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A growing list of therapies available for patients with multiple myeloma (MM) results in deep response rates, but eventually almost all patients relapse. Allogeneic hematopoietic cell transplantation (allo-SCT) is a familiar approach for MM, but responses are often short and side effects burdensome. Simultaneously, allo-SCT provides a unique platform on which novel immune therapies can be employed to improve clinical outcomes. Our work describes the characteristics and outcomes of 128 refractory myeloma patients who underwent allo-SCT at five German centers between 2010 and 2021. The median number of therapies before the transplant was 6. With a median follow-up of 6, 4 years, the median progression-free survival and overall survival were 7 and 19 months, respectively. NRM was 28% after 6 years. OS and PFS were 61% and 45% at 1 year, 49% and 34% at 2 years, and 38% and 25% at 6 years. Achieving a CR before transplant was the single most significant variable before transplant. Allo-SCT yet remains an option for fit patient's refractory to all other treatments available. It is potentially curative for a subset of patients. Finding the characteristics of patients with durable remissions is key to sparing unnecessary toxicity for those unlikely to benefit., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

The objective of this meta-analysis (MA) was to evaluate the efficacy and safety of extracorporeal photopheresis (ECP) for the treatment of steroid-refractory chronic graft-versus-host disease (SR-cGvHD). A systematic literature review (SLR) was conducted according to PRISMA guidelines, followed by a feasibility assessment (FA) to assess potential between-study heterogeneity in the meta-analysis (MA). Random-effects MAs were performed for overall survival (OS), failure-free survival (FFS), overall response rate (ORR) and skin-specific response. A subgroup analysis was conducted to explore the effect of NIH assessment criteria. The SLR identified 627 records; 45 unique studies were ultimately included in the MA. For patients treated with ECP, at Month 12, the pooled OS rate was 83.97% and the pooled FFS rate was 60.79%. ORR was 45.34% at Months 3-4 and 58.23% at Months 6-8. Subgroup analyses showed no significant difference in ORR between studies utilizing NIH criteria and those utilizing non-NIH criteria. Skin-specific response was 34.86% at Months 2-3 and 54.22% at Months 4-6. There was considerable heterogeneity across all analyses, with I 2 values ranging from 65% to 91%. This SLR and MA indicates that ECP results in favorable outcomes in the treatment of SR-cGvHD, including OS, FFS and ORR., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Background: The use of online information and communication is globally increasing in the healthcare sector. In addition to known benefits in other medical fields, possible specific potentials of eHealth lie in the monitoring of oncological patients undergoing outpatient therapy. Specifically, the treatment with immune checkpoint inhibitors (ICI) requires intensive monitoring due to various possible negative side effects. The present study explores cancer patients' perspectives on eHealth and demonstrates how eHealth applications, from the patients' point of view, can contribute to further improving outpatient immunotherapy., Methods and Findings: Our multicenter study was executed at the university hospitals in Bonn and Aachen. A structured questionnaire was distributed to patients receiving outpatient immunotherapy. Contents addressed were (1) the patients' attitude towards eHealth applications, (2) the use of modern information and communications technologies (ICT) in (2a) everyday life and (2b) health-related information search including eHealth literacy, (3) the use of internet-enabled devices as well as (4) socio-demographic data. 164 patients were included in the study, of whom 39.0% were female and 61.0% male and the average age was 62.8 years. Overall, there was a high distribution of internet-enabled devices for everyday use and a great interest in integrating eHealth applications into outpatient immunotherapy. The assessment of eHealth potentials significantly depended on age. The younger participants demonstrated a broader use of modern ICT and a higher affinity for its use in outpatient immunotherapy. In some aspects, level of education and gender were also relevant factors influencing the patients' view on eHealth., Conclusion: This study demonstrates the potential for further integration of eHealth applications into outpatient immunotherapy from the patients' perspective. It indicates a dependency on age and educational level for the further integration of eHealth into patient care in oncology. Due to particular patient needs regarding age, level of education, gender and other subgroups, specific education and training as well as target-group specific digital health interventions are necessary to fully utilize the potentials of eHealth for outpatient immunotherapy. Future studies are required to specifically address target-group specific usability of eHealth applications and eHealth literacy, as well as to address information security and data protection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Holderried, Stasik, Schmitz, Schmitz, Meyer, Stauß, Kirschner, Skowasch, Landsberg, Schmid, Brossart and Holderried.)

