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With climate, biodiversity and inequity crises squarely upon us, never has there been a more pressing time to rethink how we conceptualize, understand and manage our relationship with Earth's biodiversity. Here, we describe governance principles of 17 Indigenous Nations from the Northwest Coast of North America used to understand and steward relationships among all components of nature, including humans. We then chart the colonial origins of biodiversity science and use the complex case of sea otter recovery to illuminate how ancestral governance principles can be mobilized to characterize, manage and restore biodiversity in more inclusive, integrative and equitable ways. To enhance environmental sustainability, resilience and social justice amid today's crises, we need to broaden who benefits from and participates in the sciences of biodiversity by expanding the values and methodologies that shape such initiatives. In practice, biodiversity conservation and natural resource management need to shift from centralized, siloed approaches to those that can accommodate plurality in values, objectives, governance systems, legal traditions and ways of knowing. In doing so, developing solutions to our planetary crises becomes a shared responsibility. This article is part of the theme issue ‘Detecting and attributing the causes of biodiversity change: needs, gaps and solutions’.

Novel drugs are rapidly moving forward the treatment-paradigm of non-Hodgkin-lymphomas (NHLs). Notwithstanding, especially in aggressive subtypes, chemotherapy remains the pillar of treatment. Indeed, the combination of highly effective Maximum-Tolerated-Dose Chemotherapy (MTD-CHEMO) + “novel drugs”, has so far, fallen short from expectations, often because it caused excessive toxicity. Metronomic chemotherapy (mCHEMO), which is the frequent, long-term administration of low dose cytotoxic drugs, may allow more effective and tolerable combinations. mCHEMO pharmacodynamics, has been described as pleiotropic. In fact, it may have different cellular and molecular targets, when drugs or their schedules are modified. Although mCHEMO has been little explored in NHLs, pre-clinical studies - in lymphoma models - which addressed the activity of mCHEMO in combination with novel drugs, have shown very promising results. These included inhibitors of histone deacetylase, mTOR and PI3K/mTOR, as well as the immune checkpoint inhibitor anti-PD-L1. Moreover, a few impressive reports have recently shown all-oral mCHEMO schedules, with or without rituximab, can effectively shrink both B and T-cell aggressive NHLs. Indeed, these regimens allowed elderly-frail patients to achieve sustained remission, while toxicity proved manageable. In our opinion, all-oral mCHEMO, is an active, easy-to start, well-tolerated, and inexpensive therapeutic approach, which deserves further investigation. Most importantly, mCHEMO, holds promise to empower the activity of novel targeted therapies, without causing excessive toxicity.

CT-PET scan showing clinical response of Pt#2.

Supplementary Table I: IFN-DC release criteria and median values registered among patient-derived IFN-DC (min-max range); Supplementary Table 2: Patients MHC-I and MHC-II alleles and IGHV epitope sequences

Purpose:This study was aimed at evaluating the feasibility, safety, immunologic and clinical responses in patients with follicular lymphoma treated with monocyte-derived dendritic cells generated in the presence of IFNα and GM-CSF (IFN-DC) in combination with low doses of rituximab.Patients and Methods:Firstly, we analyzed in vitro and in vivo the immunologic properties of IFN-DC against follicular lymphoma. Thus, we performed a phase I trial in 8 patients with refractory and relapsed follicular lymphoma based on sequential intranodal injections of low-dose of rituximab and unloaded IFN-DC and report the safety, clinical, and immunologic results of the enrolled patients.Results:Preclinical studies indicated that IFN-DC can synergize with rituximab leading to increased cytotoxicity and T-cell tumor infiltration. The clinical evaluation showed that the combined treatment was totally safe. The overall response rate was 50%, PET-negative complete response rate 37%, and remission is still ongoing in 2/4 of responding patients (median follow-up 26 months, range 11–47). Notably, following the combined therapy all patients showed induction/enhancement of T-cell responses by CD107 degranulation or IFNγ ELISPOT assay against patient-specific tumor IGHV sequences.Conclusions:These results represent the proof-of-principle on the effectiveness of unloaded IFN-DC in inducing durable clinical responses and promoting induction of tumor-specific peripheral T cells, thus suggesting the occurrence of an effective endogenous antitumor vaccination. The overall findings indicate that some unique properties of IFN-DC can be successfully exploited to induce/enhance antitumor responses, thus representing a valuable antitumor strategy for novel and more effective combination therapies in patients with cancer.

CT-PET scan showing clinical response of Pt#3

The upfront treatment of very elderly and frail patients with diffuse large B-cell lymphoma (DLBCL) is still a matter of debate. Herein, we report results of the metronomic all-oral DEVEC [prednisolone/deltacortene®, vinorelbine (VNR), etoposide (ETO), cyclophosphamide] combined with i.v. rituximab (R). This schedule was administered as a first line therapy in 22 elderly/frail DLBCL subjects (median age = 84.5 years). In 17/22 (77%) patients, the Elderly-IPI-score was high. After a median follow-up of 24 months, 15 patients had died: seven (50%) for causes unrelated to DLBCL or its treatment, six (40%) for progression, and two (13%) for multiorgan failure. Six treatment-pertinent serious-adverse-events occurred. At the end of induction, 14/22 (64%) achieved complete remission; overall survival and event-free survival at 24 months were both 54% (95% CI = 32–72%), while the time to progression was 74% (95% CI = 48–88%). Furthermore, antiproliferative and proapoptotic assays were performed on DLBCL/OCI-LY3 cell-line using metronomic VNR and ETO and their combination. Both metronomic VNR and ETO had concentration-dependent antiproliferative (IC50 = 0.036 ± 0.01 nM and 7.9 ± 3.6 nM, respectively), and proapoptotic activities in DLBCL cells. Co-administration of the two drugs showed a strong synergism (combination index < 1 and dose reduction index > 1) against cell proliferation and survival. This low-dose schedule seems to compare favourably with intravenous-CHEMO protocols used in the same subset. Indeed, the high synergism shown by metronomic VRN+ETO in in vitro studies, explains the remarkable clinical responses and it allows significant dose reductions.

Purpose Peripheral T cell lymphomas (PTCLs) have an overall poor prognosis. Indeed, registry data in elderly patients show that the median progression-free survival (mPFS) following first- and second-line therapies are only 6.7 and 3.1 months, respectively. The aim of the study is to show the activity of metronomic chemotherapy, a regular administration of low chemotherapeutic drug doses allowing a favourable toxicity profile, on elderly PTCL patients. Methods We report a series of 17 PTCL patients, treated with the all-oral metronomic schedule DEVEC (prednisolone–etoposide–vinorelbine–cyclophosphamide) in four Italian centres. Patients 5/17 (29.4%) were treatment-naïve (naïve) and 12/17 (70.6%) were relapsed-refractory (RR), respectively. The median age was 83 years (range 71–87) and 71.5 years (range 56–85) for naïve and RR, respectively. In vitro activity of metronomic vinorelbine (VNR), etoposide (ETO) and their concomitant combination on HH, a PTCL cell line, was also assessed. Results Histology: PTCL-not-otherwise-specified = 12; angioimmunoblastic = 2; NK/T nasal type = 1; adult-type leukaemia lymphoma = 1, transformed Mycosis Fungoides = 1. The overall response rate was 80 and 58% in naïve and RR, respectively; whereas the PFS was 20 in naïve (95% CI 0–43) and 11 months (95% CI 4.2–17.8) in RR. The occurrence of relevant adverse events was 23.5%, which was managed with ETO dose reduction. In vitro experiments showed that both metronomic VNR and ETO caused a significant inhibitory activity on HH cells and a strong synergism when administered concomitantly. Conclusion All-oral DEVEC showed an encouraging activity and acceptable toxicity. This schedule deserves further studies in elderly PTCL also for assessing combinations with targeted drugs. Electronic supplementary material The online version of this article (10.1007/s00280-020-04172-3) contains supplementary material, which is available to authorized users.

