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Introduction: Immune checkpoint blockade of programmed death-1 (PD-1) receptor and its ligand (PD-L1) has contributed to efficacy in many tumor types, with clinical responses observed in a proportion of patients (pts) with Hodgkin lymphoma and rare non-Hodgkin lymphoma subtypes. A recent study demonstrated that combination treatment with anti-PD-L1 and anti-CD38 agents contributed to a stronger anti-tumor immune response compared with anti-PD-L1 monotherapy. Isatuximab, an anti-CD38 monoclonal antibody, is approved for use in multiple myeloma. Cemiplimab, an anti-PD-1 monoclonal antibody, is approved for use in cutaneous squamous cell carcinoma, basal cell carcinoma, and non-small cell lung cancer. Methods: This Phase 1/2 open-label study (NCT03769181) was designed to assess the safety, tolerability, and efficacy of isatuximab in combination with cemiplimab (Isa+Cemi) in pts with relapsed and refractory classic Hodgkin's lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL), and peripheral T-cell lymphoma (PTCL). The primary objectives of Phase 1 were to characterize the safety and tolerability of Isa+Cemi and to confirm the recommended Phase 2 dose. Phase 2 used a Simon's 2-stage design to assess the complete response rate in Cohort A1 (anti-PD-1/PD-L1 naïve cHL; n=18; median age, 36 years; 55.6% male; ≥2 prior regimens, 100%) and to assess the objective response rate in Cohorts A2 (cHL progressing after PD-1/PD-L1 therapy; n=12; median age, 33 years; 58.3% male; ≥2 prior regimens, 100%), B (DLBCL; n=17; median age, 64 years; 70.6% male; ≥2 prior regimens, 100%), and C (PTCL; n=11; median age, 69 years; 63.6% male; ≥2 prior regimens, 9.1%). Pts received Isa+Cemi for up to 96 weeks. In Phase 1, the isatuximab dose was 10 mg/kg every week (Cycle 1), every 2 weeks (Cycle 2-6), or every 3 weeks (Cycle 7+). The cemiplimab dose was 250 mg every 2 weeks (Cycle 1-6) or 350 mg every 3 weeks (Cycle 7+). An interim analysis was performed when the last pt in Phase 2 was followed up for 24 weeks. The efficacy evaluation was based on Simon's 2-stage design with 85% power at a 5% 1-sided alpha level for each cohort. At least 8 (44.4%) and 3 (30.0%) responses were required in Cohorts B and C, respectively, in Phase 2 Stage 1 to advance to Phase 2 Stage 2. Results: Isa+Cemi demonstrated a manageable safety profile with no new safety signals. No dose-limiting toxicities were observed, confirming the recommended Phase 2 dose. Treatment-emergent adverse events (TEAEs) were reported in 83.3% (Cohort A1) and 100% (Cohorts A2, B, C) of pts. Grade ≥3 TEAEs occurred in 5.6%, 8.3%, 70.6%, and 81.8% of pts in Cohorts A1, A2, B, and C, respectively. There were no pts in Cohorts A1 or A2 who reported TEAEs leading to definitive discontinuation; 5.9% and 27.3% of pts in Cohorts B and C experienced TEAEs leading to definitive discontinuation. No Grade 5 TEAEs with fatal outcome were reported in Cohorts A1 or A2. There were 4 deaths reported during the on-treatment period in Cohort B (progressive disease, n=2; intestinal perforation, n=1; urinary tract infection, n=1) and 2 in Cohort C (unknown, n=1; progressive disease, n=1). Infusion reactions were reported in 38.9%, 75.0%, 52.9%, and 72.7% of pts in Cohorts A1, A2, B, and C, respectively; there was 1 (9.1%) Grade ≥3 infusion reaction reported in Cohort C. Pharmacokinetics (PK) analyses suggested no effect of cemiplimab on isatuximab PK, and vice versa. Based on Lugano 2014 criteria, 55.6% (Cohort A1), 33.3% (Cohort A2), 5.9% (Cohort B), and 9.1% (Cohort C) of pts in the all-treated population achieved a complete or partial response. Median progression-free survival was 8.38 months (95% CI: 2.72-not calculable [NC]), 8.28 months (95% CI: 2.6-NC), 2.37 months (95% CI: 0.46-2.69), and 2.66 months (95% CI: 0.43-2.99) in Cohorts A1, A2, B, and C, respectively. Conclusion: In this study, Isa+Cemi had a manageable safety profile. Clinical efficacy was observed in pts with cHL, with increased responses observed in pts who had not previously received anti-PD-1/PD-L1 therapy compared with those who progressed on anti-PD-1/PD-L1 therapy. For Cohorts B (DLBCL) and C (PTCL), results of the interim efficacy analysis did not meet prespecified criteria to continue enrollment in Phase 2 Stage 2. Most pts with DLBCL were primary refractory/bulky and discontinued rapidly, which may have contributed to the lack of activity with this combination. Disclosures Carlo-Stella: ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Research Funding. Zinzani: TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sureda: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Casasnovas: TAKEDA: Consultancy, Research Funding; Gilead/Kite: Consultancy, Research Funding; BMS: Consultancy; Janssen: Consultancy; Amgen: Consultancy; ROCHE: Consultancy, Research Funding. Carpio: Regeneron, TAKEDA, Celgene, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travels and accommodation. Bouabdallah: Abbvie: Honoraria; Sandoz: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Takeda: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Kim: Celltrion: Research Funding; Dong-A Pharmaceutical: Research Funding; Kyowa Kirin: Research Funding; Sanofi: Research Funding; IGM Biosciences: Research Funding; Eisai: Research Funding; Johnson & Johnson: Research Funding; Roche: Research Funding. Cordoba: Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: 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; ADCTherapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Koh: Pfizer: Consultancy; Jassen: Honoraria; AstraZeneca: Honoraria; Novartis: Honoraria; GSK: Honoraria; Roche: Honoraria; Takeda: Honoraria. Alves: Janssen, Cilag, Gilead, Takeda, Astrazeneca, Roche, Abbvie: Consultancy, Honoraria. Chamuleau: Gilead: Research Funding; Genmab: Research Funding; Celgene: Research Funding. Lopez-Guillermo: Roche, Gilead/Kite, Celgene, Novartis, Janssen, AbbVie, Spectrum: Consultancy, Honoraria, Research Funding. Van Der Poel: Roche, Janssen, Abbvie: Honoraria. Abbadessa: Sanofi: Current Employment. Meng: Sanofi: Current Employment. Ji: Sanofi: Current Employment. Lepine: Sanofi: Other: Contractual relationship. Saleem: Sanofi: Current Employment. Ribrag: PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Epizyme: Honoraria, Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Based on the Phase III ICARIA-MM study, isatuximab (Sarclisa) is approved in a number of countries in combination with pomalidomide and dexamethasone for the treatment of adult patients with relapsed/refractory multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. Based on the Phase III IKEMA study, isatuximab in combination with carfilzomib and dexamethasone is approved in the United States for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy, and in the European Union for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. Cemiplimab (Libtayo) is an anti-PD-1 antibody approved for the treatment of the following: 1) patients with metastatic cutaneous squamous cell carcinoma or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation; 2) patients with locally advanced or metastatic basal cell carcinoma previously treated with a hedgehog pathway inhibitor or for whom a hedgehog pathway inhibitor is not appropriate; and 3) patients with NSCLC and high tumor PD-L1 expression as determined by an FDA-approved test, with no EGFR, ALK, or ROS1 aberrations, and is locally advanced where patients are not candidates for surgical resection or definitive chemoradiation or metastatic.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, including one-third of cases overexpressing MYC and BCL2 proteins (double expressor lymphoma, DEL) and 5-10% of patients with chromosomal rearrangements of MYC, BCL2 and/or BCL-6 (double/triple-hit lymphomas, DH/TH). TP53 mutations are detected in 20- 25% of DEL. We report the efficacy of dose-adjusted EPOCH and rituximab (DA-EPOCH-R) in a series of 122 consecutive patients, including DEL (n=81, 66%), DEL-MYC (n=9, 7%), DEL-BCL2 (n=13, 11%), or high-grade lymphomas (DH/TH) (n=19, 16%). Central nervous system (CNS) prophylaxis included intravenous methotrexate (n=66), intrathecal chemotherapy (IT) (n=40) or no prophylaxis (n=16). Sixty-seven patients (55%) had highintermediate or high International Prognostic Index (IPI) and 30 (25%) had high CNS-IPI. The 2-year progression-free survival (PFS) and overall survival (OS) for the entire study population were 74% and 84%, respectively. There was a trend for inferior OS for DH/TH (2-year OS: 66%, P=0.058) as compared to all the others. The outcome was significantly better for the IPI 0-2 versus IPI 3-5 (OS: 98% vs. 72%, P=0.002). DA-EPOCH-R did not overcome the negative prognostic value of TP53 mutations: 2-year OS of 62% versus 88% (P=0.036) were observed for mutated as compared to wild-type cases, respectively. Systemic CNS prophylaxis conferred a better 2-year OS (94%) as compared to IT or no prophylaxis (76% and 65%, respectively; P=0.008). DA-EPOCH-R treatment resulted in a favorable outcome in patients with DEL and DEL with single rearrangement, whereas those with multiple genetic alterations such as DEL-DH/TH and TP53 mutated cases still have an inferior outcome.

Background: Endotheliopathy is a key element in COVID-19 pathophysiology, contributing to both morbidity and mortality. Biomarkers distinguishing different COVID-19 phenotypes from sepsis syndrome remain poorly understood. Objective: To characterize circulating biomarkers of endothelial damage in different COVID-19 clinical disease stages compared with sepsis syndrome and normal volunteers. Methods: Patients with COVID-19 pneumonia (n = 49) were classified into moderate, severe, or critical (life-threatening) disease. Plasma samples were collected within 48 to 72 h of hospitalization to analyze endothelial activation markers, including soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1), von Willebrand Factor (VWF), A disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13 (ADAMTS-13) activity, thrombomodulin (TM), and soluble TNF receptor I (sTNFRI); heparan sulfate (HS) for endothelial glycocalyx degradation; C5b9 deposits on endothelial cells in culture and soluble C5b9 for complement activation; circulating dsDNA for neutrophil extracellular traps (NETs) presence, and alpha 2-antiplasmin and PAI-1 as parameters of fibrinolysis. We compared the level of each biomarker in all three COVID-19 groups and healthy donors as controls (n = 45). Results in critically ill COVID-19 patients were compared with other intensive care unit (ICU) patients with septic shock (SS, n = 14), sepsis (S, n = 7), and noninfectious systemic inflammatory response syndrome (NI-SIRS, n = 7). Results: All analyzed biomarkers were increased in COVID-19 patients versus controls (P < 0.001), except for ADAMTS-13 activity that was normal in both groups. The increased expression of sVCAM-1, VWF, sTNFRI, and HS was related to COVID-19 disease severity (P < 0.05). Several differences in these parameters were found between ICU groups: SS patients showed significantly higher levels of VWF, TM, sTNFRI, and NETS compared with critical COVID-19 patients and ADAMTS-13 activity was significantly lover in SS, S, and NI-SIRS versus critical COVID-19 (P < 0.001). Furthermore, alpha 2-antiplasmin activity was higher in critical COVID-19 versus NI-SIRS (P < 0.01) and SS (P < 0.001), whereas PAI-1 levels were significantly lower in COVID-19 patients compared with NI-SIRS, S, and SS patients (P < 0.01). Conclusions: COVID-19 patients present with increased circulating endothelial stress products, complement activation, and fibrinolytic dysregulation, associated with disease severity. COVID-19 endotheliopathy differs from SS, in which endothelial damage is also a critical feature of pathobiology. These biomarkers could help to stratify the severity of COVID-19 disease and may also provide information to guide specific therapeutic strategies to mitigate endotheliopathy progression.

The prognosis for patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) remains poor, with a need for alternatives to current salvage therapies. Loncastuximab tesirine (ADCT-402) is an antibody-drug conjugate comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin. Presented here are final results of a phase 1 dose-escalation and dose-expansion study in patients with R/R B-NHL. Objectives were to determine the maximum tolerated dose (MTD) and recommended dose(s) for expansion and evaluate safety, clinical activity, pharmacokinetics, and immunogenicity of loncastuximab tesirine. Overall, 183 patients received loncastuximab tesirine, with 3 + 3 dose escalation at 15 to 200 µg/kg and dose expansion at 120 and 150 µg/kg. Dose-limiting toxicities (all hematologic) were reported in 4 patients. The MTD was not reached, although cumulative toxicity was higher at 200 µg/kg. Hematologic treatment-emergent adverse events were most common, followed by fatigue, nausea, edema, and liver enzyme abnormalities. Overall response rate (ORR) in evaluable patients was 45.6%, including 26.7% complete responses (CRs). ORRs in patients with diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and follicular lymphoma were 42.3%, 46.7%, and 78.6%, respectively. Median duration of response in all patients was 5.4 months and not reached in patients with DLBCL (doses ≥120 µg/kg) who achieved a CR. Loncastuximab tesirine had good stability in serum, notable antitumor activity, and an acceptable safety profile, warranting continued study in B-NHL. The recommended dose for phase 2 was determined as 150 µg/kg every 3 weeks for 2 doses followed by 75 µg/kg every 3 weeks. This trial was registered at www.clinicaltrials.gov as #NCT02669017.