Background: Prophylactic antibiotics are still controversial during allogeneic hematopoietic stem cell transplantation (allo-HSCT). In our transplant center, we suspended antibiotic prophylaxis during allo-HSCT in 2017., Objective: The main objective of this study was the detailed analysis of the potentially beneficial impact of omittance of standard antibiotic prophylaxis during allo-HSCT in survival and Graft-versus-Host disease (GvHD) development, especially with consideration of confounding factors and competing events. Secondary objectives were the evaluation of the risk of severe infections and transplant-related mortality without antibiotic prophylaxis, the detailed assessment of bacterial and viral infections including multiresistant pathogens as well as occurrence of relapse in both groups. This study aims to support the development of future antibiotic strategies in allo-HSCT., Study Design: We retrospectively analyzed patient outcome in the time periods before (between December 2012 and February 2017) and after suspension (between March 2017 and June 2020) of antibiotic prophylaxis during allo-HSCT. Relevant clinical outcome parameters of the patients (n = 221) were collected by chart-review in the two groups (with antibiotic prophylaxis n = 101 versus without antibiotic prophylaxis n = 120). All patients were 18 years or older. Propensity score methods were used to adjust for potentially confounding patient characteristics. To address competing events, transitions between moderate/severe acute and chronic GvHD, relapse and death were analyzed using an inverse-propensity score weighted multistate modeling approach., Results: While we observed a trend towards an improved outcome in the cohort without antibiotic prophylaxis, the inverse-propensity-score-weighted analyses did not show significant differences between the two groups in overall survival (OS) (P = .811) or development of acute GvHD (aGvHD) grade 3/4 (P = .158) and chronic moderate/severe GvHD (cGvHD) (P = .686). Multistate analysis respecting competing events revealed comparable estimated probabilities without antibiotic prophylaxis versus with antibiotic prophylaxis in OS (35.0% [95% CI: 28.2%-42.7%] versus 35.3% [95% CI: 27.8%-41.1%]) as well as development of aGvHD grade 3/4 (7.7% [95% CI: 5.9%-12.2%] vs. 10.6% [95% CI: 7.7%-15.7%]) and moderate/severe cGvHD (21.0% [95% CI: 17.7%-30.0%] vs. 23.8% [95% CI: 19.6%-31.4%]). Similar analyses showed also no significant differences in relapse rate, transplant-related mortality, relapse-related mortality, or GvHD-free/relapse-free survival between the two groups. An observed increase in severe infections without antibiotic prophylaxis did not lead to a significantly higher mortality rate. Viral reactivation and detection of multiresistant bacteria were comparable, yet a higher incidence of Clostridioides difficile infections was observed in patients receiving antibiotic prophylaxis., Conclusion: Our study supports previous reports of noninferiority of allo-HSCT without use of antibiotic prophylaxis with close monitoring and rapid intervention, if infection is suspected. The trend towards improved outcomes without antibiotic prophylaxis, however, might not only be due to the absence of antibiotic prophylaxis but also due to additional progresses in the field over the recent years. While the present study is too small to draw definite conclusions, these results strongly warrant further multicenter studies addressing the potential benefit of omitting antibiotic prophylaxis during allo-HSCT., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Rationale of the Trial: Although the use of engineered T cells in cancer immunotherapy has greatly advanced the treatment of hematological malignancies, reaching meaningful clinical responses in the treatment of solid tumors is still challenging. We investigated the safety and tolerability of IMA202 in a first-in-human, dose escalation basket trial in human leucocyte antigen A*02:01 positive patients with melanoma-associated antigen A1 (MAGEA1)-positive advanced solid tumors., Trial Design: The 2+2 trial design was an algorithmic design based on a maximally acceptable dose-limiting toxicity (DLT) rate of 25% and the sample size was driven by the algorithmic design with a maximum of 16 patients. IMA202 consists of autologous genetically modified cytotoxic CD8 + T cells expressing a T cell receptor (TCR), which is specific for a nine amino acid peptide derived from MAGEA1. Eligible patients underwent leukapheresis, T cells were isolated, transduced with lentiviral vector carrying MAGEA1-specific TCR and following lymphodepletion (fludarabine/cyclophosphamide), infused with a median of 1.4×10 9 specific T cells (range, 0.086×10 9 -2.57×10 9 ) followed by interleukin 2. SAFETY OF IMA202: No DLT was observed. The most common grade 3-4 adverse events were cytopenias, that is, neutropenia (81.3%), lymphopenia (75.0%), anemia (50.0%), thrombocytopenia (50.0%) and leukopenia (25.0%). 13 patients experienced cytokine release syndrome, including one grade 3 event. Immune effector cell-associated neurotoxicity syndrome was observed in two patients and was grade 1 in both. EFFICACY OF IMA202: Of the 16 patients dosed, 11 (68.8%) patients had stable disease (SD) as their best overall response (Response Evaluation Criteria in Solid Tumors V.1.1). Five patients had initial tumor shrinkage in target lesions and one patient with SD experienced continued shrinkage in target lesions for 3 months in total but had to be classified as progressive disease due to progressive non-target lesions. IMA202 T cells were persistent in peripheral blood for several weeks to months and were also detectable in tumor tissue. Peak persistence was higher in patients who received higher doses., Conclusion: In conclusion, IMA202 had a manageable safety profile, and it was associated with biological and potential clinical activity of MAGEA1-targeting genetically engineered TCR-T cells in a poor prognosis, multi-indication solid tumor cohort., Trial Registration Numbers: NCT04639245, NCT05430555., Competing Interests: Competing interests: MBH, AM, AS, MK, KP, ASM, DK, and SW were employees of Immatics