The Addition of Rituximab to High Dose Sequential Chemotherapy (HDS) Programs with Autologous Transplantation Significantly Improves the Outcome of Patients with Refractory or Relapsed B-Cell Non Hogkin’s Lymphoma.
Authors: Cortelazzo Sergio , Rossi Andrea , Carlotti Emanuela , Viero Piera , Rambaldi Alessandro , Barbui Tiziano 
Published: October 2019

Abstract
The aim of the present study was to evaluate retrospectively the clinical outcome of 2 consecutive cohorts of relapsed/refractory NHL patients treated with HDS chemotherapy with and without Rituximab and autologous peripheral blood stem cell (PBSC) transplantation. A total of 110 relapsed or refractory NHL patients with different histology (SLL n= 4, FL n=24, Low grade-transformed n=31, DLBCL n=51) entered this analysis. From October 1992 up to November 2004, patients were treated with the original HDS program (n= 33, HDS: cyclophosphamide 7 gr/sqm, methotrexate 8 gr/sqm, etoposide 2 gr/sqm) (Gianni AM et al.: N.Engl.J.Med., 1997) or a modified version (n= 15) in which methotrexate was replaced by HD-Ara-C (2 g/sqm every 12 hours for 6 days). Because the addition of Rituximab could improve the antitumor activity and the response rate before transplantation, from June 1999, Rituximab (375 mg /sqm) was given twice after HD-CTX and twice after HD-Ara-C. Following the HDS chemotherapy program, a BEAM (carmustine BCNU, 300 mg/sqm; etoposide, 200 mg/sqm; Ara-C, 4000 mg/sqm; L-PAM 140 mg/sqm) conditioning regimen with autologous PBSC transplantation was planned. By quantitative PCR analysis of BCL2/IgH chimeric gene, a molecular evaluation of minimal residual disease was performed before transplantation and during follow up on bone marrow or peripheral blood obtained from 21 patients. At enrollment, 69 patients (63%) were high risk being primary refractory (39), early relapsed (7) after first line treatment or relapsed more than twice (23). Moreover, an IPI >1 was documented in 62 patients (56%) and a bone marrow infiltration in 42 (38%). Sixteen patients (15%) had received 2 or 3 lines of conventional chemotherapy and 29 (26%) involved field Radiotherapy. At the end of HDS chemotherapy, before the conditioning regimen, the Response Rate was 82% with 76 patients achieving complete remission (CR, 69%) and 14 patients partial remission (PR, 13%). After autologous transplantation, 76 patients remained in CR (69%), 5 in PR (5%), 25 (23%) showed no response or progressive disease. Four patients (3%) died during treatment. Ninety-four patients (85%) could complete the planned program and underwent autologous transplantation and a median number of 6.3 x 10^6 cells CD34+/Kg was transplanted. After transplantation, 24 patients relapsed, 1 patient developed secondary MDS and 1 patient died because of a secondary GI tract solid tumor. With a median follow-up of 28 months (range 3–146), the 5-year estimate overall survival (OS) and event-free survival (EFS) of the whole group of patients is 48% and 39%, respectively. However, the EFS of patients not receiving Rituximab was 27% as compared to 55% registered in the R-HDS program (p= 0.005). The Cox multivariate analysis confirmed an improved OS (p=0.0000) and EFS (0.001) for patients treated with R-HDS. The achievement of a durable molecular remission was achieved in 11 out of 21 analyzed and was strongly associated with the R-HDS program.
In conclusion: the response rate of relapsed or refractory NHL after HDS chemotherapy is high and more than 70% of patients can undergo conditioning regimen and autologous transplantation being in complete remission. The addition of Rituximab to HDS chemotherapy allows the collection of tumor free PBSC in most patients and significantly correlates with an improved Event Free Survival and Overall Survival.