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Background Non Hodgkin lymphoma (NHL) is one of the immune system cancers. The occurrence and progression of malignant lymphomas depends on cellular pathways deregulation. Understanding the relationship between the immune system at the genetic level and malignant transformation is critical to reach its etiology. Objective The aim of this work is to evaluate the expression of five immune related genes (PD-1, FOXP3, GrA, GrB and CD11c) in patients with diffuse large B cell non Hodgkin lymphoma (DLBCL). Materials and methods This study was conducted on fifty patients with DLBCL and fifty sex and age matched apparently healthy subjects. The participants were subjected to these laboratory investigations: complete blood count, serum lactate dehydrogenase and β2microglobulin (β2M) levels and determination of PD-1, FOXP3, GrA, GrB and CD11c gene expressions. Results The results of this study revealed that PD-1, FOXP3, GrA, GrB and CD11c gene expressions were significantly increased in DLBCL patients. Conclusion Patients with DLBCL have variablePD-1, FOXP3,GrA, GrB and CD11cgene expressions levels, which are correlated with the overall survival (OS) indicating that they can be good predictors of outcome in these patients., Highlights • The gene expression of immunity related genes are important indicators of lymphoma overall survival and prognosis. • Patients with DLBCL is usually accompanied by increased PD-1, and FOXP3 gene expression. • GrA and GrB genes expression decrease in DLBCL. • CD11c gene expression level is variable.

Background Several studies have reported on the incidence of interstitial pneumonia (IP) among patients with non-Hodgkin lymphoma (NHL) that have been treated with chemotherapy plus rituximab, however, the best means of prophylactically preventing IP remains unclear. This retrospective study was designed to explore the prophylactic effect of trimethoprim-sulfamethoxazole (TMP-SMX) on IP and to identify IP-associated risk factors in NHL patients. Methods Between March 2013 and April 2018, 498 patients (264 male, 53%) with B cell NHL undergoing first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-like chemotherapy treatment were enrolled in this study. Results These patients had a median age of 56 years, and 311 of these patients (62.4%) were administered prophylactic TMP-SMX. IP occurred in 65 patients (13.1%), with once daily prophylactic TMP-SMX treatment leading to a significant reduced IP rate (21.4% vs. 8.0%; p

Non-Hodgkin lymphoma (NHL) is a diverse class of hematological cancers, many of which arise from germinal center (GC)-experienced B cells. Thus GCs, the sites of antibody affinity maturation triggered during immune responses, also provide an environment that facilitates B cell oncogenic transformation. miRNAs provide attractive and mechanistically different strategies to treat these malignancies based on their potential for simultaneous modulation of multiple targets. Here, we discuss the scientific rationale for miRNA-based therapeutics in B cell neoplasias and review recent advances that may help establish a basis for novel candidate miRNA-based therapies for B cell-NHL (B-NHL). T.F. is supported by a PhD fellowship from the Spanish Ministerio de Ciencia, Innovacion y Universidades (BES-2017-079759), A.R.R. by CNIC funding, and V.G.d.Y. by the AECC foundation (INVES18013GARC) and by the Universidad Complutense de Madrid. This work was funded by Spanish Ministerio de Ciencia e Innovación (PID2019-107551RB-I00) and Spanish Ministerio de Ciencia, Innovacion y Universidades (SAF2016-75511-R) programs. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN), and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505). One European Patent Application titled ‘miRNA compositions for the treatment of mature B cell neoplasms’ EP16722679, EP17382740 was filed on March 3 2017. Sí

Introduction Non-Hodgkin B-cell lymphomas (B-NHLs) are a highly heterogeneous group of mature B-cell malignancies associated with very diverse clinical behaviors. They rely on the activation of different signaling pathways for proliferation and survival which might be amenable to targeted therapies, increasing the need for precision diagnosis. Unfortunately, their accurate classification can be challenging, even for expert hemato-pathologists, and secondary reviews recurrently differ from initial diagnosis. To address this issue we have developed a pan-B-NHL classifier based on a middle throughput gene expression assay coupled with a random forest algorithm. Material and Methods Five hundred ten B-NHL diagnosed according to the WHO criteria were studied, with 325 diffuse large B-cell lymphomas (DLBCL), 43 primary mediastinal B-cell lymphomas (PMBL), 55 follicular lymphomas (FL), 31 mantle cell lymphomas (MCL), 17 small lymphocytic lymphomas (SLL), 20 marginal zone lymphomas (MZL), 11 marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT) and 8 lymphoplasmacytic lymphomas (LPL). To train and validate the predictor the samples were randomly split into a training (2/3) and an independent validation cohort (1/3). A panel of 137 genes was designed by purposely selecting the differentiation markers identified in the WHO classification for their capacity to provide diagnostic and prognostic information in NHLs. Gene expression profiles were generated by ligation dependent RT-PCR applied to RNA extracted from frozen or FFPE tissue and analyzed on a MiSeq sequencer. For analysis, the sequencing reads were de-multiplexed, aligned with the sequences of the LD-RTPCR probes and counted. Results were normalized using unique molecular indexes counts to correct PCR amplification biases. Results In DLBCL, unsupervised gene expression analysis retrieved the expected GCB, ABC and PMBL signatures (Fig A). These tumors also showed higher expressions of the KI67 (proliferation), CD68 and CD163 (tumor associated macrophages), and PD-L1/2 (immune response) markers. We also observed that the dual expression of MYC and BCL2 at the mRNA level significantly associates with inferior PFS and OS, independent from the International Prognostic Index and from the GCB/ABC cell-of-origin signature, validating the capacity of the assay to identify these highly aggressive lymphomas (Fig C). Overall, low-grade lymphomas were characterized by a significant T cell component. FLs associated with the GCB (BCL6, MYBL1, CD10 and LMO2) and Tfh (CD3, CD5, CD28, ICOS, CD40L, CXCL13) signatures. Other small B-cell lymphomas tended to overexpress activated B-cell markers (LIMD1, TACI, IRF4,FOXP1...), and the expected CD5, CD10, CD23 and CCND1 differential expressions in SLL, MCL and MZL were correctly retrieved (Fig B). Surprisingly, our analysis revealed that the Ie-Ce sterile transcript, expressed from the IGH locus during IgE isotype switching, is almost exclusively expressed by FLs, constituting one of the most discriminant markers for this pathology. We next trained a random forest classifier to discriminate the 7 principal subtypes of B-NHLs. The training cohort comprised 162 DLBCLs (ABC or GCB), 28 PMBL, 35 FLs (grade 1-3A), 21 MCLs, 12 SLLs, and 25 NHLs grouped into the MZL category (13 MZLs, 8 MALT and 4 LPLs). The independent validation series comprised 90 DLBCLs classified as GCB or ABC DLBCLs by the Lymph2Cx assay, 15 PMBLs, 12 FLs (grade 1-3A), 10 MCLs, 5 SLLs and 14 MZLs (7 MZL, 3 MALT and 4 LPL). The RF algorithm classified all cases of the training series into the expected subtype, as well as 94.5% samples of the independent validation cohort (Fig D). For ABC and GCB DLBCLs, the concordance with the Lymph2Cx assay in the validation cohort was 94.3%. Conclusion We have developed a comprehensive gene expression based solution which allows a systematic evaluation of multiple diagnostic and prognostic markers expressed by the tumor and by the microenvironment in B-NHLs. This assay, which does not require any specific platform, could be implemented in complement to histology in many diagnostic laboratories and, with the current development of targeted therapies, enable a more accurate and standardized B-NHL diagnosis. Together, our data illustrate how the integration of gene expression profiling and artificial intelligence can increase precision diagnosis in cancers. Figure Disclosures Oberic: Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees. Haioun:Miltenyi: Honoraria; Takeda: Honoraria; Servier: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Janssen: Honoraria. Salles:Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria. Tilly:roche: Membership on an entity's Board of Directors or advisory committees; servier: Honoraria; merck: Honoraria; Roche: Consultancy; Celgene: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Karyopharm: Consultancy; BMS: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Jardin:celgene: Honoraria; roche: Honoraria; amgen: Honoraria; Servier: Honoraria; janssen: Honoraria.

