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Contains fulltext : 293484.pdf (Publisher’s version ) (Open Access) From 2016 EBMT and JACIE developed an international risk-adapted benchmarking program of haematopoietic stem cell transplant (HSCT) outcome to provide individual EBMT Centers with a means of quality-assuring the HSCT process and meeting FACT-JACIE accreditation requirements relating to 1-year survival outcomes. Informed by previous experience from Europe, North America and Australasia, the Clinical Outcomes Group (COG) established criteria for patient and Center selection, and a set of key clinical variables within a dedicated statistical model adapted to the capabilities of the EBMT Registry. The first phase of the project was launched in 2019 to test the acceptability of the benchmarking model through assessment of Centers' performance for 1-year data completeness and survival outcomes of autologous and allogeneic HSCT covering 2013-2016. A second phase was delivered in July 2021 covering 2015-2019 and including survival outcomes. Reports of individual Center performance were shared directly with local principal investigators and their responses were assimilated. The experience thus far has supported the feasibility, acceptability and reliability of the system as well as identifying its limitations. We provide a summary of experience and learning so far in this 'work in progress', as well as highlighting future challenges of delivering a modern, robust, data-complete, risk-adapted benchmarking program across new EBMT Registry systems. 01 juni 2023

Bacterial non-homologous end joining requires the ligase, LigD and Ku. Ku finds the break site, recruits LigD, and then assists LigD to seal the phosphodiester backbone. Bacterial Ku contains a core domain conserved with eukaryotes but has a unique C-terminus that can be divided into a minimal C-terminal region that is conserved and an extended C-terminal region that varies in sequence and length between species. Here, we examine the role of Mycobacterium tuberculosis Ku C-terminal variants, where we removed either the extended or entire C-terminus to investigate the effects on Ku–DNA binding, rates of Ku-stimulated ligation, and binding affinity of a direct Ku–LigD interaction. We find that the extended C-terminus limits DNA binding and identify key amino acids that contribute to this effect through alanine-scanning mutagenesis. The minimal C-terminus is sufficient to stimulate ligation of double-stranded DNA, but the Ku core domain also contributes to stimulating ligation. We further show that wildtype Ku and the Ku core domain alone directly bind both ligase and polymerase domains of LigD. Our results suggest that Ku-stimulated ligation involves direct interactions between the Ku core domain and the LigD ligase domain, in addition to the extended Ku C-terminus and the LigD polymerase domain.

Granulocytic myeloid-derived suppressor cells (G-MDSCs) promote tumor growth and immunosuppression in multiple myeloma (MM). However, their phenotype is not well established for accurate monitoring or clinical translation. We aimed to provide the phenotypic profile of G-MDSCs based on their prognostic significance in MM, immunosuppressive potential, and molecular program. The preestablished phenotype of G-MDSCs was evaluated in bone marrow samples from controls and MM patients using multidimensional flow cytometry; surprisingly, we found that CD11b+CD14−CD15+CD33+HLADR− cells overlapped with common eosinophils and neutrophils, which were not expanded in MM patients. Therefore, we relied on automated clustering to unbiasedly identify all granulocytic subsets in the tumor microenvironment: basophils, eosinophils, and immature, intermediate, and mature neutrophils. In a series of 267 newly diagnosed MM patients (GEM2012MENOS65 trial), only the frequency of mature neutrophils at diagnosis was significantly associated with patient outcome, and a high mature neutrophil/T-cell ratio resulted in inferior progression-free survival (P < .001). Upon fluorescence-activated cell sorting of each neutrophil subset, T-cell proliferation decreased in the presence of mature neutrophils (0.5-fold; P = .016), and the cytotoxic potential of T cells engaged by a BCMA×CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P = .0007). Most interestingly, RNA sequencing of the 3 subsets revealed that G-MDSC–related genes were specifically upregulated in mature neutrophils from MM patients vs controls because of differential chromatin accessibility. Taken together, our results establish a correlation between the clinical significance, immunosuppressive potential, and transcriptional network of well-defined neutrophil subsets, providing for the first time a set of optimal markers (CD11b/CD13/CD16) for accurate monitoring of G-MDSCs in MM.