US in the course of this work and may have securities from Immatics. SG-G, KA, SS, JH, MAK, AA, LB, MB, SB, CW, OS, AM-M, NH, and CMB were employees of Immatics Biotechnologies in the course of this work and may have securities from Immatics. AMT: Clinical trial research funding (received through the institution): OBI Pharma USA, Immatics, Parker Institute for Cancer Immunotherapy, Agenus, Tempus, Tvardi, Boston Biomedical, Karus Therapeutics; Consulting or advisory role: Vincerx, Diaccurate, BrYet, Nex-I, Macrogenics, BioEclipse. BSA: Two patents sold to GreenJay Therapeutics, privately held. IIW’s ASCO COI form is up to date. JJL: Data and safety monitoring board: Abbvie, Agenus, Amgen, Immutep, Evaxion; Scientific advisory board: (no stock) 7 Hills, Affivant, BioCytics, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio (stock) Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc. AI, OncoNano, physIQ, Pyxis, Saros, STipe, Tempest; Consultancy with compensation: Abbvie, Agenus, Alnylam, Atomwise, Bayer, Bristol-Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, Macrogenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Replimmune, Ribon, Roivant, Servier, STINGthera, Synlogic, Synthekine; Research support: (all to institutions for clinical trials unless noted) AbbVie, Astellas, Astrazeneca, Bristol-Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, Xencor; Patents: (both provisional) Serial #15/612,657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof). MW: Honoraria: Amgen, Bayer, Boehringer Ingelheim, GWT, Janssen, Lilly, Merck Serono, Novartis, SYNLAB; Consulting or advisory role: Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, ImCheck therapeutics, Immatics, ISA Pharmaceuticals, Lilly, Novartis; Research funding: Roche; Travel, accommodations, expenses: Amgen, AstraZeneca, Bristol-Myers Squibb, GEMoaB, Immatics, Merck Serono, Pfizer, Sanofi/Aventis; TAWH: Honoraria: Amgen, Bristol-Myers-Squibb, GlaxoSmithKline, Jazz; Consulting or advisory role: Amgen, Jazz, Kite/Gilead, Novartis, Sanofi, Bristol-Myers-Squibb, Pfizer, GlaxoSmithKline; Travel, accommodation, expenses: Janssen, Jazz, Abbvie, Bristol-Myers-Squibb, Amgen, Kite/Gilead, Astellas, Neovii, GlaxoSmithKline, Sanofi. VKM: Consulting or advisory role: Axiom Healthcare Strategies, Bicara Therapeutics, BioMedical Insights, Boehringer Ingelheim, Incyte; Research funding: Bicara Therapeutics, BioNTech, Bristol-Myers Squibb, EMD Serono, Immatics, Pfizer. WHA: Consulting or advisory role: Janssen; Research funding (received through institution): Affimed, BioNTech; Travel, accommodation, expenses: Immatics, Janssen, BioNTech; Honoraria: GSK, Janssen, AstraZeneca, Astellas. All other authors have no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Ruxolitinib has become the new standard of care for steroid-refractory and steroid-dependent chronic GVHD (SR-cGVHD). Our aim was to collect comparative data between ruxolitinib and extracorporeal photophoresis (ECP). We asked EBMT centers if they were willing to provide detailed information on GVHD grading, -therapy, -dosing, -response and complications for each included patient. 31 centers responded positively and we included all patients between 1/2017-7/2019 treated with ECP or ruxolitinib for moderate or severe SR-cGVHD. We identified 84 and 57 patients with ECP and ruxolitinib, respectively. We performed multivariate analyses adjusted on grading and type of SR-cGVHD (steroid dependent vs. refractory vs. intolerant to steroids). At day+180 after initiation of treatment for SR-cGVHD the odds ratio in the ruxolitinib group to achieve overall response vs. the ECP group was 1.35 (95% CI = [0.64; 2.91], p = 0.43). In line, we detected no statistically significant differences in overall survival, progression-free survival, non-relapse mortality and relapse incidence. The clinical significance is limited by the retrospective study design and the current data can't replace prospective studies on ECP in SR-cGVHD. However, the present results contribute to the accumulating evidence on ECP as an effective treatment option in SR-cGVHD., (© 2024. The Author(s).)

Background: Hospitals with their high antimicrobial selection pressure represent the presumably most important reservoir of multidrug-resistant human pathogens. Antibiotics administered in the course of treatment are excreted and discharged into the wastewater system. Not only in patients, but also in the sewers, antimicrobial substances exert selection pressure on existing bacteria and promote the emergence and dissemination of multidrug-resistant clones. In previous studies, two main clusters were identified in all sections of the hospital wastewater network that was investigated, one K. pneumoniae ST147 cluster encoding NDM- and OXA-48 carbapenemases and one VIM-encoding P. aeruginosa ST823 cluster. In the current study, we investigated if NDM- and OXA-48-encoding K. pneumoniae and VIM-encoding P. aeruginosa isolates recovered between 2014 and 2021 from oncological patients belonged to those same clusters., Methods: The 32 isolates were re-cultured, whole-genome sequenced, phenotypically tested for their antimicrobial susceptibility, and analyzed for clonality and resistance genes in silico., Results: Among these strains, 25 belonged to the two clusters that had been predominant in the wastewater, while two others belonged to a sequence-type less prominently detected in the drains of the patient rooms., Conclusion: Patients constantly exposed to antibiotics can, in interaction with their persistently antibiotic-exposed sanitary facilities, form a niche that might be supportive for the emergence, the development, the dissemination, and the maintenance of certain nosocomial pathogen populations in the hospital, due to antibiotic-induced selection pressure. Technical and infection control solutions might help preventing transmission of microorganisms from the wastewater system to the patient and vice versa, particularly concerning the shower and toilet drainage. However, a major driving force might also be antibiotic induced selection pressure and parallel antimicrobial stewardship efforts could be essential., (© 2023. The Author(s).)

