Smoldering multiple myeloma (SMM) precedes multiple myeloma (MM). The risk of progression of SMM patients is not uniform, thus different progression-risk models have been developed, although they are mainly based on clinical parameters. Recently, genomic predictors of progression have been defined for untreated SMM. However, the usefulness of such markers in the context of clinical trials evaluating upfront treatment in high-risk SMM (HR SMM) has not been explored yet, precluding the identification of baseline genomic alterations leading to drug resistance. For this reason, we carried out next-generation sequencing and fluorescent in-situ hybridization studies on 57 HR and ultra-high risk (UHR) SMM patients treated in the phase II GEM-CESAR clinical trial (NCT02415413). DIS3, FAM46C, and FGFR3 mutations, as well as t(4;14) and 1q alterations, were enriched in HR SMM. TRAF3 mutations were specifically associated with UHR SMM but identified cases with improved outcomes. Importantly, novel potential predictors of treatment resistance were identified: NRAS mutations and the co-occurrence of t(4;14) plus FGFR3 mutations were associated with an increased risk of biological progression. In conclusion, we have carried out for the first time a molecular characterization of HR SMM patients treated with an intensive regimen, identifying genomic predictors of poor outcomes in this setting.

Allogeneic haematopoietic cell transplantation (alloHCT) has curative potential counterbalanced by its toxicity. Prognostic scores fail to include current era patients and alternative donors. We examined adult patients from the EBMT registry who underwent alloHCT between 2010 and 2019 for oncohaematological disease. Our primary objective was to develop a new prognostic score for overall mortality (OM), with a secondary objective of predicting non-relapse mortality (NRM) using the OM score. AI techniques were employed. The model for OM was trained, optimized, and validated using 70%, 15%, and 15% of the data set, respectively. The top models, “gradient boosting” for OM (AUC = 0.64) and “elasticnet” for NRM (AUC = 0.62), were selected. The analysis included 33,927 patients. In the final prognostic model, patients with the lowest score had a 2-year OM and NRM of 18 and 13%, respectively, while those with the highest score had a 2-year OM and NRM of 82 and 93%, respectively. The results were consistent in the subset of the haploidentical cohort (n = 4386). Our score effectively stratifies the risk of OM and NRM in the current era but do not significantly improve mortality prediction. Future prognostic scores can benefit from identifying biological or dynamic markers post alloHCT.

In the era of immunochemotherapy, approximately 60%–70% of diffuse large B-cell lymphoma (DLBCL) patients achieve remission with first-line rituximab-based chemoimmunotherapy. However, 30-40% relapse after initial response to first line therapy and, out of them, 20% to 50% are refractory or experience early relapse. The second-line therapy algorithm for DLBCL has recently evolved, thanks to the recent approval of new therapeutic agents or their combinations. The new guidelines suggest a stratification of relapsed/refractory (R/R) DLBCL based on the time to relapse. For transplant-eligible patients, autologous stem cell transplant remains the preferred option when the patient relapses after 12 months from diagnosis, while anti-CD19 CART-cell therapy is the current preferred choice for high-risk DLBCL, defined as primary refractory or relapse ≤ 12 month. For transplant-ineligible or CAR T-cell therapy-ineligible patients, the therapeutic arsenal historically lacked effective options. However, new therapeutic options, including polatuzumab vedotin combined with bendamustine-rituximab and tafasitamab with lenalidomide, have been recently approved, and novel agents such as loncastuximab tesirine, selinexor, anti-CD19 CAR T-cell therapy and bispecific antibodies have shown promising efficacy and manageable safety in this setting offering new hope to patients in this challenging scenario.

Introduction: The emergence of novel, more potent therapeutics in the treatment of patients with large B-cell lymphoma (LBCL) has resulted in higher rates of responses and highlighted a need for additional methods, such as minimal residual disease (MRD), to determine the depth and quality of response and potentially guide duration of treatment. Epcoritamab (DuoBody®-CD3xCD20) is a subcutaneously (SC) administered bispecific antibody (bsAb) that simultaneously binds to CD3 on T cells and CD20 on malignant B cells, inducing activation and cytotoxic activity of T cells for the killing of malignant CD20 B cells. In the pivotal epcoritamab trial, a correlation was demonstrated between MRD by clonoSEQ® (Adaptive Biotechnologies) and long-term outcomes. These findings led to additional analyses to further clarify the clinical use of ctDNA. As the evaluation of ctDNA in LBCL has not been standardized, we have expanded our investigation of the utility of ctDNA measurements from the initial analysis with the clonoSEQ assay to the AVENIO ctDNA assay (Roche). Here we present additional exploratory analyses of ctDNA using the AVENIO assay. Methods: Patients with relapsed/refractory (R/R) LBCL enrolled in EPCORE NHL-1 expansion phase (NCT03625037) received SC epcoritamab administered in 28-d cycles. ctDNA was measured using the clonoSEQ and AVENIO ctDNA assays at protocol-specified timepoints. Specimens were collected in EDTA and Streck cfDNA tubes, respectively, based on the recommended sample type at the time of study initiation. Plasma ctDNA levels were quantified per sample as count per mL (CPM) and mutant molecules per mL (MMPM) for clonoSEQ and AVENIO, respectively. Results: ctDNA quantification was concordant between the assays when within the dynamic range of the clonoSEQ assay (>80% in paired samples tested); however, a greater sensitivity of the AVENIO assay was observed, allowing further exploratory analyses of ctDNA using this platform. Consistent with prior observations, baseline ctDNA levels were associated with key clinical parameters, including LDH, TMTV, ECOG, and IPI. In patients who responded to epcoritamab, ctDNA levels decreased rapidly, with the majority of patients