The coronavirus disease 2019 (COVID‐19) pandemic, a viral illness caused by the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), 1 has produced at the time of this writing nearly 33 million cases of infection, with over a million deaths in 235 countries, 2 causing an unprecedented burden on healthcare systems and a severe global socioeconomic crisis. As the pandemic spreads, knowledge on the disease course, as well as potential risk factors and predictors of severity is increasing daily, and initial data from randomised controlled studies have allowed care providers to refine therapeutic strategies. Nonetheless, mortality is markedly elevated among those presenting with severe disease, long‐term sequelae among survivors are unknown, and vaccine‐based therapies currently remain at early stages of development. Most reported cases are asymptomatic or present with mild symptoms; however, 7–26% of hospitalised patients experience severe disease, often requiring admission to intensive care units (ICUs), with progressive multiple organ dysfunction and high mortality. 3 , 4 , 5 Such differences in clinical outcomes have led physicians to initiate diverse pharmacological therapies at various stages of the disease, generating challenges as to the most appropriate therapeutic choice for COVID‐19. In this context, the use of dexamethasone has significantly reduced mortality rates in critically ill patients requiring supplemental oxygen or mechanical ventilation, 6 and remdesivir has demonstrated clinical benefit in hospitalised patients, but with unknown survival benefit to date 7 ; additional effective treatment options are therefore urgently needed. In an initial attempt to provide a uniform and widely reproducible methodology to guide systematic treatment strategies, a three‐stage classification of COVID‐19 has been proposed. 8 The Stage I or ‘early infection’ occurs at the initial establishment of disease with high viral replication, and commonly presents with a range of complaints that can include mild and often non‐specific influenza‐like signs and symptoms. Stage II is the ‘pulmonary phase’, with preferential viral‐mediated injury of the lung parenchyma and this is characterised by shortness of breath, hypoxia and pulmonary infiltrates with some degree of lung inflammation. Stage III is characterised by an exaggerated host immune‐inflammatory response to the virus, leading to acute respiratory distress syndrome (ARDS) and multi‐organ failure (MOF).

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a valid option in patients with refractory lymphomas. HLA haploidentical stem cell transplantation (haplo-SCT) expanded the accessibility to allogeneic hematopoietic cell transplantation. The aims of study were to retrospectively assess the toxicity and efficacy of haplo-SCT using nonmyeloablative conditioning in patients with advanced lymphoma. In total, 147 patients with advanced lymphoma at 2 partner institutions were included. Patients received a uniform nonmyeloablative conditioning regimen and graft-versus-host disease (GVHD) prophylaxis. The primary endpoints were progression-free survival (PFS), overall survival (OS), GVHD, nonrelapse mortality, and GVHD, relapse-free survival (GRFS). Median follow-up was 39 months (range, 6 to 114 months). The median age was 46 years (range, 19 to 71 years). Sixty-five percent of patients were in complete remission (CR) at transplantation. Cumulative incidence of grade II to IV acute GVHD was 30% (95% confidence interval [Cl], 23% to 38%). Two-year cumulative incidence of all grades of chronic GVHD was 13% (95% CI, 8% to 20%). Two-year cumulative incidence of disease relapse was 19% (95% CI, 14% to 27%), with a higher incidence in patients not being in CR at allo-HCT (CR versus not CR: 12% versus 33%, P = .006). Two-year PFS, OS, and GRFS were 66% (95% CI, 59-75), 73% (95% CI, 66-81), and 56% (95% CI, 48-65), respectively. Haplo-SCT with post-transplantation cyclophosphamide may be considered a valid option for patients with aggressive lymphoma and deserves further evaluation.

Relapse/refractory Hodgkin lymphoma patients are still a clinical concern. Indeed, despite more effective first-line chemotherapy regimens and better stratification of unresponsive patients by clinical factors and use of early PET, roughly one-third of such patients need salvage chemotherapy and consolidation with high-dose chemotherapy. In this paper, the authors review the different salvage treatments, with special emphasis on newer combinations with brentuximab vedotin or check point inhibitors. The overall response rate is constantly increasing, with a complete remission rate approaching 80%. Functional response evaluation by PET imaging is a strong predictive factor of longer survival, and more sophisticated tools, such as detection of circulating tumour DNA, are emerging to refine the disease-status assessment after treatment. Consolidation by high-dose chemotherapy is still considered the standard of care in chemosensitive patients, leading to a high fraction of patients towards long-term disease control. Maintenance therapy with BV is now approved, reducing disease relapse/progression. An increasing number of Hodgkin lymphoma patients will be cured after first- and second-line therapy, and long-term toxicity needs to be continuously assessed and avoided.

We aimed to assess the ability of radiomics, applied to not-enhanced computed tomography (CT), to differentiate mediastinal masses as thymic neoplasms vs lymphomas. The present study was an observational retrospective trial. Inclusion criteria were pathology-proven thymic neoplasia or lymphoma with mediastinal localization, availability of CT. Exclusion criteria were age

Autologous (auto-) and allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities in contemporary treatment algorithms for mantle cell lymphoma (MCL). Chimeric antigen receptor (CAR) T cell therapy recently received approval for MCL; however, its exact place and sequence in relation to HCT remain unclear. The American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and the European Society for Blood and Marrow Transplantation jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-HCT, allo-HCT, and CAR T cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated, with a few key statements as follows: in the first line setting, auto-HCT consolidation represents standard of care in eligible patients, whereas there is no clear role of allo-HCT or CAR T cell therapy outside of clinical trials. In the R/R setting, the preferential option is CAR T cell therapy, especially in patients with MCL failing or intolerant to at least one Bruton’s tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T cell therapy fails or is infeasible. Several recommendations were based on expert opinion, where the panel developed consensus statements for important real-world clinical scenarios to guide clinical practice. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MCL.

International audience; Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade. With a median follow-up among survivors of 24 months, the 2-year cumulative incidences (CIs) of non-relapse mortality and relapse were 14 and 18%, respectively; the 2-year graft-versus-host disease (GVHD) and relapse-free survival (GRFS), progression-free survival (PFS), and overall survival were 47%, 69%, and 82%, respectively. The 180-day CI of grade 3-4 acute GVHD was 15%, while the 2-year CI of chronic GVHD was 34%. In multivariable analyses, a longer interval from PD-1 to alloHCT was associated with less frequent severe acute GVHD, while additional treatment between PD-1 and alloHCT was associated with a higher risk of relapse. Notably, post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvements in PFS and GRFS. While awaiting prospective clinical trials, PTCy-based GVHD prophylaxis may be considered the optimal transplantation strategy for this patient population.

Coronavirus disease 2019 (COVID-19) is a heterogeneous clinical condition caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The initial stage of infection occurs at the time of respiratory viral invasion through angiotensin-converting enzyme 2 (ACE2) receptors in alveolar pneumocytes and macrophages. In the second stage of established pulmonary disease without and with hypoxia, viral multiplication and localized inflammation occurs. The third stage COVID-19 is the most severe, characterized by systemic hyperinflammation, acute respiratory distress syndrome (ARDS) and generalized microangiopathy, with significantly elevated biomarkers including IL-2, IL-6, IL-7, granulocyte-colony stimulating factor, macrophage inflammatory protein 1α, tumor necrosis factor-α, C-reactive protein, ferritin, D-dimer, von Willebrand factor (vWF) and thrombomodulin (TM). Evidence suggests that endothelial damage and activation play a key role in the pathobiology of the disease, and thus protecting endothelium and reversing endotheliitis may be a key therapeutic goal (Teuwen et al,Nat Rev Immunol2020). Defibrotide (DF), a complex mixture of poly-deoxyribonucleotides extracted from porcine mucosa, modulates expression of thrombogenic and inflammatory mediators produced in response to endothelial cell injury and/or leukocyte activation. DF increases tissue plasminogen activator (t-PA) and TM expression, thereby enhancing the enzymatic activity of plasmin to hydrolyze fibrin clot, while also decreasing vWF and plasminogen activator inhibitor-1 (PAI-1). Platelet adhesion is inhibited via increases in nitric oxide (NO), prostaglandin I2 (PGI2), and prostaglandin E2 (PGE2) (Falanga A et al,Leukemia 2003). Anti-inflammatory properties via inhibition of p38 MAPK pathway have been demonstrated with DF, attenuating the release of inflammatory mediators including IL-6, thromboxane A2, leukotriene B4, tumor necrosis factor-alpha, and reactive oxygen species (Mitsiades et al,Clin Cancer Res2009). Additionally, DF inhibits both the expression and activity of heparanase, which in turn modulates heparan sulfate, a vital moiety for viral infection (Richardson et al,Blood Adv2018; Koganti et al,Cell Mol Life Sci2020). DF also modulates endothelial cell injury in murine models by down-regulating the expression of endothelial cell adhesion molecules such as E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), that are critical to leukocyte adhesion and migration, and by increasing the endothelial cell release of anti-inflammatory cytokines, conferring survival benefit (Garcia-Bernal et al,J Cell Mol Med2020). DF is approved for the treatment of severe veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) complicating stem cell transplantation and has demonstrated efficacy and safety in critically ill patients with multi-organ failure, underpinned by vasculopathy, endotheliitis, immune activation and hemorrhagic risk (Richardson et al,Blood2016). This multi-target and pleiotropic approach makes DF an attractive candidate for the treatment of advanced stage COVID 19 and the systemic endothelial complications underpinning both its pathobiology and ensuing mortality (Figure 1). Various clinical studies in Spain, Italy, Ireland, the UK and USA are underway, with the larger randomized placebo-controlled prospective phase 2 study in Spain (clinicaltrials.gov: NCT04348383) leading in accrual with promising early results, demonstrating safety to date with potential efficacy, as reflected by favorable outcome in a subset of intubated patients as part of an ongoing multi-center trial. Other studies within the group have focused on safety and particularly the therapeutic role of DF in advanced disease, including those patients requiring extracorporeal membrane oxygenation (ECMO) and full dose systemic anticoagulation. These trials include common in-depth biological correlatives, assessing biomarkers including heparanase, inflammatory cytokines, immune cell sub-populations, vWF and soluble TM, as well as other novel markers and pharmacokinetics. In aggregate, these studies will hopefully help demonstrate the effects of DF on the proposed targets in COVID-19 and successfully correlate these effects with improved clinical outcome. Disclosures Moraleda: Jazz Pharmaceuticals:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis, Sandoz, Takeda:Honoraria;Gilead:Honoraria, Other: Travel expenses.Carlo-Stella:Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca:Honoraria;Boehringer Ingelheim and Sanofi:Consultancy;ADC Therapeutics and Rhizen Pharmaceuticals:Research Funding.Jara Rubio:Edwards Lifesciences, Getinge:Honoraria.Diaz-Ricart:Jazz Pharmaceuticals:Honoraria, Research Funding;German Jose Carreras Leukaemia Foundation:Research Funding.Carreras:Jazz Pharmaceuticals:Research Funding, Speakers Bureau;German Jose´ Carreras Leukaemia Foundation:Research Funding.Mo:Celgene/BMS:Membership on an entity's Board of Directors or advisory committees.Cooke:Jazz Pharmaceuticals:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.Soiffer:Be the Match/ National Marrow Donor Program:Membership on an entity's Board of Directors or advisory committees;alexion:Consultancy;Celgene:Membership on an entity's Board of Directors or advisory committees;Juno:Membership on an entity's Board of Directors or advisory committees;Novartis:Consultancy;VOR Biopharma:Consultancy;Mana Therapeutics:Consultancy;Precision Bioscience:Consultancy;Cugene:Consultancy;Rheos Therapeutics:Consultancy;Gilead:Consultancy;Kiadis:Membership on an entity's Board of Directors or advisory committees.Baron:Genetech:Consultancy;Merck:Consultancy.Pagliuca:Jazz Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees.Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm:Research Funding. OffLabel Disclosure: Defibrotide used for the treatment of endotheliitis complicating SARS-Cov-2 infection

