Rituximab-Supplemented High-Dose Sequential (HDS) Chemotherapy with Autograft Is Highly Effective in High-Risk (aaIPI 2–3) Diffuse Large B-Cell Lymphoma: Results of a Prospective Multicenter Study on 91 Consecutive Patients Treated at Diagnosis.
Authors: Zanni Manuela , Di Nicola Massimo , Patti Caterina , Castellino Claudia , Pescarollo Alessandra , Zoli Valerio , Caracciolo Daniele , Magni Michele , Devizzi Liliana , Boccadoro Mario , Majolino Ignazio , Bregni Marco , Gallamini Andrea , Mirto Salvo , Ladetto Marco , Gianni Alessandro M. , Tarella Corrado 
Published: October 2019

Abstract
Recent trials have shown that anti-CD20 monoclonal antibody Rituximab may be effectively employed in association with high-dose (hd) chemotherapy and peripheral blood progenitor cell (PBPC) autograft in the management of high-risk B-cell lymphoma. Addition of Rituximab has a dual effect: increased tumour cytoreduction and in vivo purging prior to PBPC harvesting. We here report the results of a prospective, multicenter trial evaluating Rituximab-supplemented hd-sequential chemotherapy (R-HDS) as frontline treatment in patients with high-risk Diffuse Large B-Cell Lymphoma (DLBCL). So far, 6 Italian Centres associated to GITIL have participated to the study. Eligibility criteria included: i. biopsy-proven DLBCL, with CD20+ phenotype; ii. no previous cytotoxic treatments; iii. age between 16–60 yrs.; iv. advanced stage disease with 2–3 aaIPI score. The R-HDS regimen includes an initial debulkying (3 APO courses) and then the sequential administration, at 15–20 day intervals, of: i. cyclophosphamide (CY) 7gr/sqm (day 1) + Rituximab 375mg/sqm (day +2 and +10), followed by PBPC harvest; ii. Ara-C 2gr/sqm b.i.d. for 6 days, reinfusion of 1–3x106 autologous CD34+ve cells/kg (day 7) and then Rituximab 375mg/sqm (day +8 and day +18); iii. etoposide 2.4gr/sqm day +1 + Cisplatin 100mg/sqm day +2; iv. a final myeloablative regimen (Mitoxantrone 60mg/sqm + L-Pam 180mg/sqm), with PBPC autograft (≥5x106 CD34+ve cells/kg) + Rituximab 375 mg/sqm (day +30 and +37); v. involved-field radiotherapy on areas of previous bulky lesions or residual lesions, within 2–3 mos. following autograft. Presently, 91 patients (median age: 48 yrs.) have been enrolled and are evaluable. They all had 2 (58) or 3 (33) aaIPI score; in addition, 63 (69%) presented with disease-related symptoms, 52 (57%) had extranodal disease, and 27 (30%) had BM involvement. There were 4 early toxic deaths (three due to sepsis following CY, Ara-C and autograft, respectively, and one due to leucoencephalopathy from JC-virus infection 2 mos. after autograft); one more toxic death due to pneumonia occurred at 10 mos. after R-HDS, for an overall TRM of 5.5%. In addition, 21 patients had CMV or VZV reactivation that resolved after antiviral therapy. Overall 73 patients (80 %) reached CR. So far, at a median follow-up of 24 mos., 76 patients (83.5%) are alive and 68 (75%) are in continuous CR (CCR), with 4.3-yr OS and and EFS projections of 80% and 74%, respectively. There was a trend towards a better outcome in aaIPI 2 vs. 3, although the difference was not statistically significative. Among 27 patients with BM+, 17 (63%) are presently in CCR, at a median follow-up of 25 mos. In conclusion, R-HDS was feasible at the multicenter level although the occurrence of severe infectious complications should not be underestimated. Nevertheless, both CR rate and survival curve projections compare favorably with the poor outcome usually observed in aaIPI 2–3 patients managed with conventional chemotherapy. The results here presented urge a comparative analysis between conventional vs. intensified Rituximab-supplemented chemoimmunotherapy in younger patients with high-risk DLBCL.