achieving CR having a deep ctDNA response by C3D1. Additional patients achieved MRD-negative status at later evaluations with continued therapy. MRD-negative status at C3D1, measured as absolute or relative change from baseline, was associated with longer progression free survival (PFS) and sustained MRD negativity throughout the duration of treatment. The research was funded by: Genmab A/S and AbbVie Keywords: Aggressive B-cell non-Hodgkin lymphoma, Liquid biopsy, Minimal residual disease Conflicts of interests pertinent to the abstract. D. Soong Employment or leadership position: Genmab C. Thieblemont Consultant or advisory role: AbbVie, Amgen, BMS/Celgene, Cellectis, Gilead Sciences, Kite, Novartis, Roche, Incyte, Janssen, Takeda Honoraria: AbbVie, Amgen, Bayer, Cellectis, Gilead Sciences, Incyte, Janssen, Kite, Novartis, Takeda Research funding: BMS/Celgene, Hospira, Roche Educational grants: AbbVie, Amgen, BMS/Celgene, Cellectis, Gilead Sciences, Kite, Novartis, Roche J. Karavitis Employment or leadership position: Genmab B. Hess Consultant or advisory role: ADC Therapeutics, BMS P. Caimi Consultant or advisory role: ADC Therapeutics, BMS, Beigene, Genentech, Lilly, Takeda, Kite pharma, Incyte, Novartis, MEI pharma Research funding: Genentech, Abbvie, ADC Therapeutics T. Feldman Consultant or advisory role: AbbVie, AstraZeneca, Epizyme, Genmab, Gilead/Kite, Karyopharm, Takeda, Seagen Other remuneration: Seagen: Speakers Bureau M. Hutchings Consultant or advisory role: AbbVie, Celgene, Genmab, Janssen, Roche, Takeda Research funding: Celgene, Genentech, Genmab, Incyte, Janssen, Novartis, Roche, Takeda (All Paid to Institution) A. Sureda Employment or leadership position: AbbVie Consultant or advisory role: Takeda, BMS/Celgene, Novartis, Janssen, MSD, Amgen, GSK, Sanofi, Kite, Mundipharma, Bluebird Honoraria: Takeda, BMS/Celgene, Novartis, Janssen, MSD, Amgen, GSK, Sanofi, Kite Research funding: Takeda Educational grants: Takeda, BMS/Celgene, Roche Other remuneration: Takeda, BMS/Celgene, Novartis, Janssen, MSD, Amgen, GSK, Sanofi, Kite: Speakers Bureau E. Szafer-Glusman Employment or leadership position: AbbVie M. Sacchi Employment or leadership position: Genmab M. Jure-Kunkel Employment or leadership position: Genmab N. Adya Employment or leadership position: Genmab C. Chiu Employment or leadership position: Genmab

Click to increase image sizeClick to decrease image size Disclosure statementNo potential conflict of interest was reported by the author(s)Author contributionsArribas I and Maluquer C contributed equally to this letterPatient consentWritten informed consent has been obtained to publish the details from the affected individuals.Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplantation (HCT) associated with significant morbidity and mortality. However, TA-TMA is a clinical diagnosis, and multiple criteria have been proposed without universal application. Although some patients have a self-resolving disease, others progress to multiorgan failure and/or death. Poor prognostic features also are not uniformly accepted. The lack of harmonization of diagnostic and prognostic markers has precluded multi-institutional studies to better understand incidence and outcomes. Even current interventional trials use different criteria, making it challenging to interpret the data. To address this urgent need, the American Society for Transplantation and Cellular Therapy, Center for International Bone Marrow Transplant Research, Asia-Pacific Blood and Marrow Transplantation, and European Society for Blood and Marrow Transplantation nominated representatives for an expert panel tasked with reaching consensus on diagnostic and prognostic criteria. The panel reviewed literature, generated consensus statements regarding diagnostic and prognostic features of TA-TMA using the Delphi method, and identified future directions of investigation. Consensus was reached on 4 key concepts: (1) TA-TMA can be diagnosed using clinical and laboratory criteria or tissue biopsy of kidney or gastrointestinal tissue; however, biopsy is not required; (2) consensus diagnostic criteria are proposed using the modified Jodele criteria with additional definitions of anemia and thrombocytopenia. TA-TMA is diagnosed when ≥4 of the following 7 features occur twice within 14 days: anemia, defined as failure to achieve transfusion independence despite neutrophil engraftment; hemoglobin decline by ≥1 g/dL or new-onset transfusion dependence; thrombocytopenia, defined as failure to achieve platelet engraftment, higher-than-expected transfusion needs, refractory to platelet transfusions, or ≥50% reduction in baseline platelet count after full platelet engraftment; lactate dehydrogenase (LDH) exceeding the upper limit of normal (ULN); schistocytes; hypertension; soluble C5b-9 (sC5b-9) exceeding the ULN; and proteinuria (≥1 mg/mg random urine protein-to-creatinine ratio [rUPCR]); (3) patients with any of the following features are at increased risk of nonrelapse mortality and should be stratified as high-risk TA-TMA: elevated sC5b-9, LDH ≥2 times the ULN, rUPCR ≥1 mg/mg, multiorgan dysfunction, concurrent grade II-IV acute graft-versus-host disease (GVHD), or infection (bacterial or viral); and (4) all allogeneic and pediatric autologous HCT recipients with neuroblastoma should be screened weekly for TA-TMA during the first 100 days post-HCT. Patients diagnosed with TA-TMA should be risk-stratified, and those with high-risk disease should be offered participation in a clinical trial for TA-TMA-directed therapy if available. We propose that these criteria and risk stratification features be used in data registries, prospective studies, and clinical practice across international settings. This harmonization will facilitate the investigation of TA-TMA across populations diverse in race, ethnicity, age, disease indications, and transplantation characteristics. As these criteria are widely used, we expect continued refinement as necessary. Efforts to identify more specific diagnostic and prognostic biomarkers are a top priority of the field. Finally, an investigation of the impact of TA-TMA-directed treatment, particularly in the setting of concurrent highly morbid complications, such as steroid-refractory GVHD and infection, is critically needed.