Introduction : Glofitamab (RG6026) is a novel T-cell-engaging, bispecific, full-length antibody with a 2:1 molecular configuration that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Preclinically, glofitamab had superior potency compared with other tested bispecifics with 1:1 formats (Bacac, et al. Clin Cancer Res 2018). NP30179 (NCT03075696) is an ongoing multicenter, Phase I/Ib, dose-escalation and dose-expansion trial evaluating the safety, tolerability, pharmacokinetics, biomarker responses, and efficacy of glofitamab in patients (pts) with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL). Clinical data from NP30179 demonstrated that fixed dosing of glofitamab (0.6-25mg) induced high and durable complete responses with a manageable safety profile in pts with heavily pre-treated R/R NHL (Dickinson, et al. EHA 2020). Obinutuzumab pretreatment (Gpt) was shown to be effective in mitigating the risk of cytokine release syndrome (CRS), allowing for rapid escalation of glofitamab to clinically active doses (Dickinson, et al. EHA 2020). Step-up dosing of glofitamab was used in addition to Gpt to further reduce the risk of CRS. For the first time, we present clinical data of glofitamab step-up dosing with Gpt in pts with R/R NHL. Methods: Pts received 1000mg obinutuzumab 7 days prior to first glofitamab administration. Glofitamab was given intravenously with step-up dosing on Cycle (C) 1 Day (D) 1 and 8 and then at the target dose from C2D1, every 3 weeks for up to 12 cycles (2.5/10/16mg or 2.5/10/30mg). Response rates reported are based on the Lugano criteria (Cheson, et al. J Clin Oncol 2014). Results: As of April 17, 2020, 38 pts received step-up doses of glofitamab; 17 pts received 2.5/10/16mg, and 21 pts received 2.5/10/30mg. Twenty-eight pts (73.7%) had aggressive NHL (aNHL) histologies and ten pts had indolent NHL (iNHL; Table). The median age was 68 years (range 52-85) and median number of prior lines of therapy was 3 (range 1-12). Twenty-seven (71.1%) pts were refractory to their last therapy, and 28 (73.7%) pts were refractory to prior CD20 therapy. After a median follow-up of 2.8 months, across all efficacy-evaluable pts (n=32) the overall response rate (ORR) and complete metabolic response (CMR) rate was 62.5% and 40.6%, respectively. For pts with aNHL (n=24), the ORR was 50.0% with CMR rates of 29.2%. As of the data cut-off date, 17 pts with aNHL (70.8%) had reached the first response assessment only (C3) and remain on treatment; four pts (16.7%) had reached the second response assessment (C6). For pts with iNHL (n=8), the ORR was 100.0% with 75.0% of pts achieving CMR. Across the safety-evaluable population (n=38), the most common AEs were CRS (57.9%), pyrexia (31.6%), neutropenia, thrombocytopenia and hypophosphatemia (28.9% each). No AEs led to treatment discontinuation. Of 22 patients who experienced CRS events, the CRS events only occurred in C1 and C2; 15 had CRS after the 2.5mg dose, 12 after the 10mg dose, and 5 during C2 (16 or 30mg dose; Figure). Eight pts (21.1%) and 13 pts (34.2%) experienced Grade (Gr) 1 and 2 CRS, respectively; none experienced Gr 3 CRS. One pt (2.6%) experienced Gr 4 CRS after the 30mg dose. No CRS events occurred after C2. Tocilizumab was used to manage CRS in six (15.8%) pts: n=2 for 2.5/10/16mg and n=4 for 2.5/10/30mg cohorts. CRS events were manageable and resolved for 21 pts (95.4%) at data cut-off. No Gr ≥3 neurologic adverse events were reported. Consistent with prior biomarker data from fixed-dose regimens (Bröske, et al. EHA 2020), glofitamab administered with step-up dosing induced a transient T-cell redistribution. Conclusions: Step-up dosing of glofitamab allowed escalation up to 30mg to maximize efficacy, while minimizing the risk of increased CRS. High ORR and CMR rates were observed in pts with NHL who had failed several lines of treatment. Toxicity was manageable with the main safety signal being low-grade CRS observed in early cycles. Updated results will be presented at the congress which will include data from at least 50 pts receiving glofitamab step-up dosing with Gpt. Disclosures Hutchings: Genmab, F. Hoffmann-La Roche, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Genmab, Janssen, Novartis, F. Hoffmann-La Roche, Takeda: Research Funding. Carlo-Stella:Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; Boehringer Ingelheim and Sanofi: Consultancy. Bachy:Roche, Gilead: Consultancy; Amgen: Research Funding; Roche, Celgene, Amgen, Janssen, Gilead, Novartis, Sanofi: Honoraria; Beigene: Membership on an entity's Board of Directors or advisory committees. Morschhauser:F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Servier: Consultancy; Genentech, Inc.: Consultancy. Crump:Kite/Gilead: Consultancy; Roche: Consultancy; Servier: Consultancy. Iacoboni:Novartis, Gilead, Celgene, Roche: Honoraria. Sureda Balari:BMS: Speakers Bureau; Roche: Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy; Gilead/Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria. Martinez-Lopez:Novartis: Consultancy; Janssen: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lundberg:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Dixon:Roche Products Limited: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Perez Callejo:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Relf:Roche Products Ltd: Current Employment. Carlile:AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Piccione:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Humphrey:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Dickinson:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy. OffLabel Disclosure: Glofitamab (RG6026; CD20-TCB) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent.

Introduction: Novel approaches to treating patients (pts) with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) have improved outcomes but some pts do not respond or, despite initial response, develop progressive disease and have limited treatment options. Camidanlumab tesirine (ADCT-301; Cami) is an antibody-drug conjugate composed of a human IgG1 anti-CD25 monoclonal antibody stochastically conjugated to a potent pyrrolobenzodiazepine (PBD) dimer warhead, which triggers cell death via formation of highly cytotoxic interstrand cross-links. Data from a Phase (Ph) 1 dose-escalation, dose-expansion trial demonstrated an overall response rate (ORR) in pts with cHL of 86.5% (48.6% complete response [CR] rate) at the 45 μg/kg dose. Cami had a generally acceptable safety profile at Ph 1 but there were 5/77 cases (6.5%) of Guillain-Barré syndrome (GBS)/polyradiculopathy (Preferred Terms: 4 GBS and 1 radiculopathy) (Collins et al, ICML June 18-22, 2019, Lugano, Switzerland, Abstract 055). Here, we present preliminary efficacy and safety results of a Ph 2 trial of single-agent Cami in pts with R/R cHL (NCT04052997). Methods: A single-arm, multi-center, open-label, Ph 2 trial is currently enrolling pts ≥16 yrs (US) and ≥18 yrs (outside US) with R/R cHL following ≥3 prior treatment lines (or ≥2 lines in pts ineligible for hematopoietic stem cell transplantation). Eligible pts had prior treatment with brentuximab vedotin and PD-1 blockade, measurable disease per 2014 Lugano Classification, and Eastern Cooperative Oncology Group performance status 0-2. The primary objective is to evaluate efficacy of single-agent Cami by ORR as determined by central review. Secondary objectives include further characterization of additional efficacy endpoints and safety. Pts receive 30-min IV infusions of Cami on Day 1 of each 3-week cycle at a dose of 45 μg/kg for 2 cycles, followed by 30 μg/kg for subsequent cycles for up to 1 yr or until discontinuation due to disease progression, unacceptable toxicity, or other reasons. Pts deriving clinical benefit at 1 yr may be able to continue treatment on a case-by-case basis. Treatment-emergent adverse events (TEAEs) were defined as AEs occurring/worsening from time of first dose to either 30 days post last dose or to start of new anticancer therapy/procedure, whichever occurs first. This analysis was conducted after meeting a protocol-specified criterion for pausing enrollment (≥2 cases of GBS or other relevant severe neurologic toxicity). Results: As of June 15, 2020, 47 pts with R/R cHL were enrolled and are included in this analysis. Median age was 36 (range 23-74) yrs and pts had received a median of 7 (range 3-20) lines of prior therapy, including transplant (Table 1). Pts received a median of 5 (range 2-10; mean 4.9 [SD 1.86]) cycles of Cami. ORR was 80.9% (38/47 pts), with 18 (38.3%) and 20 (42.6%) pts attaining CR and partial response, respectively; 6 pts (12.8%) had stable disease (Figure 1). TEAEs were experienced by all 47 pts; the most common (≥20% of pts) were fatigue (22, 46.8%); nausea, pyrexia, and maculopapular rash (18, 38.3% each); anemia and headache (12, 25.5% each); pruritus (11, 23.4%); arthralgia, constipation, diarrhea, hypophosphatemia, and rash (10, 21.3% each). TEAEs thought to be PBD-associated included skin reactions and nail disorders (36, 76.6%), liver function test abnormalities (14, 29.8%), and edema or effusion (7, 14.9%). There were 3 (6.4%) pts with GBS/polyradiculopathy (Preferred Terms: grade 4 subacute inflammatory demyelinating polyneuropathy, grade 2 radiculopathy, and grade 2 peripheral motor and sensory neuropathy updated to GBS after data cut-off date). In total, 27 (57.4%) pts had grade ≥3 TEAEs; the most common (≥5% of pts) were hypophosphatemia (6, 12.8%) and gamma-glutamyltransferase increased (3, 6.4%). Overall, 3 (6.4%) pts had TEAEs leading to dose reduction/delay and 6 (12.8%) pts had TEAEs leading to treatment discontinuation. Conclusions: Current data show that therapy with Cami has encouraging anti-tumor activity in heavily pretreated pts with R/R cHL. Safety was consistent with that reported at Ph 1, with no new safety concerns identified and similar incidence of GBS/polyradiculopathy. Following a positive risk-benefit assessment, the enrollment pause was lifted, and pts continue to be enrolled. Updated efficacy and safety results will be presented at the meeting. Funding: Study funded by ADC Therapeutics SA. Disclosures Herrera: Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Research Funding; Immune Design: Research Funding. Carlo-Stella:Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Boehringer Ingelheim and Sanofi: Consultancy; Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Collins:Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Celleron: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Amgen: Research Funding; BeiGene: Consultancy; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau. Maddocks:Morphosys: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Seattle Genetics: Consultancy, Honoraria; ADC Therapeutics, AstraZeneca: Consultancy; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Bartlett:Autolus: Research Funding; BMS/Celgene: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; ADC Therapeutics: Consultancy; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding. Savage:BeiGene: Other: Steering Committee; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy. Caimi:ADCT, Kite Therapeutics, Genentech, Amgen, Verastem, TG Therapeutics, Bayer: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech, ADC Therapeutics: Research Funding; Celgene: Speakers Bureau. Hess:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS, AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zinzani:ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cruz:ADC Therapeutics SA: Current Employment, Current equity holder in publicly-traded company. Wang:ADC Therapeutics America, inc: Current Employment, Current equity holder in publicly-traded company. Feingold:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wuerthner:ADC Therapeutics SA: Current Employment, Current equity holder in publicly-traded company. Ansell:Takeda: Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; ADC Therapeutics: Research Funding; Affimed: Research Funding; AI Therapeutics: Research Funding.