Background: Recent advances in the treatment of non-Hodgkin lymphoma (NHL) have transformed the landscape and provided significant benefits to patients. Novel agents that target CD19 and CD20 on B cells, such as bispecific T-cell engagers and chimeric antigen receptor T-cell (CAR-T) therapy, have demonstrated benefit for patients in the relapsed and refractory setting. However, these agents can often be associated with significant toxicity and there is a need for new therapies that can provide clinical benefit with a superior safety profile. Imvotamab is a novel CD20 x CD3 bispecific antibody utilizing an IgM backbone. This allows targeting of up to 10 CD20 binding sites for every CD3 site. In preclinical models, imvotamab demonstrated encouraging antitumor activity and stimulated T-cells in a more physiologic manner than IgG-based antibodies, which may reduce adverse events typically associated with T-cell engagers and CAR-T, such as CRS and neurotoxicity. Loncastuximab tesirine is a CD19-targeting antibody-drug conjugate approved by the US FDA and EMA for relapsed DLBCL after 2 lines of systemic therapy. Loncastuximab tesirine has shown activity in both DLBCL and FL. Combining therapies such as loncastuximab tesirine, which targets CD19 and induce apoptosis of cancer cells, with imvotamab’s ability to eliminate CD20+ tumor cells by engagement with T-cells, may improve treatment outcomes among patients with NHL via synergistic mechanisms of action. Methods: This study is a Phase 1/2, multicenter, single-arm clinical trial of imvotamab as monotherapy and in combination with loncastuximab tesirine for patients with relapsed/refractory NHL. Phase 1a Dose Escalation is complete with no DLTs or neurotoxicity AEs up to 1000mg dose titration. Phase 1b Combination will evaluate imvotamab and loncastuximab tesirine in patients with R/R 2nd line or later NHL. Phase 2 monotherapy Dose Selection is currently ongoing. The Phase 2 component randomizes patients at two different dose levels (100 mg and 300 mg plateau dose) in two separate indications (R/R DLBCL and R/R FL). Patients receive weekly dosing on Day 1, 8, and 15 of each 21- day cycle. Dosing begins at 15 mg and is increased weekly for 3-4 weeks to reach the plateau dose. Patients then stay at the plateau dose until disease progression or unacceptable toxicity. Patients who achieve a response by Week 12 may switch to a less frequent dosing interval of every 3 weeks. Primary endpoints include frequency and severity of adverse events and objective response rate (ORR) based on Lugano criteria. Correlative biomarker studies will evaluate the relationship of clinical benefit with blood and tissue biomarkers. The study is currently open with patients enrolling in Phase 2 at time of submission. Phase 1b Combination is expected to begin enrollment in the first quarter of 2023. Clinical trial information: NCT04082936. Citation Format: Catherine Diefenbach, Won Seog Kim, Chan Cheah, Ajay K. Gopal, Philippe Armand, Ian Flinn, Gareth P. Gregory, Sung-Soo Yoon, Loretta Nastoupil, Jennifer Lue, Vincent Ribrag, Javier Briones, Antonio Salar-Silvestre, Anna Sureda-Balari, Matthew Ku, Hans Cruz, Paul Thaler, Ibrahim Qazi, Rachel Wei, Maya Leabman, Genevive Hernandez, Iris Sison, Elizabeth Budde. A phase 1/2 randomized study of imvotamab monotherapy and in combination with loncastuximab tesirine in relapsed/refractory non-Hodgkin lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT052.