Introduction: Allogeneic stem cell transplantation (alloSCT) was the only curative option for younger patients (pts) with relapsed/ refractory (r/ r) LBCL (DLBCL, tFL, PMBCL). Anti-CD19 CAR T-cells (CART) entered the clinical arena around 5 years ago now being considered standard of care for such patients. As >50% of LBCL pts progress or relapse after CART treatment we were interested in identifying prognostic factors for both modalities and their relative role in the treatment of advanced r/r LBCL. Methods: Pts registered with the EBMT database from 1/2016 to 5/2021 having received either a first alloSCT or commercially available CART therapy (Yescarta® or Kymriah ®) as ≥3rd therapy of LBCL were analyzed. To correct for imbalances in patient characteristics we did propensity score analyses considering only pts with complete information on IPI including LDH at the time of cell therapy. We performed multivariate analyses in patients with either low- or high-risk r/r LBCL according to LDH level at cell therapy in pts treated with alloSCT or CART. Results: We identified 515 pts with full information on IPI at cell therapy (212 alloSCT and 303 CART). Patient groups differed significantly in median age, IPI score, and disease status at cell therapy. Median follow up was 46.3 months after alloSCT and 22.1 months after CART treatment. In univariate analysis, type of cell therapy, disease status, and IPI at cell therapy had a significant impact on OS. Amongst IPI risk factors LDH, performance status, and number of extranodal sites had a significant impact on OS, PFS an RI. At 24 months, OS was 41% after allo SCT and 49% after CART. In a propensity score analysis using all IPI factors as covariates, CART was superior to alloSCT in terms of OS (HR 0.62, 95% CI: 45–0.84, p = 0.0193) but not PFS, RI or NRM. In multivariate analysis patients with IPI (o-2) low risk at cell therapy show better OS (HR 0.81, 95% CI 0.59–1.1, p < 0.0001) and PFS (HR 0.62, CI: 0.46–0.83, p = 0.00145), comparable RI and lower NRM (HR 0.21 CI: 0.11–0.42, p = 0.00001) with CART compared to allo SCT. In IPI (3–5) high-risk patients, CART showed significantly higher RI (HR 1.45, CI: 1.03–2.04, p = 0.03549) but lower NRM (HR 0.21, CI: 0.11–0.42), p = 0.00001) compared to allo SCT. OS and PFS did not significantly differ. Refractory disease was an independent adverse prognostic factor for OS (HR 1.74, CI: 1.3–2.33, p = 0.0002), PFS (HR 1.61 CI: 1.23–2.1, p = 0.0006) and RI (HR 1.79 CI: 1.29–2.49, p = 0.0006) but not for NRM. Results at 2 years are given in Table 1. Conclusion: IPI assessed at cell therapy is of prognostic impact for both CART and allo SCT. Overall, pts given CART for ≥3rd line treatment of DLBCL showed better OS than pts treated with alloSCT. In patients with high intermediate/high IPI results of CART must be improved and allogeneic SCT remains a valuable treatment strategy due to its high anti-lymphoma activity. Keyword: Cellular therapies Conflicts of interests pertinent to the abstract. B. Glass Consultant or advisory role: Kite, BMS, Novartis, Milteneyi, Roche, Janssen, Jazz, Abbvie Honoraria: Kite, BMS, Novartis, Milteneyi, Roche, Janssen, Jazz, Abbvie Research funding: Roche, Riemser A. Sureda Consultant or advisory role: Takeda, MSD, BMS, Novartis, Janssen, Roche, Sanofi, Gilead P. Dreger Consultant or advisory role: Kite, Novartis P. Corradini Honoraria: Abbvie, Amgen, Celgene, Giled, Incyte, Janssen, Takeda, R. Ram Honoraria: Novartis, Gilead, Takeda, BMS G. Wulf Consultant or advisory role: Gilead, Novartis A. M. García-Sancho Consultant or advisory role: Roche, BMS, Kyowa Kirin, Clinigen, Eusa Pharma, Novartis, Kite Gilead, Servier, Incyte, Lilly, Takeda, ADC Therapeutics America, Miltenyi, Kern M. Stelljes Consultant or advisory role: Medac, Pfizer, Jazz, Novartis, MSD, Amgen, BMS, Kite D. Blaise Consultant or advisory role: Jazz E. Forcade Consultant or advisory role: Gilead, Jazz, Novartis, GSK, Sanofi, MSD I. Hilgendorf Consultant or advisory role: Novartis, Abbvie J. A. Perez-Simon Consultant or advisory role: Novartis, Janssen, Gilead, Jazz, Alexion, Abbvie, Pfizer W. Bethge Consultant or advisory role: Gilead, Novartis, Miltenyi, Janssen, Celgene N. Schmitz Consultant or advisory role: Allogene Stock ownership: BMS Honoraria: Allogene Research funding: Janssen, Roche Educational grants: Allogene, Milteneyi

Rationale: Very few data exist regarding morphofuntional nutritional parameters in newly diagnosed patients with hematological malignancies.

