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DLBCL is a heterogeneous disease; it has been described that around 30% of patients present a refractory/relapsing disease following R-CHOP treatment. Rituximab-containing salvage chemotherapy followed by high-dose therapy and autologous stem cell transplant (ASCT) in chemosensitive patients remains the standard of care for these patients.

Three hundred and sixty-seven patients were diagnosed of DLBCL between January 2004 to August 2016 in our center, 317/367 (86,3%) were treated with R-CHOP or R-CHOP-like in first line. Forty-four (13.9%) patients had PRD and 39 (12.3%) progressed during the follow up. Survival curves were estimated using the Kaplan-Meier method and compared using the Log-Rank test. Risk factors at diagnosis for PRD to R-CHOP were assessed. Univariate analyses were performed by Chi square test and multivariate analyses by Cox proportional hazard regression model.

Among the 44 primary refractory patients, 15 (34%), with a median age of 76 years (range 63-91), were considered unfit, 11 received supportive care and 4 were treated with palliative chemotherapy (cyclophosphamide and prednisone). Twenty nine (66%) were eligible for salvage therapy and consolidation with ASCT. Characteristics of those 29 patients at the time of salvage therapy were: median age 50 years (range 21-71), males 19 (65.5%), ECOG 2-4 16 (55.2%), Ann Arbor stage III-IV 23 (79.3%), B-symptoms 9 (31%), bulky disease (20.7%), extranodal involvement 20 (69%), leptomeningeal infiltration 4 (13.8%), high LDH 19 (65.5%), IPI 3-5 21 (72.4%). Salvage therapies used were: R-ESHAP 23 (79.4%), R-ICE 1 (3.5%), MTX-ARAC 4 (13.8%) in patients with leptomeningeal infiltration andintensive burkitt-like therapy 1 (3.4%) in a double hit patient. Twelve (41.4%) did not complete the treatment: 2 (6.8%) for toxicity (1 cardiac event and 1 septic shock) and 10 (34.4%) for progression. The intention-to-treat response rate was: CR 1 (3.5%), PR 4 (13.8%), refractory disease/progression 22 (75.8%) and not evaluable 2 (6.9%). Five patients underwent an ASTC (BEAM as conditioning regimen). One died during transplant due to septic shock and 4 progressed with a median follow-up of 5 months. One patient was rescued with a third line of treatment (R-ICE) and allogeneic transplant, and he is currently in CR at 7 months. Median PFS was 2 months (CI 95% 1.2-2.7) and median OS was 5 months (CI 95% 3.4-6.6). Among the 15 primary refractory patients who were treated with palliative intention, median PFS was 1 month (CI 95% 0.19-1.80) and median OS 1 month (CI 95% 0.19-2.42) (Figure 1). Among the 317 patients treated with R-CHOP, risk factors at diagnosis for having PRD to R-CHOP were: B-symptoms (HR 1.94, 95% CI: 1.05-3.61, p=0.034) and elevated LDH (HR 3.92, 95% CI: 1.61-9.51, p=0.003) (Table 1).

Patients with DLBCL refractory to first line R-CHOP are not rescued with current salvage therapies, and in this settingDLBCL must be considered an incurable disease with a very short survival, similar to that of patients treated with palliative care. Patients with B symptoms and elevated LDH at diagnosis have a significant higher risk to be refractory to R-CHOP. It is imperative to identify early these patients and to design new therapies for them.