Introduction: Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who fail multi-agent chemoimmunotherapy have a poor prognosis and a need for more treatment options. Loncastuximab tesirine (Lonca) comprises a humanized anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer toxin. We present updated results from a phase 2 study of Lonca in patients with R/R DLBCL who had failed established therapies, including analysis of response in high-risk DLBCL subgroups. Methods: Patients aged ≥18 years with R/R DLBCL who had failed ≥2 prior therapies were enrolled in this single-arm open-label phase 2 study (NCT03589469). Overall response rate (ORR) was assessed by independent reviewer according to the Lugano response criteria and duration of response (DoR) was defined as the time from earliest date of first response until the first date of either disease progression or death due to any cause. Pre-specified analyses of ORR and DoR by demographic and clinical characteristics were performed. Treatment-emergent adverse events (TEAEs) were reported for the all-treated population and by age group. Results: In this study, 145 patients with DLBCL received Lonca (mean 4.3 cycles [range: 1-15]) and were evaluable for safety and efficacy. As of data cutoff (April 6, 2020), follow-up was ≥6 months since first dose. The ORR was 48.3%, and complete response rate (CRR) was 24.1%. Median DoR (mDoR) for the 70 responders was 10.3 months. For patients with a CR, mDoR was 13.4 months (Figure 1). Most patients responded after 2 treatment cycles; median time to first response was 41.0 days. Responses, including CRs, were observed in several subgroups with higher-risk characteristics (Figure 2). ORR was 44.8% in patients with transformed disease, 45.8% in patients aged 65-74 years, and 52.4% in patients aged ≥75 years. For patients with double- or triple-hit DLBCL, ORR was 33.3% (notably all CRs). Patients who were refractory (no response) to first-line therapy, most recent therapy, or any prior therapy had ORRs of 37.9%, 36.9%, and 36.0%, respectively. Patients who had received a prior stem cell transplant (SCT) had a notable ORR of 58.3%. Lonca was also effective in patients who had received prior CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy (ORR 46.2%). Durable responses were noted in patients with high-risk characteristics. mDoR was not reached for patients with transformed disease. Older patients had a longer mDoR than younger patients ( Following Lonca treatment, 15 patients received CD19-directed CAR-T therapy with an investigator-assessed ORR of 46.7% (6 CR; 1 partial response), and 9 patients proceeded to SCT as consolidation after responding to Lonca. Overall, 143 (98.6%) patients had ≥1 TEAE and 105 (72.4%) patients had grade ≥3 TEAEs. The most common (≥25%) all-grade TEAEs were gamma-glutamyltransferase (GGT) increased (40.7%), neutropenia (39.3%), thrombocytopenia (33.1%), fatigue (27.6%), and anemia (26.2%). The most common (≥10%) grade ≥3 TEAEs were neutropenia (25.5%), thrombocytopenia (17.9%), GGT increased (16.6%), and anemia (10.3%). Treatment-related TEAEs leading to treatment discontinuation occurred in 24 patients (16.6%), most commonly GGT increased (14 patients; 9.7%). No increase in toxicity was seen in patients aged ≥65 years compared with younger patients. Conclusions: Lonca had substantial single-agent antitumor activity in patients with R/R DLBCL. No new safety concerns were identified and no increase in toxicity was observed for patients aged ≥65 years. Encouraging and durable responses were observed in high-risk patient groups, including double- or triple-hit, transformed or refractory DLBCL, and notably in those who had progressed after prior CAR-T cell therapy. In addition, investigator-reported ORR indicates that many patients also respond to CAR-T therapy given after Lonca. Updated DoR data will be presented at the meeting. Funding: This study is sponsored by ADC Therapeutics SA; clinicaltrials.gov/ct2/show/NCT03589469. Disclosures Caimi: Celgene: Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech, ADC Therapeutics: Research Funding; ADCT, Kite Therapeutics, Genentech, Amgen, Verastem, TG Therapeutics, Bayer: Consultancy. Ai:ADC Therapeutics, Kymera: Membership on an entity's Board of Directors or advisory committees; Nurix Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Alderuccio:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; OncLive: Honoraria; Puma Biotechnology: Other: Family member; Foundation Medicine: Other: Family member; Inovio Pharmaceuticals: Other: Family member; Oncinfo: Honoraria; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member. Ardeshna:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi, Genzyme, AstraZeneca: Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; University College London (UCL)/UCL Hospitals (UCLH) Biomedical Research Unit: Other: Supported by this organisation; Beigene: Membership on an entity's Board of Directors or advisory committees. Hamadani:Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen R&D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy; Sanofi Genzyme, AstraZeneca: Speakers Bureau. Hess:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS, AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kahl:Roche Laboratories Inc: Consultancy; Genentech: Consultancy; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics LLC: Consultancy. Radford:GlaxoSmithKline: Current equity holder in publicly-traded company, Other: Spouse; AstraZeneca: Current equity holder in publicly-traded company, Other: Spouse; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding; ADCT: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stathis:Member of the steering committee of the trial of this abstract: Other; Loxo: Honoraria, Other, Research Funding; Cellestia: Research Funding; PharmaMar: Other: Travel Grant; Abbvie: Other: Travel Grant; ADC Therapeutcis: Other, Research Funding; MEI Pharma: Other, Research Funding; Novartis: Other, Research Funding; Bayer: Other, Research Funding; Merck: Other, Research Funding; Roche: Other, Research Funding; Pfizer: Other, Research Funding. Zinzani:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau. Feingold:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ungar:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Qin:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. He:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Carlo-Stella:Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; Boehringer Ingelheim and Sanofi: Consultancy.

Cytokine release syndrome (CRS) represents a life‐threatening side effect after haploidentical stem cell transplantation (Haplo‐SCT) with posttransplant cyclophosphamide (PT‐Cy). Factors predictive of CRS development is still a matter of debate. We retrospectively analyzed 102 consecutive patients receiving a bone marrow (BM) (n = 42) or peripheral blood stem cells (PBSC) (n = 60) Haplo‐SCT with PT‐Cy. The two cohorts were similar in main patients’ characteristics besides disease type (P = .02). Cumulative incidence of grades 1, 2, and ≥3 CRS was 80%, 52%, and 15% at a median of 2, 4, and 7 days, respectively. Moderate/High‐grade fever (39°‐41°), grade 1 and grade ≥3 CRS occurred more frequently after PBSC relative to BM grafts (68% vs 33%, P = .0005; 87% vs 71%, P = .009; 20% vs 7%, P = .07). Only patients experiencing grade ≥3 CRS had a worse outcome in terms of 1‐year overall survival (OS) and nonrelapse mortality (NRM): 39% vs 80% (P = .002) and 40% vs 8% (P = .005), respectively. By univariate analysis the only factors associated with the increased risk of ≥3 CRS were pretransplant disease status (8% for complete remission, 11% for partial remission, and 38% for active disease, P = .002), HLA‐DRB1 mismatching (57% vs 14%, P = .007), and PBSC graft (P = .07). By multivariable analysis, only pretransplant disease status (hazard ratio, HR: 6.84, P = .005) and HLA‐DRB1 mismatching (HR: 17.19, P = .003) remained independent predictors of grade ≥3 CRS. Only grade ≥3 CRS is clinically relevant for the final outcome of patients receiving Haplo‐SCT with PT‐Cy, is more frequent after a PBSC graft and is associated with pretransplant active disease and HLA‐DRB1 mismatching., Severe cytokine release syndrome (CRS) may occur after T‐cell‐replete haploidentical stem cell transplantation and conditions nonrelapse mortality. Disease burden and HLA mismatch in the graft‐vs‐host‐disease direction are the main factors affecting the occurrence of severe CRS.

Background The nocebo effect is a negative effect of a pharmacological or nonpharmacological medical treatment that is induced by patients' expectations, and that is unrelated to the physiological action of the treatment. The nocebo effect can negatively affect treatment outcomes. Aim To develop evidence-based consensus recommendations for the prevention and management of the nocebo effect in biosimilar-treated patients with IBD. Methods The "NOCE-BIO Consensus Group" was composed of 19 members from five European countries, and with different fields of expertise. A literature review on the nocebo effect, with specific focus on information about its prevention and management in biosimilar-treated IBD patients, was performed. Preliminary statements were formulated and voted on during a consensus group meeting held in Milan, Italy, in July 2018. A statement was accepted if >75% of participants voted 4 ("agree") or 5 ("strongly agree") on a scale of 1-5. Results Consensus was reached on 11 recommendation statements. Seven statements reached consensus after one voting round and four statements reached consensus after two voting rounds. All statements were supported by very low-quality level of evidence. The panel agreed that patient-health-care provider relationship is a key driver of acceptance of biosimilars, which limits the risk of negative bias and the nocebo effect. Lack of knowledge among patients and health-care providers about the effectiveness and safety of biosimilars should be minimized. Education about biosimilars needs to be tailored to the individual patient, and positive framing is recommended. Conclusions The nocebo effect is under-recognised in the era of biosimilars, although it may negatively impact on the cost-savings of biosimilars. Future research should focus on the magnitude, the risk factors, the impact, and the management of the nocebo effect in biosimilars-treated IBD patients.

Objectives T‐cell–replete haploidentical stem cell transplantation (Haplo‐SCT) with post‐transplant cyclophosphamide (PT‐Cy) is at high risk of invasive fungal infections (IFI), and anti‐mold–active drug is required for primary antifungal prophylaxis (PAP) according to international guidelines. No data are available on the efficacy of caspofungin as PAP in this setting. Methods Here, we report our retrospective experience with 103 consecutive patients treated with caspofungin as PAP after Haplo‐SCT. Caspofungin was administered only during the pre‐engraftment phase. Results Hundred‐day cumulative incidence of proven‐probable IFI (PP‐IFI) was 8.7% and median day of onset was 19 post‐SCT. No patient died of PP‐IFI, and overall survival (OS) and non‐relapse mortality (NRM) hazard ratio (HR) for patients experiencing IFI were 1.02 (P = 0.9) and 0.7 (P = 0.7), respectively. Three‐year overall survival (OS) and 1‐year non‐relapse mortality (NRM) were 55% and 19%, respectively. By univariate analysis, duration of neutropenic phase and partial remission pre‐transplant disease status were associated with increased incidence of IFI, but were not confirmed by multivariate analysis. Conclusion In summary, PAP with caspofungin is an effective strategy for preventing IFI in the context of Haplo‐SCT with PT‐Cy. Further efforts are required in order to identify more potent strategies able to avoid the occurrence of breakthrough infections.

Purpose: Tumor-associated macrophages (TAMs) and the hyperactivation of the PI3K/AKT pathway are involved in the pathogenesis of Hodgkin lymphoma and affect disease outcome. Because the δ and γ isoforms of PI3K are overexpressed in Hodgkin/Reed–Sternberg (HRS) cells and the tumor microenvironment (TME), we propose that the PI3Kδ/γ inhibitor RP6530 might affect both HRS cells and TME, ultimately leading to an enhanced antitumor response. Experimental Design: Hodgkin lymphoma cell lines (L-540, KM-H2, and L-428) and primary human macrophages were used to investigate the activity of RP6530 in vitro and in vivo in Hodgkin lymphoma cell line xenografts. Results: In vitro, RP6530 besides killing and inhibiting the proliferation of Hodgkin lymphoma cells, downregulated lactic acid metabolism, switching the activation of macrophages from an immunosuppressive M2-like phenotype to a more inflammatory M1-like state. By RNA sequencing, we define tumor glycolysis as a specific PI3Kδ/γ-dependent pathway implicated in the metabolic reprogramming of cancer cells. We identify the metabolic regulator pyruvate kinase M2 as the main mediator of tumor-induced immunosuppressive phenotype of macrophages. Furthermore, we show in human tumor xenografts that RP6530 repolarizes TAMs into proinflammatory macrophages and inhibits tumor vasculature, leading to tumor regression. Interestingly, patients with Hodgkin lymphoma experiencing objective responses (complete response and partial response) in a phase I trial using RP6530 showed a significant inhibition of circulating myeloid-derived suppressor cells and an average mean reduction in serum thymus and activation-regulated chemokine levels of 40% (range, 4%–76%). Conclusions: Our results support PI3Kδ/γ inhibition as a novel therapeutic strategy that targets both malignant cells and the TME to treat patients with Hodgkin lymphoma.

Introduction Defibrotide (DF) is a polyribonucleotide with antithrombotic, pro-fibrinolytic, and anti-inflammatory effects on endothelium. These effects and the established safety of DF present DF as a strong candidate to treat viral and post-infectious syndromes involving endothelial dysfunction. Areas covered We discuss DF and other therapeutic agents that have the potential to target endothelial components of pathogenesis in viral and post-infectious syndromes. We introduce defibrotide (DF), describe its mechanisms of action, and explore its established pleiotropic effects on the endothelium. We describe the established pathophysiology of Coronavirus Disease 2019 (COVID-19) and highlight the processes specific to COVID-19 potentially modulated by DF. We also present influenza A and viral hemorrhagic fevers, especially those caused by hantavirus, Ebola virus, and dengue virus, as viral syndromes in which DF might serve therapeutic benefit. Finally, we offer our opinion on novel treatment strategies targeting endothelial dysfunction in viral infections and their severe manifestations. Expert opinion Given the critical role of endothelial dysfunction in numerous infectious syndromes, in particular COVID-19, therapeutic pharmacology for these conditions should increasingly prioritize endothelial stabilization. Several agents with endothelial protective properties should be further studied as treatments for severe viral infections and vasculitides, especially where other therapeutic modalities have failed.