Introduction: Glofitamab (Glofit) is a bispecific CD20:CD3 antibody which redirects T cells to eliminate malignant B cells. The CD79b targeted antibody-drug conjugate polatuzumab vedotin (Pola) is approved in combination with bendamustine and rituximab for the treatment of R/R DLBCL. Glofit and Pola have distinct yet complementary mechanisms of action, with little overlap in toxicity profiles. Initial data from an open-label, multicenter Phase Ib/II study (NCT03533283) support the manageable safety and encouraging efficacy of Glofit + Pola in R/R DLBCL (Hutchings et al. ASH, 2021). We present updated study results (data cutoff 25 January 2023). Methods: Patients (pts) received obinutuzumab 1000 mg on Day (D) 1 of the first 21-day cycle (C), to mitigate risk of cytokine release syndrome (CRS). Pola 1.8 mg/kg was given on C1D2 and D1 of C2–6. Glofit was given with C1 step-up dosing (C1D8 2.5 mg; C1D15 10 mg; C2–12 D1, 10/30 mg) for up to 12 cycles. Per protocol, 24-hour hospitalization was only mandatory after the first Glofit infusion. Primary objective: to establish the recommended Phase II dose of Glofit in combination with Pola (identified as 30 mg; Hutchings et al. ASH, 2021). Additional objectives: safety, efficacy, PK (secondary), and biomarkers (exploratory). Results: As of 25 January 2023, 111 pts received ≥1 dose of study drug. Median age was 68 yrs (range 23–82), 51.5% had R/R DLBCL, 24% R/R HGBCL, 23% R/R trFL, and 2% R/R PMBCL. 71% of pts were refractory to their last therapy, median prior lines of therapy was 2 (range 1–7; 39% received 1 prior line), and 25% of pts had prior CAR T-cell therapy. The most common AE was CRS (44%): majority ASTCT criteria Gr 1/2 (30%/14%). One pt had Gr 5 CRS in the context of urosepsis and herpetic stomatitis but declined intensive CRS management. Gr 3/4 AEs occurred in 61% of pts, most commonly neutropenia (30%; one febrile neutropenia event). Glofit-related neurologic AEs potentially consistent with ICANS occurred in 3 pts (Gr 1/2). Pola-related peripheral neuropathy was reported in 21% of pts (all Gr 1/2). SAEs occurred in 59% of pts and Gr 5 AEs in 6% (5/7 Gr 5 events due to COVID-19). 9% of pts discontinued treatment due to an AE (2% due to COVID-19). Of 109 efficacy-evaluable pts, best ORR (BORR) for both dosing cohorts (per Lugano 2014) was 78%, with best CR (BCR) rate of 56%. By histology, BORR and BCR, respectively were: R/R DLBCL 86% (48/56) and 61% (34/56); R/R trFL 77% (20/26) and 54% (14/26); R/R PMBCL 100% (2/2) and 100% (2/2); HGBCL 60% (15/25) and 44% (11/25). With median FU of 13.0 months (95% CI: 11.8–16.6), median PFS was 10.4 months (95% CI: 5.8–19.0; Figure) and median DoR was 17.9 months (95% CI: 10.1–NE). This study is sponsored by F. Hoffmann-La Roche Ltd. Third-party medical writing assistance, under the direction of all authors, was provided by Fiona Fernando, PhD, contract medical writer at Ashfield MedComms, an Inizio company, and Molly Heitz, PhD, of Ashfield MedComms, and was funded by F. Hoffmann-La Roche Ltd. Keywords: aggressive B-cell non-Hodgkin lymphoma, immunotherapy Conflicts of interests pertinent to the abstract M. Hutchings Consultant or advisory role: Takeda, Roche, Genmab, Janssen, Abbvie Research funding: Celgene, Genmab, Roche, Takeda, Novartis, Janssen, Merck, Abbvie, AstraZeneca A. Avigdor Consultant or advisory role: Takeda, Gilead, Novartis, Roche, BMS Honoraria: Abbvie Other remuneration: travel, accommodation, expenses—Roche A. Sureda Employment or leadership position: Institut Català d’Oncologia-L’Hospitalet, Barcelona, Spain Consultant or advisory role: Takeda, MSD, BMS/Celgene, Novartis, Kite, Sobi, Janssen, Sanofi, GenMab, Abbvie, Roche, Pierre Fabre Honoraria: Takeda, MSD, BMS/Celgene, Novartis, Kite, Janssen, Sanofi, GenMab, Abbvie, Roche, Pierre Fabre, Jazz Research funding: Takeda Other remuneration: speaker's bureau—Takeda; travel, accommodation, expenses—Kite, Jazz M. J. Terol Employment or leadership position: Department of Hematology, Hospital Clínico de Valencia, Conselleria de Sanitat, Valencia, Spain Consultant or advisory role: Roche, Janssen, Gilead, Abbvie, Astra-Zeneca, Lilly Honoraria: Roche, Janssen Research funding: Janssen, Gilead Other remuneration: leadership—Secretary of Spanish group of CLL; Head of the lymphoproliferative unit at the Hospital Clinico; travel, accommodation, expenses—Roche, Janssen, Gilead, Abbvie, Astra-Zeneca, Lilly F. Bosch Employment or leadership position: Head of Department of Hematology, Hospital Vall d’Hebron, Barcelona Consultant or advisory role: Roche, Celgene, Karyospharm, Takeda, Astrazeneca, Novartis, Abbvie, Janssen Honoraria: Roche, Novartis, Janssen, Abbvie, Gilead, Mundipharma, AstraZeneca, Celgene/BMS, Takeda, Beigene