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•ECP constitutes a promising therapeutic approach for GVHD after CAR T-cell infusion.•ECP reduces alloreactivity without compromising the functionality of CAR-T cells.

Increasing evidence suggests that the gut microbiome may modulate the efficacy of cancer immunotherapy. In a B cell lymphoma patient cohort from five centers in Germany and the United States (Germany, n= 66; United States, n= 106; total, n= 172), we demonstrate that wide-spectrum antibiotics treatment (‘high-risk antibiotics’) prior to CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is associated with adverse outcomes, but this effect is likely to be confounded by an increased pretreatment tumor burden and systemic inflammation in patients pretreated with high-risk antibiotics. To resolve this confounding effect and gain insights into antibiotics-masked microbiome signals impacting CAR-T efficacy, we focused on the high-risk antibiotics non-exposed patient population. Indeed, in these patients, significant correlations were noted between pre-CAR-T infusion Bifidobacterium longumand microbiome-encoded peptidoglycan biosynthesis, and CAR-T treatment-associated 6-month survival or lymphoma progression. Furthermore, predictive pre-CAR-T treatment microbiome-based machine learning algorithms trained on the high-risk antibiotics non-exposed German cohort and validated by the respective US cohort robustly segregated long-term responders from non-responders. Bacteroides, Ruminococcus, Eubacteriumand Akkermansiawere most important in determining CAR-T responsiveness, with Akkermansiaalso being associated with pre-infusion peripheral T cell levels in these patients. Collectively, we identify conserved microbiome features across clinical and geographical variations, which may enable cross-cohort microbiome-based predictions of outcomes in CAR-T cell immunotherapy.

CD19-directed chimeric antigen receptor (CAR) T-cell treatment has evolved as standard of care (SOC) for multiply relapsed/refractory (R/R) large B-cell lymphoma (LBCL). However, its potential benefit over allogeneic hematopoietic cell transplantation (alloHCT) remains unclear. We compared outcomes with both types of cellular immunotherapy (CI) by intention to treat (ITT). Eligble were all patients with R/R LBCL and institutional tumor board decision recommending SOC CAR T-cell treatment between July 2018 and February 2020, or alloHCT between January 2004 and February 2020. Primary end point was overall survival (OS) from indication. Altogether, 41 and 60 patients for whom CAR T cells and alloHCT were intended, respectively, were included. In both cohorts, virtually all patients had active disease at indication. CI was recommended as part of second-line therapy for 21 alloHCT patients but no CAR T-cell patients. Median OS from indication was 475 days with CAR T cells vs 285 days with alloHCT (P= .88) and 222 days for 39 patients for whom alloHCT beyond second line was recommended (P= .08). Of CAR T-cell and alloHCT patients, 73% and 65%, respectively, proceeded to CI. After CI, 12-month estimates for nonrelapse mortality, relapse incidence, progression-free survival, and OS for CAR T cells vs alloHCT were 3% vs 21% (P= .04), 59% vs 44% (P= .12), 39% vs 33% (P= .97), and 68% vs 54% (P= .32), respectively. In conclusion, CAR T-cell outcomes were not inferior to alloHCT outcomes, whether measured by ITT or from CI administration, supporting strategies preferring CAR T cells over alloHCT as first CI for multiply R/R LBCL.

CD19-directed chimeric antigen receptor (CAR) T-cell treatment has evolved as standard of care (SOC) for multiply relapsed/refractory (R/R) large B-cell lymphoma (LBCL). However, its potential benefit over allogeneic hematopoietic cell transplantation (alloHCT) remains unclear. We compared outcomes with both types of cellular immunotherapy (CI) by intention to treat (ITT). Eligble were all patients with R/R LBCL and institutional tumor board decision recommending SOC CAR T-cell treatment between July 2018 and February 2020, or alloHCT between January 2004 and February 2020. Primary end point was overall survival (OS) from indication. Altogether, 41 and 60 patients for whom CAR T cells and alloHCT were intended, respectively, were included. In both cohorts, virtually all patients had active disease at indication. CI was recommended as part of second-line therapy for 21 alloHCT patients but no CAR T-cell patients. Median OS from indication was 475 days with CAR T cells vs 285 days with alloHCT (P = .88) and 222 days for 39 patients for whom alloHCT beyond second line was recommended (P = .08). Of CAR T-cell and alloHCT patients, 73% and 65%, respectively, proceeded to CI. After CI, 12-month estimates for nonrelapse mortality, relapse incidence, progression-free survival, and OS for CAR T cells vs alloHCT were 3% vs 21% (P = .04), 59% vs 44% (P = .12), 39% vs 33% (P = .97), and 68% vs 54% (P = .32), respectively. In conclusion, CAR T-cell outcomes were not inferior to alloHCT outcomes, whether measured by ITT or from CI administration, supporting strategies preferring CAR T cells over alloHCT as first CI for multiply R/R LBCL.

