Favorable Influence of Rituximab with High Dose Sequential Chemotherapy (R-HDS) Programs and Autologous Stem Cell Transplantation (ASCT) in Salvage Treatment for Patients with Refractory or Relapsed B-Cell Non-Hodgkin’s Lymphoma.
Authors: Pintimalli Milena , Mian Michael , Rossi Andrea , Sorio Marco , Benedetti Fabio , Pizzolo Giovanni , Billio Atto , Barbui Tiziano , Rambaldi Alessandro , Cortelazzo Sergio 
Published: October 2019

Abstract
High-dose sequential (HDS) chemotherapy followed by ASCT proved to be an effective salvage therapy for patients (pts) with refractory or recurrent non-Hodgkin’s lymphoma (NHL) (Cortelazzo et al Br J Haematol, 2001). The addition of Rituximab to HDS (R-HDS) could enhance the sensitivity to rescue treatment improving the outcome of ASCT. We evaluated retrospectively clinical outcome of two consecutive cohorts of pts with low grade (LG) (n=55) or aggressive (LG-transformed=50, DLBCL=89) NHL treated with HDS chemotherapy with or without Rituximab. Regarding disease status at enrollment 135 pts (70%) were at high risk being primary refractory (n=84), early relapsed (≤12 months; n=21) or relapsed ≥2 (n=30). 86 pts were treated with HDS alone from 10/92 to 5/99 (group1), whereas 108 received R-HDS from 6/99 to 11/05 (group 2). Both groups were comparable regarding age, histology, disease status, B symptoms, bulky disease, bone marrow infiltration, median number of previous chemotherapies and IPI risk factors. After a debulking phase of 2–3 cycles of either doxorubicin- or cisplatin-containing chemotherapy pts received original HDS chemotherapy (n=91): high dose (HD)-cyclophosphamide (CTX) 7 gr/sqm, HD-methotrexate 8 gr/sqm, HD-etoposide 2 gr/sqm or a modified version (n=103) in which HD-methotrexate was replaced by HD-Ara-C (2 g/sqm every 12 hours for 6 days). Rituximab (375 mg/sqm) was given twice after HD-CTX and HD-Ara-C in 108 patients (56%). After HDS chemotherapy a BEAM or HD-mitoxantrone plus melphalan (60 and 180 mg/sqm) conditioning regimen with ASCT was planned. After HDS chemotherapy ORR was 84% in group 1 and 94% in group 2 with 29 and 81 pts achieving complete remission (CR) (34% vs. 75%; p=0.0001). Moreover, 76 pts (88%) in group 1 and 97 (90%) in group 2 underwent ASCT with a median number of 7.2 x 10^6 cells CD34+/kg (range, 3–27) transplanted. At the completion of treatment, 52 pts in group 1 and 94 in group 2 achieved CR (60% vs. 87%; p=0.0001). Regarding toxicity, 2 pts (2%) died in group 1 and one developed a bladder carcinoma, while in group 2 two pts (2%) died, one of secondary MDS and one developed a thyroid carcinoma. With a median follow-up of 36 months (range 3–154) in group 1 and 21 months (range 1–81 months) in group 2, the 5-year estimated OS, EFS and DFS were 47%, 33%, 49% and 75%, 60 %, 70% (p=0.0001). In Cox regression analysis LG histology (p=0.05), R-HDS therapy (p=0.04) and CR prior to ASCT (p=0.0001) emerged as favourable independent prognostic factors, while bulky disease (p=0.01) and ≥2 relapses (p=0.02) were adverse prognostic factors for EFS. This retrospective study shows that addition of Rituximab to HDS improves the CR rate increasing the number of transplant eligible subjects and prolongs survival of these high risk patients.