PURPOUSE: to assess the clinicopathologic features of a poorly defined subset of diffuse large b-cell lymphoma, which is characterized by the secretion of an IgM paraprotein (IgMs-DLBCL). EXPERIMENTAL DESIGN: multicentre, retrospective, and comparative study to analyse with an integrated diagnostic approach the IgMs-DLBCL subset.RESULTS: Overall, 650 DLBCL were enrolled: 102 had an associated serum IgM and 56 other paraproteins (OP), the remaining 492 cases were the reference group (REF). IgMs-DLBCL were characterized by older age, advanced stage, dissemination to extra-nodal organs, elevated LDH and poor PS. As a result, the majority of IgMs had a high IPI, NCC-IPI and CNS-IPI score (p

Purpose: This study was aimed at evaluating the feasibility, safety, immunologic and clinical responses in patients with follicular lymphoma treated with monocyte-derived dendritic cells generated in the presence of IFNα and GM-CSF (IFN-DC) in combination with low doses of rituximab. Patients and Methods: Firstly, we analyzed in vitro and in vivo the immunologic properties of IFN-DC against follicular lymphoma. Thus, we performed a phase I trial in 8 patients with refractory and relapsed follicular lymphoma based on sequential intranodal injections of low-dose of rituximab and unloaded IFN-DC and report the safety, clinical, and immunologic results of the enrolled patients. Results: Preclinical studies indicated that IFN-DC can synergize with rituximab leading to increased cytotoxicity and T-cell tumor infiltration. The clinical evaluation showed that the combined treatment was totally safe. The overall response rate was 50%, PET-negative complete response rate 37%, and remission is still ongoing in 2/4 of responding patients (median follow-up 26 months, range 11–47). Notably, following the combined therapy all patients showed induction/enhancement of T-cell responses by CD107 degranulation or IFNγ ELISPOT assay against patient-specific tumor IGHV sequences. Conclusions: These results represent the proof-of-principle on the effectiveness of unloaded IFN-DC in inducing durable clinical responses and promoting induction of tumor-specific peripheral T cells, thus suggesting the occurrence of an effective endogenous antitumor vaccination. The overall findings indicate that some unique properties of IFN-DC can be successfully exploited to induce/enhance antitumor responses, thus representing a valuable antitumor strategy for novel and more effective combination therapies in patients with cancer.

Follicular lymphoma (FL) is a remarkably immune-responsive malignancy, which is still considered incurable. As, standard immunochemotherapy is complex, toxic and not curative, improvement in FL care is now a crucial topic in hemato-oncology. Recently, we and others have shown that dendritic cell (DC)-based therapies allow a specific immune response associated with sustained lymphoma regression in a proportion of low-tumor burden FL patients. Importantly, the rate of objective clinical response (33-50%) and of sustained remission is remarkably higher compared to similar studies in solid tumors, corroborating the assumption of the immune responsiveness of FL. Our experimental intra-tumoral strategy combined injection with rituximab and interferon-α-derived dendritic cells (IFN-DC), a novel DC population particularly efficient in biasing T-helper response toward the Th1 type and in the cross-priming of CD8 + T cells. Noteworthy, intra-tumoral injection of DC is a new therapeutic option based on the assumption that following the induction of cancer-cell immunogenic death, unloaded DC would phagocytize in vivo the tumor associated antigens and give rise to a specific immune response. This approach allows the design of easy and inexpensive schedules. On the other hand, advanced and straightforward methods to produce clinical-grade antigenic formulations are currently under development. Both unloaded DC strategies and DC-vaccines are suited for combination with radiotherapy, immune checkpoint inhibitors, immunomodulators and metronomic chemotherapy. In fact, studies in animal models have already shown impressive results, while early-phase combination trials are ongoing. Here, we summarize the recent advances and the future perspectives of DC-based therapies in the treatment of FL patients.

The Garcin syndrome is a rare condition characterized by multiple unilateral cranial nerve palsy, without neither long-tract involvement nor intracranial hypertension. Non-Hodgkin lymphoma is a systemic malignant disease that localizes in a minority of cases in the central nervous system. We report a case of Garcin syndrome that revealed a diffuse large B cell lymphoma (DLBCL) located in the skull base and in the right kidney. We reached the diagnosis by mean of a nonstandard, mini-invasive, transforamen ovale biopsy of the intracranial lesion (Hartel's route).The nature of the renal mass was determined ex juvantibus. The patient responded to the polichemotherapy with a complete regression of the intracranial lesion and of the renal mass evaluated by computed tomography and total body positron emission tomography scans. We, therefore, confirmed the DLBCL location in the right kidney. Over 4 years of follow-up, the patient has showed a complete remission of the disease. In this report, we emphasize the importance of biopsy in case of Garcin syndrome.

Introduction: We recently demonstrated in a large multicentre study that sGA can identify fit older patients with aggressive lymphoma able to tolerate first-line intensive treatment with curative intent and to obtain similar results than younger people (Merli at al JCO 2021). Regardless of age, about 40% of patients with aggressive lymphoma are either refractory or will eventually relapse after treatment with curative intent. Salvage platinum-based regimens followed by ASCT in responsive disease is a standard of care to obtain longer second remission. However, in many case series, patients over 65 years are excluded from the transplant approach because of potential severe toxicities of high-dose therapy in older patients. This study was designed to evaluate the feasibility and activity of high-dose treatment followed by ASCT in older FIT patients with R/R aggressive lymphoma selected with a sGA. Methods: Patients with R/R aggressive lymphoma after one line of treatment, aged between 65 and 75, and FIT to sGA were eligible for the study. Salvage treatment could be chosen between R-DHAP, R-ICE or other platinum or gemcitabine-containing regimens and stem cells were mobilized after 1 or 2 cycles. Patients achieving at least partial response after 3 courses and who remained FIT to sGA evaluation were eligible for ASCT and were conditioned with either BEAM or FEAM. Results: From May 2014 to August 2019, seventy-five patients from 16 FIL centres were enrolled and 70 were eligible for the study. Sixty-six of them had a diffuse large B-cell lymphoma, one had follicular 3b, 2 mantle cell and 1 Burkitt histology. Salvage treatment was R-DHAP in 48 patients, R-ICE in seven and gemcitabine or oxalyplatinum containing regimens in the remaining ones. Overall response rate after three courses was 44% (21 complete and 10 partial remission). Among the 39 unresponsive patients, 29 had progressive and 4 stable disease, 2 patients died of septic shock and heart failure during salvage and 4 patients withdrew their consent to ASCT. Four patients relapsed soon after response achievement before undergoing the transplant. ASCT was performed in 27 patients with a median of 5.6 x 10 6 CD34/Kg reinfused. No differences emerged in demographic and clinical characteristics between patients reaching the ASCT timepoint or not (Tab 1a). By intention to treat analysis, 2-y overall survival (OS) and PFS of the entire intention-to-treat population were 65% (95%CI: 50-76%) and 34% (95%CI: 22-46%) respectively, without differences according to age (Tab 1b). After a median of 27 months, 2-y OS was 79% (95CI: 51-86%) and EFS 56% (95CI: 32-75%). Twenty-four patients obtained a complete remission (CR) and 20 of them are in continuous CR after more than 12 months. Three patients progressed 1-8 months after ASCT and died. Most common non-hematologic grade 3-4 adverse events were gastrointestinal (10%) and infectious (8%). Conclusion: This study shows that sGA can identify older patients with R/R aggressive lymphoma who are able to tolerate and can benefit from high-dose therapy and ASCT. The poor response to second-line immunochemotherapy remains the major drawback of this approach since less than 50% of patients could actually receive ASCT. Nevertheless the 2-y survival of 65% in the intention to treat population is remarkable and sets the stage for the evaluation of new approaches such as CAR-T or bispecific antibodies also in older patients. A next step should be to explore the usefulness of sGA in the selection of candidates to these innovative treatments. Figure 1 Figure 1. Disclosures Tucci: Takeda: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Musuraca: janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo: ROCHE: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Gilead: Speakers Bureau. Zilioli: Roche, Italfarmaco: Consultancy, Honoraria; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau; Takeda: Other: travel expenses, accommodation. Merli: EUSA Pharma: Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; MSD: Membership on an entity's Board of Directors or advisory committees; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Celgene: Other: Travel, Accomodations, Expenses. Marcheselli: sandoz: Membership on an entity's Board of Directors or advisory committees. Rossi: Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees.