Some patients with B-cell non-Hodkin lymphoma Lymphoma (NHL) become refractory to rituximab (anti-CD20 antibody) therapy associated with chemotherapy. Here, the effect of the anti-CD37 antibody-radionuclide conjugate lutetium-177 (177Lu)-lilotomab (Betalutin®) was investigated in preclinical models of NHL. In SCID mice bearing DOHH2 (transformed follicular lymphoma, FL) cell xenografts, 177Lu-lilotomab significantly delayed tumor growth, even at low activity (100 MBq/kg). In athymic mice bearing OCI-Ly8 (diffuse large B-cell lymphoma, DLBCL) or Ramos (Burkitt’s lymphoma) cell xenografts, 177Lu-lilotomab activity had to be increased to 500 MBq/kg to show a significant tumor growth delay. Clonogenic and proliferation assays showed that DOHH2 cells were highly sensitive to 177Lu-lilotomab, while Ramos cells were the least sensitive, and U2932 (DLBCL), OCI-Ly8, and Rec-1 (mantle cell lymphoma) cells displayed intermediate sensitivity. The strong 177Lu-lilotomab cytotoxicity observed in DOHH2 cells correlated with reduced G2/M cell cycle arrest, lower WEE-1- and MYT-1-mediated phosphorylation of cyclin-dependent kinase-1 (CDK1), and higher apoptosis. In agreement, 177Lu-lilotomab efficacy in vitro, in vivo, and in patient samples was increased when combined with G2/M cell cycle arrest inhibitors (MK-1775 and PD-166285). These results indicate that 177Lu-lilotomab is particularly efficient in treating tumors with reduced inhibitory CDK1 phosphorylation, such as transformed FL.

Although outcomes for children with B-cell non-Hodgkin lymphoma are excellent, between 20% and 40% demonstrate residual radiologic abnormalities at disease assessment during consolidation therapy, the significance of which remains uncertain. The authors report the outcomes for all children treated for B-cell non-Hodgkin lymphoma at our center over an 11-year period. Twenty-four of 64 (38%) children had residual radiologic abnormalities at disease remission assessment. Seven (29%) underwent histologic biopsies that were normal. No children with residual radiologic abnormalities experienced disease relapse or death, suggesting that imaging at this time point creates clinical uncertainty without indicating residual disease or predicting relapse.

B-cell lymphoma; DNMT; EZH2 Linfoma de células B; DNMT; EZH2 Limfoma de cèl·lules B; DNMT; EZH2 In the last 10 years, major advances have been made in the diagnosis and development of selective therapies for several blood cancers, including B-cell non-Hodgkin lymphoma (B-NHL), a heterogeneous group of malignancies arising from the mature B lymphocyte compartment. However, most of these entities remain incurable and current treatments are associated with variable efficacy, several adverse events, and frequent relapses. Thus, new diagnostic paradigms and novel therapeutic options are required to improve the prognosis of patients with B-NHL. With the recent deciphering of the mutational landscapes of B-cell disorders by high-throughput sequencing, it came out that different epigenetic deregulations might drive and/or promote B lymphomagenesis. Consistently, over the last decade, numerous epigenetic drugs (or epidrugs) have emerged in the clinical management of B-NHL patients. In this review, we will present an overview of the most relevant epidrugs tested and/or used so far for the treatment of different subtypes of B-NHL, from first-generation epigenetic therapies like histone acetyl transferases (HDACs) or DNA-methyl transferases (DNMTs) inhibitors to new agents showing selectivity for proteins that are mutated, translocated, and/or overexpressed in these diseases, including EZH2, BET, and PRMT. We will dissect the mechanisms of action of these epigenetic inhibitors, as well as the molecular processes underlying their lack of efficacy in refractory patients. This review will also provide a summary of the latest strategies being employed in preclinical and clinical settings, and will point out the most promising lines of investigation in the field. The authors received financial support from Fondo de Investigacion Sanitaria PI15/00102 and PI18/01383, European Regional Development Fund (ERDF) "Una manera de hacer Europa" (to GR). The authors received fundings from TG Therapeutics and Celgene Corp to support researches unrelated to the present work. Funders were involved neither in the design, nor in the writing of this review.

Chimeric antigen receptor (CAR) T cells are emerging as a novel treatment for patients with refractory/relapsed B-cell non-Hodgkin lymphoma (B-NHL), and combination with PD1 inhibitors may further improve the efficacy of anti-CD19 CAR (CD19 CAR)-T cells in the treatment of lymphomas. In a single-center study, we evaluated the safety and efficacy of a combination therapy with CD19 CAR-T cells and an anti-PD-1 antibody (nivolumab) in patients with relapsed/refractory B-NHL. A total of 11 patients with refractory/relapsed B-NHL were recruited and subsequently received CD19 CAR-T cells and nivolumab. The primary end points were safety and feasibility. The infusions were safe, and no dose-limiting toxicities occurred. Grade 1 or 2 cytokine release syndrome (CRS) was observed in 25% (3/11) and 50% (6/11) of the patients, respectively, and only one patient (1/11) experienced neurotoxicity. The objective response rate (ORR) and complete response (CR) rate were 81.81% (9/11) and 45.45% (5/11), respectively. The median follow-up time was 6 (1~15) months. The median progression-free survival (PFS) time was 6 months (1~14 months), and 3 patients continued to have a response at the time of this writing. Our study demonstrated that the combination of CD19 CAR-T cells and nivolumab was feasible and safe and mediated potent anti-lymphoma activity, which should be examined further in prospective clinical trials in refractory/relapsed B-NHL.

B-cell non-Hodgkin’s lymphomas are tumors of B-cells that arise following clonal expansion and consequent invasion of immune organs by B-cells blocked at a certain step of the differentiation process. Genetic abnormalities with altered gene expression are common in the transformed state of B-cells at any stage of B-cell development. These stages are regulated by a combination of transcription factors, epigenetic modifications, microRNAs, and extrinsic signals. MicroRNAs are a class of short non-coding single-stranded RNAs implicated in the regulation of mRNA function and translation. Each microRNA can regulate multiple transcripts; and a transcript is under potential control by multiple microRNAs. Their dysregulation can contribute to the pathogenesis of B-cell non-Hodgkin lymphomas, and they could be used as a potential target for diagnosis, evaluation of prognosis and therapy monitoring. The mechanisms of microRNA dysregulation range from dysregulation of the DNA sequences encoding the microRNAs to transcriptional regulation of microRNA loci. In this review, we summarized the microRNA profiles of the most common B-cell Non-Hodgkin Lymphomas for the pathogenesis, diagnosis and their potential therapeutic implications.

B-cell non-Hodgkin’s lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL such as diffuse large B-cell lymphoma (DLBCL) have been comprehensively interrogated at the genomic level. But rarer subtypes such as mantle cell lymphoma (MCL) remain sparsely characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth; including DLBCL, MCL, follicular lymphoma (FL), and Burkitt lymphoma (BL). We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumor from each subtype, including the frequent genetic deregulation of the ubiquitin proteasome system (UPS). In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.

2508 Background: Relapse due to loss of the CD19 targeted epitope presents a therapeutic challenge of CD19 CAR-T therapy. These patients universally have a poor outcome and the unmet medical need is high. CD20 is a proven therapeutic target for B-NHL, supported by approved and widely used monoclonal antibody therapy. C-CAR066 is a novel 2nd generation chimeric antigen receptor T (CAR-T) therapy targeting CD20 antigen. Preclinical studies suggest that C-CAR066 has superior anti-tumor activity compared to CAR-Ts derived from scFVs of Leu16, Rituximab and Obinutuzumab and anti-CD19 BBZ CAR with FMC63. Methods: A phase I clinical trial (NCT04036019) was conducted to evaluate the safety and efficacy of C-CAR066 in subjects with r/r B-NHL who were previously treated with anti-CD19 CAR-T therapy. Patients (≥ 18 years) with r/r DLBCL, r/r FL or r/r MCL, ECOG < 2 were eligible. GMP manufacture of C-CAR066 was in a serum free and fully closed semi-automatic system. A 3-day cyclophosphamide plus fludarabine regimen was followed by a single infusion of C-CAR066. Bridging therapy was allowed. Results: As of Jan 31, 2021, 7 patients (6 DLBCL, 1 tFL) were enrolled and infused with C-CAR066 at dose ranges of 2.0 x 106 to 4.8x106 CAR-T cells/kg. The manufacturing success rate was 100%. The median age was 51 (range, 41-62) years, and 42.9% (3/7) patients were male. The median number of prior lines of therapy was 5 (range, 2-6). One patient (14.3%) underwent autologous stem cell transplant (ASCT) and one patient received bridging therapy. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT 2019 criteria. All 7 patients experienced CRS and most (85.7%) were grade 1 or 2. One patient had grade 4 CRS and recovered after treatment with tocilizumab and corticosteroids. Median time to onset of CRS was 5 days (range, 1-9), with median duration of 4 days (range, 2-17). There were no episodes of ICANS. Grade ≥3 neutropenia, anemia, thrombocytopenia, and infections were reported in 57.1%, 42.9%, 28.6%, and 14.3% of patients, respectively. At a median follow-up of 7.8 months, the best overall response rate was 100%, with 71.4% (5/7) achieving complete response (CR). Median time to response was 1.0 month (range, 0.9-2.7). Median time to CR was 2.7 months (range, 0.9-2.8). By the cutoff date, 3 patients (2 PR, 1 CR) had disease progression. Median duration of response was not reached. Conclusions: C-CAR066 has shown a favorable safety profile and promising efficacy in patients with r/r B-NHL following failure of CD19 CAR-T therapy. These results show that C-CAR066 has a different mechanism of action compared to anti-CD-19 CAR-T therapy and could provide a solution to address the unmet medical need in B-NHL patients that have failed anti-CD19 CAR-T therapy. Clinical trial information: NCT04036019.