Objectives Trachyspermum khasianum H. Wolff is a rare medicinal plant characteristically used by the traditional healers in traditional medicine for the treatment of throat-pain, toothache, and stomach ache. The study was designed to determine the anthelmintic and analgesic properties of the aerial parts of Trachyspermum khasianum H. Wolff (Family Apiaceae). The aqueous and ethanol extract of T. khasianum H. Wolff was prepared and subjected for evaluation to determine the possible therapeutic effects. Methods Anthelmintic activities of the extracts were determined by observing the time taken to paralyze and the time taken for the death of earthworms (Eisenia foetida) as compared to the standard drug-Albendazole (20 mg/ml) and control. Analgesic potential of the extracts was evaluated using Eddy's hot plate method to understand the analgesic activity in rats (Wistar rats) at 100 mg/kg and 200 mg/kg body weight doses and compared with the standard reference (Diclofenac sodium 10 mg/kg of animals). Results The extracts showed a significant dose-dependent anthelmintic effect at the different concentrations (10, 20, and 40) mg/ml, compared to that of the standard drug (20 mg/ml). Also, the results suggested that the plant extracts possess significantly analgesic activity in rats. Conclusion The studies indicate that Trachyspermum khasianum shows anthelmintic and potent analgesic activities. Further research should be carried out to identify the specific phytoconstituents responsible for both analgesic and anthelmintic activities and its possible mechanism of action.

Tractament mèdic; Tractament amb irradiació; Mieloma múltiple Medical treatment; Irradiation treatment; Multiple myeloma Tratamiento médico; Tratamiento con irradiación; Mieloma múltiple El mieloma múltiple (MM) és una neoplàsia de cèl·lules plasmàtiques que representa al voltant de l’1% del total de neoplàsies i el 10% de les neoplàsies hematològiques. Té una incidència aproximada de 4-5 nous casos/100.000 habitants/any i presenta una incidència màxima entre els 70 i 75 anys d’edat. Un 35% dels afectats té menys de 65 anys. Els objectius d'aquesta guia són: desenvolupar i difondre la ICO-ICSPraxi per al tractament del mieloma múltiple; disminuir la variabilitat terapèutica entre els pacients tractats en els diferents centres d’aquesta institució; implementar i avaluar els resultats de la terapèutica en els pacients amb mieloma múltiple tractats d’acord amb les recomanacions d’aquesta guia.

Es indudable que la evolución tecnológica está transformando todos los ámbitos de nuestra sociedad desde la simple acción de comprar una barra de pan hasta el desarrollo de la implantación de la tecnología 5G. No se excluye dentro de esta ola de cambio tecnológico el ámbito de la información, que hoy en día es un pilar fundamental para nuestra sociedad gracias a las diferentes plataformas que se disponen como carteles, banners, plataformas web, diarios de papel o digitales... La información no deja de ser un conjunto de datos y conocimientos previamente seleccionados y ordenados con un propósito específico, por lo tanto, como futuros ingenieros nos centraremos en la parte analítica y tratamiento de los datos. Para obtener dichos datos se crea una plataforma web que dispone información de una necesidad o nicho de mercado en que el usuario esté interesado, en este proyecto se basa sobre las instalaciones de pistas de pádel en una zona. Esta plataforma tiene como objetivo extraer información para estudiar qué características de los centros de pádel son relevantes para sus usuarios. Para poder determinar que campos de interés se incluyen en la plataforma web, y posteriormente realizar el análisis de dichas características, se elabora un estudio de mercado donde se examina el perfil de usuario de pádel, los rasgos de los centros de pádel que pueden atraer a los usuarios y la competencia. Antes de obtener los datos, previamente se deberá realizar unas estructuras de bases de datos para poder almacenarlos y posteriormente tratarlos. Los datos que se obtienen de la plataforma, vendrán dados por las visitas de los usuarios, en que cada visita formará un registro en que su forma vendrá dada según la estructura construida previamente. Dichos registros se almacenan en tablas, que serán los medios para guardar los datos. Una vez obtenidas las bases de datos, se tratan, y a continuación se analizan mediante técnicas del Business Intelligence donde se usarán herramientas de carácter práctico utilizadas por muchas empresas del sector “big data” como son Power BI, MySQL, Python y R. Una vez efectuado el análisis se extrae una información relevante sobre los centros que ofrecen la posibilidad de jugar al pádel, que servirá de interés para el sector de dicho deporte de raqueta.