Research funding: Roche, Celgene, Karyospharm, Takeda, Astrazeneca, Novartis, Abbvie, Janssen Other remuneration: speaker's bureau—Roche, Novartis, Janssen, Abbvie, Gilead, Mundipharma, AstraZeneca, Celgene/BMS, Takeda, Beigene; Expert Testimony—Abbvie; travel, accommodation, expenses—Abbvie, Roche, Janssen, AstraZeneca, Celgene/BMS P. Corradini Consultant or advisory role: Abbvie, Amgen, Celgene, Daiichi Sankyo, Gilead Sciences, Incyte, Janssen, Jazz Pharmaceuticals, Kite/Gilead, Kyowa Kirin, Novartis, Roche, Sanofi, Takeda, Nerviano Medical Sciences Honoraria: Abbvie, Amgen, Celgene, Daiichi Sankyo, Gilead Sciences, Kite/Gilead, Janssen, Kyowa Kirin, Novartis, Roche, Sanofi, Takeda Other remuneration: travel, accommodation, expenses—Abbvie, Celgene, Gilead Sciences, Janssen, Kite/Gilead, Novartis, Takeda T. Stauffer Larsen Consultant or advisory role: Roche, Gilead, Novartis, Celgene/BMS Research funding: Genentech A. Rueda Domínguez Consultant or advisory role: Roche, BMS, Takeda, Merck, Gilead Other remuneration: speaker's bureau—Roche, BMS, Takeda, Merck, Gilead A. Skarbnik Consultant or advisory role: Alexion, AstraZeneca, Abbvie, Celgene, Epizyme, Genentech, Janssen, GenMab, Pharmacyclics, Kite Pharma, Jazz Pharmaceuticals, Lilly, Beigene Other remuneration: speaker's bureau—AstraZeneca, Abbvie, Beigene, ADC Therapeutics, Genentech, Janssen, Kite Pharma, Jazz Pharmaceuticals, Pharmacyclics, SeaGen J. Jørgensen Consultant or advisory role: Roche, BMS/Celgene, Novartis, Gilead/Kite, Orion, Abbvie, Incyte, Sobi Other remuneration: travel, accommodation, expenses—Gilead, Abbvie N. Goldschmidt Other remuneration: all disclosures to be confirmed R. Gurion Employment or leadership position: Rabin Medical Center, Petach Tikva, ISRAEL Consultant or advisory role: Novartis, Gilead, Medison, Roche Honoraria: Takeda, Roche, MSD, Novartis, AsraZeneca, Sanofi, Janssen, Medison, Gilead Research funding: Roche P. L. Zinzani Consultant or advisory role: MSD, Eusapharma, Novartis, Secura Bio, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Sandoz, AstraZeneca, Takeda, Roche, Kyowa-Kirin, ADC Therapeutics, Incyte, Beigene Other remuneration: speaker's bureau—Celltrion, Gilead, Janssen-Cilag, BMS, Servier, MSD, AstraZeneca, Takeda, Roche, Eusapharma, Kyowa-Kirin, Novartis, Incyte, Beigene A. Pinto Consultant or advisory role: scientific advisory boards (F. Hoffmann-La Roche AG, Merck Sharp and Dohme, Incyte) Honoraria: speaking engagements—Educational Lectures (F. Hoffmann-La Roche AG, Incyte –Italy, Merck Sharp and Dohme, Servier Affaires Medicales, BMS-CELGENE) Other remuneration: speaker's bureau—Incyte, F. Hoffmann-La Roche AG R. Cordoba Consultant or advisory role: AbbVie, Janssen, AstraZeneca, Kite, BMS, Genmab, Roche, Takeda, Kyowa-Kirin, Beigene, Lilly Research funding: Pfizer Other remuneration: speaker's bureau—AbbVie, Janssen, AstraZeneca, Kite, BMS, Roche, Takeda A. Bottos Employment or leadership position: F. Hoffmann-La Roche Stock ownership: F. Hoffmann-La Roche Z. Huang Employment or leadership position: Roche Stock ownership: Roche S. Simko Employment or leadership position: Genentech Stock ownership: Roche J. Relf Employment or leadership position: Roche Products Limited Stock ownership: Roche, F-Star Therapeutics and Harpoon Therapeutics A. Filézac de L’Etang Employment or leadership position: F. Hoffmann-La Roche AG Stock ownership: F. Hoffmann-La Roche AG G. Sellam Employment or leadership position: Roche Stock ownership: Roche Other remuneration: travel, accommodation, expenses—Roche G. Gritti Consultant or advisory role: Roche, Takeda, Gilead/Kite, Ideogen, Genmab Other remuneration: speaker's bureau—Clinigen, Ideogen, Beigene, Incyte, Novartis; travel, accommodation, expenses—Janssen, Beigene, Sandoz

Introduction: Follicular lymphoma (FL) is a heterogeneous disease. Early progression after initial treatment with chemoimmunotherapy, or POD24, occurs in approximately 20% of patients and strongly predicts poor outcomes. There is no standard treatment approach for patients with high-risk, relapsed or refractory (R/R) FL (high-risk subgroups in Table). Novel treatment options are needed to improve efficacy in patients with high unmet need. Epcoritamab, a subcutaneous T-cell–engaging bispecific antibody, demonstrated impressive single-agent antitumor activity and a manageable safety profile in R/R FL (Hutchings et al. Lancet, 2021) and shows promise combined with standards of care. Here we present pooled analyses from cohorts 2a and 2b of the ongoing phase 1/2 EPCORE™ NHL-2 trial (NCT04663347) of epcoritamab with rituximab + lenalidomide (R2). Methods: Patients with R/R