International audience; Introduction - Patients with relapsed/refractory Hodgkin lymphoma (R/R HL) experience high response rates upon anti-PD1 therapy. In these patients, the optimal duration of treatment and the risk of relapse after anti-PD1 discontinuation are unknown. Methods - We retrospectively analyzed patients with R/R HL who responded to anti-PD1 monotherapy and discontinued the treatment either because of unacceptable toxicity or prolonged remission. A machine learning algorithm based on 17 candidate variables was trained and validated to predict progression-free survival (PFS) landmarked at the time of discontinuation of anti-PD1 therapy. Results - Forty patients from 14 centers were randomly assigned to training (n = 25) and validation (n = 15) sets. At the time of anti-PD1 discontinuation, patients had received treatment for a median duration of 11.2 (range, 0-time to best response was not statistically significant in discriminating patients with PFS lesser or greater than 12 months). Considering PFS status as a binary variable (alive or dead) at a specific time point (12 months) is convenient, intuitive and allows for comparing the value of potential predicting variables in these two groups of patients. Nonetheless, this approach has two drawbacks: first, it binarizes outcome; second, it excludes patients alive with a time to last follow up lesser 12 months. Therefore, it is less powerful to demonstrate statistically significant association with PFS even if it exists 5 months. Patients discontinued anti-PD1 treatment either because of prolonged remission (N = 27, 67.5%) or unacceptable toxicity (N = 13, 32.5%). Most patients were in CR (N = 35, 87.5%) at the time of anti-PD1 discontinuation. In the training set, the machine learning algorithm identified that the most important variables to predict PFS were patients' age, time to best response, and presence or absence of CR. The performance observed in the training set was validated in the validation set. Conclusion - In this pilot, proof of concept study using a machine learning algorithm, we identified biomarkers capable of predicting the risk of relapse after anti-PD1 discontinuation (age, time to best response, quality of response). Once confirmed, these simple biomarkers will represent useful tools to guide the management of these patients.

Context Patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) who are ineligible for, or relapse after, salvage chemotherapy/stem cell transplant (SCT) have a poor prognosis. Lonca comprises a humanized anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer toxin. Objective To assess updated efficacy and safety findings from a Phase 2 study evaluating Lonca in patients with R/R DLBCL (LOTIS-2; NCT03589469). Design Multicenter, open-label, single-arm Phase 2 study in adult patients (≥18 years) with pathologically defined R/R DLBCL and ≥2 prior systemic treatments. Intervention Lonca (150 µg/kg every 3 weeks [Q3W] for 2 cycles; 75 µg/kg Q3W thereafter). Main Outcomes Measures Primary efficacy endpoint: Overall response rate (ORR), assessed by central review. Secondary efficacy endpoints: Duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Safety analyses: Treatment-emergent adverse events (TEAEs). Follow-up period: Q12W for ≤3 years after end of treatment. Results 145 patients with R/R DLBCL received ≥1 Lonca dose. Median age was 66 years (range 23–94). Patients received a median of 3 prior therapies (range 2–7). At data cut-off (October 26, 2020, ≥12 months since first dose), 2 patients continued treatment. Patients received a mean of 4.6 Lonca cycles (std 4.1; range 1–22). ORR was 48.3% (complete response [CR]: 24.8%; partial response [PR]: 23.4%). Median DoR was 12.6 months for patients with CR or PR (n=70); not reached for patients with CR. Median PFS and OS were 4.9 and 9.5 months, respectively. Post-Lonca treatment, 15 patients received CD19-directed chimeric antigen receptor T-cell therapy with an investigator-assessed ORR of 46.7%, and 11 patients proceeded to SCT as consolidation after Lonca response. Most common (≥25.0%) all-grade TEAEs were increased gamma-glutamyltransferase (41.4%), neutropenia (40.0%), thrombocytopenia (33.1%), fatigue (27.6%), and anemia (26.2%). Grade ≥3 TEAEs occurred in 107 (73.8%) patients. Treatment-related TEAEs leading to treatment discontinuation and dose delays occurred in 26 (17.9%) and 62 (42.8%) patients, respectively. Conclusions After longer follow-up of patients in LOTIS-2, durable responses to Lonca continue to be observed in heavily pre-treated patients with R/R DLBCL. No new safety concerns occurred. Research funding ADC Therapeutics SA.

Background: Clinical and analytical data on patients suffering from coronavirus disease-2019 (COVID-19) indicate that endothelial damage plays a key role in the pathophysiology of the disease and is responsible for the pulmonary complications and the thrombotic microangiopathy affecting multiple organs, which contribute directly to mortality (Ackerman et al. N Engl J Med 2020). Detection of biomarkers of endothelial injury in circulating blood may provide critical diagnostic and prognostic information on the disease course (Goshua et al. Lancet Haematology 2020). Endothelial injury is also a cornerstone of pathobiology in other septic and potentially life-threatening inflammatory syndromes. Objectives: To identify circulating markers of endothelial damage in COVID-19 patients, and compare their levels with those observed in other septic syndromes. Methods: Plasma samples from non-critically ill patients with confirmed COVID-19 pneumonia (positive nasopharyngeal swab and confirmatory radiological chest imaging) requiring admission (n=42) were collected during the first 36h of hospitalization. Endothelial damage was evaluated by measuring in plasma: i) markers of endothelial function and activation (sVCAM-1, VWF, ADAMTS-13 activity, Protein C and α2-antiplasmin as a marker of fibrinolysis); ii) heparan sulfate (HS) levels, as indicators of endothelial glycocalyx degradation and loss of endothelial barrier function; and iii) C5b9 deposits on endothelial cells in culture, and soluble C5b9 (sC5b9) levels, to measure complement activation. Circulating dsDNA was analyzed as an indicator of the presence of neutrophil extracellular traps (NETs). ELISA tests were used for sVCAM-1, Protein C, HS, and sC5b9 levels. ADAMTS-13 activity was evaluated by FRETS. VWF, Protein C, and α2-antiplasmin were measured at the Atellica COAG 360 (Siemens Healthineers). C5b9 deposits were assessed by immunofluorescence and dsDNA levels by Quant-iT PicoGreen assay kit. Results were compared with those obtained in healthy donors (controls, n=45), and patients with non-infectious systemic inflammatory response syndrome (NI-SIRS, n=8) and septic shock (SS, n=8). Results: Levels of sVCAM-1 were significantly higher in COVID-19 patients vs. controls, NI-SIRS and SS (159±12 vs. 79±4, 57±8 and 80±10 ng/mL, respectively, p Conclusions: Our data clearly demonstrate the presence of endothelial stress products in the circulating blood of non-critically ill COVID-19 patients. These biomarkers of endothelial injury are suggestive indicators of different aspects of the disease: specifically, release of acute phase reactants, degradation of the endothelial cell glycocalyx, and activation of the complement system. Furthermore, this profile of biomarkers in COVID-19 appears specific, with a differential behavior in comparison with septic shock, in which endothelial damage is also known to be critical. Additional studies are needed to validate these biomarkers as diagnostic and prognostic tools of the endothelial complications in COVID-19 patients, both in early disease and later, as well as supporting specific forms of therapeutic intervention. Figure Disclosures Carreras: Jazz Pharmaceuticals: Research Funding, Speakers Bureau; German Jose´ Carreras Leukaemia Foundation: Research Funding. Carlo-Stella:Boehringer Ingelheim and Sanofi: Consultancy; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Moraleda:Sandoz: Consultancy, Other: Travel Expenses; Novartis: Consultancy, Other: Travel Expenses; Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding; Takeda: Consultancy, Other: Travel Expenses. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Diaz-Ricart:German Jose Carreras Leukaemia Foundation: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding.

Summary Background Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who do not respond to or who have progressive disease after salvage therapies have a poor prognosis. Loncastuximab tesirine is a CD19-directed antibody–drug conjugate with encouraging phase 1 single-agent antitumour activity and acceptable safety in non-Hodgkin lymphoma. We aimed to evaluate the antitumour activity and safety of loncastuximab tesirine in patients with relapsed or refractory DLBCL. Methods We did a multicentre (28 hospital sites in the USA, UK, Italy, and Switzerland), open-label, single-arm, phase 2 trial (LOTIS-2) in patients aged 18 years or older with relapsed or refractory DLBCL after two or more multiagent systemic treatments, who had measurable disease and Eastern Cooperative Oncology Group performance status 0–2. Eligible patients received loncastuximab tesirine intravenously on day 1 of each 21-day cycle, at 150 μg/kg for two cycles, then 75 μg/kg thereafter, for up to 1 year or until disease relapse or progression, unacceptable toxicity, death, major protocol deviation, pregnancy, or patient, investigator, or sponsor decision. The primary endpoint was overall response rate assessed by central review. Primary antitumour activity and safety analyses were done in the as-treated population (patients who received at least one dose of loncastuximab tesirine), when all responding patients had at least 6 months of follow-up after initial documented response. Enrolment is complete. This trial is registered with ClinicalTrials.gov , NCT03589469 . Findings Between Aug 1, 2018, and Sept 24, 2019, 184 patients were assessed for eligibility and 145 (79%) were enrolled and received at least one dose of loncastuximab tesirine, including patients with high-risk characteristics for poor prognosis, such as double-hit, triple-hit, transformed, or primary refractory DLBCL. 70 of 145 patients had complete or partial response (overall response rate 48·3% [95% CI 39·9–56·7]); 35 had complete response and 35 had partial response. The most common grade 3 or higher treatment-emergent adverse events were neutropenia (37 [26%] of 145 patients), thrombocytopenia (26 [18%]), and increased gamma-glutamyltransferase (24 [17%]). Serious adverse events were reported in 57 (39%) of 145 patients. Treatment-emergent adverse events with a fatal outcome occurred in eight (6%) of 145 patients; none were considered related to loncastuximab tesirine. Interpretation Loncastuximab tesirine has substantial single-agent antitumour activity and produces durable responses with an acceptable safety profile, potentially offering a new therapeutic option for heavily pretreated patients with relapsed or refractory DLBCL. Funding ADC Therapeutics.

We investigated the feasibility and activity of an intensified dose-dense ABVD (dd-ABVD) regimen in patients with early-stage unfavorable Hodgkin lymphoma (HL). This prospective, multicenter, phase II study enrolled 96 patients with newly diagnosed, unfavorable stage I or II classical HL. The patients received four cycles of dd-ABVD followed by radiotherapy. Interim PET (PET-2) was mandatory after two courses. Primary endpoints were the evaluation of dd-ABVD feasibility and activity (incidence of PET-2 negativity). The feasibility endpoint was achieved with 48/52 (92.3%) patients receiving > 85% of the programmed dose. The mean dose intensity in the overall patient population (n = 96) was 93.7%, and the median duration of dd-ABVD was 85 days (range, 14–115) versus an expected duration of 84 days. PET-2 was available for 92/96 (95.8%) patients, of whom 79 were PET-2 negative (85.9%). In total, 90 (93.8%) patients showed complete response at the end of treatment. With a follow-up of 80.9 months (3.3–103.2), the median progression-free survival (PFS) and overall survival (OS) were not reached. At 84 months, PFS and OS rates were 88.4% and 95.7%, respectively. No evidence for a difference in PFS or OS was observed for PET-2-negative and PET-2-positive patients. Infections were documented in 8.3% and febrile neutropenia in 6.2% of cases. Four patients died: one had alveolitis at cycle 3, one death was unrelated to treatment, and two died from a secondary cancer. dd-ABVD is feasible and demonstrates activity in early-stage unfavorable HL. The predictive role of PET-2 positivity in early-stage unfavorable HL remains controversial. The study was registered in the EudraCT (reference number, 2011–003,191-36) and the ClinicalTrials.gov (reference number, NCT02247869) databases.

Allogeneic stem cell transplantation from haploidentical donors using unmanipulated bone marrow and posttransplantation cyclophosphamide has been largely employed to cure high-risk lymphomas. However, the increased incidence of relapse associated with the use of a nonmyeloablative conditioning regimen is still considered a concerning issue. The aim of our study was to prospectively evaluate the efficacy and feasibility of a reduced-intensity conditioning regimen, including thiotepa, cyclophosphamide, and fludarabine, in high-risk lymphoma patients. This was a prospective multicenter study. We enrolled 49 patients, of whom 47 were evaluable. Graft source (bone marrow) and graft-versus-host disease (GVHD) prophylaxis were the same for all patients. The primary endpoint was the proportion of patients free of disease progression at 1 year. The primary endpoint was met, as 29 out of 47 patients were alive and free of disease at 1 year (1-year progression-free survival, 60%). Forty-five recipients engrafted and achieved full donor chimerism at day 100. The cumulative incidences (CIs) of ANC engraftment at 30 days and platelet engraftment at 60 days were 89% and 83%, respectively. Two patients experienced graft failure. The CIs of day 100 grades 2 to 4 acute GVHD and 2-year moderate-to-severe chronic GVHD were 26% and 16%, respectively. With a median follow-up of 47.5 months (range, 22 to 74), the 4-year progression-free survival and overall survival were 54% and 64%, respectively. The 4-year CI of relapse was 28%, and the 4-year nonrelapse mortality was 15%. Thiotepa-based reduced-intensity conditioning was well tolerated with encouraging survival in a cohort of patients with poor-prognosis lymphoma. Both the incidence of relapse and nonrelapse mortality were acceptable.