INTRODUCTION Treatment of Diffuse Large B cell lymphoma (DLBCL) in the elderly population is challenging as many patients (pts) are not eligible to receive standard curative therapy, due to comorbid conditions and to a higher susceptibility to the side effects of standard anthracycline containing regimens. Among currently available active drugs, Lenalidomide has been used in the setting of relapsed/refractory DLBCL both as monotherapy and in combination with rituximab, showing a good activity and an acceptable safety profile. We started a prospective, multicenter, single arm, phase II trial to demonstrate activity and safety of a chemo-free combination of lenalidomide + rituximab in older (≥ 70 years) untreated pts with DLBCL who were prospectively defined as frail according to the simplified comprehensive geriatric assessment (sCGA) (Tucci A. et al., Leuk Lymphoma. 2015 Apr). PATIENTS AND METHODS Pts were eligible if they were previously untreated DLBCL patients, older than 69 years and defined as frail according to sCGA. The treatment consisted of a 28-day cycle (R2) combining oral Lenalidomide (20 mg on days 1 to 21) and i.v. Rituximab (375 mg/m2 on day 1); a maximum number of 6 cycles was planned; response assessment was performed after cycles 4 and 6. At the end of the 6 th cycle, patients with partial or complete response continued treatment with Lenalidomide 10mg/d on days 1 to 21 every 28 days, until cycle 12or unacceptable toxicity. Final response was evaluated within 28 days after the last study drug administration. Primary study endpoint was Overall Response Rate (ORR) after 6 R2 cycles, defined according to Lugano 2014 criteria; co-primary endpoint was the rate of extra-hematological toxicity with CTCAE grade >2 and of death for any cause during the treatment The study was planned according to a two stage Simon design. A total of 68 pts had to be enrolled to complete the study. With 34 responses the study would be able to demonstrate the initial hypothesis of an improvement of response rate from 45% (p0) to 65% (P1) RESULTS From August 2018 to June 2021, 68 newly diagnosed frail DLBCL were enrolled in 18 Italian centers. Median age was 83 years (range 70-91) and 73% had stage III/IV; 57% had High risk IPI (i.e. 3-5 risk factors). 64 pts were confirmed eligible and started R2 treatment. The planned 6 courses of R2 were completed in 36 pts (56%). The median number of R2 cycles was 6 (1-6). Treatment was discontinued in 28 pts due to lymphoma progression (11 cases), extra-hematological toxicity (7), hematological toxicity (1), lost after 1 cycle and investigator choice after 5 cycles in CR in 1 case each, death in 7 cases (1 each for infection, pancytopenia, cachexia, ischemia and bowel infarction, and from unknown causes in 2 cases). At the end of 6 th R2 cycle 26 patients achieved a response (ORR 41%), 13 CR and 13 PR. After a median follow-up of 17 months, the overall survival, and progression free survival at 12 months were 69% (95CI 56-79%) and 55% (95%CI 42-66%), respectively. The duration of remission at 12 months was 72%. Regarding safety 46 events were reported including 31 extra-hematological toxicities > CTCAE grade 2: 7 cardio-vascular (1 resulting in death), 4 nervous system disorders (1 resulting in death), 10 gastro-intestinal, 3 infections, 6 skin and subcutaneous tissue disorders, 5 respiratory events (all resolved). The rate of grade 3-4 adverse events was higher than the highest allowed limit of 28. CONCLUSIONS The Reri is the first study to evaluate activity and safety of a chemo-free therapy in patients with diffuse large B-Cell Lymphoma who are not eligible for conventional cytotoxic therapy. Even if this study was not able confirm the initial activity hypothesis, activity of the R2 combination was observed in a significant proportion of cases warranting further exploration of chemo-free approach of elderly frail patient with DLBCL. Disclosures Tucci: janssen: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Fabbri: Takeda: Honoraria; Servier/Pfizer: Honoraria; Takeda: Other: Travel, Accomodations, Expenses. Musuraca: janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Zilioli: Takeda: Other: travel expenses, accommodation; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau; Roche, Italfarmaco: Consultancy, Honoraria; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations. Luminari: Roche, Celgene, Teva Pharmaceuticals, Gilead Sciences, and Takeda Pharmaceuticals: Honoraria.