BACKGROUND: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma have few treatment options. We aimed to establish the safety and recommended phase 2 dose of epcoritamab, a novel bispecific antibody that targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells.METHODS: For the dose-escalation part of this phase 1/2 study, we enrolled adults (aged ≥18 years) with relapsed or refractory CD20+ B-cell non-Hodgkin lymphoma at ten sites across four countries (Denmark, the Netherlands, the UK, and Spain). Eligible patients received priming and intermediate doses followed by full doses of subcutaneous epcoritamab administered in 28-day cycles; each subsequent cohort involved escalation of the priming, intermediate, or full dose (0·0128-60 mg). The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Safety, antitumour activity, pharmacokinetics, and immune biomarkers were also assessed. This study is registered with ClinicalTrials.gov, NCT03625037, with the dose-expansion part ongoing.FINDINGS: Between June 26, 2018, and July 14, 2020, we enrolled 73 patients with relapsed, progressive, or refractory CD20+ mature B-cell non-Hodgkin lymphoma. 68 patients received escalating full doses (0·0128-60 mg) of subcutaneous epcoritamab. No dose-limiting toxic effects were observed, and the maximum tolerated dose was not reached; the full dose of 48 mg was identified as the recommended phase 2 dose. All 68 patients received at least one dose of epcoritamab and were included in safety analyses: common adverse events were pyrexia (47 patients [69%]), primarily associated with cytokine release syndrome (CRS; 40 [59%], all grade 1-2), and injection site reactions (32 [47%]; 31 grade 1). There were no grade 3 or higher CRS events. No discontinuations occurred due to treatment-related adverse events or treatment-related deaths. Overall response rate in patients with relapsed or refractory diffuse large B-cell lymphoma was 68% (95% CI 45-86), with 45% achieving a complete response at full doses of 12-60 mg. At 48 mg, the overall response rate was 88% (47-100), with 38% achieving a complete response. Patients with relapsed or refractory follicular lymphoma had an overall response rate of 90% (55-100), with 50% achieving a complete response at full doses of 0·76-48 mg. Epcoritamab induced robust and sustained B-cell depletion, and CD4+ and CD8+ T-cell activation and expansion, with modest increases in cytokine levels.INTERPRETATION: Single-agent subcutaneous epcoritamab for treatment of patients with relapsed or refractory B-cell non-Hodgkin lymphoma merits investigation in ongoing phase 2 and phase 3 studies.FUNDING: Genmab and AbbVie.

TPS7569 Background: Patients (pts) with DLBCL who are refractory to/or have relapsed (R/R) after treatment with chemotherapy and anti-CD20 monoclonal antibody (mAb) have a poor prognosis. There is a need for new treatment options to improve outcomes. Epcoritamab, a novel subcutaneous (SC) bispecific antibody, binds to CD3 on T-lymphocytes and CD20 on B-cell non-Hodgkin lymphoma (NHL) cells to induce potent and selective killing of malignant CD20+ B-cells. In an ongoing phase 1/2 dose-escalation trial in heavily pretreated pts with B-cell NHL (N = 68), epcoritamab demonstrated a tolerable safety profile and substantial single-agent anti-tumor activity, with a complete response (CR) rate of 55% and an overall response rate (ORR) of 91% in pts with R/R DLBCL (at ≥48 mg doses; n = 12) (NCT04663347; Hutchings, ASH, 2020). Furthermore, all 4 evaluable R/R DLBCL pts previously treated with chimeric antigen receptor T-cell (CAR-T) therapy achieved an objective response with 2 achieving CR. These encouraging data support the potential for epcoritamab to improve clinical outcomes in pts with R/R DLBCL. Here we describe the phase 3 trial of epcoritamab versus standard of care (SOC) treatments in pts with R/R DLBCL (NCT04628494). Methods: GCT3013-05 is a randomized, open-label, worldwide, multicenter, phase 3 study designed to evaluate the efficacy of epcoritamab versus investigator’s choice of SOC with R-GemOx (rituximab, gemcitabine, oxaliplatin) or BR (bendamustine, rituximab) in adults with R/R disease of one the following CD20+ B-cell NHL histologies: I) DLBCL, not otherwise specified including de novo DLBCL or DLBCL histologically transformed from follicular lymphoma; II) “double-hit” or “triple-hit” DLBCL (high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 translocations); or III) follicular lymphoma grade 3B. Other key eligibility criteria include: ≥1 line of prior chemotherapy that included treatment with an anti-CD20 mAb, Eastern Cooperative Oncology Group performance status 0–2, and prior failure of/ineligibility for autologous stem cell transplantation. Prior CAR-T therapy is allowed. A total of 480 pts will be randomized 1:1 to receive either SC epcoritamab at the recommended phase 2 dose (28-day cycles; weekly, biweekly, or monthly schedule depending on cycle number) until disease progression or unacceptable toxicity; or up to 4 cycles of biweekly treatment with intravenous (IV) R-GemOx (8 doses); or up to 6 cycles of IV BR (6 doses; dosing every 3 weeks). The primary endpoint is overall survival. Key secondary endpoints include progression-free survival, ORR, duration of response, time to response, and safety. The study is currently enrolling in Australia, Belgium, Denmark, France, Spain, and will open for enrollment in additional countries. Clinical trial information: NCT04628494.