2507 Background: C-CAR039 has been developed as a novel 2nd generation 4-1BB bi-specific CAR-T targeting both CD19 and CD20 antigens with an optimized bi-specific antigen binding domain. C-CAR039 can eradicate CD19/CD20 single or double positive tumor cells in vitro and in vivo. The tissue cross reactivity and whole genome membrane proteome array studies further confirmed the specificity of C-CAR039. Methods: GMP manufacturing of C-CAR039 was carried out in a serum free and fully closed semi-automatic system. Dose escalation and expansion studies were conducted to evaluate the safety and efficacy of C-CAR039 in r/r B-NHL patients. C-CAR039 was administered as a single intravenous dose after a 3-day cyclophosphamide plus fludarabine conditioning regimen. Results: As of 1/31/2021, 28 patients were infused and 25 (DLBCL, n = 22; PMBCL, n = 1; tFL, n = 1; FL, n = 1) were evaluable for safety and efficacy at dose ranges of 1.0 x 106 to 5.0x106 CAR-T cells/kg. The median age was 54 (range, 28-71) years, median number of prior lines of therapy was 3 (range, 1–5), 76% (19/25) of patients were in Ann Arbor Stage III/IV, and 80% (20/25) were refractory to their last treatment. 5 patients (20%) received bridging therapy. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT 2019 criteria. Of the 25 patients, 24 (96%) experienced CRS, 23 (92%) were grade 1 or 2, 1 patient was grade 3. Median time to onset of CRS was 3 days (range, 0-10), with median duration of 4 days (range, 1-25). 2 patients had a grade 1 ICANS. Grade≥3 neutropenia, anemia, thrombocytopenia and infection were reported in 88%, 40%, 16% and 0% of patients, respectively. The best overall response rate was 92%, complete response (CR) rate was 84% and median time to response was 1.0 month (range, 0.9-1.2). With a median follow-up of 5.3 months, 76% remained in CR. Kaplan Meyer estimation of PFS at 6 months was 87.3% (95% CI, 71.2 to 100.0). Median duration of response has not been reached. Furthermore, C-CAR039 showed an encouraging cellular kinetic profile. In 25 evaluable patients, the median Tmax was 11 day, the median Cmax was 139,497 copies/mg gDNA, and the median AUC0̃28DAY of 1,673,844 day*copies/μg gDNA. Conclusions: C-CAR039 demonstrated a favorable safety profile and promising efficacy in this early clinical trial in patients with r/r B-NHL that might allow it to differentiate from existing therapies. The early clinical efficacy signal is encouraging and compares favorably to anti-CD19 CAR-T and peer therapies. These findings will be evaluated in more patients with longer follow-up to confirm safety, efficacy and duration of response. Clinical trial information: NCT04317885 , NCT04655677 , NCT04696432 , NCT04693676 .

Summary This phase 1/2 study evaluated the safety, pharmacokinetic behavior and anti‐tumour activity of ublituximab, a unique type I, chimeric, glycoengineered anti‐CD20 monoclonal antibody, in rituximab‐relapsed or ‐refractory patients with B‐cell non‐Hodgkin lymphoma (B‐NHL) or chronic lymphocytic leukaemia (CLL). Induction therapy (doses of 450–1200 mg) consisted of 4 weekly infusions in cycle 1 for NHL and 3 weekly infusions in cycles 1 and 2 for CLL. Patients received ublituximab maintenance monthly during cycles 3–5, then once every 3 months for up to 2 years. Enrolled patients with B‐NHL (n = 27) and CLL (n = 8) had a median of 3 prior therapies. No dose‐limiting toxicities or unexpected adverse events (AEs) occurred. The most common AEs were infusion‐related reactions (40%; grade 3/4, 0%); fatigue (37%; grade 3/4, 3%); pyrexia (29%; grade 3/4, 0%); and diarrhoea (26%; grade 3/4, 0%). Common haematological AEs were neutropenia (14%; grade 3/4, 14%) and anaemia (11%; grade 3/4, 6%). The overall response rate for evaluable patients (n = 31) was 45% (13% complete responses, 32% partial responses). Median duration of response and progression‐free survival were 9·2 months and 7·7 months, respectively. Ublituximab was well‐tolerated and efficacious in a heterogeneous and highly rituximab‐pre‐treated patient population.

Patterns of myeloid growth factor (GF) usage and febrile neutropenia (FN) were examined in patients 60 years of age with diffuse large B-cell non-Hodgkin lymphoma (DLBCL) enrolled on CALGB 9793/ECOG-SWOG 4494, receiving initial therapy with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or rituximab + CHOP (R-CHOP). Myeloid GFs were administered to 256/520 (49%) patients. Indications for use were: prevent dose reduction/dose delay (81%, 207/256); treat FN or non-febrile neutropenia (NFN) (19%, 48/256). One or more FN episodes occurred in 41% (212/520) of patients, with FN most often in cycle 1 (38% of episodes). In multivariate analysis, risk factors for FN included age 65 years (odds ratio (OR) = 2.6, 95% CI: [1.4, 4.9]) and anemia (hemoglobin 12 g/dl) (OR =2.2, 95% confidence intervals (CI): [1.4, 3.5]. Myeloid GF use was common in this older DLBCL population receiving CHOP-based therapy, as was FN, especially during cycle one. Risk factors predictive for FN should be used prospectively to identify patients for whom myeloid GFs are best utilized.

A Phase II, multicenter clinical trial of bendamustine plus rituximab (BR) regimen was conducted in previously untreated patients with high-tumor-burden indolent B-cell non-Hodgkin lymphoma (B-NHL) and previously untreated elderly patients with mantle cell lymphoma (MCL) in Japan. Bendamustine 90 mg/m2/day on days 1 and 2, as well as rituximab 375 mg/m2 on day 1 were administered intravenously up to six cycles. The primary endpoint was the complete response (CR) rate as assessed by the International Workshop Response Criteria (1999). Sixty-nine patients (59 with indolent B-NHL and 10 with MCL) were treated. The median number of delivered cycles was six (range 1–6). The CR rates were 67.8% [95% confidence interval (CI) 54.4–79.4%] and 70.0% (95% CI 34.8–93.3%) for indolent B-NHL and MCL, respectively. Estimated progression-free survival at 30 months was 72.1% (95% CI 58.5–82.0%) in indolent B-NHL and was 67.5% (95% CI 29.1–88.2%) in MCL. Major grade 3/4 toxicities were hematologic and included lymphopenia (97%), CD4 lymphopenia (91%), neutropenia (86%), and leukopenia (83%). No treatment-related death was found. The BR regimen showed high efficacy as evidenced by the expected CR rate and durable response, as well as an acceptable safety profile for the study populations.

A small percentage of nodular lymphocytic predominant Hodgkin lymphoma (NLPHL) progresses to diffuse large B-cell lymphoma (DLBCL). There have also been rare reports of gray zone lymphoma with features intermediate between classical Hodgkin lymphoma (CHL) and DLBCL. We report a very rare case of composite lymphoma (CHL and NLPHL) progressing to DLBCL, and highlight the diagnostic difficulty faced during its fine-needle aspiration (FNA) cytology diagnosis. A 65-year-old woman presented with a right axillary swelling which was subjected to FNA cytology. The routine FNA cytology diagnosis was anaplastic large cell lymphoma (ALCL) but immunocytochemistry did not support this diagnosis completely. The histopathological diagnosis of the excised lymph node was NLPHL with progression to DLBCL in our hospital but in a hospital abroad where the patient was treated, the reviewed diagnosis was CHL. The patient had a rapid downhill course with development of terminal pleural effusion and died approximately one year from initial diagnosis.The review of the cyto-histologic material along with additional immunocyto/histochemical studies and the clinical course of the disease support the diagnosis of a composite lymphoma (CHL and NLPHL) with progression to DLBCL. It is suggested that all the three lesions were clonally related. Diagn. Cytopathol. 2017;45:262-266. © 2016 Wiley Periodicals, Inc.