Introduction:Obesity is a major health care burden and has been linked to numerous adverse outcomes including alterations of antitumor immunologic responses. Patients with high body mass index (BMI) undergoing autologous or allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies were repeatedly shown to have higher rates of non-relapse mortality (NRM) and relapse, translating into a reduced overall survival (OS). However, the impact of obesity on outcomes after CAR T-cell therapy has not been studied at large scale. The present study aims to investigate whether high BMI is associated with outcomes in patients receiving anti-CD19 CAR T-cell therapy.

Background

Hematological toxicity represents the most common adverse event after chimeric antigen receptor (CAR) T-cell therapy. Cytopenias can be profound, long lasting, and can predispose for severe infectious complications. In a recent worldwide survey, we demonstrated that there remains considerable heterogeneity in regard to current practice patterns. Here, we sought to build consensus on the grading and management of immune effector cell–associated hematotoxicity (ICAHT) after CAR T-cell therapy. For this purpose, a joint effort between the European Society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA) involved an international panel of 36 CAR T-cell experts who met in a series of virtual conferences, culminating in a 2-day meeting in Lille, France. On the basis of these deliberations, best practice recommendations were developed. For the grading of ICAHT, a classification system based on depth and duration of neutropenia was developed for early (day 0-30) and late (after day +30) cytopenia. Detailed recommendations on risk factors, available preinfusion scoring systems (eg, CAR-HEMATOTOX score), and diagnostic workup are provided. A further section focuses on identifying hemophagocytosis in the context of severe hematotoxicity. Finally, we review current evidence and provide consensus recommendations for the management of ICAHT, including growth factor support, anti-infectious prophylaxis, transfusions, autologous hematopoietic stem cell boost, and allogeneic hematopoietic cell transplantation. In conclusion, we propose ICAHT as a novel toxicity category after immune effector cell therapy, provide a framework for its grading, review literature on risk factors, and outline expert recommendations for the diagnostic workup and short- and long-term management.

Blumenberg: Gilead: Consultancy, Research Funding; Novartis: Research Funding; Celgene: Research Funding. Schubert:Kite / Gilead: Consultancy; Takeda: Consultancy. Buecklein:Amgen: Consultancy; Pfizer: Consultancy; Celgene: Research Funding; Novartis: Research Funding; Gilead: Consultancy, Research Funding. Müller-Tidow:Pfizer: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; BiolineRx: Research Funding; Janssen-Cilag GmbH: Speakers Bureau. Dreger:Gilead: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; Roche: Consultancy, Speakers Bureau; Neovii: Research Funding; Riemser: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy, Speakers Bureau. Schmitt:Apogenix: Research Funding; Hexal: Other: Travel grants , Research Funding; Novartis: Other: educational activities and conferences, Research Funding; Kite: Other: Travel grants, educational activities and conferences; MSD: Membership on an entity's Board of Directors or advisory committees, Other: PI of clinical trials on letermovir; TolerogenixX Ltd: Other: Co-Founder and shareholder. Subklewe:Roche AG: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; AMGEN: Consultancy, Honoraria, Research Funding; Janssen: Consultancy; Pfizer: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Morphosys: Research Funding; Celgene: Consultancy, Honoraria.

In patients with steroid-refractory/resistant graft-versus-host disease (GvHD), extracorporeal photopheresis (ECP) has been identified as a promising therapeutic strategy due to its safety profile and convincing clinical response rates.

Introduction

Introduction

Background:In the past years, chimeric antigen receptor T (CAR-T) cell therapy targeting CD19 have been shown to be a new and effective treatment option in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL). However, infections with severe and potentially life-threatening complications can be induced by either lymphodepleting chemotherapy and/or the infusion of CAR-T cells, while side effects such as cytokine release syndrome (CRS) might further complicate differential diagnosis.

Introduction:After approval of CD19.CAR-T cell therapy by both FDA and EMA, chimeric antigen receptor T (CAR-T) cell therapy has been established as a new and innovative therapy method for patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). Because of this, there is great need for reliable methods for CAR-T cell monitoring by clinicians to further assess cell expansion, distribution and persistence in patients. This is both necessary for CAR-T cell manufacturing sites and researchers to assess transduction efficiency and vector copy numbers per cell. Therefore, we analyzed CAR expression of CD19.CAR-T cells using flow cytometry as well as quantitative polymerase chain reaction (qPCR).

