Rituximab as Adjuvant to Dose-Dense and High Dose Chemotherapy (HDC) with Autologous Stem Cell Transplantation (ASCT) as First Line Treatment in Stage III–IV Diffuse Large B-Cell Lymphoma (DLBCL) at Poor Prognosis: Final Analysis of Phase II GIMURELL Trial.

Introduction: the efficacy of Rituximab (R) with standard chemotherapy in DLBCL is well known. We investigated efficacy and safety of Rituximab as adjuvant to dose-dense and HDC as part of first line treatment in untreated pts with aa-IPI at Intermediate-High (IH) or High (H) risk with DLBCL.

Patients and methods: 77 previously untreated pts <61 years with DLBCL, stage III–IV at aaIPI IH or H risk were enrolled into R-HDC trial (study group; January 2001–December 2004). Treatment consisted in an induction lasting two months with 4 courses of R-MegaCEOP chemotherapy (R 375 mg/m2 day1, CTX 1200 mg/m2 + EPI 110 mg/m2 + VCR 1.4 mg/m2 day3 and PDN 40 mg/m2 days 3–7) every 14 days with G-CSF support; then 2 courses of intensified chemoimmunotherapy R-MAD (Mitoxantrone 8 mg/m2 + ARAC 2000 mg/m2/12h + Dexamethasone 4 mg/m2/12h for 3 days and R 375 mg/m2 day4 and before PBSC harvest) followed by ASCT with BEAM as conditioning regimen.

Results: median age was 45 yrs (19–60); 47% were at H risk; 31% had bone marrow involvement, 78% had LDH level >normal and 35% extranodal sites>1. Complete Response at the end of the treatment was achieved in 60 pts (78%), PR in 2 (3%) and 11 pts (14%) did not response. Four pts (5%) died of toxicity during treatment. Few severe early toxicities (WHO grade 3–4) were reported and late toxicity was minor, with no MDS or ANLL or solid tumour. With a median follow-up of 39 months, 3-yr FFS and 3-yr OS rates were: 71% and 78%. These results were compared to those ones achieved into 41 pts, with the same clinical characteristics, enrolled in a previous phase II clinical trial with up-front HDC and ASCT but without R. Treatment in HDC control group consisted in an induction treatment lasting two months with MACOPB chemotherapy × 8 weekly infusions followed by the same intensified and HDC regimens (MAD× 2 courses + BEAM and ASCT). Three-yr FFS and OS in control group were: 46% and 54%. To properly evaluate the efficacy of R-HDC therapy, a Cox’s model was performed to adjust the effect of treatment for competing risk factors (age, IPI, BM involvement, number of extranodal sites). In this multivariate analysis the risk of failure and death was confirmed as significantly reduced in R-HDC group: adjusted hazard ratio (R-HDC vs HDC) was 0.56 (95% CI=0.30–1.01, p=.05) for FFS and 0.42 (95% CI=0.21–0.88, p=.02) for OS. PBSC harvest and time to engraftment were similar into two groups, with no statistically significant differences: all pts in both groups collected more than 2×106 CD34+/kg; median time to neutrophils engraftment (neutrophils >500/mm3) was 9 days in R-HDC group and 10 days in HDC group and median time to platelets engraftment (platelets >50000) was 15 vs 16 respectively. Conclusions: these results suggest that Rituximab as adjuvant to dose-dense and HDC may improve the outcome of DLBCL at poor prognosis. This promising new treatment strategy need to be compared to Rituximab dose-dense chemotherapy without HDC as R-CHOP14. Such a randomized trial is currently undergoing conducted by Intergruppo Italiano Linfomi.