Background: Aggressive non-Hodgkin lymphoma (aNHL) relapsing after high-dose therapy or, in not transplant-eligible patients, after 1st-line chemotherapy represents an unmet clinical need. Therefore, we aimed at evaluating a salvage combination regimen based on pixantrone, an aza-anthracenadione recently approved in Europe for patients with multiply relapsed aNHL. Etoposide and bendamustine were chosen as companion compounds due to available feasibility data in combination with anthracenadions, and a well-documented efficacy in salvage regimens for relapsed aNHL. Rituximab was added, if the relapse tumor biopsy was CD20+. Aim: The aim of the present analysis was to summarize the preliminary clinical experience with the PREBEN/PEBEN regimen gathered, on a compassionate need basis, at different European sites and representing the platform for a currently ongoing Nordic phase 1/2 trial in relapsed aNHL. Methods: The adopted schedule consisted of pixantrone 50 mg/m2 i.v. day 1+8, etoposide 100 mg i.v. day 1, bendamustine 90 mg i.v. day 1 with or without the addition of rituximab 375 mg/m2 i.v. day 1 (PREBEN/PEBEN). If feasible, each cycle was given at 3-weekly intervals for a maximum of 6 cycles. All patients were assessed for chemosensitivity with PET/CT, already after cycle 1 or 2. G-CSF support was applied and administered according to local practice. Results: A total of 30 heavily pre-treated patients (19 males and 11 females, age range 49-81 yrs; mean N of previous regimens: 3, range 1-7) with aNHL were treated according to the PREBEN/PEBEN schedule. Seventeen had diffuse large B-cell (DLBCL), six transformed indolent (tIND), and seven peripheral T-cell lymphoma (PTCL). All patients had intermediate or high risk IPI prior to start of salvage therapy. Eight patients (27%) had a complete metabolic response (CMR) and seven (23%) a partial one (PMR), resulting in an overall response rate (ORR) of 50%. Among the histological subtypes, the patients with DLBCL, PTCL and tIND had an ORR of 53% (CMR 35%), 57% (CMR 14%), and 33% (CMR in one out of two responders), respectively. Most responses were achieved early (prior to course nr. 4). Response durations ranged between 2 and 23+ months. Among the 17 patients with DLBCL, nine were frail, non transplant-eligible with relapsed disease, six had primary refractory lymphoma progressing through anthracycline-containing 1st line and platinum-containing salvage therapies, and two had relapses occurring after a post-transplant remission period. While most of the relapsed patients with DLBCL responded , i.e. seven (five CMR and two PMR) of the nine (78%) frail relapsed patients and one of the two (50%) patients with post-transplant relapses, only one out six (17%) primary refractory patients exhibited some chemosensitivity. Interestingly, four out of seven PTCL patients achieved a PMR or CMR allowing them to undergo non-myeloablative allogeneic transplant with subsequent sustained response durations. The treatment schedule was feasible and most patients received it on an out-patient basis. The most common grade 3-4 toxicity was of hematological type (mainly neutropenia and thrombocytopenia), occurring in 52% of the patients. Grade 3-4 infections were observed at a frequency of 21%. No septic deaths were recorded. A previously anthracycline exposed, heavily pre-treated 60-year old female PTCL patient developed symptomatic congestive heart failure effectively reversed by angiotensin converting enzyme inhibitors with normalization of the myocardial ejection fraction. One previously ibritumomab tiuxetan exposed, heavily pretreated patient with tIND developed acute myeloid leukemia with therapy-related cytogenetic features. Conclusions: The PREBEN/PEBEN salvage regimen was feasible in a heavily pre-treated cohort of elderly patients with high-risk aNHL. In individual patients it elicited substantial and durable responses early in the course of therapy. In some younger patients, it proved useful as bridging strategy to a non-myeloablative allogeneic transplant. A phase 1/2 study in relapsed (non-refractory) aNHL was launched in June 2016 (ClinicalTrial.gov identifier: NCT02678299; EudraCT number: 2015-000758-39) and is currently accruing (N=5 pr. Aug 1st, 2016). Clausen:Takeda: Research Funding; Novartis: Other: Travel expences; Abbvie: Other: Travel expences. Leppa:Mundipharma: Research Funding; Roche: Honoraria, Other: Travel expenses, Research Funding; Bayer: Research Funding; Janssen: Research Funding; Takeda: Honoraria, Other: Travel expenses; CTI Life Sciences: Honoraria; Amgen: Research Funding; Merck: Other: Travel expenses. Willenbacher:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; European Commision: Research Funding. d'Amore:Servier: Honoraria, Other: Advisory Boards; CTI LIfe Sciences: Honoraria, Other: Advisory Boards.