7518 Background: Epcoritamab is a CD20xCD3 bispecific antibody that induces T-cell–mediated killing of CD20–positive malignant B-cells. We present updated data, including progression-free survival (PFS) from the dose escalation part of the first-in-human phase 1/2 study of epcoritamab in pts with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL; NCT03625037). Methods: Adults with R/R CD20+ B-NHL received flat-dose 1 mL SC epcoritamab (step-up dosing approach) in 28-day cycles (q1w: cycles 1–2; q2w: cycles 3–6; q4w thereafter) until disease progression or unacceptable toxicity. Step-up dosing and standard prophylaxis were used to mitigate severity of cytokine release syndrome (CRS). Results: At data cut off (1/31/2021), 68 pts with B-NHL were enrolled across histologies including diffuse large B-cell lymphoma (DLBCL; n = 46 [67.6%]; de novo and transformed), follicular lymphoma (FL; 12 [17.6%]), mantle cell lymphoma (MCL; 4 [5.9%]), and others (6 [8.8%]). Majority were heavily pretreated (median [range] prior lines: DLBCL, 3 [1–6]; FL, 4.5 [1–18]); including prior CAR-T (n = 6) and prior ASCT (n = 10). At median follow-up of 14.1 mo (DLBCL, 10.2 mo; FL, 15.2 mo), treatment was ongoing in 15 (22%) pts. Most common treatment-emergent adverse events (AEs) were pyrexia (69%), CRS (59%), and injection site reaction (47%). CRS events were all grade 1 or 2 and most occurred in cycle 1; neurotoxicity was limited (6%; grade 1: 3%; grade 3: 3%; all transient). One case of tumor lysis syndrome was observed (1.5%; grade 3); there were no cases of febrile neutropenia or treatment-related death. Overall response is shown for DLBCL ≥12 mg and ≥48 mg and FL ≥12 mg, corresponding to the minimal efficacy threshold (Table). Responses deepened over time (PR converted to CR: DLBCL, 6 pts; FL, 3 pts). Median time to response was 1.4 mo (DLBCL) and 1.9 mo (FL). Among DLBCL pts achieving CR with ≥6 mg (n = 11), none relapsed while on treatment. The median PFS for pts with DLBCL ≥12 mg (n = 22) was 9.1 mo (95% CI: 1.6, NE; median follow-up 9.3 mo) and for pts with DLBCL ≥48 mg (n = 11) median PFS was not reached (median follow-up 8.8 mo). Updated analyses will be presented. Conclusions: With longer follow-up, SC epcoritamab demonstrated substantial single-agent activity, inducing deep and durable clinically meaningful responses, with a consistent safety profile. Notably no severe (grade ≥3) CRS events, no febrile neutropenia, and limited neurotoxicity was observed. Clinical trial information: NCT03625037. [Table: see text]

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: DARA is a human IgGκ monoclonal antibody targeting CD38 and is approved for intravenous (IV) infusion across lines of therapy for MM. In phase 3 clinical studies, DARA IV plus Rd for RRMM (POLLUX) and DARA IV plus VMP for transplant-ineligible (TIE) NDMM (ALCYONE) led to deep and durable responses and reduced the risk of disease progression or death by ≥56% (Kaufman J, Blood 2019. 