The addition of rituximab to CHOP-21 significantly improved clinical outcome in elderly patients with DLBCL (Coiffier et al., 2002). In young patients, the MInT trial, where young good-prognosis patients were randomized to receive a CHOP-like regimen or the same CHOP-like regimen plus rituximab, had to be stopped early because of superiority of the rituximab arm, and results were published with a median follow-up of 34 months (Pfreundschuh et al., Lancet Oncology 2006;379–91).
Because the MInT study was the first study to show a survival benefit of the addition of rituximab to a CHOP-like regimen in young good-prognosis patients, it is important to analyze the effect of different chemotherapy regimens on long-term outcome.
In a phase III intergroup study with participating cooperative groups from 18 countries, previously untreated young (18-60 years) patients with good-prognosis DLBCL (age-adjusted IPI 0 or 1, stages II-IV and stage I with bulky disease) were randomized to receive 6 cycles of a CHOP-like regimen (CHEMO) or the same chemotherapy plus rituximab 375 mg/m2, given on day 1 of each 3-weekly regimen and on days 1, 22, 43, 64, 85 and 106 of the 2-week regimens, respectively (R-CHEMO). Radiotherapy (30-40 Gy) was planned to sites of initial bulky disease and/or extranodal involvement. The primary endpoint was event-free survival (EFS) with events defined as failure to achieve complete remission, progressive disease, relapse, death or additional (unplanned) therapy.
Between 05/2000 and 10/2003 a total of 823 patients were recruited of whom 396 were allocated to receive CHOP-21, 361 to CHOEP-21, 34 to MACOP-B, and 32 to PMitCEBO with or without rituximab. Patients`characteristics were not different between the treatment arms with the exception that patients in the MACOP-B and R-MACOP-B arm had a more favorable prognostic profile. Toxicity, incidence of adverse events and severe adverse events in the different CHEMO and the R-CHEMO arms were not significantly different. After a median observation time of 70 (0.03-117) months, the 6-year EFS rates of patients assigned to CHEMO only were 50.4%, 60%, 41.7%, and 78.6% for CHOP-21, CHOEP-21, PMitCEBO, and MACOP-B, respectively. In an adjusted multivariate Cox regression model for EFS restricted to CHEMO patients, only the CHOEP-21 hazard ratio (HR) was significant (HR=0.73; p=0.05) compared to CHOP-21, while the hazard ratios of the different chemotherapies were not significantly different for PFS and OS (6 year PFS-rates: 60.2%, 64.8%, 67.5%, 86.2%; and 6 year OS-rates: 78.8%, 80.2%, 65.5%, and 100.0%, respectively). In patients assigned to R-CHEMO, 6-year EFS rates were 74.9%, 75%, 36.5%, and 86.7% for CHOP-21, CHOEP-21, PMitCEBO and MACOP-B, respectively. Likewise, PMitCEBO patients tended to have lower PFS (6-year rates: 79.1%, 81.9%, 58.9, and 86.7%, respectively) and OS (6-year rates: 91.9%, 89.4%, 80.0 and 94.1%, respectively). The poor outcome after R-PMitCEBO in contrast to R-CHOP was confirmed by multivariable Cox regression restricted to R-CHEMO and adjusting for aaIPI and bulky disease. Hazard ratio of PMitCEBO was significant for EFS (HR 4.35, p<0.001) and PFS (HR 3.62, p=0.002), with a strong trend for OS (HR 3.11, p=0.073).
While the addition of rituximab to CHOP-like regimens usually results in reduced differences between chemotherapy regimens (“chemo-equalizer” effect, e.g. disappearance of the superiority of CHOEP over CHOP after the addition of rituximab), combination of rituximab with some regimens might result in an unexpectedly poor outcome. Therefore, rituximab should not be combined with regimens other than CHOP outside randomized trials. Supported by Roche, Deutsche Krebshilfe and KML.
Jäger:Roche: Honoraria, Research Funding. Pettengell:Roche: Honoraria. Pfreundschuh:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.
Asterisk with author names denotes non-ASH members.