NEW ORLEANSCombining 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-Hodgkins
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.
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).
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
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
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
patients24 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.