Background Allogeneic stem cell transplantation from haploidentical donor using an unmanipulated graft and post-transplantation cyclophosphamide (PT-Cy) is growing. Haploidentical transplantation with PT-Cy showed a major activity in Hodgkin lymphoma (HL), reducing the relapse incidence. The most important predictive factor of survival and toxicity was disease status before transplantation, which was better in patients with well controlled disease. Methods We included 198 HL in complete (CR) or partial remission (PR) before transplantation. Sixty-five patients were transplanted from haploidentical donor and 133 from a HLA identical donor (both sibling and unrelated donors). Survival analysis was defined according to the EBMT criteria. Survival curves were generated by using Kaplan-Meier method and differences between groups were compared by the log rank test or by the log rank test for trend when appropriated. Results The PFS, OS, and RI were significantly better in patients in CR compared to PR (55% vs 29% p = 0.001, 74% vs 55% p = 0.03, 27% vs 55% p p = 0.03), without difference in OS. The 1-year NRM was not different. The 2-year relapse incidence (RI) was lower in the HAPLO group (24% vs 44%, p = 0.008). Patients in CR receiving haplo HSCT showed higher 2-year PFS and lower 2-year RI than those allografted with HLA-id donor (75% vs 47%, p p Conclusions Nonetheless this is a retrospective study, limiting the wide applicability of results, data from this analysis suggest that HLA mismatch can induce a strong graft versus lymphoma effect leading to an enhanced PFS.

SummaryBackground BI 836826 is a chimeric mouse–human monoclonal antibody directed against human CD37, a transmembrane protein expressed on mature B lymphocytes. This open-label, phase I dose-escalation trial (NCT02624492) was conducted to determine the maximum tolerated dose (MTD), safety/tolerability, and preliminary efficacy of BI 836826 in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Methods Eligible patients received intravenous infusions of BI 836826 on day 8 and gemcitabine 1000 mg/m2 plus oxaliplatin 100 mg/m2 on day 1, for up to six 14-day treatment cycles. Dose escalation followed the standard 3 + 3 design. Results Of 21 treated patients, 17 had relapsed/refractory DLBCL and four had follicular lymphoma transformed to DLBCL. BI 836826 dosing started at 25 mg and proceeded through 50 mg and 100 mg. Two dose-limiting toxicities (DLTs) occurred during cycle 1, both grade 4 thrombocytopenia lasting > 7 days, affecting 1/6 evaluable patients (17%) in both the 50 mg and 100 mg cohorts. Due to early termination of the study, the MTD was not determined. The most common adverse events related to BI 836826 treatment were neutropenia (52%), thrombocytopenia (48%), and anemia (48%). Eight patients (38%) experienced BI 836826-related infusion-related reactions (two grade 3). Overall objective response rate was 38%, including two patients (10%) with complete remission and six patients (29%) with partial remission. Conclusions BI 836826 in combination with GemOx was generally well tolerated but did not exceed the MTD at doses up to 100 mg given every 14 days.

We read with interest the letter by Maccio et al., which postulates a role for defibrotide (DF) in the treatment of coagulation disorders observed in COVID-19 [1]. Their commentary effectively explores the contribution of macrophages towards the coagulopathy observed in COVID-19, while highlighting the similarities between COVID-19 associated vascular lesions and veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS) and commonly referred to as VOD/SOS. DF has indeed been shown to improve overall survival in patients with severe VOD/SOS [2] and may be beneficial in the treatment of COVID-19, but not exclusively because of the observed similarities to VOD/SOS.

Follicular lymphoma (FL) is the second most common histotype of lymphoma and is considered an incurable disease. The need for new treatment options has led to the development of innovative targeted agents, including inhibitors of the phosphatidylinositol-3-kinase (PI3K) pathway.Copanlisib, an intravenous pan-class I PI3K inhibitor, has been approved by the US Food and Drug Administration (FDA) for the treatment of relapsed FL in patients who have received at least two prior systemic therapies. In this article, we critically review the mechanism of action, clinical efficacy, safety, dosage, administration, and role of copanlisib in the treatment of relapsed FL.Treatment with copanlisib results in clinically relevant and durable responses in heavily pretreated patients with relapsed or refractory FL. In addition, copanlisib has a manageable safety profile in this population, with low rates of severe hepatic transaminitis, diarrhea, colitis, and noninfectious pneumonitis. Further investigations of copanlisib within combination regimens will potentially allow to move copanlisib to an earlier line of therapy for FL. However, results of the CHRONOS-4 clinical trial evaluating copanlisib with standard chemoimmunotherapy (rituximab with bendamustine or CHOP) are not yet available.

Background According to published data, radiomics features differ between lesions of refractory/relapsing HL patients from those of long-term responders. However, several methodological aspects have not been elucidated yet. Purpose The study aimed at setting up a methodological framework in radiomics applications in Hodgkin’s lymphoma (HL), especially at (a) developing a novel feature selection approach, (b) evaluating radiomic intra-patient lesions’ similarity, and (c) classifying relapsing refractory (R/R) vs non-(R/R) patients. Methods We retrospectively included 85 patients (male:female = 52:33; median age 35 years, range 19–74). LIFEx (www.lifexsoft.org) was used for [18F]FDG-PET/CT segmentation and feature extraction. Features were a-priori selected if they were highly correlated or uncorrelated to the volume. Principal component analysis-transformed features were used to build the fingerprints that were tested to assess lesions’ similarity, using the silhouette. For intra-patient similarity analysis, we used patients having multiple lesions only. To classify patients as non-R/R and R/R, the fingerprint considering one single lesion (fingerprint_One) and all lesions (fingerprint_All) was tested using Random Undersampling Boosting of Tree Ensemble (RUBTE). Results HL fingerprints included up to 15 features. Intra-patient lesion similarity analysis resulted in mean/median silhouette values below 0.5 (low similarity especially in the non-R/R group). In the test set, the fingerprint_One classification accuracy was 62% (78% sensitivity and 53% specificity); the classification by RUBTE using fingerprint_All resulted in 82% accuracy (70% sensitivity and 88% specificity). Conclusions Lesion similarity analysis was developed, and it allowed to demonstrate that HL lesions were not homogeneous within patients in terms of radiomics signature. Therefore, a random target lesion selection should not be adopted for radiomics applications. Moreover, the classifier to predict R/R vs non-R/R performed the best when all the lesions were used.

We propose to test whether the new refined Minnesota risk score, which represents a new tool for acute Graft-versus-Host-Disease (aGVHD) grading, may be useful to predict the final outcome of patients with aGVHD after haploidentical stem cell transplantation (Haplo-SCT) with post-transplant cyclophosphamide (PT-Cy). Hundred consecutive patients with grade 2–4 aGVHD were included. Twenty-two percent of the patients had high-risk (HR) aGVHD and had a lower chance to respond at day 28: 41% of non-responders (NR) were in the HR vs 13% in the standard-risk (SR) group (p = 0.003). By multivariate analysis, grade 3–4 aGVHD according to the traditional Keystone classification was the main independent predictor of non-response to front-line treatment at day 28, while HR aGVHD by the new refined Minnesota score remained the main independent variable associated with adverse NRM and OS. The new Minnesota refined risk score is a useful tool to predict the outcome of patients with aGVHD after Haplo-SCT with PT-Cy. Due to the few patients exchanging between categories in the two classifications, it is not possible to discriminate which system better predicts the outcome of patients with aGVHD in the setting of Haplo-SCT. Extending these preliminary observations to a larger cohort is warranted.

Supplemental Digital Content is available in the text, While classical nodal mantle cell lymphoma (cMCL) is often associated with involvement of multiple extranodal sites, isolated extranodal disease (ED) at the time of diagnosis is a rare event; data on the outcome of these forms are lacking. On behalf of the European MCL Network, we conducted a retrospective analysis on the clinical characteristics and outcomes of MCL presenting with isolated or predominant ED (MALT MCL). We collected data on 127 patients with MALT MCL diagnosed from 1998 to 2015: 78 patients (61%) were male with a median age of 65 years. The involved sites include: upper airways + Waldeyer ring (40; 32%), gastrointestinal tract (32; 25%), ocular adnexa (17; 13%), oral cavity and salivary glands (17; 13%) and others (13; 1%); 7 patients showed multiple extranodal sites. The median follow-up was 80 months (range: 6–182), 5-year progression-free survival (PFS) was 45% (95% CI: 35–54) and 5-year overall survival (OS) was 71% (95% CI: 62–79). In an explorative setting, we compared MALT MCL with a group of 128 cMCL patients: MALT MCL patients showed a significantly longer PFS and OS compared with nodal cMCL; with a median PFS of 4.5 years vs 2.8 years (p = 0.001) and median OS of 9.8 years vs 6.9 years (p = 0.018), respectively. Patients with MALT MCL at diagnosis showed a more favorable prognosis and indolent course than classical nodal type. This clinical variant of MCL should be acknowledged to avoid possible over-treatment.

Allogeneic hematopoietic stem cell transplantation (SCT) represents a potential curative strategy for patients with Hodgkin lymphoma (HL) relapsing after autologous SCT (ASCT), but the incidence of disease relapse is still high. We performed a retrospective study on 64 patients with HL relapsing after ASCT to compare outcomes after HLA-identical SCT (HLAid-SCT; n = 34) and haploidentical SCT with post-transplantation cyclophosphamide (PT-Cy) (Haplo-SCT; n = 30). All patients engrafted, with a significantly shorter median time for neutrophil and platelet engraftment after HLAid compared with Haplo-SCT (14 days versus 19 days and 11 days versus 23 days, respectively; P

Background: MCL is an aggressive non-Hodgkin lymphoma (NHL) subtype and pts with progressive disease (PD) after BTKi therapy have a poor prognosis (Martin et al. Blood 2016). Glofitamab is a T-cell-engaging, CD20xCD3 bispecific antibody with a novel 2:1 molecular configuration with bivalency for CD20 on B cells and monovalency for CD3 on T cells. Glofitamab with obinutuzumab pretreatment (Gpt) has shown promising efficacy with frequent, durable complete responses (CR) and manageable tolerability with fixed dosing (NCT03075696; Dickinson et al. EHA 2020) and step-up dosing (SUD; Hutchings et al. J Clin Oncol 2021) in NHL. Glofitamab and obinutuzumab compete for binding to CD20 receptors; as a result, Gpt reduces the receptor occupancy (RO) of glofitamab. Pts with MCL have a 2-fold higher clearance of obinutuzumab vs other NHL histologies (Gibiansky et al. CPT Pharmacometrics Syst Pharmacol 2014), leading to lower obinutuzumab concentrations and higher glofitamab RO at the start of glofitamab treatment (Djebli et al . Blood 2020). A higher dose of Gpt prior to glofitamab SUD may therefore further reduce the risk of cytokine release syndrome (CRS) in MCL. We report preliminary data from the NP30179 Phase I/II trial in pts with R/R MCL who received a 1000mg or 2000mg dose of Gpt prior to glofitamab monotherapy. Methods: All pts received Gpt 7 days prior to the first glofitamab dose. Intravenous glofitamab SUD was given on days 1 and 8 of Cycle (C)1, then at the target dose from C2 day (D)1 (from C3D1 for SUD starting at 0.5mg), every 3 weeks for up to 12 cycles (0.5/2.5/10/30, 2.5/10/16 or 2.5/10/30mg after 1000mg Gpt, or 2.5/10/30mg after 2000mg Gpt). Pts on fixed dosing received glofitamab (0.6, 16 or 25mg) after 1000mg Gpt from C1 for up to 12 cycles. Response rates are based on the Lugano criteria (Cheson et al. J Clin Oncol 2014). Results: As of May 18, 2021, 29 pts had received glofitamab: fixed dosing after 1000mg Gpt (n=3); SUD after 1000mg Gpt (n=7; 1 pt received SUD starting at 0.5mg) or 2000mg Gpt (n=19). Median age was 69 years (range, 41-84; 69% male), 83% of pts had Ann Arbor Stage III-IV disease and 62.1% had MCL international prognostic index score ≥6 at study entry. Median prior lines of therapy was 3 (range, 1-6), 69% (n=20) had prior BTKi therapy and 14% (n=4) had prior lenalidomide therapy. Many pts were refractory to their first line of therapy (52%; n=15) and/or their last prior therapy (69%; n=20). Median time since last therapy was 1.7 months (range, 0.1-107.5). In efficacy-evaluable pts (n=21), the overall response rate was 81.0% (n=17) and complete metabolic response rate was 66.7% (n=14; Table 1). Similar response rates were observed in pts who had received prior BTKi therapy vs pts who had not (Table 2). Median duration of CR follow-up was 2.4 months (range, 0.0-25); 85.7% (12/14) pts with a CR remained in remission at the data cut-off (median duration of response and median duration of CR were not reached). In safety-evaluable pts (n=29), the most common adverse events (AEs) were CRS (58.6%) and infusion-related reactions (24.1%). All CRS events were Grade (Gr) 1-2 (by ASTCT criteria), except for 1 Gr 4 CRS in the 1000mg Gpt + SUD cohort (3.4%; pt died due to cardiopulmonary insufficiency as a result of rapid PD; at time of death CRS was persisting). CRS rates were lower in the 2000mg Gpt + SUD cohort (9/19; 47.4%) vs the 1000mg Gpt + SUD (5/7; 71.4%) and 1000mg Gpt + fixed dosing (3/3; 100%) cohorts. Overall, median time to first CRS event and duration of CRS event were 16.8 hrs and 38.8 hrs, respectively. All CRS events were manageable (tocilizumab used in 4 pts, low-flow oxygen in 2 pts) and most resolved at data cut-off. Neurologic AEs occurred in 6 pts (20.7%, all Gr 1 [n=5] or Gr 2 [n=1]). Immune effector cell-associated neurotoxicity syndrome (ICANS)-like AEs occurred in 1 pt (3.4%): Gr 1 confusional state and Gr 2 ataxia, both resolving in 1 day. Tumor flare events occurred in 3 pts (10.3%, all Gr 1 [n=2] or Gr 2 [n=1]). No pts discontinued treatment due to AEs. Three deaths were reported and considered unrelated to study treatment: PD (n=2); cardiac arrest (n=1). Conclusions: Glofitamab SUD as monotherapy after Gpt induced high response rates in pts with MCL, most of whom had failed prior BTKi therapy. CRS rates were manageable and mostly low grade. ICANS-like AEs were infrequent, low grade and resolved within 1 day. No treatment discontinuations due to AEs were observed. Further analyses will be presented. Figure 1 Figure 1. Disclosures Phillips: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding; ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; BMS: Consultancy, Research Funding; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding. Dickinson: Celgene: Research Funding; Amgen: Honoraria; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Research Funding; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Morschhauser: Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: 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; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; Chugai: Honoraria; Genentech, Inc.: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Crump: Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Epizyme: Research Funding. Trněný: MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Celgene: Consultancy; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Bartlett: Washington University School of Medicine: Current Employment; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Autolus: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Janssen: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zaucha: Takeda: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Roche: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Humphrey: Roche: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Perez-Callejo: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Lundberg: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Relf: Roche Pharmaceutical Ltd: Current Employment, Current equity holder in publicly-traded company; F-Star Therapeutics: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Harpoon Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months. Filézac de L'Étang: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Carlile: AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months; F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Clark: Roche Products Ltd: Current Employment. Carlo-Stella: Sanofi: Consultancy, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Janssen Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Glofitamab is a full-length, humanized, immunoglobulin G1 bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent.