Total body irradiation (TBI) remains an important component in many conditioning regimens before allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because of its frequent toxicity, patient selection is crucial, making it of interest to identify factors improving engraftment. In this retrospective single center analysis, the characteristics of 48 adult such patients were studied. Mean overall survival (OS) was 22.2 months after allo-HSCT. Interestingly, people with an interval ≥3 days between TBI completion and allo-HSCT showed improved OS, when compared to a shorter interval (p = 0.10). Peripheral blood kinetics after successful engraftment also differed, with a longer interval resulting in a higher platelet count and lower leukocyte and neutrophil (p < 0.05) count. These data suggest that the exact timing of TBI before allo-HSCT might directly impact a patient's survival and could help single out those at higher risk of graft failure who might benefit from an altered conditioning regimen., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Internet penetration worldwide has increased rapidly over the recent years. With this growth, modern information and communication technologies (ICT) have become increasingly important. They do not only change daily life but also patient-physician interaction and health related information search, which can be summarized as electronic Health (eHealth). eHealth was already known before the emergence of the coronavirus disease 2019 (COVID-19), but this pandemic substantially challenged health systems, physicians and hospitals so profoundly that new services and methods of patient-physician interaction had to be implemented rapidly. This study investigates the attitude of cancer patients towards eHealth and the potential impact of COVID-19 on its use., Methods and Findings: The study was a multicentered study carried out at the university hospitals Bonn and Aachen. Patients were asked to answer a structured questionnaire in the time span between September 2019 and February 2021. Due to the COVID-19 pandemic, no patients were addressed between March 2020 and July 2020. The questionnaire focused on socio-demographic data, the dissemination of internet-enabled devices, the patients' attitude towards eHealth and the use of modern ICT in daily life and for health-related information search. In total, 280 patients have filled the questionnaire of which 48% were female and 52% were male. Men have a slightly more positive attitude towards the overall potential of eHealth than women which was shown by a significant influence for receiving medical information via e-mail. Hematological-oncological patients with a higher education level reported a significantly higher willingness to send personal health information to their physician and health insurance. A frequency of medical consultation of more than 5 times during the previous year has a significantly positive impact regarding the use of online communication, online video consultation and treatment quality. Younger patients have more concerns about data security than older patients. The study shows a different attitude towards the influence of eHealth on the patient-physician relationship in different therapy situations. While there were no significant changes in patients' attitude towards eHealth after the start of the COVID-19 pandemic, there was a trend towards an increasingly embracing attitude in patients, who answered the questionnaire during COVID-19 pandemic situation., Conclusions: Overall, cancer patients had a positive attitude towards eHealth and the dissemination of internet-enabled devices was high. The study shows that the potential of eHealth is high among hematological-oncological patients. Further eHealth technologies and especially telemedically supported care processes should be implemented to improve patient-physician interaction and cross-sectoral care. COVID-19 pandemic led to a fast initiation and acceleration of new structures and routines for physicians, hospitals and patients. These new processes should be used to promote digitalization in hematological and oncological telemedicine. To successfully implement new eHealth technologies, future research should focus on patients' concerns about data privacy and data availability especially in the context of exchange of medical information in cross sectoral and interdisciplinary care processes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Holderried et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Anti-CD38 monoclonal antibodies have consistently shown increased efficacy when added to standard of care for patients with multiple myeloma. We aimed to assess the efficacy of isatuximab in addition to lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed transplantation-eligible multiple myeloma., Methods: This open-label, multicentre, randomised, active-controlled, phase 3 trial was done at 67 academic and oncology practice centres in Germany. This study is ongoing and divided into two parts; herein, we report results from part 1. Eligible patients were aged 18-70 years; had a confirmed diagnosis of untreated multiple myeloma requiring systemic treatment and a WHO performance status