Benefit of Rituximab Addition to High-Dose Programs with Autograft for B-Cell Lymphoma: A Multicenter GITIL Survey on 957 Patients.
Authors: Tarella Corrado , Zanni Manuela , Magni Michele , Benedetti Fabio , Barbui Tiziano , Boccadoro Mario , Patti Katia , Ciceri Fabio , Gallamini Andrea , Cortelazzo Sergio , Zoli Valerio , Mirto Salvatore , Passera Roberto , Corradini Paolo , Pizzolo Giovanni , Gianni Alessandro M. , Rambaldi Alessandro 
Published: October 2019

Abstract
Background: The outcome of B-cell lymphoma has definitely improved since the introduction of the anti-CD20 Rituximab, which can be effectively combined into conventional chemotherapy regimens. Rituximab can also be added to high-dose chemotherapy programs with autograft. However, the clinical benefit of combining Rituximab and autograft-based programs has not been proved yet. This issue is addressed in the present study.
Patients and Methods: Data have been retrospectively collected on 957 B-cell lymphoma patients receiving a high-dose sequential (HDS) chemotherapy program, at 10 Italian Centers associated to GITIL (Gruppo Italiano Terapie Innovative nei Linfomi). Although the HDS schedule has been introduced almost 20 yrs. ago, most patients were treated in the last decade. They received most frequently either the HDS scheme adapted for follicular lymphoma (Tarella C et al. Leukemia 2000) or the hd-Ara-C-supplemented scheme developed for mantle-cell and diffuse large cell lymphoma (Magni M et al, Blood 2000; Cuttica A et al., Cancer 2003); overall, Rituximab was added to HDS (R+) in 483 (50.5%) patients, the remaining 474 (49.5%) received Rituximab-free HDS (R−). All patients entered the HDS-protocols due to high-risk prognostic features, their median age was 49 yrs. (range 17–70). The series included 403 patients (232 R+) with low-grade and 554 (251 R+) with intermediate/high grade B-cell lymphoma subtypes; HDS was delivered to 542 (259 R+) patients at diagnosis and to 415 (224 R+) at first or subsequent relapse.
Results: at a median follow-up of 5 yrs, the 5-yr Overall Survival (OS) and Event-free Survival (EFS) projections were 66% and 55%, respectively, with a significantly better outcome for patients treated at diagnosis (5-yr OS: 72%, EFS: 61%) compared to patients at relapse (5-yr OS: 56%, EFS: 45%). In all instances, Rituximab addition was associated with significant improvements; in particular, the 5-yr EFS projections were:patients at diagnosis: 68% for R+ vs. 57% for R−;patients at relapse: 59% for R+ vs. 34% for R−;low-grade subtypes: 65% for R+ vs. 41% for R− (Figure 1A);intermediate/high-grade subtypes: 64% for R+ vs. 52% for R− (Figure 1B).
In the Cox multivariate survival analysis, two factors had a significant impact on the EFS, i.e. relapse status at HDS (HR: 1.74, c.i.: 1.43–2.13) and Rituximab addition to HDS (HR: 0.60, c.i.: 0.49–0.75).
Conclusions: the addition of Rituximab to high-dose programs with autograft may improve response and long-term outcome in high-risk B-cell lymphoma patients.
Figure 1. EFS according to Rituximab [R] administration, in (A) low-grade and (B) intermediate/high-grade, B-cell lymphoma patients treated with a HDS program Figure 1. EFS according to Rituximab [R] administration, in (A) low-grade and (B) intermediate/high-grade, B-cell lymphoma patients treated with a HDS program