CD20+ FL received subcutaneous epcoritamab + R2 for 12 cycles (28 d each). Epcoritamab was dosed QW in cycles 1–3, Q2W in cycles 4–9, and Q4W in cycles ≥10 (2a) or QW in cycles 1–2 and Q4W in cycles ≥3 (2b) for ≤2 y. Results: As of 31 October 2022, 109 R/R FL patients had received epcoritamab 48 mg + R2 in 2a and 2b. Median age was 65 y, 56% of patients had FLIPI 3–5, 61% had stage IV disease, and 59% had only 1 prior treatment line. Most had received alkylating agents (92%) or anthracyclines (62%); 2 had prior CAR T. At a median follow-up of 8.8 mo (range, 1.2–18.5), 82% were still on treatment. The most common treatment-emergent AEs were CRS and neutropenia (48% each), injection-site reactions (38%), and fatigue (33%). CRS events were mostly low grade (G; 46% G1–2, 2% G3) and mostly occurred following the first full dose on cycle 1 day 15; all resolved and none led to discontinuation. ICANS occurred in 2 patients (G1, G2) and resolved. In 101 efficacy-evaluable patients, overall response rate (ORR) was 97%, with complete metabolic response (CMR) in 86%. Median time to any response and CMR was 1.4 mo. Estimated 6-mo progression-free survival was 93%. Notably, patients achieved higher ORR/CMR rates with epcoritamab + R2 versus their immediate prior treatment line (ORR, 97% vs. 85%; CMR, 86% vs. 60%). In second-line patients with POD24, ORR/CMR rates were 95%/90% (additional high-risk subgroup data in Table). Additional data with longer follow-up will be presented. Conclusions: Epcoritamab + R2 showed potent antitumor activity and a manageable safety profile in a large R/R FL population. Encouraging responses were seen in patients with high-risk disease, suggesting subcutaneous epcoritamab may abrogate negative effects of high-risk features. A separate POD24 cohort is planned, and epcoritamab + R2 is being studied in the phase 3 EPCORE FL-1 trial (NCT05409066). Encore Abstract—previously submitted to ASCO 2023 The research was funded by: This study was funded by Genmab A/S and AbbVie. Keywords: immunotherapy, indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract D. Belada Research funding: Genmab L. Falchi Consultant or advisory role: AbbVie, Genentech, Genmab, Roche, ADC Therapeutics, AstraZeneca, Seagen Research funding: AbbVie, Genentech, Genmab, Roche S. Leppä Consultant or advisory role: BeiGene, Genmab, Gilead, Incyte, Novartis, Orion, Roche Honoraria: Gilead, Incyte, Novartis Research funding: Bayer, Celgene, Genmab, Hutchmed, Novartis, Nordic Nanovector, Roche (Paid to Institution) H. Holte Consultant or advisory role: Incyte, Novartis, Roche, Takeda, Gilead, Roche Research funding: Incyte Other remuneration: Genmab, Nordic Nanovector: Safety Committee M. Hutchings Consultant or advisory role: AbbVie, Celgene, Genmab, Janssen, Roche, Takeda Research funding: Celgene, Genentech, Genmab, Incyte, Janssen, Novartis, Roche, Takeda (All Paid to Institution) P. Lugtenburg Consultant or advisory role: Takeda, Servier: Research Grants; Celgene, Roche, Takeda, Genmab, AbbVie, Incyte, Regeneron Honoraria: Takeda, Servier: Research Grants; Celgene, Roche, Takeda, Genmab, AbbVie, Incyte, Regeneron P. Abrisqueta Consultant or advisory role: AbbVie, AstraZeneca, BMS, Janssen Other remuneration: AbbVie, AstraZeneca, BMS, Janssen: Speakers Bureau M. Nijland Consultant or advisory role: AbbVie Research funding: Nordic Nanovector, Takeda R. W. Merryman Consultant or advisory role: AbbVie, Adaptive Biotechnologies, BMS, Epizyme, Genmab, Intellia Research funding: BMS, Genentech/Roche, Genmab, Merck (All Paid to Institution) B. E. Wahlin Consultant or advisory role: Roche Research funding: Roche, Gilead Sciences K. M. Linton Consultant or advisory role: AbbVie, BeiGene, BMS, Celgene, Genmab, Kite/Gilead, Roche Research funding: AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, BMS, Celgene, CellCentric, Genmab, Janssen, Kite/Gilead, MorphoSys, MSD, Nurix, Regeneron, Roche, Step Pharma, Viracta (All Paid to Institution) Educational grants: Celgene Other remuneration: Genmab: Member of the Epcoritamab Global Council; AbbVie, Celgene: Speakers Bureau L. Wang Employment or leadership position: Genmab A. Abbas Employment or leadership position: Genmab A. Rana Employment or leadership position: Genmab S. Quadri Employment or leadership position: AbbVie A. Sureda Consultant or advisory role: Takeda, BMS/Celgene, Novartis, Janssen, MSD, Amgen, GSK, Sanofi, Kite, Mundipharma, Bluebird Honoraria: Takeda, BMS/Celgene, Novartis, Janssen, MSD, Amgen, GSK, Sanofi, Kite Research funding: Takeda Educational grants: Takeda, BMS/Celgene, Roche Other remuneration: Takeda, BMS/Celgene, Novartis, Janssen, MSD, Amgen, GSK, Sanofi, Kite: Speakers Bureau.