of 0-2; and were eligible for induction therapy, high-dose melphalan and autologous haematopoietic stem-cell transplantation, and maintenance treatment. Patients were randomly assigned (1:1) to receive three 42-day cycles of induction therapy either with isatuximab plus lenalidomide, bortezomib, and dexamethasone (isatuximab group) or lenalidomide, bortezomib, and dexamethasone alone (control group) using a web-based system and permuted blocks. Patients in both groups received lenalidomide (25 mg orally on days 1-14 and 22-35), bortezomib (1·3 mg/m 2 subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32), and dexamethasone (20 mg orally on days 1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, and 32-33). Isatuximab was given as 10 mg/kg intravenously on days 1, 8, 15, 22, and 29 of cycle 1 and on days 1, 15, and 29 of cycles 2 and 3. The primary endpoint was minimal residual disease (MRD) negativity assessed by flow cytometry, in the intention-to-treat (ITT) population. This study is registered with ClinicalTrials.gov, NCT03617731., Findings: Between Oct 23, 2018, and Sep 22, 2020, 660 patients were included in the ITT analysis (331 in the isatuximab group and 329 in the control group). 654 (99%) patients were White, two were African, one was Arabic, and three were Asian. 250 (38%) were women and 410 (62%) were men. The median age was 59 years (IQR 54-64). MRD negativity after induction therapy was reached in 166 (50%) patients in the isatuximab group versus 117 (36%) in the control group (OR 1·82 [95% CI 1·33-2·48]; p=0·00017). Median follow-up time from start to end of induction therapy was 125 days (IQR 125-131) versus 125 days (125-132). At least one grade 3 or 4 adverse event occurred in 208 (63%) of 330 patients versus 199 (61%) of 328 patients. Neutropenia of grade 3 or 4 occurred in 77 (23%) versus 23 (7%) patients and infections of grade 3 or 4 occurred in 40 (12%) versus 32 (10%) patients. Among 12 deaths during induction therapy, one death due to septic shock in the isatuximab group and four deaths (one cardiac decompensation, one hepatic and renal failure, one cardiac arrest, and one drug-induced enteritis) in the control group were considered treatment-related., Interpretation: Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone for induction therapy improved rates of MRD negativity with no new safety signals in patients with newly diagnosed transplantation-eligible multiple myeloma., Funding: Sanofi and Bristol Myers Squibb (Celgene)., Competing Interests: Declaration of interests HG reports financial and trial medication support for this GMMG-HD7 trial from Bristol Myers Squibb and Sanofi; consulting from Adaptive Biotechnology, Amgen, Bristol Myers Squibb, and Janssen; honoraria from Amgen, Bristol Myers Squibb, Celgene, Chugai, GlaxoSmithKline, Janssen, and Novartis; research funding from Amgen, Bristol Myers Squibb, Celgene, Chugai, Incyte, Janssen, Molecular Partner, MSD, Mundipharma, and Novartis; grants from Amgen, Celgene, Chugai, Janssen, and Johns Hopkins University. EKM reports consulting or advisory role, honoraria, research funding, travel accommodation, and expenses from Bristol Myers Squibb (Celgene), GlaxoSmithKline, Janssen-Cilag, Sanofi, Stemline, and Takeda. RF reports consulting or advisory role, honoraria, travel accommodation, and expenses from Amgen, Bristol Myers Squibb (Celgene), GlaxoSmithKline, Janssen, and Takeda. BB reports honoraria from Amgen, GlaxoSmithKline, Janssen, Sanofi, and Takeda; and travel accommodation, and expanses from Janssen. JD reports honoraria from Celgene, Janssen, and Roche; advisory role, travel accommodation, and expenses from Amgen, AstraZeneca, Abbvie, Bristol Myers Squibb, Celgene, Janssen, and Takeda; and speakers bureau from Celgene and Janssen. RS reports consulting for Bristol Myers Squibb, Gilead (Kite), Janssen, and Novartis; and honoraria from Bristol Myers Squibb, Gilead (Kite), Janssen, Roche, and Sanofi. IvM reports consulting for Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Pfizer, Sanofi, and Takeda; honoraria from Sanofi; and travel accommodation and expenses from Takeda. MHa reports consulting for Amgen, Bayer Vital, Celgene, Gilead, GlaxoSmithKline, Jazz Pharmaceuticals, Novartis, Pfizer, Roche, and Takeda; and honoraria from Novartis. CM reports consulting for Celgene. AMA reports honoraria from Bristol Myers Squibb (Celgene), GlaxoSmithKline, and Pfizer. BH reports consulting for Sanofi-Aventis. NW reports an advisory role for Glaxo Smith Kline; and research Funding from Bristol Myers Squibb. KK reports honoraria from Sanofi. TAWH reports a consulting or advisory role for Celgene, Gilead Sciences, GlaxoSmithKline, Jazz Pharmaceuticals, Novartis, and Sanofi; speakers bureau for Amgen and MSD; and travel accommodation and expenses from AbbVie, Daiichi Sankyo, Eurocept Pharmaceuticals, Janssen, Medac, and Therakos. KT-G reports consulting, an advisory role, honoraria, travel accommodation, and expenses from GlaxoSmithKline, Novartis, and Takeda. DG reports consulting and honoraria from Amgen, Bristol Myers Squibb, Celgene, and Takeda. MK-H reports honoraria from Amgen, Bristol Myers Squibb, Janssen-Cilag, Roche, and Takeda; and an advisory