Background: Despite recent advances, prognosis for pts with NHL who undergo multiple lines of therapy remains poor. Novel drugs that provide durable complete responses (CRs) are needed for these pts. Glofitamab (RG6026) is a novel T-cell-engaging, bispecific antibody that binds bivalently to CD20 on B cells, and monovalently to CD3 on T cells. In study NP30179 (NCT03075696), an ongoing Phase I/II dose-escalation and expansion study, glofitamab fixed-dosing (0.6-25mg) with obinutuzumab pre-treatment (Gpt) achieved high, durable CRs with manageable safety in pts with heavily pre-treated R/R NHL (Dickinson et al. EHA 2020). Step-up dosing (SUD) of glofitamab, in addition to Gpt, allowed dose-escalation up to the highest planned dose of 30mg to maximize efficacy, while mitigating cytokine release syndrome (CRS; [Hutchings et al. J Clin Oncol 2021]). We present updated duration of response (DoR) data from the glofitamab monotherapy fixed-dosing and SUD cohorts of study NP30179 in pts with R/R NHL. Methods: Pts received 1000mg obinutuzumab 7 days prior to first dose of glofitamab. Glofitamab was given intravenously at a fixed dose (0.6-25mg) every 2 weeks or every 3 weeks (q3w) or with SUD (2.5/10/16mg or 2.5/10/30mg [recommended Phase II dose; RP2D]) on Cycle (C) 1 Day (D) 1 and 8, and then at the target dose from C2D1 q3w, for up to 12 cycles. Response rates are based on Lugano criteria (Cheson et al. J Clin Oncol 2014). Results: As of May 18, 2021, 258 pts were enrolled in the previously specified cohorts. Median age was 64.0 (range, 22‒86) years, 62.0% were male, and the median number of prior therapies was 3 (range, 1‒12). A total of 183 (70.9%) pts had aggressive NHL (aNHL), and 75 (29.1%) had indolent NHL (iNHL). Of the pts with aNHL, 98 had diffuse large B-cell lymphoma, 26 had mantle cell lymphoma, 31 had transformed follicular lymphoma (FL), and 11 had Richter's transformation. All pts with iNHL had Grade (Gr) 1‒3a FL. Response rates are reported across all doses investigated. Highest responses were seen with the RP2D (2.5/10/30mg) in pts with aNHL (Table). At the clinical cut-off date (CCOD), median duration of follow-up in pts with aNHL was 13.4 (range: 0‒36) months. In efficacy-evaluable pts with aNHL (n=175), the overall response rate (ORR) was 53.7% and the CR rate was 39.4%. Median duration of CR had not yet been reached (95% confidence interval [CI]: 21.4‒not estimable [NE], n=69; Figure); 72.5% of pts with a CR (50/69) were still in CR at the time of analysis. Median DoR (CR plus partial response) was 29.4 months (95% CI: 6.0‒NE; responders, n=94). In pts with iNHL (n=75), ORR was 81.3% and CR rate was 69.3%; median follow-up was 8.6 (range: 0‒37) months. Median duration of CR had not yet been reached (95% CI: 10.5‒NE, n=52; Figure); 82.7% of pts with a CR (43/52) were still in CR at the time of the analysis. Median DoR had not been reached (95% CI: 10.5‒NE; responders, n=61). A total of 149/258 pts (57.8%) experienced a serious adverse event (AE). CRS was the most prevalent AE, occurring in 152/258 pts (58.9%). The majority of CRS events were mild: Gr 1-2, 139 (53.9%) pts; Gr 3, 9 (3.5%) pts; Gr 4, 4 pts (1.6%). Four pts (1.6%) experienced a glofitamab-related AE that led to withdrawal of the study drug. Ninety-two (35.7%) pts experienced a neurological AE; the majority of events were Gr 1 (56/258; 21.7%) or Gr 2 (33/258; 12.8%). Three pts experienced a Gr 3 neurological AE (facial paralysis, syncope, radiculopathy), which were considered unrelated to glofitamab treatment. Immune effector cell-associated neurotoxicity syndrome (ICANS)-like events related to glofitamab occurred in 9 pts (3.5%); all events were Gr 1 or Gr 2, and all but one (Gr 1 tremor) resolved at CCOD. Conclusions: The current dataset on DoR is the largest presented to date for a CD20xCD3 bispecific antibody, with median follow-up exceeding 13 months for pts with aNHL. Glofitamab, with a fixed treatment duration and 'off-the-shelf' accessibility, has demonstrated high levels of monotherapy activity in heavily pretreated pts with R/R NHL, including those who have received two or more lines of systemic therapy. Glofitamab has shown promising response rates and durable responses a range of different doses for both aNHL and iNHL. Duration of responses in pts with aNHL were in the range of those observed in pts with refractory aNHL from an early chimeric antigen receptor T-cell data set (Neelapu et al. N Engl J Med 2017). Figure 1 Figure 1. Disclosures Dickinson: Amgen: Honoraria; Celgene: Research Funding; Takeda: Research Funding; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Carlo-Stella: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Research Funding. Morschhauser: Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; Genentech, Inc.: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees. Patel: BeiGene: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Fate Therapeutics: Research Funding; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; Juno Pharmaceuticals: Consultancy; Kite: Consultancy, Research Funding, Speakers Bureau; MEI Pharma: Consultancy, Research Funding; TG Therapeutics: Consultancy, Speakers Bureau; Trillium Therapeutics: Research Funding; Sunesis Pharmaceuticals: Research Funding; Pharmacyclics/Janssen: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy; Xencor: Research Funding; Curis, Inc: Research Funding; Abbvie: Consultancy; Millenium/Takeda: Research Funding; Velos Bio: Research Funding; Aptevo Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Khan: Genentech: Research Funding, Speakers Bureau; Astrazeneca: Research Funding, Speakers Bureau; Epizyme: Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; Abbvie: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Karyopharm: Speakers Bureau; SeaGen: Speakers Bureau; Morphosys: Speakers Bureau; Kite: Speakers Bureau; GSK: Speakers Bureau. Bartlett: Affimed: Research Funding; Autolus: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Janssen: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Washington University School of Medicine: Current Employment. Iacoboni: BMS/Celgene, Gilead, Novartis, Janssen, Roche: Honoraria. Hertzberg: Roche: Honoraria, Speakers Bureau; MSD: Honoraria; BMS: Honoraria; Takeda: Honoraria; Gilead: Honoraria. Leppä: Genmab: Research Funding; Orion: Consultancy; CHO Pharma USA: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; University of Helsinki and Helsinki University Hospital: Current Employment; Takeda: Research Funding; Bayer: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Van Den Neste: Novartis: Consultancy, Research Funding; Roche: Research Funding; Celgene: Consultancy. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Salar: Beigene: Consultancy; BMS/Celgene: Consultancy, Speakers Bureau; EusaPharma: Consultancy; Janssen: Consultancy, Speakers Bureau; Hospital del Mar: Current Employment; Abbvie: Research Funding. Perez-Callejo: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Lundberg: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Relf: F-Star Therapeutics: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Harpoon Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Roche Pharmaceutical Ltd: Current Employment, Current equity holder in publicly-traded company. Clark: Roche Products Ltd: Current Employment. Humphrey: Roche: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Hutchings: Novartis: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Genmab: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Genentech: Honoraria, Research Funding. OffLabel Disclosure: Glofitamab is a full-length, humanized immunoglobulin G1 bispecific antibodywith a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent.