Introduction: The efficacy of combined-modality treatment (Tx) with chemotherapy (CT) and radiotherapy (RT) in early-stage Hodgkin Lymphoma (eHL) is offset by long-term morbidity, with a cumulative incidence of 2nd primary malignancy at 40 years of 48.5% (Schaapveld 2015). The RAFTING trial (NCT Id. 04866654) is a phase-2 prospective single-cohort international study to explore the effectiveness of a risk-adapted Tx in non-bulky stage I-IIA eHL, based on the risk of CT failure (TxF) in a single-patient (p.) basis and in a personalized medicine design. Methods: p. are first stratified in 3 classes of TxF risk, depending on (a) modified EORTC criteria (m-EORTC), in which bulky is replaced by a Large Nodal Mass (LNM), defined by a longest ∅ measuring ≥5 cm in CT or PET/CT, (b) Metabolic Tumor Volume (MTV), with a SUVmax threshold method of 41% and cutoff value of 84 ml, and (c) PET-2 result (5-point scale). Tx stratification: Group 1: PET-2 neg. & low MTV p., treated either with 2 (group 1a) or 4 (group 2b) ABVD depending on no or ≥1 m-EORTC criterion presence, addressed, once in CR, to a 3-monthly cell-free tumor DNA (ctDNA) assay (CAPPSeq. Method, Spina 2018); Group 2: group 1 p. with < CR after ABVD or in “limited” relapse (LR), defined by eHL relapse in old and up to 3 new nodal areas, addressed to Involved-Node RT (INRT) and Nivolumab (N), 240 mg. i.v. twice a month for 24 doses; Group 3: PET-2+ and/or high MTV p., treated with the triplet ABVD × 4, INRT, 20 or 30 Gy (A-RxT-N). All PET/CT scans are centrally reviewed by an expert panel. The trial primary endpoint is a 3-Y PFS ≥90% in group 1 p. The secondary endpoints are: (a) Effectiveness of RxT (36 Gy) and N (same schedule of Group 3), in rescue p. with LR (b) effectiveness of the triplet A-RxT-N in high-risk (Group 3) eHL; (c) predictive value of ctDNA in detecting an impending eHL relapse after CT alone. Results: Preliminary results of risk stratification upon enrolment of the first 104/180 (58%) of the pre-planned sample size: in a per-protocol analysis, 88/104 (85%) turned out eligible and 73 stratified for risk. Non-eligibility reasons were higher HL stage, or bulky (10 p.) and early Tx stop, for p./investigator decision: (6p.). Out of 73 p. stratified, 53 (73%) were low-risk (Group 1), and 20 (27%) high risk (Group 3). Out of 53 low-risk p., 16 were in Group 1a: one of them was addressed to salvage Tx with ASCT because of an extended relapse 3 months after CT end. As many as 37 (70%) of low-risk p. belonged to Group 1b, mostly because of the presence of a LNM; two of them had a LR (entering Group 2) and started RxT-N rescue. Twenty p. (27%) had high-risk disease, most (14) for a high MTV, and a minority (6) for a positive PET-2. Updated results will be presented. The research was funded by: Polish Medical Agency ABM Ongoing Trial Keywords: Liquid biopsy, Ongoing Trials, PET-CT No conflicts of interests pertinent to the abstract.

In the era of immunochemotherapy, approximately 60%-70% of diffuse large B-cell lymphoma (DLBCL) patients achieve remission with first-line rituximab-based chemoimmunotherapy. However, 30%-40% relapse after initial response to first-line therapy and, out of them, 20%-50% are refractory or experience early relapse. The second-line therapy algorithm for DLBCL has recently evolved, thanks to the recent approval of new therapeutic agents or their combinations. The new guidelines suggest a stratification of relapsed/refractory (R/R) DLBCL based on the time to relapse. For transplant-eligible patients, autologous stem cell transplant remains the preferred option when the patient relapses after 12 months from diagnosis, while anti-CD19 CART-cell therapy is the current preferred choice for high-risk DLBCL, defined as primary refractory or relapse ≤12 months. For transplant-ineligible or CAR T-cell therapy-ineligible patients, the therapeutic arsenal historically lacked effective options. However, new therapeutic options, including polatuzumab vedotin combined with bendamustine-rituximab and tafasitamab with lenalidomide, have been recently approved, and novel agents such as loncastuximab tesirine, selinexor, anti-CD19 CAR T-cell therapy, and bispecific antibodies have shown promising efficacy and manageable safety in this setting offering new hope to patients in this challenging scenario.

Introduction: Primary cutaneous B-cell lymphomas (PCBCL) are rare lymphoproliferative disorders characterized by an indolent course and a life-long tendency to relapse. The management has always been based on radiotherapy and/or intravenous rituximab (IVR). To minimize toxicity, intralesional rituximab (ILR) has been applied with encouraging results. Methods: We retrospectively collected data on patients diagnosed with primary cutaneous marginal zone lymphoma (PCMZL) and follicular center lymphoma (PCFCL) who received at least one cycle of ILR from 2010 to 2022 at our Center. A cycle consisted of three doses in a week of intralesional rituximab (10 mg each). In some patients, subsequent cycles were administrated to reach a deeper response. Statistical analysis was conducted to identify variables associated with response and recurrence. Cox regression models were used to estimate hazard ratios and their 95% confidence intervals. Results: With a median follow-up of 86 months (range 1–153), ILR was administered to 26 patients, 73% with PCMZL histology. The median age at diagnosis was 51 years, with a predominance of males (62%). Fourteen (54%) were classified as T2 according to TNM staging and 11 (42%) patients presented with 3 or more lesions (Table 1). All patients experienced at least a partial response (PR), with 58% of complete responses (CR), the majority (80%) reached with only one ILR cycle. Patients with head localization presented a lower CR rate (17%, p-value = 0.007), without other significant factors associated to CR. Twenty-one (81%) patients relapsed, in a median time of 7 months (range 2–118) and the median time to next treatment was 10.8 months (range 4–119). Sixteen patients (62%) were retreated with ILR, achieving an overall response of 93% (CR 81%). PCFCL histology showed a significant association with recurrence (HR = 4.07, 95% CI, 1.29–12.87). Neither infusion reactions nor infectious complications were seen. The median progression-free survival was 7 months (2–134 months), and 6 patients are still in CR. Conclusion: Our study confirms the efficacy and safety of ILR in the management of PCBCL. With a very well-tolerated profile, all patients achieved at least PR, without losing efficacy at retreatment. Factors such as the localization of lesions and the subtype of lymphoma emerged associated with response and relapse, respectively. Keywords: Cutaneous non-Hodgkin lymphoma, Immunotherapy No conflicts of interests pertinent to the abstract.

