Dose Escalated CHOP + Etoposide Followed by Repetitive Autologous Stem Cell Transplantation (MegaCHOEP) with or without Rituximab for Primary Treatment of Aggressive NHL.

Abstract

Whilst safety and efficacy of adding rituximab to standard therapy has been reported, less information is available on the combination of rituximab (R) with HDT and autologous SCT. The German Study Group for High-Grade NHL (DSHNHL) developed a repetitive HDT program consisting of 4 courses dose escalated CHOP + Etoposide +/− R. Patients aged 18 to 60 years and elevated LDH at diagnosis were included. Mega-CHOEP consisted of four cycles of chemotherapy. Cycles 2 to 4 were followed by autologous SCT. At dose level 3 (DL3) cumulative doses of drugs were as follows: C 19.5 g/m2, H 280 mg/m2, O 8 mg, E 5.04 g/m2, P 2000 mg. When feasibility and safety of MegaCHOEP at DL3 had been demonstrated, rituximab was added (DL3R). Six cycles of rituximab (375 mg/m2) were given: one dose of rituximab prior to each cycle of chemotherapy and two additional doses 3 and 6 weeks after the last cycle of chemotherapy, respectively. From September 1999 to may 2001 35 pts with validated diagnosis of aggressive B-NHL received MegaCHOEP DL3, from June 2001 to February 2003, 72 pts received DL3R. There was a higher percentage of B-cell NHL patients with ECOG performance status > 1 at DL3 (42.9 %) than at DL3R (19.7 %, p = 0.012) and as consequence more patients with age-adjusted IPI high risk at DL3 (34.3 %) than at DL3R (12.7 %, p = 0.029). We observed significant differences in the incidence of WHO grade III/IV infections (DL3 9 of 123 cycles (7.3%), DL3R 48 of 236 cycles (20.3%); p=0.001) and in the percentage of patients receiving the complete program of chemotherapy (DL3:91 %, DL3R 71%; p=0.017). There were no relevant differences in other types of non-hematologic toxicity or hematopoietic recovery between treatment groups. Median observation times of patients at DL3 and DL3R were 2.6 years and 4.5 years, respectively. In univariate analysis, there was a trend to better overall survival with rituximab (75%) than without rituximab (57%) at three years (p=0.168) and a significantly better freedom from treatment failure in patients receiving DL3R as compared to DL3 with 70 % vs 50 % at 3 years (p = 0.040). In a Cox regression model adjusted for IPI, there was a trend to a higher relative risk of treatment failure of MegaCHOEP without rituximab (RR 1.8); this, however, was not statistically significant (p = 0.087). Rituximab may have beneficial influence on lymphoma control in this setting; its use, however, is accompanied by higher incidence of serious infections which subsequently compromise the dose intensity of this aggressive treatment program. The DSHNHL is currently performing a randomized study comparing MegaCHOEP+R with CHOEP−14+R.