134[Suppl 1]:1866; Mateos M, Lancet 2020). In the phase 1b MMY1001 study of DARA IV plus carfilzomib/dexamethasone (Kd) in RRMM, DARA IV plus Kd was well tolerated and demonstrated deep responses, regardless of prior lenalidomide treatment (Chari A, Blood 2019.134[Suppl 1]:1876). In the phase 3 CANDOR study, DARA IV plus Kd reduced the risk of disease progression or death by 37% in pts with RRMM (Dimopoulos M, Lancet 2020). A formulation of DARA for subcutaneous administration (DARA SC) was developed (1,800 mg DARA co-formulated with recombinant human hyaluronidase PH20 [rHuPH20]; ENHANZE® drug delivery technology, Halozyme, Inc.). Advantages of DARA SC include reduced administration time (3-5 minutes) and lower rates of infusion-related reactions (IRRs). The phase 2 PLEIADES study is evaluating the safety and efficacy of DARA SC combined with SoC for MM, including D-Kd for RRMM, D-Rd for RRMM, and D-VMP for TIE NDMM. In the primary analysis of the D-Rd and D-VMP cohorts in PLEIADES, D-Rd and D-VMP demonstrated clinical activity and safety comparable to corresponding DARA IV regimens, with low rates of IRRs, leading to approval in the United States (Chari A, Clin Lymphoma Myeloma Leuk 2019.19[10]:e16-e17). Here, we present the primary analysis of the D-Kd cohort and updated data for the D-Rd and D-VMP cohorts of PLEIADES. Methods: RRMM pts with 1 prior line of therapy (including 2 consecutive cycles of lenalidomide therapy) received 28-day cycles of Kd (K: 20 mg/m2 IV Cycle 1 Day 1, escalated to 70 mg/m2 on Cycle 1 Days 8 and 15, then 70 mg/m2 on Days 1, 8 and 15 of each cycle thereafter; d: 40 mg IV or PO QW) with DARA SC (QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W for Cycles 7+). RRMM pts with ≥1 prior line received 28-day cycles of Rd (R: 25 mg PO Days 1-21; d: 40 mg IV or PO QW for each cycle) with DARA SC (QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W for Cycles 7+). TIE NDMM pts received 9, 6-week cycles of VMP (V: 1.3 mg/m2 SC twice weekly in Cycle 1 and QW in Cycles 2-9; M [9 mg/m2] and P [60 mg/m2] PO on Days 1-4 of Cycles 1-9) with DARA SC (QW for Cycle 1, Q3W for Cycles 2-9, and Q4W for Cycles 10+ in 28-day cycles). All pts were treated until disease progression/unacceptable toxicity. Overall response rate (ORR) was the primary endpoint for each cohort. Additional outcomes were VGPR or better rate, CR or better rate, duration of response, minimal residual disease (MRD)-negativity rate, DARA serum concentrations, and safety. Results: At the time of the clinical cutoff for the D-Kd cohort, 66 pts were treated and the median duration of follow-up was 8.7 months. The ORR for D-Kd was 84.8% (90% CI, 75.7-91.5; Table) and response rates were consistent with DARA IV plus Kd in CANDOR (Dimopoulos M, Lancet 2020). For the updated analysis of the D-Rd cohort (n=65), median follow-up was 23.1 months, and the ORR was 93.8% (90% CI, 86.5-97.9; Table). Response rates for D-Rd were consistent with DARA IV plus Rd in POLLUX (Kaufman J, Blood 2019. 134[Suppl 1]:1866). For the updated analysis of the D-VMP cohort (n=67), median follow-up was 22.6 months. The ORR for D-VMP was 89.6% (90% CI, 81.3-95.0; Table), and response rates were consistent with DARA IV plus VMP in ALCYONE (Mateos M, Lancet 2020). The median duration of DARA SC administration was 5 minutes for all D-Kd injections. The safety profile of D-Kd was consistent with DARA IV as combination therapy with SoC regimens. The rates of IRRs and injection-site reactions were comparable to those observed