Introduction Non-pegylated liposomal doxorubicin (NPLD) is considered a good alternative to conventional doxorubicin for the treatment of older patients (pts) with aggressive lymphomas and/or at high risk for cardiological toxicity. The use of R-COMP for the treatment of older pts with DLBCL has been supported by several small retrospective studies . In this report we describe the characteristics and outcomes of pts who were prospectively enrolled in the Elderly Project (EP) and who were treated with R-COMP and compared them with pts treated with conventional R-CHOP. Methods. This analysis was conducted starting from the dataset of the EP study. The use of NPLD was allowed according to 648/96 law, treatment decision was left to physician discretion and was independent of frailty status. For the purposes of this analysis, we included all pts who were treated with full doses of R-CHOP and R-COMP. The study endpoint were progression free survival (PFS) and overall survival (OS). A propensity score analysis was conducted to account for the main confounding factors. Results Overall 691 out of 1163 pts of the EP were treated with R-CHOP (383; 55%) or R-COMP (308; 45%); median age was 71 and 76 years for R-CHOP and R-COMP, respectively (p < 0.001) (Table 1). Pts were similarly distributed among different IPI groups for R-COMP or R-CHOP. Based on simplified Geriatric Assessment (sGA) 88%, 11% and Conclusions Data from the prospective observational EP study did not show significant differences in terms of efficacy comparing R-COMP to standard R-CHOP. The higher frequency of UNFIT and FRAIL pts among those treated with NPLD suggests R-COMP is a good strategy to offer a curative treatment to these groups of pts. Figure 1 Figure 1. Disclosures Merli: EUSA Pharma: Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; MSD: Membership on an entity's Board of Directors or advisory committees; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Celgene: Other: Travel, Accomodations, Expenses. Tucci: janssen: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Rigacci: Merck: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cavallo: ROCHE: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Gilead: Speakers Bureau. Fabbri: Servier/Pfizer: Honoraria; Takeda: Other: Travel, Accomodations, Expenses; Takeda: Honoraria. Puccini: Takeda: Membership on an entity's Board of Directors or advisory committees. Ferrero: Incyte: Membership on an entity's Board of Directors or advisory committees; Morphosys: Research Funding; Gilead: Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Speakers Bureau; Clinigen: Membership on an entity's Board of Directors or advisory committees. Zilioli: Roche, Italfarmaco: Consultancy, Honoraria; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau; Takeda: Other: travel expenses, accommodation. Nassi: Takeda: Consultancy; Kyowa Kirin: Consultancy; Incyte: Consultancy; Roche: Consultancy. Musuraca: Janssen, Incyte, Roche: Consultancy; Janssen, Roche, Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen, Roche, Incyte: Honoraria. Flenghi: Janssen: Other: Travel, Accomodations, Expenses; Roche: Other: Travel, Accomodations, Expenses. Marcheselli: sandoz: Membership on an entity's Board of Directors or advisory committees. Luminari: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Janssen: Other: Travel, Accomodations, Expenses; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy; GENELAB SRL: Consultancy.

Although health care managers often prefer to hire employees without tattoos, the source of this bias is unclear. One explanation is that tattoos are associated with being less responsible. An alternative explanation is that managers are concerned tattoos will hurt their organization's image. A sample of 187 dentists were shown a picture of a dental hygienist either with no tattoo, a small tattoo, or a large tattoo, and then asked about the hygienist. Results show that dentists do not associate tattoos with irresponsibility but are concerned about the fit of tattoos with the image of the practice. This means that dentists make hiring decisions based on stereotypes about customer stereotypes.

BACKGROUND: In 2014 we identified a new subset of DLBCL, defined as "IgM-secreting" (Cox MC & Di Napoli A , PLOS One 2014). This was characterised by poor prognostic features and outcome as well as frequent central nervous (CNS) system localizations. Furthermore, IgM-secretion, was an independent prognostic factor in multivariate analysis. Here we report on the largest series of IgM-secreting-DLBCL, from a multicentre Italian study. METHODS: The observational and biological study was approved by the Ethical Committee of the AUO Sant'Andrea, Italy. Enrolment criteria were: DLBCL with an associated IgM paraprotein diagnosed between 1st January 2010 and 31st December 2018 (IgM-secreting). Data were collected both prospectively and retrospectively from 17 Centres participating in the study. In addition, histopathology samples were centrally revised for immunohistochemistry (IHC) and FISH analyses. The control group (CTRL) consisted in a series of consecutive DLBCL, without an associated IgM-paraprotein (diagnosed between 01/01/2013 and 30/06/2016, enrolled in the Lymphoma Registry of the Lazio region (ReLLi Network). Last follow-up was carried out on 31st December 2019. RESULTS: 569 DLBCL cases were enrolled: 102 (17.9%) were IgM-secreting; 48 (8.4%) had a non-IgM paraprotein (IgA, IgG, or other), and 414 (72.7%) had no associated paraprotein (CTRL). IgM-secreting cases within the consecutive DLBCL patients enrolled in the ReLLi Registry were 41/466 (8.8%, 95CI 6.4-11.7%) while non IgM-paraprotein DLBCL cases were 11/466 (2.4%, 95CI 1.2-4.2%). The median level of IgM paraprotein was 17gr/L (range: 60 (p=.001); 2] advanced stage (pUNL (p=.008) ; 5] ≥2 Extra-nodal sites involved (p60, B-symptoms, bulky disease, IPI >low risk and IgM-secreting IgM showed a worse survival (all with p CONCLUSION: Our data confirm that IgM-secreting DLBCL: 1) represents a sizable proportion of non-DH DLBCL; 2) have poor prognostic features and 3) have mostly a non-GC phenotype. Furthermore, IgM secretion appears to be an independent prognostic factor for both PFS and OS. Studies to define the biological features of this new subset are ongoing. Disclosures Cantonetti: Mundipharma: Consultancy; Takeda: Consultancy; Vifor: Consultancy; Roche: Consultancy. Re:BerGenBio ASA: Research Funding. Abruzzese:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria.

The perspective of combining cancer vaccines with immunomodulatory drugs is currently regarded as a highly promising approach for boosting tumor-specific T cell immunity and eradicating residual malignant cells. The efficacy of dendritic cell (DC) vaccination in combination with lenalidomide, an anticancer drug effective in several hematologic malignancies, was investigated in a follicular lymphoma (FL) model. First, we evaluated the in vitro activity of lenalidomide in modulating the immune responses of lymphocytes co-cultured with a new DC subset differentiated with IFN-α (IFN-DC) and loaded with apoptotic lymphoma cells. We next evaluated the efficacy of lenalidomide and IFN-DC-based vaccination, either alone or in combination, in hu-PBL-NOD/SCID mice bearing established human lymphoma. We found that lenalidomide reduced Treg frequency and IL-10 production in vitro, improved the formation of immune synapses of CD8 + lymphocytes with lymphoma cells and enhanced anti-lymphoma cytotoxicity. Treatment of lymphoma-bearing mice with either IFN-DC vaccination or lenalidomide led to a significant decrease in tumor growth and lymphoma cell spread. Lenalidomide treatment was shown to substantially inhibit tumor-induced neo-angiogenesis rather than to exert a direct cytotoxic effect on lymphoma cells. Notably, the combined treatment with the vaccine plus lenalidomide was more effective than either single treatment, resulting in the significant regression of established tumors and delayed tumor regrowth upon treatment discontinuation. In conclusion, our data demonstrate that IFN-DC-based vaccination plus lenalidomide exert an additive therapeutic effect in xenochimeric mice bearing established lymphoma. These results may pave the way to evaluate this combination in the clinical ground.

Several studies have demonstrated the prognostic value of neutrophil-lymphocyte ratio (NLR) in patients with solid tumors and non–Hodgkin lymphoma. In contrast, there is only sparse data on its prognostic role in patients with classical Hodgkin lymphoma (cHL). The aim of our study was to establish whether NLR could serve as an independent prognostic factor in a cohort of 990 patients with nodular sclerosis (NS)-cHL. After analysis of the log hazard ratio (HR) as a function of NLR, we chose the value 6 as cutoff. Patients with NLR >6 had a worse progression-free survival and overall survival compared to those with NLR ≤6; 84% vs 75% and 92% vs 88%, at 5 years, with an HR of 1.65 and 1.82, respectively. Multivariate analysis showed that the risk remained high with HR 1.44 and HR 1.54 in progression-free survival and overall survival, respectively. In summary, our study shows that NLR is a robust and independent prognostic parameter in NS-cHL, both in early and advanced disease. It is inexpensive and simple to apply. Thus, we conclude that NLR, possibly in combination with the international prognostic score and absolute monocyte count, is a useful guide for physicians treating NS-cHL patients.

Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma. This malignancy is considered virtually incurable, with high response rates to therapy but frequent relapses. We investigated the ability of monocyte-derived dendritic cells generated in the presence of IFN-α and GM-CSF (IFN-DC) and loaded with apoptotic lymphoma cells to activate immune responses against FL cells, with the ultimate goal of designing novel patient-specific vaccination strategies for the treatment of FL. In this article, we show that apoptotic tumor cell–loaded IFN-DC from FL patients, which were cultured for 2 wk with autologous lymphocytes, led to Th1 response skewing, based on significantly higher levels of IFN-γ production and a remarkable increase in CD8+ and NK cell frequency, consistent with the detection of enhanced cytotoxic effector function toward autologous FL cells. IFN-DC were found to promote efficient NK cell activation, increased expression of cytotoxicity receptors, and extensive IFN-γ production in the virtual absence of IL-10. Moreover, direct recognition and killing of primary autologous lymphoma cells by activated NK cells from FL patients was also demonstrated. A critical role was demonstrated for MHC class I–related chain A and B and membrane-bound IL-15 in IFN-DC–mediated NK cell activation and early IFN-γ production. The overall results indicate that IFN-DC loaded with autologous apoptotic FL cells represent a valuable tool for improving the potency of therapeutic cancer vaccines through the efficient induction of NK cell activation and promotion of CD8+ T cell antitumor immunity.

Clinical trial results indicate that romidepsin, a histone deacetylase inhibitor, is a promising treatment in relapsed/refractory T-cell lymphomas (TCLs). This retrospective multicenter study was conducted in patients with relapsed/refractory TCL treated with romidepsin monotherapy through a Named Patient Program (NPP) in Italy. Principal endpoints were overall response rate (ORR), safety, and overall survival (OS). The ORR in 33 evaluable patients was 24.2% with an ORR in the cutaneous TCL of 35.7%. Global OS was 39.3% at 30 months. There were not any specific differences on hematological and extrahematological adverse events. Data from patients treated with romidepsin outside a controlled clinical trial give additional information about the clinical use, efficacy, and toxicity of the drug given to relapsed or refractory TCL patients in a real life context as TCLs are rare diseases and more information is needed. These findings suggest that romidepsin is effective and safe for heavily pretreated TCL patients.

Bendamustine is used in combination with rituximab (BR) to treat indolent non-Hodgkin lymphomas (iNHL) and mantle cell lymphoma (MCL). The variability in treatment efficacy and toxicity could be related to single nucleotide polymorphisms (SNPs) in immune response genes. We would like to show a correlation between SNPs and treatment outcome in iNHL and MCL patients receiving BR. We investigated some SNPs that had already been associated with NHL outcome. Samples were genotyped for the IL2 (rs2069762), IL10 (rs1800890, rs10494879), VEGFA (rs3025039), IL8 (rs4073), CFH (rs1065489) and MTHFR (rs1801131) SNPs by allelic discrimination assays. We enrolled 70 patients that received rituximab 375 mg/m2 and bendamustine 90 mg/m2 every 28 days, both as first-line treatment and ≥ second-line regimens. Overall response rate was 97·1% (complete response [CR] rate 73·9%). Treatment toxicity included grade 3-4 neutropenia (24/70 patients), infections (21/70 patients; 1/70 grade 3), skin rash (26/70 patients; 2/70 grade 3). After a median follow-up of 24 months we did find any correlation between the analysed SNPs, CR rate and PFS. However, we demonstrated an association between the SNP in IL2 (rs2069762) and the onset of skin rash (P = 0·0001). Our study suggests a role for cytokine SNPs in bendamustine-related toxicity, which could represent a promising research field.

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not suitable for high dose chemotherapy with autologous stem cell transplantation (ASCT) has a dismal prognosis and no standard therapy. We designed an Italian multicenter retrospective study aimed at evaluating the safety and efficacy of rituximab plus bendamustine (R-B) as salvage treatment in patients not eligible for ASCT because of age and/or comorbidity or in patients with post-ASCT recurrence. Fifty-five patients with a median age of 76 years were included. The overall response rate was 50%, including 28% complete remission and 22% partial remission. The median overall survival (OS) was 10.8 months. The median progression free survival (PFS) was 8.8 months. Eleven patients are still alive and in complete remission at last follow-up (12-71 months). Toxicity was moderate, mainly grades 1 and 2. R-B showed promising efficacy results with an acceptable toxicity profile and should be further investigated, possibly in combination with novel drugs.

In Hodgkin Lymphoma (HL), about 20% of patients still have relapsed/refractory disease and late toxic effects rate continue to rise with time. 'Early FDG-PET' and tissue macrophage infiltration (TAM) emerged as powerful prognostic predictors. The primary endpoint was to investigate the prognostic role of both early FDG-PET and TAM; the secondary endpoint was to test if early FDG-PET positivity could correlate with high TAM score. A cohort of 200 HL patients was analysed. Induction treatment plan consisted of two to six courses of ABVD and, if indicated, involved field radiation therapy. All patients repeated CT scan and FDG-PET after two cycles and after the completion of therapy. TAM in diagnostic specimens was determined by immunohistochemistry with a monoclonal antibody (anti-CD68 KP1). Overall, early FDG-PET was negative in 163 patients (81.5%) and positive in 37 patients (18.5%), showing a significant correlation with the achievement of CR (p

Postpartum tubal ligation is one of the safest and most effective methods of contraception. Yet, not all women who desire it actually undergo the procedure. We studied clinical and demographic factors that were associated with receipt of tuba ligation among West Virginia Medicaid patients. A retrospective study was performed evaluating Medicaid patients in West Virginia requesting postpartum sterilization from May 2012 to November 2014 (N = 153). Demographic information was obtained on these patients. Clinical factors complicating pregnancy were analyzed. For those patients choosing not to undergo tubal sterilization, contraceptive plan at discharge was also evaluated. Statistical tests included Chi square and Fisher’s Exact Test where appropriate. 71% (n=96) received tubal ligation before discharge. 21% (n = 29) requesting post-partum tubal ligation went unsterilized. Women with a history of cesarean section (83% vs. 61%; p =

The progressive improvement of lymphoma therapies has led to a significant prolongation of patient survival and life expectancy. However, lymphoma survivors are at high risk of experiencing a range of early and late adverse effects associated with the extent of treatment exposure. Among these, second malignancies and cardiopulmonary diseases can be fatal, and neurocognitive dysfunction, endocrinopathy, muscle atrophy, and persistent fatigue can affect patients' quality of life for decades after treatment. Early recognition and reduction of risk factors and proper monitoring and treatment of these complications require well-defined follow-up criteria, close coordination among specialists of different disciplines, and a tailored model of survivorship care. We have summarized the major aspects of therapy-related effects in lymphoma patients, reviewed the current recommendations for follow-up protocols, and described a new hospital-based model of survivorship care provision from a recent multicenter Italian experience.

