Concurrent Rituximab with Dose-Dense MegaCEOP Chemotherapy and High Dose Mitoxantrone, Ara-C and Dexamethasone (MAD) Followed by BEAM and Autologous Stem Cell Transplantation (ASCT) Is Feasible and Effective in High Risk Diffuse Large B-Cell Lymphoma (B-DLCL): A Multicenter Pilot Study.
Authors: Vitolo Umberto , Liberati Anna Marina , Cabras Maria Giuseppina , Rossi Giuseppe , Levis Alessandro , Pavone Enzo , Angelucci Emanuele , Boccomini Carola , Bonello Lisa , Botto Barbara , Chiappella Annalisa , Di Vito Francesco , Palumbo Isabella , Pogliani Enrico , Rota-Scalabrini Delia , Salvi Flavia , Tonso Anna , Tucci Alessandra , Gallo Eugenio 
Published: October 2019

Abstract
Introduction: the addition of Rituximab to standard chemotherapy CHOP improves the outcome of advanced stage B-DLCL, however pts at high risk continue to have a poor outcome. The combination of Rituximab with dose-dense and intensified chemotherapy is still poorly studied so far.
Patients and methods: from January 2001 to June 2004, 92 previously untreated pts <61 yrs affected by B-DLCL at age-adjusted IPI intermediate-high (IH) or high (H) risk and/or with BM involvement were enrolled. They were treated with an intensified chemoimmunotherapy regimen R-MegaCEOP (Rituximab 375 mg/m2 day 1, Cyclophosphamide 1200 mg/m2 + Epirubicin 110 mg/m2 + Vincristine 1.4 mg/m2 day 3 and Prednisone 40 mg/m2 day 3 to 7) every 14 days with G-CSF support for 4 courses ± 2 courses of DHAP in case of less than PR; 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 days 1 to 3 and Rituximab 375 mg/m2 day 4 and before peripheral blood stem cell (PBSC) harvest as in vivo purging followed by myeloablative therapy with BEAM and ASCT± IF RT to previous bulky areas. All pts were given antibacterial and antifungal prophylaxis throughout the whole treatment. At diagnosis, PCR molecular analysis for the presence of Ig heavy chain gene rearrangement was analyzed on lymphonode or BM sample in 37 patients.
Results: Median age was 47 years (19–60); 6% were at LI risk (enrolled because of BM involvement), 53% at IH and 41% at H risk according to IPI; 27% had BM involvement and 80% LDH level >normal. So far, 72 pts who completed the treatment are evaluable for response and toxicity. Fifty-seven pts (79%) achieved a CR;one a PR (1.4%); ten pts (14%) progressed before (7 pts) or shortly after (3 pts) ASCT. Four pts (5.6%) died of infectious toxicities (2 bacterial sepsis and 2 pneumonia) which occurred during neutropenic period post MAD (3 pts) or after ASCT (1 pt). Sixteen pts did not completed the planned treatment because of disease progression before ASCT (7 pts) or inadequate PBSC yield (5 pts) or toxicity (4 pts). With a median follow-up of 2 yrs, only 2 pts relapsed. Two-yrs FFS and OS were: 72% and 77%. Fourteen pts developed infections (WHO>2): 2 interstitial pneumonia, 5 neutropenic Gram- and 2 Gram+ sepsis, 1 disseminated herpes zoster, 1 Ps. Aeruginosa and 1 Staph. aureus pneumonia, 1 bacterial pancreatitis and 1 perianal abscess. A molecular marker has been detected at diagnosis in 27 patients. So far, 12 PBSC harvest has been analyzed and 11/12 were PCR negative.
Conclusions: this interim analysis suggests that the concurrent use of Rituximab with dose-dense and high dose chemotherapy followed by myeloablative therapy with ASCT support is effective to achieve a high CR and a high 2-yr FFS rate in a group of B-DLCL patients at poor prognosis. Furthermore, the addition of Rituximab during mobilitation procedure with R-MAD may allow to collect lymphoma-free PBSC harvest.