Rituximab (R) in Addition to Dose-Dense Chemotherapy MegaCEOP and Intensification with R-MAD Followed by High Dose Chemotherapy BEAM with Autologous Stem Cell Transplantation (ASCT) Is Safe and Effective in Untreated High Risk Diffuse Large B-Cell Lymphoma (DLBCL).

Introduction: The addition of R to dose-dense chemotherapy CHOP and to high-dose chemotherapy seems to improve the outcome of advanced stage DLBCL.

Patients and methods: From August 2000 to September 2006, 120 previously untreated patients (pts) <61 years affected by aggressive DLBCL were enrolled into 12 GIMURELL centers. Inclusion criteria were: advanced stage II, III-IV with age-adjusted (aa)-IPI score 2–3 or BM involvement (any aa-IPI score), viral markers negativity. Treatment plan consisted in a dose-dense chemoimmunotherapy R-MegaCEOP (R 375 mg/m² d1, CTX 1200 mg/m² + EPI 110 mg/m² + VCR 1.4 mg/m² d3 and PDN 40 mg/m² dd3–7) every 14 days with G-CSF support for 4 courses; pts in CR or PR received two courses of intensified chemotherapy R-MAD (Mitoxantrone 8 mg/m² + ARA-C 2000 mg/m²/12h + Dexamethasone 4 mg/m²/12h dd1–3 and R 375 mg/m² d4 and before peripheral blood stem cell harvest as in vivo purging) followed by ASCT with BEAM as conditioning regimen ± IF-RT. All pts received antibacterial and antifungal prophylaxis throughout the whole treatment. In pts with BM and/or CNS risk involvement, 4 IT-MTX 15 mg were planned as intrathecal prophylaxis.

Results: All 120 pts were evaluable: median age 47 years (19–60); 65 males and 55 females; 6% were at Low-Intermediate, 52% at Intermediate-High and 42% at High risk according to aa-IPI score; PS ≥2 65%, 27% BM involvement, 48% bulky disease, 80% LDH >normal and stage II/III/IV 8/19/73% respectively. Complete response at the end of treatment was achieved in 98 pts (82%), PR in 5 (4%), 12 (10%) did not respond and 5 (4%) died of toxicity. IF-RT was performed as consolidation of bulky disease or residual disease on 36% of pts. With a median follow-up of 42 months, 4-yr FFS and 4-yr OS rates were: 77% and 80%. In 101 pts (84%), PBSC yeald was good, with a median of 9.7 × 10⁶ cells CD34/kg (range 2.5–56.3). Nineteen pts (16%) were not autografted: 5 because of inadequate PBSC yield, 9 of progression disease and 5 of toxicity. All 101 pts who underwent ASCT achieved a complete hematological engraftment with a median of 9 days (3–27) to neutrophil counts >0.5 × 10⁹/L and a median of 14 days (1–72) to a self-sustaining platelet count >50 × 10⁹/L. Transfusional support was: platelets and red-cell package respectively in 8% and 24% of pts during 4 R-MegaCEOP, 92% and 70% during 2 R-MAD and 96% and 74% during BEAM consolidation. Few severe toxicities (WHO grade 3–4) were reported; most frequent (12%) were infection and mucositis during R-MAD and BEAM phase. Five patients died of toxicity due to: E.coli sepsis in 2 pts respectively after R-MegaCEOP and R-MAD, one of sepsis ndd after R-MAD, one of Staphilococcus pneumonia after R-MAD and one of P.aeruginosa pneumonia after BEAM regimen. There are no secondary MDS or ANLL or solid tumour.

Conclusions: This study suggests that Rituximab as adjuvant to dose-dense and high dose chemotherapy with ASCT support is effective and safe in high risk DLBCL.