An 84-year-old man presented with a history of repeated syncope and decreased heart rate and blood pressure over the last month. On physical examination, a mass sized ~3×3 cm was palpable in the left submandibular area; the mass was hard, poorly mobile, without tenderness or local skin irritation. The computed tomography angiography examination revealed a soft tissue mass in the neck, at the level of the left carotid bifurcation and above. The left common carotid artery bifurcation and internal and external carotid artery segment were embedded in the mass, and there were multiple enlarged lymph nodes in the left neck. The diagnosis of diffuse large B-cell non-Hodgkin lymphoma was confirmed by a percutaneous biopsy of the left submandibular mass. To the best of our knowledge, this is the first reported case of non-Hodgkin lymphoma involvign the carotid space.

Lenalidomide, an immunomodulatory drug that the US Food and Drug Administration (FDA) approved for the treatment of multiple myeloma, 5q- myelodysplasia and mantle-cell lymphoma (MCL), has encouraging efficacy in other B-cell malignancies. Its unique mechanism of action is in part due to altering the tumor microenvironment and potentiating the activity of T and natural-killer (NK) cells. Impressive clinical activity and excellent tolerability allows broad applicability. Lenalidomide has been used in a wide range of B-cell malignancies for years, but in 2013, the FDA marked its approval as a single agent only in relapsed/refractory mantle-cell lymphoma. Perhaps most impressive is the efficacy of lenalidomide when combined with monoclonal antibodies. Impressive efficacy and toxicity profiles with the combination of lenalidomide and rituximab in B-cell lymphomas in both the upfront and relapsed/refractory setting may allow a shift in our current treatment paradigm in both indolent and aggressive non-Hodgkin lymphoma (NHL). This review will summarize the current data in the relapsed/refractory and front-line setting of NHL with single-agent lenalidomide as well as its use in combination with other agents.

BACKGROUND: The clinical course of gastric lymphoma is heterogeneous and clinical symptoms and some factors have been related to prognosis. OBJECTIVE: The present study aims to identify prognostic factors in gastric diffuse B-cell non-Hodgkin lymphoma diagnosed and treated in different countries. METHODS: A consecutive series of gastric diffuse B-cell non-Hodgkin lymphoma patients diagnosed and treated in Brazil, Portugal and Italy, between February 2008 and December 2014 was evaluated. RESULTS: Of 104 patients, 57 were female and the median age was 69 years (range: 28-88). The distribution of the age-adjusted international prognostic index was 12/95 (13%) high risk, 20/95 (21%) high-intermediate risk and 63/95 (66%) low/low-intermediate risk. Symptoms included abdominal pain (63/74), weight loss (57/73), dysphagia (37/72) and nausea/vomiting (37/72). Bulky disease was found in 24% of the cases, anemia in 33 of 76 patients and bleeding in 22 of 72 patients. The median follow-up time was 25 months (range: 1-77 months), with 1- and 5-year survival rates of 79% and 76%, respectively. The multivariate Cox Regression identified the age-adjusted international prognostic index as a predictor of death (hazard risk: 3.62; 95% confidence interval: 2.21-5.93; p-value

The last 5 years have seen significant advances in our understanding of the molecular pathogenesis of B-cell lymphomas. This has led to the emergence of a large number of new therapeutic agents exploiting precise aspects of the tumor cell's signaling pathways, surface antigens or microenvironment. The purpose of this comprehensive review is to provide a detailed analysis of the breakthrough agents in the field, with a focus on recent clinical data. We describe agents targeting the B-cell receptor pathway, Bcl-2 inhibitors, emerging epigenetic therapies, new monoclonal antibodies and antibody drug conjugates, selective inhibitors of nuclear export, agents targeting the programmed cell death axis and chimeric antigen receptor T cells.

Despite representing 30% to 40% of newly diagnosed cases of adult non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL) rarely presents (1) in the leukemic phase (2) with dysregulation of the TP53 tumor suppressor gene and (3) an elevated serum lactic acid level. In this case report and literature review, we highlight this unfortunate triad of poor prognostic features associated with an aggressive and fatal clinical course in a 53-year-old man with recrudescent DLBCL. A leukemic presentation of de novo or relapsed DLBCL is rare and may be related to differential expressions of adhesion molecules on cell surfaces. In addition, TP53 gene mutations are present in approximately 20% to 25% of DLBCL cases and foreshadow worse clinical outcomes. Finally, an elevated serum lactic acid level in DLBCL that is not clearly associated with sepsis syndrome is a poor prognostic factor for survival and manifests as type B lactic acidosis through the Warburg effect.

Simple Summary The activity of novel therapies that utilize patient’s own T-cells to induce remission of B-cell non-Hodgkin lymphoma (B-NHL), including chronic lymphocytic leukemia (CLL), is still suboptimal. In this review, we summarize the clinical efficacy of T-cell-based therapies in B-NHL and provide a biologic rationale for the observed (lack of) responses. We describe and compare the acquired T-cell dysfunctions that occur in the different subtypes of B-NHL. Furthermore, we discuss new insights that could enhance the efficacy of T-cell-based therapies for B-NHL and CLL. Abstract The next frontier towards a cure for B-cell non-Hodgkin lymphomas (B-NHL) is autologous cellular immunotherapy such as immune checkpoint blockade (ICB), bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T-cells. While highly successful in various solid malignancies and in aggressive B-cell leukemia, this clinical success is often not matched in B-NHL. T-cell subset skewing, exhaustion, expansion of regulatory T-cell subsets, or other yet to be defined mechanisms may underlie the lack of efficacy of these treatment modalities. In this review, a systematic overview of results from clinical trials is given and is accompanied by reported data on T-cell dysfunction. From these results, we distill the underlying pathways that might be responsible for the observed differences in clinical responses towards autologous T-cell-based cellular immunotherapy modalities between diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). By integration of the clinical and biological findings, we postulate strategies that might enhance the efficacy of autologous-based cellular immunotherapy for the treatment of B-NHL.

Background: LAG3 is one of the immune check point receptors that are expressed on activated cytotoxic T-cells and regulatory T cells. Physiologically, T-cell proliferation and memory T-cell differentiation is negatively regulated by LAG3-MHC interaction. In cancer tissues, T-cells that are chronically exposed to tumor antigens might upregulate LAG3 and receive inhibitory stimuli to enter an exhaustion state limiting anti-tumor immune responses. Currently, clinical trials using double blockade of LAG3/PD1 are active in several solid tumours, but there are only a small number of clinical trials using LAG3 monoclonal antibodies in lymphoma. Recently, we published a characteristic LAG3+ T-cell population as a mediator of immune suppression in classical Hodgkin lymphoma (Aoki & Chong et al. Cancer Discovery 2020). However, the abundance and variability of LAG3 positive T-cell populations across a spectrum of B-cell lymphoma has not been well studied and it remains an open question if LAG3 expression is associated with treatment outcome under standard-of-care conditions. Methods: We performed a LAG3 immunohistochemical (IHC) screen in a large cohort of B-cell Non-Hodgkin lymphoma (diffuse large B-cell lymphoma (DLBCL); N=341, follicular lymphoma (FL); N=198 (grade 1-3A), transformed FL to aggressive lymphoma (tFL); N=120, mantle cell lymphoma (MCL); N=179, primary mediastinal large B-cell lymphoma (PMBCL); N=61) and classical Hodgkin lymphoma (HL; N=459) to assess LAG3 expression in the tumor microenvironment (TME). Moreover, we characterized LAG3+ T-cell populations using multi-color immmunohistochemistry (IHC) (LAG3, PD1, CD4, CD8, FOXP3, CD20) in various lymphoma subtypes. Clinical parameters including treatment outcome were correlated with the abundance of LAG3+ T-cell populations in the TME. Results: On average, HL (7%) and PMBCL (6%) showed higher LAG3+ cellular frequency than the other B-cell lymphoma subtypes studied (DLBCL and FL: 2%, MCL: 0.8%). Comparing the frequency of LAG3+ cells according to MHC class I/II status, DLBCL showed a significant correlation with MHC class I status, and LAG3 expression correlated with MHC class II status in HL. Next, we performed multi-color IHC to describe subtype-specific expression patterns of LAG3 in T cell subsets. LAG3+PD1- T-cells were predominantly found in HL and PMBCL with only rare LAG3+PD1+ cells in HL. The majority of LAG3+ T-cells co-expressed CD4 in HL, in contrast to CD8 in PMBCL. DLBCL showed a mixed population pattern with a 1:1 ratio of LAG3+PD1- and LAG3+PD1+ T-cells. In FL, the majority of LAG3+ T-cells were CD4+PD1+, suggesting a more exhausted TME phenotype in FL than in other lymphoma subtypes. Cellular distance analysis showed that LAG3+CD4+ T-cells were in close vicinity to CD20+ lymphoma cells in FL, while in DLBCL and PMBCL, the nearest neighbors of malignant cells were LAG3+CD8+. Triple-positive LAG3+PD1+CD8+ T-cells significantly correlated with high infiltrating M2 macrophage (Pearson's correlation test, P < 0.001) content and the ABC cell-of-origin subtype (Pearson's correlation test, P = 0.002) in DLBCL. The abundance of LAG3+CD8+PD1- cells correlated with a high FLIPI score (Pearson's correlation test, P = 0.033), disease specific survival (HR = 2.8, 95% CI = 1.3-5.9, P = 0.006), time to progression (HR = 2.8, 95% CI = 1.6-5.0, P = 0.001) and transformation (HR = 4.0, 95%CI = 1.7-9.6, P = 0.002) in FL treated with R-CVP (N = 135). Assessing LAG3 expression by single color IHC in FL (cut-off at 5%), patients with LAG3-positive samples showed significantly higher FL transformation rates (P = 0.023) and tFL samples showed higher abundance of LAG3+ cells than the corresponding primary pretreatment FL samples (primary FL: 1.5±1.7% vs. tFL: 4.2±3.8%, t-test, P = 0.01). The increased transformation risk was validated in an independent FL cohort treated with R-CHOP/CVP (N=97, HR = 6.2, 95% CI = 2.8-13.9, P < 0.001). Conclusion: The highest abundance of LAG3+ T-cells in the TME was found in HL and its related entity PMBCL. The differential outcome correlations and co-expression patterns in LAG3+ T cells across B-cell lymphoma subtypes indicate heterogeneity in TME composition and related pathogenic mechanisms. Our results suggest that LAG3 expression patterns will be important in the interpretation of ongoing studies and highlight populations that may benefit from LAG3 checkpoint inhibition. Disclosures Sehn: AstraZeneca: Consultancy, Honoraria; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Chugai: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; Verastem Oncology: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Acerta: Consultancy, Honoraria. Savage:Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy; BeiGene: Other: Steering Committee; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria. Scott:Celgene: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy; NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Roche/Genentech: Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; Janssen: Consultancy, Research Funding. Steidl:Bayer: Consultancy; Juno Therapeutics: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy; Curis Inc: Consultancy.

