Effect of Adding Rituximab (R) to Induction Treatment and High Dose Chemotherapy (HDC) Prior to Autologous Stem Cell Transplantation (ASCT) as First Line Therapy in Stage III-IV Diffuse Large B-Cell Lymphoma (B-DLCL) at Poor Prognosis.

Introduction: We investigated efficacy and safety of adding Rituximab (R) to induction and intensified HDC as part of first line treatment in pts with aa-IPI at Intermediate-High (IH) or High (H) risk with B-DLCL at diagnosis. We compared two groups of similar pts enrolled in two consecutive non-randomized phase II clinical trials with up-front HDC and ASCT with or without R with identical inclusion criteria conducted by GIMURELL.

Patients and methods: 118 previously untreated pts <61 years with B-DLCL, stage III-IV at aaIPI IH or H risk were treated: 41 pts were enrolled into HDC trial (control group; August 1991-August 1995) and 77 pts into R-HDC trial (study group; January 2001-December 2004). Treatment in R-HDC study group consisted in an induction treatment lasting two months with four 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 two 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. Treatment in HDC control group consisted in an induction treatment lasting two months with MACOPB chemotherapy x 8 weekly infusions followed by the same intensified and HDC regimens (MADx 2 courses + BEAM and ASCT). All pts were given antibacterial and antifungal prophylaxis throughout the whole treatment. IF RT was given to areas of previous bulky disease in both trials.

Results: Pts characteristics in both trials were comparable with no statistically significant differences: median age was 45 years (19–60); 51% were at H risk; 36% had bone marrow (BM) involvement, 80% had LDH level >normal and 42% extranodal sites>1. Complete Response at the end of the treatment was: 60 pts (78%) in R-HDC group and 28 (68%) in HDC group (p=.25). Failures (17% vs 24%) and toxic deaths (5% vs 7%) were comparable between the two groups (R-HDC vs HDC). Short-term toxicity appeared similar. Median follow-up was 27 months in study group and 69 months in control group. Two-year failure-free survival (FFS) and 2-yr overall survival (OS) rates in R-HDC group compared to HDC group were: FFS 70% vs 49% (p=.036); OS 78% vs 56% (p=.009). A better outcome for pts treated with R-HDC was confirmed in both IPI groups (IH and H risk). 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 0.54 (95% CI=0.30–0.98, p=.02) for FFS and 0.42 (95% CI=0.21–0.84, p=.03) for OS. Germinal center and non germinal center subtype analysis is ongoing in both treatment groups.

Conclusions: these results suggest that the addition of Rituximab to induction and intensified chemotherapy before BEAM and ASCT is effective and safe in B-DLCL at poor prognosis improving the outcome of these pts.