results appear to be superior to those previously reported with CHOP alone. The combination of rituximab plus CHOP is currently being explored in a phase III trial within the Eastern Cooperative Oncology Group (ECOG) and Cancer and Leukemia Group B (CALGB) in patients ³ 60 years of age.