role for Amgen, Bristol Myers Squibb, Janssen, and Sanofi. CK reports honoraria from AstraZeneca, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Pfizer, Sanofi, and Takeda; and research funding from AstraZeneca and Sanofi. WK reports consulting for AstraZeneca, BeiGene, and Janssen; honoraria from AbbVie, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Celgene, Janssen, and Sanofi. CS reports honoraria from AbbVie, Amgen, Bristol Myers Squibb, Glaxo Smith Kline, Janssen, Pfizer, Oncopeptides, Sanofi, and Takeda; travel accommodation and expanses from Bristol Myers Squibb, Janssen, Novartis, and Takeda; and research funding from Janssen, Novartis, and Takeda. MMun reports consulting for AbbVie, Bristol Myers Squibb, Glaxo Smith Kline, Janssen, Sanofi, and Takeda; honoraria from Amgen, Bristol Myers Squibb, Janssen, and Takeda; research funding from Incyte; and travel accommodation and expenses from Amgen. MHo reports consulting for Sanofi-Aventis. MSR reports consulting or an advisory role for AbbVie, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Novartis, Roche, and Sanofi; honoraria from AbbVie and GlaxoSmithKline; and research funding from Novartis and Sanofi. HJS reports honoraria and an advisory role from AbbVie, Amgen, Bristol Myers Squibb (Celgene), Chugai, GlaxoSmithKline, Janssen-Cilag, Oncopeptides, Pfizer, Roche, Sanofi, Sebia, TAD Pharma, and Takeda; travel accommodation and expenses from Amgen, Bristol Myers Squibb (Celgene), GlaxoSmithKline, Janssen-Cilag, and Sanofi. KCW reports consulting for AbbVie, Adaptive Biotech, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Novartis, Oncopeptides, Pfizer, Roche, Sanofi, Stemline, and Takeda; honoraria from AbbVie, Adaptive Biotech, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Novartis, Oncopeptides, Pfizer, Roche, Sanofi, Stemline, and Takeda; research funding from Amgen, Bristol Myers Squibb, Celgene, Glaxo Smith Kline, Janssen, and Sanofi; travel accommodation and expenses from AbbVie, Adaptive Biotech, Amgen, Bristol Myers Squibb, Celgene, Janssen, Glaxo Smith Kline, Karyopharm, Oncopeptides, Roche, Sanofi, Stemline, and Takeda. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

To investigate the efficacy and toxicities of CPX-351 outside a clinical trial, we analyzed 188 patients (median age 65 years, range 26-80) treated for therapy-related acute myeloid leukemia (t-AML, 29%) or AML with myelodysplasia-related changes (AML-MRC, 70%). Eighty-six percent received one, 14% two induction cycles, and 10% received consolidation (representing 22% of patients with CR/CRi) with CPX-351. Following induction, CR/CRi rate was 47% including 64% of patients with available information achieving measurable residual disease (MRD) negativity (<10 -3 ) as measured by flow cytometry. After a median follow-up of 9.3 months, median overall survival (OS) was 21 months and 1-year OS rate 64%. In multivariate analysis, complex karyotype predicted lower response (p = 0.0001), while pretreatment with hypomethylating agents (p = 0.02) and adverse European LeukemiaNet 2017 genetic risk (p < 0.0001) were associated with lower OS. Allogeneic hematopoietic cell transplantation (allo-HCT) was performed in 116 patients (62%) resulting in promising outcome (median survival not reached, 1-year OS 73%), especially in MRD-negative patients (p = 0.048). With 69% of patients developing grade III/IV non-hematologic toxicity following induction and a day 30-mortality of 8% the safety profile was consistent with previous findings. These real-world data confirm CPX-351 as efficient treatment for these high-risk AML patients facilitating allo-HCT in many patients with promising outcome after transplantation., (© 2021. The Author(s).)

Objective: ABO mismatch between donor and recipient occurs in 40% of allogeneic hematopoietic stem cell transplantations (HCT). Different strategies have been described to reduce isohemagglutinins (IHA) before HCT. We describe the effect of selective ABO immunoadsorption (ABO IA) on erythrocyte transfusion rate and the development of post-transplant pure red cell aplasia (ptPRCA)., Methods: 63 patients with major ABO incompatibility were retrospectively analyzed. Nine patients with major ABO incompatibility and high-IHA titer were treated by ABO IA before HCT. We analyzed the need for transfusion and the occurrence of ptPRCA. We compared the outcome with patients treated by other methods to reduce IHA., Results: In all nine patients treated by ABO IA, IHA decreased in a median four times. PtPRCA occurred in one patient. The median number of transfusions was 8 (range: 0-36) between d0 and d100. In 25 patients with high-IHA titer without treatment or treated by other methods to reduce IHA, the need for transfusions was comparable. No difference in the incidence of ptPRCA was observed., Conclusions: Selective ABO IA is a feasible, safe, and effective method to reduce IHA before HCT in major ABO incompatibility. No effect on transfusion rate or ptPRCA compared to other strategies could be observed., (© 2021 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Rationale: Steroid refractory graft-vs-host disease (sr-GvHD) represents a challenging complication after allogeneic