Introduction: The prognosis of patients (pts) with diffuse large B-cell lymphoma (DLBCL) and involvement of the central nervous system (CNS) remains dismal. Anti-CD19 chimeric antigen receptor T-cells (CART) are considered standard treatment for pts with refractory or relapsed (r/r) DLBCL. Pts with involvement of the CNS were excluded from most CART trials; however, anecdotal reports suggest that CART might be an effective treatment option for such pts. This EBMT registry study aimed at compiling data of a larger cohort of pts with primary (PCNSL) or secondary CNS lymphoma (SCNCL) to better define the role of CART in these settings. Methods: All centres contributing to the EBMT database were asked for consecutive cases of PCNSL and SCNSL, which had been treated with any type of CART between January 2018 and December 2021. Reported pts were identified in the database and analysed for major patient characteristics, pre-treatment aspects, and major clinical endpoints. Kaplan Meier estimates were used to calculate overall survival (OS) and progression-free survival (PFS), whereas cumulative incidence was used for relapse incidence (RI), and non-relapse mortality (NRM). Results: 74 pts with PCNSL (n = 10) or SCNSL (n = 64) and complete information on major endpoints after CART and a median follow-up of 20.2 months [CI: 13.25–23.5] were analysed. Median age was 61.6 years (range 31–80), 31 pts were female. 37 of 57 pts (64.9%) had three or more prior treatment lines, 36.5% of pts had undergone autologous hematopoietic cell transplantation. 14 of 70 pts (20%) had ECOG ≥2. Disease-status at CART was complete (CR) or partial remission (PR) for 31.5% (6.8% and 24.7%, respectively) of pts, 68.5% of pts were in relapse, refractory, or had progressive disease. For one patient information on disease status was missing. 40 pts received axicabtagene ciloleucel (Yescarta®), 34 pts were treated with tisagenlecleucel (Kymriah®). OS- and PFS-rates at 12 months were 51.1% [CI: 40.2–64.8] and 33.7% [CI: 24.3–46.7] for the whole cohort. RI at 12 months was 59.4% [CI: 46.9–69.8]. NRM was 7% [CI: 2.5–14.5]. OS and PFS for pts in CR/PR were 53.0% [CI: 35.5–79.3] and 42.1% [CI: 25.9–68.7]. For the refractory cohort OS and PFS were 51.7% [CI: 38.7–69.0] and 30.6% [CI: 19.9–46.9], respectively. Conclusion: With a 51% OS-rate at 12 months CART seem to be a very effective therapeutic option in heavily pre-treated r/r PCNSL or SCNSL, particularly for pts being refractory to prior therapy. These results compare favourably with those of conventional treatment (including a minority of pts treated with autoSCT) in SCNSL with a median overall survival of 3.5 months (Schmitz et al., 2016) and 12-months OS-rate of 20% (Thieblemont et al., 2023). Pts with CNS involvement and r/r LBCL should be considered for treatment with CART. The research was funded by: Lymphoma Working Party of the EBMT GoCART coalition Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies Conflicts of interests pertinent to the abstract. S. Fuhrmann Consultant or advisory role: KiteGilead, BMS Celgene, Janssen D. Beauvais Honoraria: Merck & Co N. Kröger Consultant or advisory role: Takeda Honoraria: Takeda, Sanofi, Kite, Neovii, Amgen, BMS, Novartis, Jazz Research funding: Neovii, Riemser, DKMS, BMS, Novartis M. Stelljes Consultant or advisory role: MSD, Amgen, Novartis, Pfizer, Jazz, BMS, Kite Honoraria: MSD, Medac, Novartis, Pfizer, Jazz, BMS, Kite Research funding: Pfizer B. von Tresckow Consultant or advisory role: Allogene, BMS/Celgene, Cerus, Incyte, IQVIA, Gilead Kite, Miltenyi, Novartis, Noscendo, Pentixapharm, Roche, Amgen, Pfizer, Takeda, Merck Sharp & Dohme, Gilead Kite Honoraria: AstraZeneca, BMS, Incyte, Novartis, Roche Pharma AG, Takeda, Merck Sharp & Dohme Research funding: Novartis, Merck Sharp & Dohme, Takeda Educational grants: AbbVie, AstraZeneca, Gilead Kite, Merck Sharp & Dohme, Roche, Takeda, and Novartis P. Dreger Honoraria: Novartis, Kite, BMS, Miltenyi A. Sureda Consultant or advisory role: Takeda, BMS/Celgene, Novartis, Janssen, Gilead, Sanofi Honoraria: Takeda, BMS/Celgene, MSD, Janssen, Amgen, Novartis, Gilead, Kite, Sanofi, Roche, Alexion Research funding: Takeda, BMS/Celgene Other remuneration: Speaker's bureau: Takeda, Non-profit organisations: Presidency of the GETH-TC, Presidency of the EBMT N. Schmitz Stock ownership: BMS Honoraria: Allogene Research funding: Astra Zeneca, Janssen, Roche Educational grants: Allogene, Miltenyi B. Glaß Honoraria: Novartis, JAZZ, Gilead, BMS, Roche, Abbvie, Miltenyi Research funding: Riemser, Roche