Background: Real world multi-institutional data of anti-CD19 CAR-T therapy from across the US shows similar response rates and toxicities as that of the registration trials. For axicabtagene ciloleucel (axi-cel), bridging therapy (BT) during CAR-T manufacturing was not allowed. Real world data shows that patients who received BT had lower complete remission (CR) rates, duraiton of response (DOR) and overall survival (OS). Whether the poorer outcome is due to the effect of the BT or the aggressive biology of the disease is unknown. Patients with lower disease burden had higher response rate in the registration study ZUMA-1 for axi-cel. We examined the impact of response to BT on CAR-T outcome. Specifically, we also describe our experience using polatuzumab vedotin, bendamustine and rituximab (Pola-BR), also a recently approved therapy for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), prior to CAR-T as salvage (ST) and BT. Methods: A retrospective review of 63 patients who received axi-cel for NHL from June 2016 - March 2020 at Mayo Clinic, Rochester was performed. ST was defined as the last therapy prior to leukapheresis and grouped into categories - autologous stem cell transplant (ASCT), and non-ASCT (chemotherapy and immunotherapy) . BT was defined as lymphoma-directed therapy given between leukapheresis and CAR-T infusion. Response to all lymphoma-directed therapy was evaluated using 2014 Lugano criteria. Event free survival (EFS) was defined as time from axi-cel infusion to progression, next treatment, or death. Overall survival (OS) was defined as time from axi-cel infusion to death. Results: Patients received BT if there were concerns for symptomatic progression of disease during CAR-T manufacturing that would reduce the likelihood of eligibility to receive CAR-T. The decision and choice of BT was at the discretion of the treating physician. Sixty-eight percent (n=43) of the patients received BT (19 chemo, 24 immunotherapy). Demographics of the patients based on their response to BT are shown in table 1. More patients in the BT responder group had received chemotherapy as type of bridge (58% vs. 33%). With a median follow up of 12-months for those still alive, significant improvement in EFS was seen in patients who had partial response (PR) or stable disease (SD) to BT than patients who continued to progress (median 12 months vs. 3 months, p = 0.01) [Figure 1A]. OS however, was not significant between the two groups (median OS 18 months - responders vs. 12 months non-responders, p = 0.19) [Figure 1B]. We also describe in the case series below 11 patients who received Pola-BR in salvage setting (ST) and/or BT (Table 2). Due to the lymphopenic effects of bendamustine, it was avoided before T-cell collection if possible. Two patients, however, received bendamustine as part of Pola-BR for salvage therapy as its need was determined per the managing physician. Axi-cel was successfully manufactured for all 10 patients. One patient did not have measurable disease after Pola-BR BT and remains on observation. A second patient died before CAR-T infusion from progressive disease. Four of the nine patients treated with CAR-T remained in response. Updated outcome will be presented. Conclusion: While patients who received BT have worse EFS than those who didn't, having some control of lymphoma after BT was associated with better EFS compared to patients who continued to have progressive disease after BT. Preliminary data from Pola-BR case series shows 60% (6/10) patients achieved PR/SD before CAR-T infusion, but requires longer follow up for its impact on survival. Disclosures Bennani: Purdue Pharma: Other: Advisory Board; Kite/Gilead: Research Funding; Affimed: Research Funding; Verastem: Other: Advisory Board. Ansell:AI Therapeutics: Research Funding; Takeda: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; ADC Therapeutics: Research Funding; Trillium: Research Funding. Lin:Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Legend BioTech: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy.

R-CHOP chemoimmunotherapy is first line therapy for diffuse large B cell non Hodgkin lymphoma (DLBCL), although R-CHOP may be suboptimal treatment for some subtypes of DLBCL, in particular double-hit (DH) or triple-hit (TH) lymphoma. For assessment of response to chemoimmunotherapy, it has been proposed that PET-CT scan may be superior to CT scan and, in particular, demonstration of metabolic complete response (CR) by PET-CT scan at end of treatment (EOT) may be an important indicator of long term survival. However, the usefulness of follow up scans in asymptomatic patients remains debatable. We wished to assess the role of an interim CT or PET-CT scan (after 3-4 courses of chemoimmunotherapy) in predicting overall survival in patients at our centre with stage II- IV DLCBCL (Lugano Modification of Ann Arbor Classification) who received chemoimmunotherapy with curative intent. We also recorded results of scans at EOT and any further follow up scans. Between 1/7/15 and 1/7/19, 43 consecutive patients receiving R-CHOP had an interim CT or PET-CT scan. 3 of 4 patients with DH lymphoma by FISH testing changed to dose adjusted R-EPOCH after one course of R-CHOP. 39 patients had no evidence of DH, with 37 showing either partial response (PR) (N = 11) or CR (N=26) on interim CT or PET-CT scan. Of these 37 cases, one patient died of neutropenic sepsis, whilst 36 remain alive with 35 in complete remission. 30 of these 37 patients had CT scan and/or PET-CT scan at EOT: 27 were in CR, 2 were in stable PR and 1 patient (in CR on interim PET -CT scan) showed relapse on PET-CT scan. 16 patients in CR at EOT had 55 follow up surveillance scans (median 2, range 1-8) -two further relapses were detected on PET-CT scan, both 4 months after EOT. Two of the relapsed cases are in CR following further chemoimmunotherapy and allogeneic stem cell transplant whilst the other relapsed case is currently responding to further chemoimmunotherapy. 2 patients without evidence of DH showed disease progression on interim scan and were refractory to further chemotherapy, dying within 3 months and 18 months of diagnosis. All 4 patients with DH lymphoma had PR or CR at interim scan but relapsed within 5 to 8 months after diagnosis and proved chemotherapy refractory with death in 3. One patient with DH lymphoma remains in CR following local radiation and maintenance therapy with rituximab, lenalidomide and metformin. In our experience, patients with DLBCL, without DH or TH, who have evidence of response to R-CHOP at interim scan have an excellent prognosis. In this patient cohort, 85 EOT and follow up scans detected 3 relapses, suggesting that the detection rate of follow up scans in asymptomatic patients in this good prognosis group is low and of questionable usefulness. The 3 relapsed patients were readily salvageable by further chemoimmunotherapy with or without allogeneic stem cell transplant. In contrast, patients with DH lymphoma or evidence of disease progression on interim scan have very poor prognosis and urgently require alternative therapy approaches. Disclosures No relevant conflicts of interest to declare.