hematopoietic cell transplantation (allo-HCT). Intestinal microbiota (IM) diversity and dysbiosis were identified as influencing factors for the development of acute GvHD. Fecal microbiota transfer (FMT) is hypothesized to restore IM dysbiosis, but there is limited knowledge about the significance of FMT in the treatment of sr-GvHD., Objectives: We studied the effects of FMT on sr-GvHD in allo-HCT patients from two German tertiary clinical centers (n = 11 patients; period: March 2017 until July 2019). To assess safety and clinical efficacy, we analyzed clinical data pre- and post-FMT (day -14 to +30 relative to FMT). Moreover, IM were analyzed in donor samples and in a subset of patients pre- and post-FMT by 16S rRNA sequencing., Results: Post-FMT, we observed no intervention-associated, systemic inflammatory responses and only minor side effects (5/11 patients: abdominal pain and transformation of peristalsis-each 3/11 and vomiting-1/11). Stool frequencies and volumes were significantly reduced [pre- vs post-FMT (d14): P < .05, respectively] as well as clear attenuation regarding both grading and staging of sr-GvHD was present upon FMT. Moreover, IM analyses revealed an increase of alpha diversity as well as a compositional shifts toward the donor post-FMT., Conclusions: In our study, we observed positive effects on sr-GVHD after FMT without the occurrence of major adverse events. Although these findings are in line with published data on beneficial effects of FMT in sr-GvHD, further randomized clinical studies are urgently needed to better define the clinical validity including mode of action., (© 2021 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Patients with incurable cancer usually receive palliative treatment with significant toxicity and limited efficacy. Methylation analysis of circulating cell-free DNA (ccfDNA) in blood from cancer patients represents a promising approach for minimally invasive, real-time monitoring of treatment response. Short stature homeobox 2 (SHOX2) and septin 9 (SEPT9) methylation was analyzed in N = 8865 malignant and N = 746 normal adjacent tissues across 33 different malignancies from The Cancer Genome Atlas. Furthermore, we performed quantitative SHOX2 and SEPT9 ccfDNA methylation analysis in plasma obtained before and consecutively during treatment from prospectively enrolled N = 115 patients with various advanced cancers. SHOX2 and/or SEPT9 hypermethylation in malignant tissues is present in various carcinomas, sarcoma, melanoma, brain tumors, mesothelioma, and hematopoietic malignancies. Among the prospectively enrolled cancer patients, 61% (70/115) of patients had a baseline-positive blood cumulative ccfDNA methylation score (CMS) and were eligible for response monitoring. Dynamic changes of CMS during treatment were strongly associated with treatment response. A CMS increase indicated response up to 80 days before conventional monitoring. SHOX2 and SEPT9 ccfDNA methylation represents a pan-cancer biomarker and has the potential to be a powerful tool for monitoring treatment response in patients with solid tumors and lymphomas. The early identification of nonresponders might allow for a timely change of treatment regimen., (Copyright © 2020 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: PD-L1 (programmed cell death 1 ligand 1) expression in melanoma has been associated with a better response to anti-PD-1 (programmed cell death 1) therapy. However, patients with PD-L1-negative melanomas can respond to anti-PD-1 blockade, suggesting that the other PD-1 ligand, PD-L2 (programmed cell death 1 ligand 2), might also be relevant for efficacy of PD-1 inhibition. We investigated PD-L2 expression and methylation as a prognostic and predictive biomarker in melanoma., Methods: DNA methylation at five CpG loci and gene expression of PD-L2 were evaluated with regard to survival in 470 melanomas from The Cancer Genome Atlas. PD-L2 promoter methylation in correlation with PD-L2 mRNA and protein expression was analyzed in human melanoma cell lines. Prognostic and predictive value of PD-L2 methylation was validated using quantitative methylation-specific PCR in a multicenter cohort of 129 melanoma patients receiving anti-PD-1 therapy. mRNA sequencing data of 121 melanoma patients receiving anti-PD-1 therapy provided by Liu et al. were analyzed for PD-L2 mRNA expression., Results: We found significant correlations between PD-L2 methylation and mRNA expression levels in melanoma tissues and cell lines. Interferon-γ inducible PD-L2 protein expression correlated with PD-L2 promoter methylation in melanoma cells. PD-L2 DNA promoter hypomethylation and high mRNA expression were found to be strong predictors of prolonged overall survival. In pre-treatment melanoma samples from patients receiving anti-PD-1 therapy, low PD-L2 DNA methylation and high PD-L2 mRNA expression predicted longer progression-free survival., Conclusion: PD-L2 expression seems to be regulated via DNA promoter methylation. PD-L2 DNA methylation and mRNA expression may predict progression-free survival in melanoma patients receiving anti-PD-1 immunotherapy. Assessment of PD-L2 should be included in further clinical trials with anti-PD-1 antibodies.