INTRODUCTION MCL is an incurable disease and treatment approach should be adapted to patient's characteristics: age, PS, co-morbidities, social conditions, presence of caregiver, etc. In this study we describe the experience of RELLI in real life about old MCL pts followed in Latium region and diagnosed and registered in our database between January 2013 to December 2017. MATHERIALS and METHODS Data were collected in a regional data base. All new diagnosis of lymphoproliferative disease were considered medical history, clinical characteristics and lymphoma related characteristics were registered starting from an existing data base or medical records of single Institutions. RESULTS In the database were registered 91 pts with MCL (70M/21F) older than 65 years with a median age of 74 yrs (range 66-87). At diagnosis 11/91 (12.1%) were in stage I-II and 80/91 (87.9%) in stage III-IV; only 6 (6.6%) pts presented systemic symptoms. High levels of LDH were present in 45.1% of pts, at least one extranodal localization was reported in 4.4% and Ki67 > 30% in 48.5%. Prognostic score was evaluated at diagnosis: MIPI (LR 46.5%, IR 19.7%, HR 33.8%) and MIPI-c (LR 36.6%, ILR 22.5%, IHR 22.5%, HR 18.4%). Treatment was evaluated according to the age of pts: 65 -70 and >70 years; in the first group immuno-chemotherapy (ICT) was: Benda containing regimen 43.5% (R-BAC 17.4%, R-B 26.1%) and CHOP-like regimen 36.1% (R-CHOP21 17.4%, R-COMP21 8.7%). In contrast in older pts the choice of ICT was: Benda containing regimen 64% (R-BAC 14.8%, RB49.2%), and CHOP-like regimen 13.1% (R-CHOP21 8.2%, R-COMP 4.9%).The overall response rate (ORR), progression free-survival (PFS) and overall survival (OS) were calculated from the start of treatment and evaluated in the two groups of pts: ORR was 100% in younger (CR 69.6%, PR 30.4%) and 68.8% in older (CR 50.8%, PR 18%). According to the type of ICT, as expected, pts treated with bendamustine containing regimens (+/- Cytarabine) have better response and longer survival. With a median follow-up of 34.5 months, media OS of the entire population isn't reached and PFS is projected at 50% at 60 months. CONCLUSIONS In the era before new biologic drugs the approach to treatment of MCL was sufficiently homogeneous in the Lazio region. In real life Ky67 was principal factor influencing OS. MIPI and MIPI-c score divided the entire population into two groups at high and low risk. Age not change the OS but only the response rate to treatment (Figure 1). Disclosures Abruzzese: BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Di Rocco:Roche: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau; Sandoz: Consultancy. Martelli:F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; Servier: Honoraria.

Introduction: Management of elderly patients with Diffuse Large B-Cell Lymphoma (DLBCL) is challenging. A simplified Comprehensive Geriatric Assessment (sCGA) based on ADL (Activity of Daily Living), IADL (Instrumental ADL) and CIRS-G (Comorbidity Index Rating Scale for Geriatrics) scales has demonstrated to be better than clinical judgement to stratify patients' outcome but has never been included in initial assessment. To further assess the impact of sCGA on patients' outcome, we conducted a prospective observational study on a large series of elderly patients with DLBCL. Methods: Patients were enrolled if 65 year old or older, with an untreated de novo DLBCL. sCGA was available at a web based platform that classified patients as FIT, UNFIT, and FRAIL, as shown in Table 1. Treatment choice was left at physician discretion. According to anthracycline dose, therapy was classified as curative (≥70% of full anthracycline dose), intermediate ( Results: From December 2013 to December 2017, 1353 patients have been registered by 37 centres and 1207 were eligible. Median age was 76 years (65-94), 68% had stage III-IV, and 55% had an International Prognostic Index(IPI) ≥3; 500 (42%), 304 (25%), and 403 (33%) were classified as FIT, UNFIT and FRAIL, respectively. Data on treatment were available in 1164 patients: rituximab was used in 96% of patients; treatment was curative in 89%, 53%, and 36% of FIT, UNFIT, and FRAIL patients, respectively; intermediate in 10%, 39%, and 31%, palliative in 0%, 8%, and 33% of patients. The OS was available in 1158 out 1164 cases. With a median follow up of 30 months (1-59) 3y-OS was 64% (95% CI 61% to 67%). According to sCGA the OS was significantly different among the 3 geriatric groups. Correlation with OS was improved when sCGA was integrated with age < or ≥ 80 years to define 3 groups of patients (Table 2): FIT and UNFIT younger than 80 years (sCGA Group 1; 55%, 3 yr OS 75%), UNFIT ≥ 80 years and FRAIL younger than 80 years (sCGA Group 2: 28%, 3yr OS 58%), FRAIL ≥ 80 years (sCGA Group 3: 17%; 3yr OS 43%). Univariable and multivariable analysis for OS was conducted using the 3 sCGA groups and other clinical and laboratory features. The 3 sCGA groups were shown as independent prognostic factors with IPI and with anemia (Hb < 12 g/dl). We used results of multivariable analysis to build a categorical prognostic index assigning different weights to prognostic features based on their Hazard Ratio (HR) (Table 3). The Elderly Prognostic Index (EPI) was defined as the score obtained from the sum of the weights and allowed to define 3 risk groups: Low Risk (LR: score 0-1; 23% of patients); Intermediate Risk (IR; score 2-4; 48%); High Risk (HiR; score 5-7; 29%). The 3 EPI risk groups had a different 3 year OS of 87%(95%CI 81-91), 69%(95%CI 63-73), and 42% (95%CI 36-49); HR for IR vs LR 2.57 (1.72, 3.84); HiR vs LR 6.21(4.17 -9.25), HiR vs IR 2.42 (1.91-3.05) (Figure1). Regarding treatment modality, curative, intermediate and palliative therapies were adopted in 89%, 10%, and 1% of the LR group; 70%, 24%, 7% of the IR group, and 37%, 35%, 28% of the HiR group. The model was internally validated by means of 1000 procedures confirming good performance (slope shrinkage 0.935 and c-Harrell 0.675 in validation sample compared with 0.682 in training sample). The EPI was also tested in an external validation data set that was identified from the pivotal study of sCGA in DLBCL (N=172 patients, Tucci A. et al, Leuk Lymph, 2015) (Figure 1). Conclusion: Using data from this large prospective observational study on elderly DLBCL patients we were able to build a new prognostic index that allows to identify 3 risk groups with significant differences in terms of 3 years OS. The EPI is the first index that integrates geriatric assessment with clinical features and contributes to improving management and clinical research in elderly patients with DLBCL. Disclosures Spina: Servier: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; Sandoz: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other; Roche: Other: lecture fee; Teva: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; GILEAD: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; Celgene: Other: lecture fee; BMS: Other: lecture fee; Sanofi Genzyme: Other: lecture fee; CTI: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; Menarini: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee, Research Funding; Takeda: Other: lecture fee; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: lecture fee; Pfizer: Membership on an entity's Board of Directors or advisory committees. Merli:Janssen: Honoraria; Takeda: Honoraria, Other: Travel Expenses; Gilead: Honoraria; Mundipharma: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses. Cavallo:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Ladetto:Roche: Honoraria; AbbVie: Honoraria; J&J: Honoraria; Celgene: Honoraria; ADC Therapeutics: Honoraria; Acerta: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Chiappella:Celgene: Other: advisory board, Speakers Bureau; Janssen: Other: advisory board, Speakers Bureau; Servier: Other: advisory board, Speakers Bureau; Roche: Speakers Bureau; Teva: Speakers Bureau. Nassi:Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. Ferrero:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau; Servier: Speakers Bureau; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees. Luminari:ROCHE: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; GILEAD: Other: Lecturer; TAKEDA: Other: Travel Grant.