Introduction: Treatment options are limited in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Combined therapy using agents with different mechanisms of action, such as an antibody-drug conjugate (ADC) with an inhibitor of Bruton's tyrosine kinase (BTK), may improve therapeutic outcomes. Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca) is an ADC comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin, approved for the treatment of patients with R/R DLBCL after ≥2 lines of prior systemic therapy. Ibrutinib, a small-molecule inhibitor of BTK, has shown antitumor activity - particularly as a combination treatment - in patients with R/R DLBCL (Depaus et al, abstract 2099, ASH Dec 5-8, 2020). Here, we present the results of a planned interim analysis in patients with DLBCL (irrespective of cell of origin), non-germinal center B-cell-like DLBCL (non-GCB DLBCL), and GCB DLBCL. Methods: In this ongoing, Phase 2, open-label, single-arm study, patients aged ≥18 years with R/R DLBCL, measurable disease (per 2014 Lugano classification), and ECOG performance status 0-2 were enrolled. Patients were treated with Lonca 60 μg/kg once every 3 weeks for 2 cycles (patients who had a complete response [CR], partial response [PR], or stable disease were permitted to have an additional Lonca dose at Day 1 of Cycles 5, 6, 9, and 10), plus ibrutinib 560 mg/day taken orally for up to 1 year. The primary objective of the study was to evaluate the complete response rate (CRR) achieved with Lonca plus ibrutinib in patients with R/R non-GCB DLBCL (cell of origin, as determined by the investigator), assessed by central review. A Simon's 2-stage design was used in this study with a planned interim analysis conducted when the 22nd patient in the non-GCB DLBCL cohort had 2 tumor assessments. The objective of this planned interim analysis was to determine if CRR in the non-GCB DLBCL cohort warranted continuation of patient enrollment for study completion; if ≥6 patients achieved a CR the study was planned to proceed to the next stage. Thirteen patients with GCB DLBCL who met the defined cut-off for the interim analysis were also included in the dataset. Results: As of April 21, 2021, 35, 22, and 13 patients with DLBCL overall, non-GCB DLBCL, and GCB DLBCL, respectively, were included in the planned interim analysis. In the overall DLBCL cohort, patients had a median age of 72 years (range 19-82) and had received a median of 3 prior therapies (range 1-6), including stem cell transplant. Patients in the overall DLBCL cohort received a median of 2 (range 1-6) cycles of Lonca and 4 (range 1-10) cycles of ibrutinib. CRRs among the planned interim analysis population were 34.3% (12/35; 95% CI: 19.1-52.2), 27.3% (6/22; 95% CI: 10.7-50.2), and 46.2% (6/13; 95% CI: 19.2-74.9) in the overall DLBCL cohort, non-GCB DLBCL cohort, and GCB DLBCL cohort, respectively. ORR (CR + PR) was 57.1% (20/35; 95% CI: 39.4-73.7) in the overall DLBCL cohort, and 45.5% (10/22; 95% CI: 24.4-67.8) and 76.9% (10/13; 95% CI: 46.2-95.0) in the non-GCB DLBCL and GCB DLBCL cohorts, respectively (Figure 1). Median (95% CI) duration of response in the overall DLBCL cohort was 5.49 (5.49-not reached) months and was not reached in the non-GCB DLBCL or GCB DLBCL cohorts. In the overall DLBCL cohort, non-GCB DLBCL cohort, and GCB DLBCL cohort, 32 (91.4%), 21 (95.5%), and 11 (84.6%) patients, respectively, had at least 1 treatment-emergent adverse event (TEAE). In total, 16 (45.7%) patients in the overall DLBCL cohort (15 [68.2%] with non-GCB DLBCL; 1 [7.7%] with GCB DLBCL) had Grade ≥3 TEAEs; the most common (≥10%) were neutropenia in 7 (20%) patients and thrombocytopenia in 4 (11.4%) patients. Overall, 17 (48.6%) patients had TEAEs leading to dose reduction, delay, or interruption. TEAEs leading to treatment discontinuation occurred in 8 (22.9%) patients. Conclusions: At the doses tested, treatment with Lonca plus ibrutinib showed encouraging anti-tumor activity and a manageable safety profile in patients with R/R DLBCL. The study protocol will be amended to investigate whether Lonca given at each cycle in combination with ibrutinib improves efficacy outcomes in patients with R/R DLBCL. Funding: ADC Therapeutics SA (NCT03684694). Figure 1 Figure 1. Disclosures Carlo-Stella: AstraZeneca: Honoraria; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Honoraria; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Research Funding. Zinzani: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Janakiram: FATE Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; Kyowa Kirin Therapeutics: Honoraria; ADC Therapeutics: Research Funding. Dia: ADC Therapeutics America, Inc.: Current Employment, Current equity holder in publicly-traded company. He: ADC Therapeutics America, Inc.: Current Employment, Current equity holder in publicly-traded company; State University of New York Research Foundation: Current Employment. Ervin-Haynes: ADC Therapeutics America, Inc.: Current Employment, Current equity holder in publicly-traded company. Depaus: Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Takeda: Consultancy. OffLabel Disclosure: Ibrutinib is not approved for DLBCL.

Background. Risk stratification is particularly important to tailor the therapeutic strategy and avoid unnecessary toxicity for the treatment of relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). Early assessment of chemo-sensitivity by fluoro-deoxy-glucose ([18F]FDG) positron emission tomography (PET) scan is the strongest predictor of outcome in first line setting; however, data are limited in r/r cHL. Circulating tumor DNA (ctDNA) profiling is emerging as a powerful tool for outcome prediction and response monitoring.The BEGEV (BEndamustine, GEmcitabine,Vinorelbine) regimen is routinely offered as salvage strategy prior to autologous (auto) or allogeneic (allo) stem cell transplantation (SCT) in r/r cHL (Santoro, 2016). Early identification of patients who fail this program may have a significant clinical impact in the selection of the optimal therapeutic strategy for r/r cHL. Aim. We performed a retrospective analysis in r/r cHL patients treated with BEGEV to assess the efficacy of baseline ctDNA quantification in predicting outcome. Additionally, we evaluated whether integrating ctDNA genotyping with interim [18F]FDG PET scan may further improve outcome prediction. Methods. 42 patients with r/r cHL treated with four cycles of BEGEV followed by auto- or allo-SCT were included in the study; median age was 32 years (range, 19-69). In all patients, response was assessed by an interim [18F]FDG PET (iPET) after two BEGEV cycles. Response was assessed using the 5-point scale Deauville score according to the Lugano criteria with complete metabolic response (CMR) defined as score of 1-3. Blood samples collected at baseline were profiled by CAPP-Seq strategy (Spina, 2018). A targeted resequencing panel optimized to include the coding exons and splice sites of 133 genes (320 Kb) that are recurrently mutated in B-cell lymphomas was used. Sequencing was performed using the Nextseq 550 platform (Illumina) to obtain a depth of coverage >2000x in >80% of the target region in all samples. We performed partitioning analysis to evaluate the predictive value of baseline ctDNA load combined with iPET, as assessed by further therapy within 18 months from end of BEGEV. Patients failing the BEGEV program beyond 18 months were censored. Additional variables also included advanced stage, bulky disease, extranodal disease, B symptoms, chemosensitivity to first-line therapy. Results. In response to first-line therapy, 31% were chemo-sensitive and 69% refractory. BEGEV was administered as second-line therapy in 59.5 % of the patients whereas 39.5% received BEGEV beyond second-line. The median number of previous therapies was 2 (range, 1-6). After induction therapy 52% of patients underwent auto-SCT and 23% proceeded to allo-SCT. The median baseline ctDNA value reported as haploid genome equivalent per ml (hGE/ml) was 44 (range, 4-796), with ctDNA detected in PD patients being significantly higher as compared to CR patients (P=.0002) (Figure 1). After 2 cycles of BEGEV, 15 (36%) patients were positive at the iPET (DS 4 or 5), while 27 (64%) were negative. Among the variables included in the partitioning analysis, baseline ctDNA and iPET resulted the strongest predictors. Baseline ctDNA, taken individually, was able to predict need for retreatment with an overall accuracy rate of 81% (sensitivity 53%, specificity 96%). iPET predicted the need for retreatment with overlapping accuracy rate (81%), but with a higher sensitivity (66%) and a lower specificity (88%). Integrating baseline ctDNA and iPET resulted in an increased predictive value (accuracy rate 88%, sensitivity 73% and specificity 96%) which allowed to correctly classify 88% of patients treated with BEGEV (Table 1). Based on the results of the partitioning analysis, three categories of BEGEV-treated patients were defined (Figure 2). Patients with positive iPET and high baseline ctDNA (>33 hGE/ml) showed a significantly inferior treatment-free survival with 91,7% (95% CI 82.7-99.7) of patients in this category who needed further treatment at 18 months (p Conclusion. Our data suggest that patients with high baseline ctDNA and positive interim PET have a limited benefit from completing the BEGEV regimen. Despite the small number of evaluated patients, early switch to non-chemotherapeutic agents such as targeted and immune-based drugs should be evaluated in prospective trials to improve outcome in high-risk patients. Figure 1 Figure 1. Disclosures Rossi: Abbvie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Verastem: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Cellestia: Honoraria, Research Funding. Santoro: Sandoz: Speakers Bureau; Eli-Lilly: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Speakers Bureau; Roche: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; Sanofi: Consultancy; Arqule: Consultancy, Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Carlo-Stella: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Janssen Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Research Funding.

Introduction: Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca) is an FDA-approved CD19-directed antibody-drug conjugate (ADC) indicated for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma after ≥2 lines of systemic therapy, including patients with high-grade B-cell lymphoma. In the Phase 2 LOTIS-2 trial (NCT03589469), Lonca was evaluated as a single agent in patients with R/R diffuse large B-cell lymphoma (DLBCL) and the overall response rate (ORR) was 48.3% (Caimi PF, et al. Lancet Oncol. 2021; 22:790-800). In an analysis of the 11 patients from the LOTIS-2 clinical trial with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBCL; data cutoff: April 6, 2020), 45.5% (n=5) achieved an overall response. In this patient subgroup, the median duration of response was 13.37 months, and the median progression-free survival was 9.13 months. The aim of this analysis (data cut off: March 1, 2021) was to further characterize the clinical characteristics and efficacy of Lonca in patients with HGBCL enrolled in the LOTIS-2 clinical trial. Methods: The methodology for the LOTIS-2 trial has been published. Briefly, Lonca (0.15 mg/kg for the first 2 cycles followed by 0.075 mg/kg for subsequent cycles) was administered as a single 30-minute infusion, once every 3 weeks for up to 1 year, until progressive disease or unacceptable toxicity. The primary outcome was ORR defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR), assessed by independent review. Investigator assessment of histopathology according to the 2016 WHO classification was used to define HGBCL. Results: The demographics and disease characteristics of the 11 patients with HGBCL are shown in Table 1. The median age was 74 years; 5 patients (45.5%) were age ≥75 years. The majority of patients received ≥3 prior lines of therapy (n = 8; 72.7%). One patient had a prior stem cell transplant (autologous; 9.1%). Of the 11 patients with HGBCL, the overall response rate was 45.5%, with all 5 patients achieving CR. The median (min, max) time to first CR or PR response was 43.0 (38, 148) days and the median time to first CR response was 79.0 (38, 148) days. All five responding patients (45.5%) had a duration of response ≥1 year; median duration of response has not been reached at the time of data cutoff. Conclusions: Efficacy data from this small subgroup of patients with HGBCL enrolled in the LOTIS-2 clinical trial are consistent with the overall trial population. These results suggest that Lonca is active in the treatment of this high-risk lymphoma subgroup, achieving comparable response rates with other risk groups and with long-term disease control in responding patients. Funding: This study was funded by ADC Therapeutics; medical writing support was provided by CiTRUS Health Group. Figure 1 Figure 1. Disclosures Alderuccio: Inovio Pharmaceuticals: Other: Family member; Agios Pharmaceuticals: Other: Family member; Puma Biotechnology: Other: Family member; ADC Therapeutics: Consultancy, Research Funding; Oncinfo / OncLive: Honoraria; Forma Therapeutics: Other: Family member. Ai: Kymria, Kite, ADC Therapeutics, BeiGene: Consultancy. Radford: ADC Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Speakers Bureau; BMS: Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Current holder of individual stocks in a privately-held company. Solh: Jazz Pharmaceuticals: Consultancy; BMS: Consultancy; Partner Therapeutics: Research Funding; ADCT Therapeutics: Consultancy, Research Funding. Ardeshna: Gilead, Beigene, Celegene, Novartis and Roche: Honoraria; Norvartis, BMS, Autolus, ADCT, Pharmocyclics and Jansen: Research Funding; Gilead, Beigene, Celegene, Novartis and Roche: Membership on an entity's Board of Directors or advisory committees. Lunning: AbbVie: Consultancy; Novartis: Consultancy; Beigene: Consultancy; ADC Therapeutics: Consultancy; Daiichi-Sankyo: Consultancy; Spectrum: Consultancy; Acrotech: Consultancy; AstraZeneca: Consultancy; Myeloid Therapeutics: Consultancy; Janssen: Consultancy; Verastem: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Kite, a Gilead Company: Consultancy; Kyowa Kirin: Consultancy; Karyopharm: Consultancy; TG Therapeutics: Consultancy; Morphosys: Consultancy; Legend: Consultancy. Hess: BMS: Speakers Bureau; ADC Therapeutics: Consultancy. Zinzani: EUSAPHARMA: Consultancy, Other, Speakers Bureau; SANDOZ: Other: Advisory board; ROCHE: Other, Speakers Bureau; MSD: Consultancy, Other: Advisory board, Speakers Bureau; NOVARTIS: Consultancy, Other, Speakers Bureau; TG Therapeutics: Other: Advisory board, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; Beigene: Other, Speakers Bureau; Incyte: Other, Speakers Bureau; ADC Therap.: Other; SERVIER: Other: Advisory board, Speakers Bureau; BMS: Other: Advisory board, Speakers Bureau; JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau. Stathis: Abbvie and PharmaMar: Other: travel grant; Pfizer, ADC Therapeutics, Bayer, Roche, Merck, Novartis, MEI Therapeutics and Abbvie: Research Funding; Bayer / Eli Lilly: Consultancy. Carlo-Stella: Sanofi: Consultancy, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Janssen Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hamadani: Sanofi, Genzyme, AstraZeneca, BeiGene: Speakers Bureau; Janssen, Incyte, ADC Therapeutics, Omeros, Morphosys, Kite: Consultancy; Takeda, Spectrum Pharmaceuticals and Astellas Pharma: Research Funding. Kahl: AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding; AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy. Ungar: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kilavuz: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Yu: ADC Therapeutics: Current Employment. Qin: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Caimi: TG Therapeutics: Honoraria; Amgen Therapeutics.: Consultancy; XaTek: Patents & Royalties: Royalties from patents (wife); ADC Theraputics: Consultancy, Research Funding; Seattle Genetics: Consultancy; Verastem: Consultancy; Genentech: Research Funding; Kite Pharmaceuticals: Consultancy.