Context: CD3×CD20 bispecific antibodies (bsAbs) have demonstrated promising results in R/R B-NHL. Epcoritamab is a novel subcutaneously-administered bsAb with a favorable safety profile and encouraging preliminary anti-tumor activity in both aggressive and indolent B-NHL in a Phase I/II trial ( NCT03625037 ). Objective: Determine recommended phase 2 dose, safety, and anti-tumor activity of epcoritamab. Participants: Adults with R/R CD20+ B-NHL. Intervention: SC 1 mL injection of flat-dose epcoritamab (dosing escalation range 0.0128–48 mg preceded by a priming and intermediate dose) administered in 28-day cycles until disease progression or unacceptable toxicity. Results: As of 24 April 2020, 58 patients with a median (range) age 68 (21–84) years were enrolled. Most patients had DLBCL (67.2%) or FL (19.0%) and received a median (range) of 3 (1–6) and 5 (1–18) prior lines of treatment, respectively. No dose-limiting toxicities were observed (median follow-up [range]: 2.7 [0.2–16.4] months). MTD has not been reached. Majority of TEAEs were mild (Grade 1–2); the most common TEAEs (>35%) were pyrexia (69.0%), fatigue (41.4%), and injection site reaction (41.4%; all Grade 1). AEs of special interest included CRS (56.9%; no Grade ≥3 events occurred; all resolved) and neurotoxicity (6.9%; median [range] duration of events: 1 [ Conclusions: The safety, efficacy, and pharmacokinetics data support epcoritamab 48 mg SC (1 mL, single dose) to be explored in the expansion phase. SC epcoritamab continues to demonstrate a favorable safety profile consistent with previous reported data. Notably, there were no treatment-related deaths, no febrile neutropenia, tumor lysis syndrome, or Grade ≥3 CRS events. Epcoritamab has the potential for outpatient administration. Epcoritamab induces rapid, deep responses in heavily pretreated patients across different B-NHL subtypes. Funding: Genmab A/S.

Diffuse large b-cell non-Hodgkin lymphoma is an aggressive neoplasm, uncommon in the oral cavity and characterized by morphologic, immunophenotypic, and molecular heterogeneity. In this case report, a 67-year-old, obese, white, male patient reported a recent loss of 10 kg of weight in the last 5 months and instability of the maxillary denture. On intraoral examination, it was observed a nodule with inaccurate limits, discreetly purplish coloration in the right hard palate. An incisional biopsy of the lesion on the palate was performed and morphologic findings and immunohistochemical panel with immunoreactivity for ACL, CD20, and ki67 (> 90%); BCL2, CD3, and MUM1 led us to the diagnosis of diffuse large b-cell lymphoma. The patient was submitted to chemotherapy with 6 cycles of R-CHOP with systemic control of the disease and is under medical follow-up.

Purpose Coxiella burnetii has been suggested as a potential cause of B-cell non-Hodgkin lymphoma (B-NHL), as C. burnetii was detected in B-NHL tissues. To further investigate this potential relationship, we hypothesized that among subjects previously exposed to C. burnetii, the bacterium is more frequently detectable in tissues of patients with B-NHL (cases) compared to patients without B-NHL (controls). Methods We aimed to evaluate this hypothesis by assessing the presence of C. burnetii with polymerase chain reaction (PCR), immunofluorescence staining (IF) and fluorescent in-situ hybridization (FISH). Eligible patients were those previously exposed to C. burnetii. Results Samples were available for 13 cases and 16 controls. C. burnetii was demonstrated in tissues of 8/29 patients in total (28%), with either PCR, IF or FISH: in 5/13 cases (38%) and 3/16 controls (19%), p = 0.41. Negative and positive control samples were all negative and positive appropriately for all three diagnostic methods. Conclusions In patients previously exposed to C. burnetii the bacterium was detected in tissue samples from subjects with and without B-NHL, without significant differences in the proportion positive samples. Therefore, we conclude that detection of C. burnetii in tissues of patients previously exposed to C. burnetii is a non-specific finding.

e15020 Background: Durable responses were seen in registration trials for CAR-T in NHL across poor prognostic groups including early relapse post stem cell transplant (ASCT). Multi-center reports of real-world practice noted patients who received BT prior to CAR-T had decreased survival. The impact of last ST and response to BT on clinical outcome are examined here. Methods: Retrospective chart review was performed on 47 patients who received axicabtagene ciloleucel from June 2016 – September 2019 at Mayo Clinic, Rochester. ST was defined as last therapy prior to leukapheresis and grouped into categories – non-ASCT (chemotherapy, and immunotherapy), and ASCT. BT was defined as therapy given between leukapheresis and CAR-T. Response to therapy was evaluated using 2014 Lugano criteria. Event free survival (EFS) was defined as time from CAR-T infusion to progression, next treatment, or death. Results: The ST distribution was 77% non-ASCT [chemo 66% (31), and immunotherapy 11% (5)], and 23% (11) ASCT. EFS was significantly prolonged for the ASCT (median not reached) vs non-ASCT (median 3.8 months, p = 0.03) despite no difference in median prior lines of therapy. This may reflect more aggressive disease in the non-ASCT arm, as time from start of ST to leukapheresis was shorter (median non-ASCT 2.2 months vs. ASCT 4.4 months, p = 0.0008). Patients received BT if there were concerns for symptomatic progression during CAR-T manufacturing that would reduce the likelihood to receive CAR-T. Sixty-two percent (29) patients received BT (11 chemo, and 18 immunotherapy). The EFS did not differ between the type of BT. However, patients who progressed after BT had worse EFS than those who achieved stable disease or partial response (median 2.8 vs 8.7 months, p = 0.03). Conclusions: Patients who received CAR-T as the next treatment after ASCT had better EFS than those after other types of ST. While patients who received BT have worse survival than those who didn’t, having some control of lymphoma progression with BT was associated with better EFS than those who continued to have progressive disease.

8009 Background: CD3×CD20 bispecific antibodies (bsAbs) have demonstrated promising results for the treatment of pts with R/R B-NHL. Epcoritamab is a novel subcutaneously administered bsAb with a favorable safety profile and encouraging preliminary anti-tumor activity at low doses in both aggressive and indolent B-NHL. Here we present updated safety and efficacy data from the ongoing trial (NCT03625037). Methods: Adults with R/R CD20+ B-NHL received a single SC injection of flat-dose epcoritamab in 28-day cycles (q1w: cycle 1–2; q2w: cycle 3–6; q4w thereafter) until disease progression or unacceptable toxicity. Primary objectives are determination of maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives include anti-tumor activity. Results: As of 8 Jan 2020, 41 pts with median age of 66 (range: 21–82) were enrolled. Most pts had DLBCL/HGBCL (73%) or FL (20%) and received a median (range) of 3 (1–6) and 5 (2–18) prior lines of treatment. No DLTs were observed (median follow-up: 4.7 mo; range: 3.7– 5.6). MTD has not been reached. Most common TEAEs (>35%) were pyrexia (71%), fatigue (46%), and injection site reaction (39%; all Gr 1). AEs of special interest included cytokine release syndrome (59%; all Gr 1/2; all resolved) and cytokine release-related decreased CARTOX-10 score (n=1). There was no clinical tumor lysis syndrome or treatment-related deaths. Treatment is ongoing in 13 pts. Anti-tumor activity was observed at minimal efficacy threshold (based on PK modelling) for DLBCL/HGBCL and FL (Table). Complete dose escalation data and RP2D will be presented. Conclusions: SC epcoritamab continues to demonstrate a favorable safety profile across all doses with no ≥Gr 3 CRS and no DLTs. Dose escalation data show improved efficacy as doses reach above the modeled predicted exposure threshold, inducing CRs in heavily pretreated DLBCL pts. All pts achieving CRs remain in remission. Clinical trial information: NCT03625037 . [Table: see text]

