Rituximab Plus Gemcitabine and Oxaliplatin (R-GemOx) in Refractory/Relapsed (R/R) DLBCL. a Real Life Study in Patients Ineligible for Autologous Transplantation
Authors: Cazelles Clarisse , Belhadj Karim , Vellemans Helene , Camus Vincent , Copie Christiane , Veresezan Liana , Itti Emmanuel , Becker Stephanie , verlinde Carvalho Muriel , Dupuis Jehan , Le Bras Fabien , Lemonnier Francois , Roulin Louise , El Gnaoui Taoufik , Jardin Fabrice , Mounier Nicolas , Tilly Herve , Haioun Corinne 
Published: November 2019

Introduction: There is no standard treatment of refractory or relapsed (R/R) patients (pts) with DLBCL ineligible for autologous stem-cell transplantation (ASCT). However, R-GemOx is widely used in these circumstances.
We here report the results of a retrospective analysis of a cohort of patient treated in two academic centers in France. The main objectives were to evaluate the activity and safety profile of this regimen in a large series of R/R DLBCL pts in a real life setting.
Methods:
Patients selected had to have de novo or transformed DLBCL, R/R after at least one line of treatment containing doxorubicin and rituximab, to be ineligible for ASCT and to have received at least one cycle of R-GEMOX. Rituximab 375 mg/m2 was administered on D1, gemcitabine 1000 mg/m2 on D2 and oxaliplatin 100 mg/m2 on D2 as previously described (Mounier N. et al. Haematologica 2013; 98:1726-31). Cycles were given every 2 weeks and 8 cycles were planned if at least a partial response (PR) was obtained after 4 cycles.
Results:
Between May 2002 and May 2017, 196 pts were treated. Baseline characteristics were: median age: 72 y (range, 24-89), international prognostic index (IPI) 3-5: 63%, refractory state to last treatment (tx): 42%, history of indolent lymphoma: 45%, prior ASCT: 16%. The median number of previous line was 1 (range 1-7) with 112 pts having received R-GemOx in second line. One hundred and thirty-six pts received at least 4 cycles, 86 pts completed 6 cycles and 61 pts 8 cycles. After 4 cycles, the overall response rate (ORR) according to IWC (Cheson 1999 or 2007) was 54 % and the complete response (CR) rate was 23 %. At the end of treatment, the ORR and CR rates were 38 % and 33 %, respectively. With a median follow-up of 22 months, median (m) progression-free survival (PFS) and overall survival (OS) were 5 and 10 months (mo), respectively. mOS was significantly longer in case of prior history of indolent lymphoma (21 vs 8 mo, p < 0.001), age<75y (16 v 7mo, p < 0.001), IPI <3 (p < 0.001), non-refractory status to last treatment (18 v 7mo, p < 0.001). The mOS of patients who attained a CR was 40 mo. Among pts who were treated with R-GemOx in second line, the CR rate was similar (32%), the same factors influenced the OS and duration of a first remission longer than 12 months was a favorable factor (p=0.006). Based on data collected from the population who received the first four cycles, (136 patients and 848 cycles) the median received dose intensities of oxaliplatin and gemcitabine were 73.1 %, and 75.8% of the theoretical dose, respectively. The most common toxicities during treatment were hematological and manageable. Grade 3-4 toxicities occurred in 30.6% of pts. Grade 1-2 peripheral neuropathy related to oxaliplatin was observed in 26% of the patients, with only 2 patients presenting a grade 3 peripheral neuropathy.
Summary/Conclusion: This real life study of R/R DLBCL, confirms the activity and safety of R-GemOx. This combination represents a platform to be combined with targeted therapies as it is currently proposed with nivolumab in the phase 3 NIVEAU trial (NCT03366272) and planned with polatuzumab vedotin (POLARGO trial). However, facing this very high unmet medical need, new approaches including CAR T-cells should also be considered in this patient population.

Disclosures
Belhadj: Janssen: Honoraria; Celgene: Honoraria, Other: personal fees from Celgene, personal fees from Amgen, personal fees from Takeda, personal fees from Janssen, outside the submitted work; Takeda: Honoraria; Amgen: Honoraria. Le Bras:Pfizer: Other: Travel grant; Takeda: Research Funding; Jansen: Other: Travel grant. Jardin:amgen: Honoraria; Servier: Honoraria; celgene: Honoraria; roche: Honoraria; janssen: Honoraria. Tilly:Roche: Consultancy; Celgene: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Karyopharm: Consultancy; BMS: Honoraria; Janssen: Honoraria; Gilead: Honoraria; merck: Honoraria; servier: Honoraria; roche: Membership on an entity's Board of Directors or advisory committees. Haioun:F. Hoffmann-La Roche Ltd: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Servier: Honoraria; Miltenyi: Honoraria; Takeda: Honoraria.