INTRODUCTION Treatment of Diffuse Large B cell lymphoma (DLBCL) in the elderly population is challenging as many patients (pts) are not eligible to receive standard curative therapy, due to comorbid conditions and to a higher susceptibility to the side effects of standard anthracycline containing regimens. Among currently available active drugs, Lenalidomide has been used in the setting of relapsed/refractory DLBCL both as monotherapy and in combination with rituximab, showing a good activity and an acceptable safety profile. We started a prospective, multicenter, single arm, phase II trial to demonstrate activity and safety of a chemofree combination of lenalidomide + rituximab in elderly (≥ 70 years) untreated pts with DLBCL who were prospectively defined as frail according to a simplified comprehensive geriatric assessment (sCGA) (Tucci A. et al., Leuk Lymphoma. 2015 Apr). PATIENTS AND METHODS Pts were eligible if they were previously untreated DLBCL patients, older than 69 years and defined as frail according to sCGA. The treatment consisted of a 28-day cycle (R2) combining oral Lenalidomide (20 mg on days 1 to 21) and i.v. Rituximab (375 mg/m2 on day 1); a maximum number of 6 cycles was planned; response assessment was performed after cycles 4 and 6. At the end of the 6thcycle, patients with partial or complete response continued treatment with Lenalidomide 10mg/d on days 1 to 21 every 28 days, until cycle 12or unacceptable toxicity. Final response was evaluated within 28 days after the last study drug administration. Primary study endpoint was Overall Response Rate (ORR) after 6 R2 cycles, defined according to Lugano 2014 criteria; co-primary endpoint was the rate of extra-hematological toxicity with CTCAE grade >2 and of death for any cause during the treatment The study was planned according to a two stage Simon design. A total of 68 pts had to be enrolled to complete the study: 23 pts were required in the first stage. Second stage could be activated withat least 12 patients showing a Partial or Complete Response (PR/CR) in stage I. According to the Ray and Rai method less than 15/23 adverse events were also required for the safety coprimary endpoint. RESULTS From January 2017 to December 2017, 24 newly diagnosed frail DLBCL were enrolled in 8 Italian centers. Median age was 83 years (range 76-89) and 79% had stage III/IV; 42% of pts were male, and 44%, had elevated LDH, 45% had High risk IPI (i.e. 3-5 risk factors). All pts were confirmed eligible and started R2 treatment. The planned 6 courses of R2 were completed in 13 pts (54%). The median number of R2 cycles was 6 (1-6). Treatment was discontinued in 11 pts for the following reasons: lymphoma progression in 4 cases, second malignancy in 2, extra-hematological toxicity in 3 cases, consent withdrawal and investigator choice after 4 cycles in CR in 1 case each. Response assessment after 6 R2 cycles showed12 responding pts (ORR 50%), 4 CR and 8 PR, that was higher than by the inferior limit required by the Simon optimal design. Regarding safety coprimary endpoint 13 events were reported including 9 extra-hematological toxicities > grade 2 CTCAE (3 cardio-vascular and 6 respiratory events, all resolved) and 4 deaths (2 patients due visceral arterial ischemia and 2 due infectious disease). The rate of adverse events was lower than the superior limit of 15 allowed the first stage of the study.Since August 2018 the enrollment in the stage II of the trial has been resumed and it is currently ongoing with 45 patients enrolled. CONCLUSIONS The ReRi is the first study to evaluate activity and safety of a chemo-free therapy in patients with diffuse large B-Cell Lymphoma who are not eligible for conventional cytotoxic therapy. The results of the planned interim analysis of our study confirmed the initial efficacy and safety hypotheses of R2 combination in untreated elderly pts with DLBCL. Treatment of elderly frail DLBCL pts with R2 holds promise in terms of both ORR and safety. Disclosures Bassan: Amgen Inc.: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Shire: Honoraria. Merli:Sandoz: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Janssen: Honoraria; Takeda: Honoraria, Other: Travel Expenses; Gilead: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Mundipharma: Honoraria. Liberati:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Janssen: Honoraria; Novartis: Other: Clinical trial support. Luminari:ROCHE: Other: Role as Advisor ; CELGENE: Other: Role as Advisor & Travel Grant; TAKEDA: Other: Travel Grant; GILEAD: Other: Lecturer .

In this study we assessed the prognostic significance of absolute monocyte count and selected the best cut-off value at diagnosis in a large cohort of patients with diffuse large B-cell lymphoma. Data were retrieved for therapy-naïve patients with diffuse large B-cell lymphoma followed in Israel and Italy during 1993-2010. A final cohort of 1017 patients was analyzed with a median follow up of 48 months and a 5-year overall survival rate of 68%. The best absolute monocyte count cut-off level was 630/mm(3) and the 5-year overall survival for patients with counts below this cut-off was 71%, whereas it was 59% for those with a count630 mm(3) (P=0.0002). Of the 1017 patients, 521 (51%) were treated with chemo-immunotherapy, and in this cohort, using multivariate analysis, elevated monocyte count retained a negative prognostic value even when adjusted for International Prognostic Index (HR1.54, P=0.009). This large study shows that a simple parameter such as absolute monocyte count (630/mm(3)) can easily be used routinely in the evaluation of newly diagnosed diffuse large B-cell lymphoma to identify high-risk patients with a worse survival in the rituximab era.

Hematologic malignancies can be associated to dermatological manifestations, with two possible etiopathogenetic mechanisms: a direct invasion of skin by neoplastic cells or a paraneoplastic phenomenon. The eosinophilic dermatosis can be included in the latter class and arc a group of polymorphous dermatitis, clinically characterized by papules, plaques, nodules or vescico-bullous lesions, mainly involving sun-exposure sites. Clinical pictures are similar to an insect bite reaction, but in most cases the patients deny any arthropod contacts. Therefore, they arc now considered as a hypersensitive reaction to different stimuli induced by lymphoproliferative malignancies and the associated immune-deficient state. Herein, we describe two cases of patients affected by a non-Hodgkin lymphoma (NHL), in whom a diagnosis of insect bite-like reaction (IBLR) was made.

Primary rectal MALT lymphoma is a very rare entity among extranodal MALT lymphomas and its therapeutic management has not been standardized. Different approaches including surgery, chemotherapy and radiotherapy have been proposed in the last decades. There have been reports on complete responses after anti-Helicobacter pylori therapy, also in patients without serological or histological evidence of Helicobacter pylori infection. In our patient we obtained a complete response with anti-Helicobacter pylori therapy and a disease-free survival of 34 months. Endoscopic ultrasound was useful for diagnosis and follow-up. Although the mechanisms that determined this response remain a matter of debate, anti-Helicobacter pylori therapy can be considered as first-line therapy in stage IE, nonbulky primary rectal MALT lymphoma. Endoscopic ultrasound could play a relevant role in the management of this rare condition.