e22504 Background: Pediatric/YA pts with r/r B-NHL are rare and have heterogenous, aggressive histology and poor prognosis. We report early results for tisagenlecleucel (anti-CD19 CAR-T cell therapy) in pediatric/YA pts with r/r B-NHL. Methods: BIANCA (NCT03610724) is a phase 2, single-arm, global, open-label trial of tisagenlecleucel in pediatric/YA pts with CD19+ r/r B-NHL. Pts must have confirmed mature B-NHL r/r to ≥1 prior lines of therapy and no active CNS involvement. Primary endpoint is ORR. Secondary outcomes include DOR, EFS, safety and pharmacokinetics. Results: As of Nov 4, 2019, 8 pts were enrolled, of whom 4 had large B-cell lymphoma (LBCL), 3 Burkitt lymphoma (BL), and 1 gray zone lymphoma (GZL) (Table). Five pts had ≥2 lines of prior therapy. Suitable apheresis product was harvested in all 8 pts. Five pts were infused and 3 were pending infusion at data cut off. Product was successfully manufactured within specifications for all infused pts. Median time from enrollment to infusion was 33 days (range 30-67). All 5 pts have ≥28 days follow up; 2 pts have ≥3 months follow up (median [range] 85 days [69-97]). All 8 pts received bridging chemotherapy (including 1 pt who also had surgery and 1 who also had radiotherapy). Tisagenlecleucel dose range was 0.3-1.1 × 108 CAR+ viable T cells (weight-based: 0.9-1.7 × 106 CAR+ viable T cells/kg). Cmax (range: Cmax= 8520-14,200 copies/µg; time to Cmax= 2-21 days; n = 4) was within range of expansion observed in pediatric/YA acute lymphoblastic leukemia and adult diffuse LBCL. All 5 pts had CRS; no grade ≥3 CRS was recorded. Three pts had neurologic events, including 2 grade 3/4 events. One pt died due to disease progression. Conclusions: Pediatric/YA pts with r/r B-NHL (including BL) were successfully infused with tisagenlecleucel in the BIANCA trial with a manageable safety profile. Apheresis/manufacturing were feasible in this cohort of rapidly progressing disorders. Tisagenlecleucel was shown to expand in vivo. BIANCA provides the first systematic data on CAR-T cell therapy in highly aggressive, pediatric/YA B-NHL. Planned enrollment is 35 pts (26 infused and evaluable). Clinical trial information: NCT03610724. [Table: see text]

8040 Background: Patients (pts) with aggressive large B-cell NHL who are R/R after first-line immunochemotherapy and not eligible for high-dose chemotherapy and HSCT have a poor prognosis and no established standard of care. The ongoing, open-label phase 2 PILOT study is the first to assess the safety and efficacy of liso-cel, an investigational, CD19-directed, defined composition, 4-1BB CAR T cell product infused at equal target doses of CD8+ and CD4+ CAR+ T cells, as 2L therapy in TNE pts (NCT03483103). Methods: Eligible pts had aggressive R/R diffuse large B-cell lymphoma NOS (de novo or transformed follicular lymphoma [FL]), high-grade B-cell lymphoma, or FL grade 3B with 1 line of prior therapy containing an anthracycline and anti-CD20 agent. Pts were deemed TNE by meeting ≥1 criteria: age ≥70 y, ECOG PS 2, or impaired organ function (DLCO ≤60% [but SaO2 ≥92% and CTCAE ≤1 dyspnea], LVEF ≥40% to < 50%, creatinine clearance > 30 to < 60 mL/min, or AST/ALT > 2 to ≤5 × ULN). Liso-cel (100 × 106 CAR+ T cells) was administered 2–7 days after lymphodepletion (LD) with fludarabine/cyclophosphamide. The primary endpoint is ORR; key secondary endpoints are AEs and CR rate. Results: At data cutoff, 25 pts had LD followed by liso-cel infusion. Pt characteristics are summarized in the Table. Overall, 48% (n = 12) had high tumor burden and 48% were primary refractory. 18/25 (72%) pts had grade ≥3 treatment-emergent AEs, 40% of which were cytopenias. No grade 5 AEs occurred within the first 30 days after liso-cel. Five pts (20%) had cytokine release syndrome (CRS) and 3 (12%) had neurological events (NEs). No grade 3/4 CRS was observed; 2 pts (8%) had grade 3/4 NEs. Five pts (20%) received tocilizumab and/or dexamethasone for CRS/NEs. At a median follow-up of 3.5 mo, the ORR was 80% (95% CI, 59–93; n = 20); 48% of pts (n = 12) achieved CR. Conclusions: These interim data suggest that elderly and/or comorbid pts with R/R aggressive large B-cell NHL, who are not eligible for high-dose chemotherapy and HSCT, can receive 2L liso-cel with similar safety and efficacy to 3L+ pts as previously reported (Abramson, ASH 2019 #241). Updated data with longer follow-up will be presented. Clinical trial information: NCT03483103 . [Table: see text]

Patients with relapsed, refractory or advanced stage B non-Hodgkin lymphoma (NHL) continue to have a dismal prognosis. This review summarises current and novel cellular and immunotherapy for these high-risk populations, including haematopoietic stem cell transplant, bispecific antibodies, viral-derived cytotoxic T cells, chimeric antigen receptor (CAR) T cells, and natural killer (NK) cell therapy, as discussed at the 6(th) International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma on September 26(th)-29th 2018 in Rotterdam, the Netherlands, and explores the future of NK/CAR NK therapies.

Aggressive B-cell non-Hodgkin lymphoma (aNHL) accounts for ∼50% of all NHL cases. The only potentially curative, broadly available treatment for patients with relapse, failing frontline treatment, is high-dose therapy followed by autologous stem cell transplantation (ASCT); patients ineligible for/who have failed ASCT have limited standard-of-care options. We conducted a structured review of treatments for relapsed/refractory patients with aNHL based on literature published between 2006 and 2017. Of the 22 publications identified for inclusion, most described phase II, single-arm trials (N = 25-217), and only three were randomized studies (phase II [N = 96], phase II/III [N = 111] and phase III [N = 338]). The majority of treatments evaluated resulted in only modest efficacy (median progression-free survival, 2.1-20.0 months) and ultimately poor health outcomes (median overall survival, 25 weeks-15.5 months). In conclusion, there is an unmet need for novel, effective, and tolerable treatments for patients with relapsed/refractory aNHL who are ineligible for/have failed ASCT.

BACKGROUND Selection biases can impair the generalizability of clinical trials. Studies investigating aggressive diseases such as Diffuse Large B-cell Lymphoma (DLBCL) can be particularly affected by such biases since clinical urgency and need for therapy may not allow the requisite extensive screening and consent processes for trials. Diagnosis-to-Treatment Interval (DTI) has recently been proposed as a novel metric to capture this phenomenon (Maurer et al, JCO, 2018), and short DTI is associated with both adverse clinical factors and adverse clinical outcomes. Intriguingly, DTI was independent of clinical risk factors like the International Prognostic Index (IPI) suggesting that widely applied prognostic scores do not adequately reflect risk factors considered for clinical decision making. In this study, we aim to assess whether pretreatment levels of circulating tumor DNA (ctDNA) are associated with shorter DTI and may constitute an objective measure of clinical urgency. METHODS We quantified pretreatment ctDNA levels in plasma samples from 178 patients treated in 5 US and European centers for large cell lymphoma (DLBCL, Follicular lymphoma grade 3b, or High-grade-B-cell-lymphoma) using Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) as previously described (Kurtz, JCO 2018; Scherer, STM 2016). Pretreatment ctDNA levels were correlated with DTI, clinical factors and treatment outcome. RESULTS Pretreatment ctDNA was detectable in 175/178 cases. Median number of single nucleotide variants (SNV) detected per patient was 129 (range 0-628). Pretreatment ctDNA levels ranged from 0 - 1.4 x105 haploid genome equivalents per milliliter of plasma (hGE/ml, median 239). Median DTI was 19 days (range 0-141, Figure 1A) and was similar in distribution to 2 previously described cohorts from the US and Europe (Maurer et al, JCO 2018). Shorter DTI was associated with higher ctDNA levels (RS=-0.39, P= 1.4 x10-7, Figure 1B). Patients with longer DTI had improved Event-Free Survival (EFS, Hazard Ratio (HR) for DTI: 0.9/week, P= 0.03). However, this association was lost when adjusting for pretreatment ctDNA levels (HR for DTI: 0.95/week, P= 0.39; HR for log10(ctDNA): 1.7, P= 5.8 x10-5). In a multivariate analysis including DTI, ctDNA and IPI, only ctDNA levels were significantly associated with EFS (HR for log10(ctDNA): 1.6, P= 0.002, n=178, Figure 1C). Pretreatment ctDNA levels remained the only prognostic factor for EFS in a second multivariate analysis also considering pretreatment metabolic tumor volume (MTV, HR for log10(ctDNA): 1.8, P= 0.01, n=93, Figure 1D). DISCUSSION Shorter DTI is associated with higher pretreatment ctDNA levels in patients with aggressive B-cell lymphomas. When comparing to established factors (DTI, IPI, MTV), pretreatment ctDNA levels appear to best predict clinical outcomes. This suggests that quantification of ctDNA better reflects disease burden and treatment urgency than existing clinical biomarkers. Pretreatment ctDNA level may therefore be a valuable metric for disease aggressiveness of patients included in clinical trials, and may help identify studies suffering from selection bias. This may be particularly useful for noncontrolled Phase I/II single arm trials, but also for stratification in randomized trials. Disclosures Kurtz: Roche: Consultancy. Dührsen:Alexion: Honoraria; Novartis: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Honoraria; Takeda: Consultancy, Honoraria; Celgene: Research Funding; CPT: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Teva: Honoraria; Roche: Honoraria, Research Funding. Hüttmann:Takeda: Honoraria; Gilead: Honoraria; University Hospital Essen: Employment. Westin:Juno: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Unum: Research Funding; MorphoSys: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra-Zeneca: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Consultancy, Honoraria. Rossi:Abbvie: Honoraria, Other: Scientific advisory board; Janseen: Honoraria, Other: Scientific advisory board; Roche: Honoraria, Other: Scientific advisory board; Astra Zeneca: Honoraria, Other: Scientific advisory board; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Diehn:Novartis: Consultancy; BioNTech: Consultancy; AstraZeneca: Consultancy; Quanticell: Consultancy; Roche: Consultancy. Alizadeh:Pfizer: Research Funding; Chugai: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy; Roche: Consultancy.