Purpose:

Dreger: BMS: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Bluebird Bio: Consultancy; AbbVie: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Schubert: Gilead: Consultancy. Holtick: Sanofi: Honoraria; Celgene: Honoraria. Subklewe: Miltenyi: Research Funding; Takeda: Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Klinikum der Universität München: Current Employment; MorphoSys: Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Roche: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy, Speakers Bureau; Janssen: Consultancy; BMS/Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau. Bastian: Abbvie: Other; Amgen: Consultancy, Honoraria; Astra Zeneca: Honoraria, Other; BMS and Celgene: Consultancy, Honoraria, Other; Kite-Gilead: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Other, Research Funding; Novartis: Consultancy, Honoraria, Other, Research Funding; Pentixafarm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other, Research Funding. Ayuk: Gilead: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Miltenyi Biomedicine: Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Novartis: Honoraria. Marks: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria; Merck: Consultancy; AbbVie: Other: Meeting attendance. Penack: Priothera: Consultancy; Takeda: Research Funding; Incyte: Research Funding; Neovii: Honoraria; Pfizer: Honoraria; Therakos: Honoraria; Novartis: Honoraria; MSD: Honoraria; Jazz: Honoraria; Gilead: Honoraria; Astellas: Honoraria; Shionogi: Consultancy; Omeros: Consultancy. Koenecke: EUSA Pharm: Consultancy; Kite/Gilead: Consultancy; BMS/Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy. Von Bonin: Daiichi Sankyo: Other: traveling support and advisory fees; Novartis: Other: traveling support and advisory fees; Kite/Gilead: Other: traveling support and advisory fees. Stelljes: Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau. Glass: BMS: Consultancy; Helios Klinik Berlin-Buch: Current Employment; Kite: Consultancy; Novartis: Consultancy; Riemser: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. Vucinic: MSD: Honoraria; Novartis: Honoraria; Gilead: Honoraria, Other: Travel Sponsoring; Janssen: Honoraria, Other: Travel Sponsoring; Abbvie: Honoraria, Other: Travel Sponsoring. Topp: Universitatklinikum Wurzburg: Current Employment; Celgene: Consultancy, Research Funding; Janssen: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy, Research Funding; Gilead: Research Funding; Regeneron: Consultancy, Research Funding; Macrogeniecs: Research Funding; Amgen: Consultancy, Research Funding. Schroers: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Honoraria. Hanoun: AstraZeneca: Honoraria; Abbvie: Other: travel expenses; Novartis: Research Funding. Thomas: AbbVie: Honoraria, Speakers Bureau; Art tempi: Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other; Kite/Gilead: Honoraria, Other, Research Funding, Speakers Bureau; Medigene: Consultancy, Honoraria, Other; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; Pfizer: Consultancy, Honoraria, Other, Speakers Bureau. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Bethge: Novartis: Consultancy, Honoraria, Speakers Bureau; Miltenyi Biotec: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite-Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau.

Schubert: Gilead: Consultancy. Hegenbart: Alnylam: Honoraria; Akcea: Honoraria; Janssen: Consultancy, Research Funding; Prothena: Research Funding; Pfizer: Consultancy, Honoraria. Schönland: Prothena: Honoraria, Other: Travel grants; Takeda: Honoraria, Other: Travel grants; Pfizer: Honoraria; Janssen: Honoraria, Other: Travel grants, Research Funding; Sanofi: Research Funding. Müller-Tidow: Pfizer: Research Funding; Bioline: Research Funding; Janssen: Consultancy, Research Funding. Dreger: Riemser: Consultancy, Research Funding, Speakers Bureau; Bluebird Bio: Consultancy; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; BMS: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau. Schmitt: MSD: Membership on an entity's Board of Directors or advisory committees; Hexal: Other: Travel grants, Research Funding; Kite Gilead: Other: Travel grants; TolerogenixX: Current holder of individual stocks in a privately-held company; Bluebird Bio: Other: Travel grants; Novartis: Other: Travel grants, Research Funding; Apogenix: Research Funding. Schmitt: Therakos/Mallinckrodt: Research Funding; TolerogenixX Ltd: Current Employment; Jazz Pharmaceuticals: Other: Travel grant; Hexal: Other: Travel grant.

Sauer: Abbvie: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Matterhorn Biosciences AG: Consultancy, Other: DSMB/SAB Member; Takeda: Consultancy, Other: DSMB/SAB Member. Schubert: Gilead: Consultancy. Müller-Tidow: Janssen: Consultancy, Research Funding; Bioline: Research Funding; Pfizer: Research Funding. Schmitt: TolerogenixX: Current holder of individual stocks in a privately-held company; Novartis: Other: Travel grants, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; Kite Gilead: Other: Travel grants; Apogenix: Research Funding; Hexal: Other: Travel grants, Research Funding; Bluebird Bio: Other: Travel grants. Schmitt: Hexal: Other: Travel grant; Therakos/Mallinckrodt: Research Funding; Jazz Pharmaceuticals: Other: Travel grant; TolerogenixX Ltd: Current Employment.