Rituximab has provided a revolutionary contribution to the treatment of B-cell non-Hodgkin's lymphomas (NHL). A high prevalence of hepatitis C virus (HCV) infection has been described in B-cell NHL patients. Cases of liver dysfunction in HCV-positive patients have been reported with rituximab-containing regimens.to evaluate the liver-related effects of rituximab-containing regimens on HCV-positive CD20-positive B-cell NHL patients.Retrospective analysis of 104 consecutive patients. HCV status was determined, and development of hepatitis flares analysed.Nine patients (8.6%) were HCV-positive. No correlation was shown between viral load and alanine transaminase levels. Three of the 9 HCV-positive, and none of the 95 HCV-negative developed hepatitis flares (p0.001). At the 12-month follow-up hepatitis flare patients were alive and in remission for their haematological disease and no hepatitis flares, liver-related death had developed.HCV-positive status may represent a risk factor for the development of hepatic flares in B-cell NHL patients receiving rituximab-containing regimens. Despite the increase in liver function tests, there were no major clinical events.

BACKGROUND: About one third of patients with diffuse large B-cell lymphoma (DLBCL) eventually die from their disease. Thus, it is extremely important to identify powerful and reliable predictive and prognostic markers. In real life patient management, the clinical relevance of the assessment of the Cell of Origin (COO), of MYC and BCL2 protein overexpression, is still not fully clarified. The aim of the study is to evaluate the predictive and prognostic value of COO with Lympho2Cx assay by Nanostring technology and BCL2 and MYC overexpression by immunohistochemistry (IHC), in a real-life context. METHODS: This is a retrospective multicenter study which recruited 154 DLBCL patients treated with R-containing regimen between June 2010 and December 2016 in Modena, Rome (Italy) and Haifa (Israel). All clinical data were recorded at diagnosis and during follow up, including response assessment and survival outcome. COO was determined on formalin-fixed paraffin-embedded diagnostic specimens either by IHC using a panel of antibodies which included CD10, BCL6, MUM1 (i.e. Hans algorithm), or at RNA level with Lymph2Cx assay by Nanostring technology. Expression of MYC and BCL2 was evaluated by IHC. Event free survival (EFS) is defined as the time from diagnosis to the time of last follow-up, or to one of the following events: any response other than complete remission (CR) at the end of therapy or death from any cause. It is assessed by Kaplan-Meier estimates and groups of risk are compared using the log rank test. RESULT: We have currently evaluated the data of 60% (95 out of the 154) of the patients enrolled in the study (Tab 1). After a median follow up of 49 months, EFS is 63% (95CI 51-72%). In univariate analysis, the variables with the greatest impact on the response and on EFS are absolute granulocyte count and BCL2 expression (MYC ongoing). Patients with low IPI showed better survival in comparison with patients with high IPI, but the difference is not statistically significant. By IHC non-GCB subtype was more common than GCB (56% vs. 44%); by Nanostring ABC, GCB and unclassified subtypes were 33%, 50% and 17%, respectively, and K statistics was 0,647, showing a substantial agreement between the results obtained by IHC and by Lympho2Cx assay. No statistically significant differences were observed in EFS among ABC, GCB and unclassified subtypes. However, BCL2 protein overexpression in ABC subtype is associated with shorter EFS. CONCLUSION: Early retrospective studies showed a survival advantage for GCB-type disease. Clinical trial data evaluating the impact of COO determined by GEP on prognosis have shown inconsistent results with 2 studies observing inferior survival of ABC subtype and 2 German studies showing no significant differences in PFS or OS among COO subtypes. Determination of COO by Lympho2Cx is attractive as it is relatively easy and rapid to perform and potentially applicable to clinical practice. However, these preliminary results do not support, at this point, its use as prognostic factor in clinical practice. The analysis of the remaining 59 patients will help to clarify the role Lympho2Cx assay in the context of real life. Table 1. Patients baseline characteristics. Disclosures Tadmor: ABBVIE: Consultancy; ROCHE: Research Funding; JNJ: Consultancy; NOVARTIS: Consultancy; PFIEZER: Consultancy.

Purpose: We have developed a novel DC population differentiated from human monocytes in the presence of GM-CSF and IFN-alpha (IFN-DC), which is highly efficient in internalizing tumour cell antigens and in the cross-priming of CD8+T cells, promoting efficient anti-lymphoma response. Preclinical results prompted us to start a clinical trial of IFN-DC combined with low-dose Rituximab(RTX) in patients with Follicular lymphoma (FL), which is an indolent, immune-responsive, but still incurable cancer. Patients and Methods: In October 2014 we started a phase I clinical trial (EudraCT: 2013-003158-25) testing safety, immunogenicity and systemic clinical responses of low-dose RTX combined with autologous IFN-DC, administered by intra-nodal injections. Patients features: age 18-75y, indolent FL, relapsed or refractory (R/R), stage III-IV low tumour burden, with at least 1 superficial pathologic lymph node. One leukapheresis was scheduled at study entry for harvesting mononuclear cells. Eight cycles of RTX (5-20mg) and IFN-DC (30±10x106) were planned: the first 4 every two weeks, followed by other 4 cycles administered monthly. All injections were delivered with the aid of an ultrasound guide. Blood test for immune-responses and autoimmunity markers were scheduled at 0,+72d, +132 days ; +9; +18;+24 months. Results: as of the 31st July 2018, 8 patients have completed treatment and have been evaluated for response (median follow-up=24 months; range=8-45 mo). Median age of the study population was 60 years (range 27-76). All subjects had disseminated disease and enlarged lymph nodes or lesions greater than 1.5 cm at multiple sites available for local injections and monitoring for distant response. All patients were R/R after previous systemic therapy (median lines=2, range1-4) and 3/8 (37.5%) after auto-transplantation. The treatment was very well tolerated and manageable. No relevant adverse events were observed. Four out of 8 (50%) patients had objective response (OR) with 3/8(37.5%) attaining complete remission (CR); 2/8 (25%) are in stable disease at +8 and +25 months; 2/8 (25%), who did not achieve OR, progressed at +8 and +14 respectively. One patient progressed 4 months after achieving CR (Figure1). In all patients who achieved OR or who are in stable disease, induction of a tumour specific immune response was observed. Conclusions: local RTX and IFN-DC combined therapy was effective in eliciting in 50% of R/R FL with low tumour burden systemic and durable responses, which were associated with induction of specific anti-FL T cell responses. Disclosures No relevant conflicts of interest to declare.

Background Improved treatment have modified survival outcome in patients with diffuse large B-cell lymphoma (DLBCL) and altered the importance of previously recognized prognostic markers. Design and methods To evaluate International Prognostic Index (IPI) score before and after rituximab introduction and to validate the absolute lymphocyte count (ALC)/revised International Prognostic Index (R-IPI) model, we carried out a retrospective analysis on a total of 831 patients with DLBCL. Results Our results show that IPI lost its discriminating power with the introduction of rituximab. The analysis of our second set allowed us to validate the ALC/R-IPI model. The R-IPI and ALC/R-IPI could still be used for designing clinical trials, but both have difficulty recognizing a high percentage of poor prognosis patients, though it remains an important goal of a good prognostic model considering the modest impact of salvage treatments on survival. Conclusions A new model on the basis of significant variables in the rituximab era and built on a large database of patients treated with rituximab is urgently needed. As prognostic models are changing with the efficacy and mechanisms of action of treatment utilized, looking for a new prognostic score is a never-ending story in which researchers are trying to hit a continuously moving target.

7563Background: Metronomic chemotherapy (MC) is an emerging approach in solid tumours. Since MC has been poorly investigated in aggressive lymphomas in 2011, we formulated a new oral MC regimen ter...