Combination Rituximab/CHOP Therapy Produces Prolonged Results in NHL

NEW ORLEANS—Combining rituximab (Rituxan) with the conventional CHOP regimen can produce prolonged disease-free survival in low-grade lymphomas and can increase complete response (CR) rates to over 60% in patients with intermediate-grade or high-grade non-Hodgkin’s lymphoma (NHL). These results from two separate studies were reported at poster presentations at the American Society of Hematology (ASH) meeting.

Rituximab is a monoclonal antibody directed at the CD20 antigen, which is expressed on most B-cell lymphomas. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) is the most widely used front-line combination chemotherapy regimen for treating NHL. Rituximab and CHOP were studied in combination because each is active in low-grade NHL and because they have non-cross-resistant mechanisms of action. In addition, in vitro studies had shown that rituximab is synergistic with various cytotoxic drugs against cultured B-cell lymphoma cell lines, according to Myron Czuczman, MD, of Roswell Park Memorial Institute in Buffalo, New York.

100% Response

Dr. Czuczman reported 3-year follow-up data showing that adding rituximab to CHOP increases overall response to 100% and CR to 63% in patients with low-grade or follicular NHL. Median duration of response was 39.7+ months, and median progression-free survival had not been reached after an observation time of 41.1+ months. “Twenty-four patients are still in remission beyond 3 years and up to 54+ months,” Dr. Czuczman added.

The objectives of this pilot study were to evaluate the safety and efficacy of treatment with 6 infusions of rituximab (each at 375 mg/m²) combined with CHOP. CHOP cycles were repeated every 3 weeks for 6 cycles.

Two doses of rituximab were given both at the beginning and at the end of therapy, and single doses were given before the third and fifth CHOP cycles.

Only 9 of the 40 study participants had been previously treated. At diagnosis, 88% had stage III/IV disease and 80% had extranodal disease. Among the 38 patients that were treated and evaluable, 35 received all 6 rituximab infusions and all 6 CHOP cycles.

“The CR rate was 58% in the 38 evaluable patients,” Dr. Czuczman stated. “The PR rate was 42%. In the 35 patients who received all planned therapy, the CR rate was 63%, and the PR rate was 37%”(see Table 1).

Molecular Remissions

The researchers also assessed bcl-2 cytogenetic status in the peripheral blood and bone marrow at baseline and at various points throughout the study. (Clearing of the bcl-2 (14;18) translocation has been associated with improved survival, and CHOP alone does not produce complete molecular remissions.)

Baseline and follow-up data were available for eight patients who were positive for the bcl-2 translocation at baseline, and complete molecular remissions (conversion to bcl-2 negativity) occurred in seven of them following treatment with rituximab/CHOP. One patient reverted to bcl-2 positive at 9 months but responded when treated again with rituximab. The other six patients remain in molecular and clinical remission.

“Twenty-four patients have ongoing clinical remissions,” Dr. Czuczman reported. “There was no statistical difference in the responses achieved in patients naive to lymphoma treatment and those who had received treatment previously. Clinical and molecular responses suggest that additive therapeutic benefit is achieved by combining rituximab and CHOP therapy, while toxicity is not significantly increased.”

Higher-Grade Disease

Julie Vose, MD, and colleagues at the University of Nebraska at Omaha reported similar promising results in patients with previously untreated intermediate-grade or high-grade NHL treated with rituximab/CHOP. This phase II multi-institution study included 33 patients—24 with stage III/IV disease, 8 with stage II, and 1 with bulky stage IE disease. Six patients had one single mass of greater than 10 cm, and 18 had extranodal disease. Two-thirds of patients had diffuse large-cell disease.

“All 33 patients completed the planned rituximab plus 6 cycles of CHOP and were evaluable for response,” Dr. Vose reported. “The overall response rate was 97% (32/33), with 20 complete responses, 12 partial responses, and 1 patient with progressive disease. With median follow-up of 24 months, the median response duration is 18+ months (12 to 32+).”

There had been concern that adding rituximab would interfere with delivery of CHOP at the planned doses. Dr. Vose reported that CHOP was delivered at a normalized dose intensity of 95% and that rituximab was administered at greater than 95% of the planned dose. “Rituximab does not prohibit delivery of planned CHOP,” she concluded.

As in the Roswell Park study, adding rituximab to CHOP also removed bcl-2 positivity, in this case in 11 of 13 patients who were bcl-2 at baseline, with 10 of those 11 remaining negative. Dr. Vose said that serious adverse events were comparable to those seen with CHOP alone, including: seven patients with neutropenic fever, two with dehydration, one with cholecystitis, and two with bowel rupture or obstruction. One patient had a rituximab-induced infusion reaction.

“Rituximab plus CHOP in intermediate- or high-grade NHL is safe, and initial data indicate that this regimen has an excellent overall response rate,” Dr. Vose concluded. “Longer follow-up is needed to determine response durability, but a phase III trial is underway to evaluate the potential of cure with the combination of rituximab plus CHOP.”