Schmitt: TolerogenixX: Current holder of individual stocks in a privately-held company; Apogenix: Research Funding; Hexal: Other: Travel grants, Research Funding; Kite Gilead: Other: Travel grants; MSD: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Travel grants, Research Funding; Bluebird Bio: Other: Travel grants.

Schubert: Gilead: Consultancy. Schmitt: TolerogenixX Ltd: Current Employment; Hexal: Other: Travel grant; Jazz Pharmaceuticals: Other: Travel grant; Therakos/Mallinckrodt: Research Funding. Müller-Tidow: Pfizer: Research Funding; Janssen: Consultancy, Research Funding; Bioline: Research Funding. Dreger: Riemser: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy; BMS: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Bluebird Bio: Consultancy; Roche: Consultancy, Speakers Bureau. Schmitt: MSD: Membership on an entity's Board of Directors or advisory committees; TolerogenixX: Current holder of individual stocks in a privately-held company; Kite Gilead: Other: Travel grants; Bluebird Bio: Other: Travel grants; Novartis: Other: Travel grants, Research Funding; Hexal: Other: Travel grants, Research Funding; Apogenix: Research Funding.

Schubert: Gilead: Consultancy. Sauer: Pfizer: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Matterhorn Biosciences AG: Consultancy, Other: DSMB/SAB Member; Takeda: Consultancy, Other: DSMB/SAB Member. Schmitt: Hexal: Other: Travel grant; TolerogenixX Ltd: Current Employment; Therakos/Mallinckrodt: Research Funding; Jazz Pharmaceuticals: Other: Travel grant. Müller-Tidow: Bioline: Research Funding; Pfizer: Research Funding; Janssen: Consultancy, Research Funding. Dreger: AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Bluebird Bio: Consultancy; BMS: Consultancy; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Schmitt: Bluebird Bio: Other: Travel grants; MSD: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Travel grants, Research Funding; Hexal: Other: Travel grants, Research Funding; Kite Gilead: Other: Travel grants; Apogenix: Research Funding; TolerogenixX: Current holder of individual stocks in a privately-held company.

Schmitt: Therakos Mallinckrodt: Other: Financial Support . Sellner:Takeda: Employment. Müller-Tidow:MSD: Membership on an entity's Board of Directors or advisory committees. Dreger:AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia. Schmitt:Therakos Mallinckrodt: Other: Financial Support; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia.

Derigs: MSD: Honoraria. Müller-Tidow:MSD: Membership on an entity's Board of Directors or advisory committees. Luft:Neovii: Research Funding; JAZZ: Research Funding. Dreger:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; Neovii, Riemser: Research Funding; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau. Schmitt:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Therakos Mallinckrodt: Other: Financial Support.

Müller-Tidow: MSD: Membership on an entity's Board of Directors or advisory committees. Dreger:Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau. Schmitt:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Therakos Mallinckrodt: Other: Financial Support. Schmitt:Therakos Mallinckrodt: Other: Financial Support.

Background:

Background:Morbidity and mortality after allogeneic hematopoietic cell transplantation (alloHCT) are still essentially affected by reactivation of cytomegalovirus (CMV). Letermovir is the first drug approved for prophylaxis of CMV reactivation in seropositive patients who have undergone alloHCT. Letermovir shows neither myelo- nor nephrotoxicity, and significantly reduced the incidence of CMV reactivation in a pivotal phase III trial (NEJM 2017;377:2433). Therefore, we have adopted letermovir prophylaxis according to the label as standard policy in our institution in March 2018: in seropositive recipients letermovir is given from engraftment until day +100 or CMV reactivation. The purpose of this study was to investigate if the positive trial results could be reproduced under real-world conditions.

Introduction

Introduction:Genetically modified T cells expressing chimeric antigen receptors (CARTs) are currently among the most encouraging treatment approaches in cancer immunotherapy. Efficacy and persistence of adoptively transferred CARTs are linked to the proportion of naïve-like T cells (TN) and stem cell memory-like (TSCM) T cells defined by stem cell-like properties such as a high proliferative and self-renewal capacity. Optimization of CART production is important to shift the balance towards these subsets. The PI3K/mTOR/AKT pathway is one of the main pathways involved in T cell differentiation. In the current study we evaluated the inhibition of PI3K by the clinically approved small molecule idelalisib during culturing of CARTs in order to increase less differentiated T cell subpopulations in the final cell product.

Wuchter: Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hexal: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Dreger:Gilead: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Gilead: Speakers Bureau; Novartis: Speakers Bureau; Roche: Consultancy.

Introduction