The first clinical trial of rituximab (Rituxan) in combination with CHOP
chemotherapy (cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine
[Oncovin], prednisone) was initiated in April 1994 (J Clin Oncol 17:268, 1999).
This study showed the safety and efficacy of the combination in low-grade
non-Hodgkin’s lymphoma (NHL) and enabled progression to phase II trials in
intermediate-grade NHL (J Clin Oncol 19:389, 2001). In addition, the Groupe d’Etude
des Lymphomes de l’Adulte (GELA) randomized phase III study has shown a
statistically significant increase in progression-free survival for
rituximab/CHOP as compared with CHOP alone (Blood 96:223a [abstract 950]).
Characteristics of the 40 patients with low-grade/follicular NHL
(International Working Formulation A, 9 patients; IWF B, 17; IWF C, 13; IWF D,
1) entered on our study are as follows: 21 males, 19 females (31 naive, 9
previously treated); median age, 48 years (range: 29-77 years); and 83% stage
III/IV at diagnosis. CHOP was administered at standard doses every 3 weeks for
six cycles, along with six infusions of rituximab (375 mg/m²/dose). Two doses of
rituximab were given both at the beginning and end of therapy, as well as single
doses before the third and fifth cycles of CHOP.
Adverse events were mostly grade 1/2. Of all events, 17% were grade 3/4 and
consisted primarily of hematologic or infectious toxicities felt to be
associated with CHOP chemotherapy. Human antimouse antibody and human
antichimeric antibody responses were not seen. Of 40 patients registered, 38
were treated (two received no therapy) and 35 completed all therapy.
All patients treated responded (58% complete responses [CR], 42% partial
responses [PR]), and the overall response rate in patients who completed all
therapy was 100% (63% CR, 37% PR). Median duration of response is 63.6+ months,
with median progression-free survival (PFS) not reached after a median
observation time of 65.1+ months. Twenty-one patients are still in remission at
46.8+ and up to 86.3+ months. Seven of eight bcl-2-positive patients converted
to polymerase chain reaction (PCR) negativity in blood and marrow (molecular
complete remissions). Of these seven patients, six remain in CR and four remain
PCR negative by serial analyses.
Naive and previously treated patients had similar demographics. Kaplan-Meier
graphs for PFS are not significantly different, although there is a trend for
longer time to progression for the naive patients (P = .409, log rank). The PR
and CR patients had similar demographics. Kaplan-Meier graphs for PFS show a
significantly longer time to progression for the CR patients (P = .017, log
CONCLUSION: Rituximab can be safely combined with CHOP, resulting in a high
response rate and a prolonged PFS, without causing significant additional
toxicity. The conversion of bcl-2 from positive to negative by PCR in blood and
marrow indicates clearance of minimal residual disease. The prolonged PFS seen
in this study exceeds that reported in CHOP (alone) studies.