with DARA SC monotherapy in the COLUMBA study (Mateos M, Lancet Haematol 2020). Additional data will be presented including MRD-negativity rates for all cohorts and updated safety data for the D-Rd and D-VMP cohorts. Conclusions: The primary analysis of the D-Kd cohort demonstrated comparable clinical activity and safety to DARA IV plus Kd. With extended follow-up in the D-Rd and D-VMP cohorts, clinical activity was comparable to corresponding DARA IV-containing regimens (DARA IV plus Rd [POLLUX]; DARA IV plus VMP [ALCYONE]). A low incidence of IRRs and a short duration of administration were reported in the D-Kd cohort in PLEIADES. Table 1 Disclosures Moreau: Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria. Chari:Janssen, Celgene, Novartis, Amgen, Pharmacyclics, Seattle Genetics, Millennium/Takeda: Research Funding; Janssen, Celgene, Novartis, Amgen, Bristol-Myers Squibb, Karyopharm, Sanofi, Genzyme, Seattle Genetics, Oncopeptides, Millennium/Takeda, Antengene, Glaxo Smith Kline, Secura Bio: Consultancy. Haenel:Amgen, Novartis, Roche, Celgene, Takeda, Bayer: Honoraria. Oriol:Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rodriguez-Otero:Abbvie: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy, Honoraria; Kite: Consultancy, Honoraria. McCarthy:Janssen: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees. Suzuki:Bristol-Myers Squibb, Celgene and Amgen: Research Funding; Takeda, Amgen, Janssen and Celgene: Consultancy; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria. Sureda Balari:BMS: Speakers Bureau; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria. Hulin:Celgene/Bristol-Myers Squibb, Janssen, GlaxoSmithKline, and Takeda: Honoraria. Magen:AbbVie: Research Funding; Merck Sharpe and Dohme: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Sano: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding. Iida:Bristol-Myers Squibb: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Merck Sharpe Dohme: Research Funding; AbbVie: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Sanofi: Honoraria, Research Funding. Maisnar:Janssen, Amgen, Takeda, Celgene/Bristol-Myers Squibb, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Karlin:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Sanofi: Honoraria; Celgene: Other: Personal fees. Touzeau:Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Yang:Janssen: Current Employment. Kosh:Janssen: Current Employment. Delioukina:Maria Delioukina: Current Employment. Heuck:Christoph Heuck: Current Employment, Current equity holder in publicly-traded company. Goldschmidt:GlaxoSmithKline (GSK): Honoraria; Merck Sharp and Dohme (MSD): Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; Mundipharma GmbH: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Incyte: Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Molecular Partners: Research Funding. OffLabel Disclosure: This abstract includes discussion of a combination therapy with subcutaneous daratumumab plus carfilzomib and dexamethasone, which is currently under investigation in clinical trials, but has not yet been approved. Subcutaneous daratumumab is approved as monotherapy and in combination with other standard-of-care regimens for the treatment of multiple myeloma.