Objectives. To assess whether there are shared exposures associated with Sjogren’s syndrome (SS), dry eye syndrome (DES), and B-cell non-Hodgkin lymphoma (B-NHL), in order to determine whether they are etiologically related. Methods. In a clinic-based case-control study, 702 participants (91 SS, 120 DES, 211 (age and sex frequency-matched) controls, and 280 B-NHL cases) were recruited and interviewed regarding exposures, medical history, and family history. Results. Female predominance was noted in SS (ratio 9.2 : 1). Eye dryness was severest in SS compared to DES and controls (P<0.001). Compared to controls, alcohol consumption was inversely associated with NHL, DES, and SS (odds ratio OR=0.47, 95% confidence interval (CI): 0.31-0.71; OR=0.54, 95% CI: 0.33-0.88; and OR=0.26, 95% CI: 0.14-0.49, respectively), while a previous history of infection requiring hospitalization was positively associated with all three conditions: NHL (OR=1.92; 95% CI: 1.23-2.99), DES (OR=3.29; 95% CI: 1.97-5.47), and SS (OR=4.74; 95% CI: 2.66-8.44). NHL patients were more likely to report first-degree relatives with hematologic cancer, while having first-degree relatives with an autoimmune disease (AID) was associated with SS (OR=5.25; 95% CI: 2.59-10.63) and DES (OR=3.55; 95% CI: 1.83-6.91) compared to controls. Conclusions. Some exposures are associated with all three conditions (such as an inverse association with alcohol consumption and a positive association with serious past infection), while a family history of AID appears to be shared by DES and SS, but not NHL subjects. Shared risk factors for all three conditions indicate possible mutual etiological pathways.

Background: The prevalence of Hepatitis C virus in Egypt reaches 15%, which is considered the highest in the world. Genotype 4 represents 93 % of Egyptian HCV infections. Non-Hodgkin lymphoma (NHL) is the 5th most common cancer in Egypt. The association between HCV infection and occurrence of B-cell NHL is well known while data are scarce in Eastern countries. Objectives: We aimed to evaluate the prevalence of HCV infection among patients with B-cell NHL and the clinical characteristics of HCV associated B-cell NHL in Delta region (Mansoura-Egypt). Methods: Between March 2012 and March 2013, 110 adult patients newly diagnosed with B-cell NHL were enrolled in the current study. This study was carried out at Oncology Center, Mansoura University. Study subjects provided serum for HCV testing and for HCV RNA. Results: The prevalence of HCV infection among these patients was 61% (67/110 patients) which is the highest reported value in literature. Among them, 80% (32/40 tested patients) presented with viremia. Contrasting with the histological distribution previously described in Northern regions, the majority of HCV associated lymphomas were DLBCLs (72 %) followed by SLL/CLL (13 %), follicular lymphomas (7.5%) and 7.5% of marginal zone lymphomas. In conclusion: B-cell lymphomas are highly associated with HCV infection in Egypt. Further developments are needed to give access to antiviral treatment for those patients in Delta region.

Objectives CAR T cell therapy has generally been limited to inpatient treatment. Infusion and management of CAR T cell therapy in the outpatient setting may lead to wider use in nonuniversity centers and improved access. We report on patients (pts) with R/R large B cell NHL treated with liso-cel in the outpatient setting in TRANSCEND NHL 001 (NCT02631044) and two phase 2 studies (≥3rd-line therapy: OUTREACH, NCT03744676; 2nd-line TNE: PILOT, NCT03483103). Methods Eligible pts had R/R large B cell NHL (TRANSCEND/OUTREACH: ≥2 lines of prior therapy and ECOG PS ≤1; PILOT: 1 line of prior therapy and deemed TNE for autologous hematopoietic stem cell transplant based on ECOG PS, organ function, or age). After lymphodepletion with fludarabine/cyclophosphamide, liso-cel was administered. All studies allowed outpatient treatment at nonuniversity (OUTREACH) or university and nonuniversity medical centers (TRANSCEND/PILOT), with hospitalization at the first sign of fever or neurological events (NEs) per management guidelines. Results At data cutoff, 37 pts across studies received liso-cel on study Day 1 and were monitored as outpatients, including pts aged ≥65 years (n = 15) and those with SPD ≥50 cm2 (n = 10) or LDH ≥500 UL (n = 2). Results are shown in the Table. Sixteen pts had any grade cytokine release syndrome (CRS) and 12 had any grade NEs (19 pts had CRS and/or NEs). Only 2 pts had had grade 3 or 4 CRS or NEs, which were reversible. Three pts received tocilizumab and corticosteroids for CRS and/or NEs; none received tocilizumab alone. Overall, 59% of pts (n = 22/37) required hospitalization at any time; all were from TRANSCEND or OUTREACH. Of 37 pts, 3 (8%) were admitted on study Day 3 or earlier (all for CRS) and 1 (3%) required ICU-level care (length of stay, 3 days). Median time to hospitalization post treatment was 5 (range, 2‒22) days; median length of stay was 6 (range, 2‒23) days. Overall, 41% of pts (15/37), including all 5 pts from PILOT, did not require hospitalization in the first 29 days post liso-cel infusion. Across all studies, most pts achieved an objective response (76%), including complete responses. Conclusions A subset of pts with R/R large B cell NHL were successfully treated with liso-cel and monitored for CAR T cell–related toxicity in the outpatient setting, including elderly pts and pts with high tumor burden. Incidences of severe CRS, NEs, and early hospitalization were low; 41% of pts did not require hospitalization in the first month post treatment. Most pts achieved an objective response.

Altres ajuts: This work was carried out at the Esther Koplowitz Center, Barcelona. Genmab and Janssen pharmaceuticals funded this research. Additional grants that contributed to this work included: [...], and CIBERONC (CB16/12/00334 and CB16/12/00225). CD38 is expressed in several types of non-Hodgkin lymphoma (NHL) and constitutes a promising target for antibody-based therapy. Daratumumab (Darzalex) is a first-in-class anti-CD38 antibody approved for the treatment of relapsed/refractory (R/R) multiple myeloma (MM). It has also demonstrated clinical activity in Waldenström macroglobulinaemia and amyloidosis. Here, we have evaluated the activity and mechanism of action of daratumumab in preclinical in vitro and in vivo models of mantle cell lymphoma (MCL), follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), as monotherapy or in combination with standard chemo-immunotherapy. In vitro, daratumumab engages Fc-mediated cytotoxicity by antibody-dependent cell cytotoxicity and antibody-dependent cell phagocytosis in all lymphoma subtypes. In the presence of human serum, complement-dependent cell cytotoxicity was marginally engaged. We demonstrated by Selective Plane Illumination Microscopy that daratumumab fully penetrated a three-dimensional (3D) lymphoma organoid and decreased organoid volume. In vivo, daratumumab completely prevents tumor outgrowth in models of MCL and FL, and shows comparable activity to rituximab in a disseminated in vivo model of blastic MCL. Moreover, daratumumab improves overall survival (OS) in a mouse model of transformed CD20 FL, where rituximab showed limited activity. Daratumumab potentiates the antitumor activity of CHOP and R-CHOP in MCL and FL xenografts. Furthermore, in a patient-derived DLBCL xenograft model, daratumumab anti-tumor activity was comparable to R-CHOP and the addition of daratumumab to either CHOP or R-CHOP led to full tumor regression. In summary, daratumumab constitutes a novel therapeutic opportunity in certain scenarios and these results warrant further clinical development.