Outcomes in Diffuse Large B-Cell Lymphoma (DLBCL) Patients Relapsing after Autologous Stem Cell Transplantation (ASCT): An Analysis of Patients Included in the Coral Study
Authors: Van Den Neste Eric , Schmitz Norbert , Mounier Nicolas , Gill Devinder , Trneny Marek , Milpied Noel , Radford John A. , Ketterer Nicolas , Shpilberg Ofer , Dührsen Ulrich , Ma David , Briere Josette , Thieblemont Catherine , Salles Gilles A. , Moskowitz Craig , Glass Bertran , Gisselbrecht Christian 
Published: November 2019

Abstract
Introduction and Methods: Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation (ASCT) is standard care for relapsed/refractory DLBCL. In the CORAL study, 477 patients were assigned to one of two salvage regimens (R-DHAP or R-ICE). Only the 240 responding patients underwent per protocol ASCT and were randomly assigned to rituximab or observation. The four-year event-free survival (EFS) post ASCT were 52 and 53% for the rituximab and observation groups, respectively (p=.7). Secondary IPI (sIPI) independently predicted EFS, PFS and OS after ASCT (Gisselbrecht et al, JCO 2010 & 2012). Outcome data are limited in DLBCL patients who relapse after ASCT, with reported overall survival (OS) of 9.9 months in rituximab-pretreated patients (Nagle et al, AJH 2013). To shed more light on outcome and prognostic factor in this population, 75 patients included in the CORAL study who relapsed after scheduled BEAM/ASCT were reviewed.
Results:
Median time between ASCT scheduled in CORAL and relapse was 7.1 months (range 3.1-61.9) with 32.9% relapsing > 12 months. Median age was 56.1y (range 20.9-67.7), M/F ratio 51/24, sIPI 0-2 in 71.6%, >2 in 28.4%. 49.3% were in the rituximab and 45.3% in the observation arm of the CORAL. All patients had previously received rituximab. Third-line therapy consisted of ICE-type (17.3%), DHAP-type (24%), gemcitabine-containing (28%), CHOP-like (13.3%), and miscellaneous regimens (17.3%). Overall response rate to third-line chemotherapy was 44%, with 32% complete response (CR)/CR unconfirmed (CRu), and 12% PR. Among the 75 patients, 16 (21.6%) could eventually be transplanted 3 ASCT and 13 allogeneic SCT with conditioning regimens including fludarabine. Median OS, calculated from time of relapse until death, was 10.0 months (95% CI 6.6-12.6; min: 0.9-max: 55.2 months; median follow-up: 32.8 months) with an estimated 1-y OS of 39.1%. Median OS was statistically different (p=.0007) according to sIPI at CORAL failure: sIPI 0-2: 12.6 months (1-y OS 51.3%), sIPI > 2: 5.3 months (1-y OS 21.6%, HR 2.805). Median OS in patients achieving CR/CRu, PR, or no response after third-line regimen was 37.7 m (1-y OS 90.5%, p<.0001, HR 0.132), 10.0 m (1-y OS 44.4%, p=.03, HR 0.375), and 6.3 months (1-y OS 13.4%), respectively. Median OS of patients who could eventually be transplanted was 17.4 months (1-y OS 68.2%), as compared to a median OS of 8.0 months in those who were not transplanted (1-y OS 31.2%) with a HR of 0.575 (p=.11). Median OS was particularly dismal among patients who relapsed < 6 months after CORAL-scheduled ASCT (5.7 months, n=28), as compared to those relapsing either > 6 and < 12 months (11.3 months, n=21) or > 12 months after ASCT (12.6 months, p=0.01, fig. 1)). In multivariate Cox analysis (with the following variables entered: age, sex, sIPI, response to third line and time between CORAL ASCT and relapse), sIPI >2 (HR 2.464, p=0.01), achievement of CR (HR 0.1, p<.0001) or PR (HR 0.242, p=0.02), and post-ASCT remission lasting < 6 months (HR 2.270, p=0.05) independently predicted for OS.
Conclusions: Overall, the outcome of DLBCL patients relapsing after second-line R-DHAP/R-ICE followed by ASCT is poor. However, prognostic factors predicting better outcome in this group are late (> 6 months) relapse, lower sIPI and achieving at least PR after third-line salvage followed by transplantation. In the transplanted patients (allo SCT or second ASCT) a 2-year OS of 50% was observed. Thus, new salvage regimens can be a bridge to transplantation in patients with late relapse and/or low sIPI,. New drugs improving salvage efficacy are urgently needed, especially for patients relapsing < 6 months following ASCT.
Figure 1. OS (months) in DLBCL patients relapsing after CORAL-scheduled ASCT according to interval between ASCT and relapse (<6 months, 6-12 months, > 12 months) Figure 1. OS (months) in DLBCL patients relapsing after CORAL-scheduled ASCT according to interval between ASCT and relapse (<6 months, 6-12 months, > 12 months)

Disclosures
Schmitz: Roche, Takeda, Gillead, Riemser und ctilifesciences: Other: Advisory board, Speakers Bureau. Gill:Sanofi Aventis: Research Funding; Roche: Honoraria; AbbVie: Honoraria; Roche: Research Funding. Milpied:Celgene: Honoraria, Research Funding. Briere:St. Louis Hospital, Paris, France: Employment. Thieblemont:St. Louis Hospital, Paris, France: Employment. Salles:Celgene Corporation; Roche and Gilead Sciences: Research Funding; Celgene Corporation; Roche: Speakers Bureau; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy. Gisselbrecht:roche: Research Funding, Speakers Bureau.