Introduction Tisagenlecleucel (tisa-cel) is a second generation, CD19-targeted Chimeric Antigen Receptor (CAR) T-cell therapy for relapsed or refractory (R/R) large B-cell lymphoma (LBCL). The pivotal phase 2 trial JULIET included 93 patients and reported an overall response rate (ORR) of 52% and a complete response rate of 40% among treated patients. However, very little is known regarding its safety and efficacy in the commercial or real-world setting as well as from an intention-to-treat perspective. In our study, we report clinical outcomes of patients with R/R LBCL treated with commercial tisa-cel in 10 Spanish institutions. Methods Data were collected retrospectively from all consecutive patients with R/R LBCL who underwent apheresis for tisa-cel at a Spanish site from December 2018 until June 2020. Evaluable patients included those who received a CAR-T infusion and had at least 1 month of follow-up. Adverse events after infusion were graded according to the ASTCT consensus and efficacy outcomes were assessed according to the Lugano criteria. Efficacy outcomes were calculated in the patients who received a CAR T-cell infusion and in all patients who underwent apheresis for tisa-cel (intention-to-treat). Results During the study period 91 patients with R/R LBCL underwent apheresis for tisa-cel. At the study cutoff, 69 (76%) patients had received a CAR T-cell infusion whereas 22 (24%) had not due to progressive disease (n=10, 45%), pending manufacturing process (n=7, 32%), out of specification (OOS) or manufacturing failure (n=4, 18%), or others (n=1, 5%). Sixty-one patients had at least the first disease response evaluation at 1-month post-infusion. Baseline characteristics of the whole cohort and the infused patients are summarized in Table 1. Among infused patients, median age was 57 years (range 24-77) and 65% were male. Most of the patients had a high-risk International Prognostic Index score (62%), an advanced stage at diagnosis (91%) and were refractory to the previous therapy (80%). Median follow-up after CAR T-cell infusion was 4 months (1-16). Fifty-six patients (81%) received bridging therapy before infusion, including chemotherapy in most cases (n=51, 91%). All patients received fludarabine and cyclophosphamide as lymphodepleting chemotherapy. Median time from apheresis to infusion was 53 days (range 29-225). Median infused cell dose was 2.2 x 108 CAR positive viable T-cells (range 0.4-4.2 x 108). Eleven (16%) products were considered OOS although 45% of them were infused. Among the infused patients, 47 (68%) and 9 (13%) developed any grade of cytokine release syndrome (CRS) and neurotoxicity, respectively. Grade >2 CRS and neurotoxicity events occurred in 3 (4%) and 0 patients, respectively. Tocilizumab was administered to 21 (30%) patients and steroids to 13 (19%) patients. Nine (13%) patients required admission to the Intensive Care Unit. By day 100, 2 (3%) patients experienced non-relapse mortality. Other adverse events including infections and tumor lysis syndrome are summarized in table 2. Best response achieved among the infused patients included complete remission in 17 (28%) patients and partial remission in 22 (36%) patients, with an ORR of 64%. Stable disease and progressive disease were the best response in 4 (7%) and 18 (29%) patients, respectively. Considering all patients who underwent apheresis, CR and PR were obtained in 19% and 24% (ORR 43%), respectively. Median progression-free survival (PFS) and overall survival (OS) for infused patients were 3 months (95%CI 2.1-3.4) and 8 months (95%CI 5.7-10.8), respectively. In the univariate analysis, patients with ECOG score >1 (HR 4.3 95%CI 1.5 - 40.9) (p < 0.001) and IPI score >2 (HR 4.8 95%CI 1.6 - 14.4) (p = 0.002) were associated with lower PFS while an ECOG score >1 was also associated with lower OS (HR 3.4 95%CI 1.15 - 34.4) (p = 0.04). In the intention-to-treat analysis for all patients who underwent apheresis, median PFS and OS from apheresis were 4 months (95%CI 2.8-5.8) and 9 months (95%CI 5.8-11.8), respectively. Conclusions Treatment with tisa-cel was able to induce disease response with a good toxicity profile in a population of patients with LBCL treated in a European country. Poor performance status at the time of CAR T-cell infusion was associated with lower PFS and OS. Disclosures Iacoboni: Novartis, Gilead, Celgene, Roche: Honoraria. Guerreiro:Novartis: Honoraria. Mussetti:Novartis, Gilead: Honoraria, Research Funding. Sancho:Roche, Janssen, Celgene, Novartis, Gilead, Sandoz, Mundipharma y Takeda; Advisory y/o consultor para Roche, Janssen, Celgene, Novartis, Gilead, Sandoz, Celltrion y Kern-Pharma.: Honoraria. Hernani:Gilead: Honoraria. Sureda Balari:Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; BMS: Speakers Bureau; Roche: Honoraria. Martin Garcia-Sancho:Celgene, Eusa Pharma, Gilead, iQuone, Kyowa Kirin, Roche, Morphosys: Consultancy; Roche, Celgene, Janssen, Servier, Gilead: Honoraria. Kwon:Jazz: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Reguera:Celgene, Novartis: Consultancy; Novartis, Gilead: Honoraria. Barba:Novartis, Celgene, Gilead, Pfizer, Amgen, Roche: Honoraria.