Cellular therapies utilize the powerful force of the human immune system to target malignant cells. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the most established cellular therapy, but chimeric antigen receptor (CAR) T cell therapies have gained attention in recent years. While in allo-HCT an entirely novel allogeneic immune system facilitates a so-called Graft-versus-tumor, respectively, Graft-versus-leukemia (GvT/GvL) effect against high-risk hematologic malignancies, in CAR T cell therapies genetically modified autologous T cells specifically attack target molecules on malignant cells. These therapies have achieved high success rates, offering potential cures in otherwise detrimental diseases. However, relapse after cellular therapy remains a serious clinical obstacle. Checkpoint Inhibition (CI), which was recently designated as breakthrough in cancer treatment and consequently awarded with the Nobel prize in 2018, is a different way to increase anti-tumor immunity. Here, inhibitory immune checkpoints are blocked on immune cells in order to restore the immunological force against malignant diseases. Disease relapse after CAR T cell therapy or allo-HCT has been linked to up-regulation of immune checkpoints that render cancer cells resistant to the cell-mediated anti-cancer immune effects. Thus, enhancing immune cell function after cellular therapies using CI is an important treatment option that might re-activate the anti-cancer effect upon cell therapy. In this review, we will summarize current data on this topic with the focus on immune checkpoints after cellular therapy for malignant diseases and balance efficacy versus potential side effects.

Elucidating key factors that regulate immune-mediated pathology in vivo is critical for developing improved strategies to treat autoimmune disease and cancer. NK cells can exhibit regulatory functions against CD8 + T cells following viral infection. Here we show that while low doses of lymphocytic choriomeningitis virus (LCMV-WE) can readily induce strong CD8 + T cell responses and diabetes in mice expressing the LCMV glycoprotein on β-islet cells (RIP-GP mice), hyperglycemia does not occur after infection with higher doses of LCMV. High-dose LCMV infection induced an impaired CD8 + T cell response, which coincided with increased NK cell activity during early time points following infection. Notably, we observed increased NKp46 expression on NK cells during infection with higher doses, which resulted in an NK cell dependent suppression of T cells. Accordingly, depletion with antibodies specific for NK1.1 as well as NKp46 deficiency ( Ncr1 gfp / gfp mice) could restore CD8 + T cell immunity and permitted the induction of diabetes even following infection of RIP-GP mice with high-dose LCMV. Therefore, we identify conditions where innate lymphoid cells can play a regulatory role and interfere with CD8 + T cell mediated tissue specific pathology using an NKp46 dependent mechanism., (Copyright © 2020 Lang, Crome, Xu, Lang, Chapatte, Deenick, Grusdat, Pandyra, Pozdeev, Wang, Holderried, Cantor, Diefenbach, Elford, McIlwain, Recher, Häussinger, Mak and Ohashi.)

Background: The T cell immunoglobulin and mucin-domain containing-3 receptor TIM-3 (also known as hepatitis A virus cellular receptor 2, encoded by HAVCR2) and its ligand galectin 9 (LGALS9) are promising targets for immune checkpoint inhibition immunotherapies. However, little is known about epigenetic regulation of the encoding genes. This study aimed to investigate the association of TIM-3 and LGALS9 DNA methylation with gene expression, patients' survival, as well as molecular and immune correlates in malignant melanoma., Results: Methylation of all six TIM-3 CpGs correlated significantly with TIM-3 mRNA levels (P ≤ 0.05). A strong inverse correlation (Spearman's ρ = - 0.49) was found in promoter regions, while a strong positive correlation (ρ = 0.63) was present in the gene body of TIM-3. High TIM-3 mRNA expression (hazard ratio (HR) = 0.88, 95% confidence interval (CI) [0.81-0.97], P = 0.007) was significantly associated with better overall survival. Seven of the eight LGALS9 CpG sites correlated significantly with LGALS9 mRNA levels (P ≤ 0.003). Methylation at five CpG sites showed a strong inverse correlation (Spearman's ρ = - 0.67) and at two sites a weak positive correlation (Spearman's ρ = 0.15). High LGALS9 mRNA expression was significantly associated with increased overall survival (HR = 0.83, 95%CI [0.75-0.93], P = 0.001). In addition, we found significant correlations between TIM-3 and LGALS9 methylation and mRNA expression with immune cell infiltrates and significant differences among distinct immune cell subsets., Conclusions: Our study points toward an epigenetic regulation of TIM-3 and LGALS9 via DNA methylation and might provide an avenue for the development of a predictive biomarker for response to immune checkpoint blockade.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment option for many malignant high-risk hematological diseases. The Graft-vs.-Tumor (GvT) effect is the major hallmark of this treatment approach. However, disease relapse remains a major limitation. Boosting the GvT effect by checkpoint inhibitors (CI) is an attractive option in this desperate situation although potentially triggering Graft-vs.-Host Disease (GvHD). Early reports in patients with Hodgkin's lymphoma support the idea that CI therapy after HSCT is feasible and effective. We have retrospectively analyzed CI therapy for treatment of disease recurrence after allo-HSCT other than Hodgkin's lymphoma including 21 patients from eight German transplant centers. The median follow-up was 59 days. The overall response rate (ORR) was 43%. Patients receiving donor lymphocyte infusion (DLI) in combination with CI had superior response (ORR 80%). Severe acute GvHD grade III-IV and moderate to severe chronic GvHD were observed in 29% of all patients. Taken together, CI therapy in relapsed patients after HSCT, especially in combination with DLI, is effective but induces severe GvHD in a considerable proportion of patients. Thus, prospective trials or EBMT registry-based validation of different dosing and application schedules including immunosuppressive regimens in those patients are urgently needed.