Maintenance of fertility is important to patients undergoing haematopoietic stem cell transplant because many are of childbearing age and treatment is frequently sterilising. Pre-transplant fertility preservation counselling is currently limited by a paucity of data. Pregnancy post-transplant is an infrequent event and while small studies provide anecdotal information, interpretation of larger data sets can be confounded by lack of detail. In this multicentre study, patients transplanted between January 1995-December 2015 who subsequently became pregnant/partners became pregnant, were identified by centres registered with the European Society for Blood and Marrow Transplantation (EBMT). The association of pregnancy with underlying condition, transplant type and conditioning protocols was evaluated using robust data sets from the EBMT registry. The role of assisted reproductive techniques (ART) in pregnancy were also investigated and pregnancy outcomes described. From a data set of 54,323 transplanted patients, there were 621 pregnancies among 419 patients/partners, and 581 live births. There was substantial variation in likelihood of pregnancy following different conditioning protocols with highest rates in women observed after reduced intensity conditioning (RIC). ART were used by 33% of females and 56% of partners of male patients, with highest use following allografts using total body irradiation and lowest following RIC. Among females, pregnancy was more frequently associated with donor eggs than the use of their own stored eggs, embryos or tissue. Widespread use of ART distorts the association between pregnancies post-transplant and preservation of gonadal function, however our data highlight multiple factors relevant to contemporary pre-transplant counselling and fertility preservation services.

Chimeric antigen receptor (CAR) T cell-mediated B cell depletion has demonstrated efficacy in several autoimmune diseases. Here we report clinical and molecular data obtained during the nonrandomized phase 1 part of the phase 1/2 COMPARE trial, evaluating safety and efficacy of mivocabtagene autoleucel (miv-cel), an autologous fully human CD19 CAR T cell therapy, in rheumatoid arthritis (RA). Six patients (three men, three women) with severe, treatment-refractory, anti-citrullinated protein antibody (ACPA)-positive RA received a single infusion of miv-cel after stopping all disease-modifying antirheumatic drug treatments and after standard lymphodepletion therapy. Patients were followed for 36-52 weeks for safety and efficacy. Primary endpoints were the incidence and severity of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and adverse events (AEs) within the first 4 weeks after treatment. Secondary and explorative endpoints assessed clinical efficacy and cellular and humoral immune responses. CRS occurred in all patients and was limited to grade 1 and 2 events. No ICANSs or serious AEs occurred; one dose-limiting toxicity was recorded (grade 3 transaminase elevation, resolved without sequelae). The primary endpoint was met with acceptable safety findings, allowing advancement to phase 2. CAR T cell therapy resulted in depletion of CD19+ B cells across blood and tissue, coinciding with a continuous decline of autoantibodies with seroconversion in four of the six patients for ACPAs against mutated citrullinated vimentin and five of six for rheumatoid factor immunoglobulin M. Despite cessation of immunosuppressive treatments, disease activity improved in all patients (median 34% DAS28-CRP reduction at the latest follow-up with DAS28-CRP remission and American College of Rheumatology 70% response in 3 of 6 patients). CD19 CAR T cells showed acceptable short-term tolerability in patients with treatment-refractory RA, justifying further evaluation. ClinicalTrials.gov identifier: NCT06475495 .

Purpose To evaluate different patient reported outcome measures (PROMs) and their relationship with distinct clinical parameters in patients with and without chronic ocular graft-versus-host disease (coGVHD) after allogeneic hematopoietic stem cell transplantation. Methods In this prospective cross-sectional study, 68 patients after alloHSCT were included and allocated in two groups: with coGVHD and without coGVHD (n=34 each). Clinical ophthalmological parameters were assessed and the following PROMs were used: Ocular Surface Disease Index (OSDI), National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), Syndrome Assessment in Dry Eye Questionnaire (SANDE), Generalized Anxiety Disorder Scale 7 (GAD-7). Statistical analysis was performed by using group adjusted correlation and multiple linear regression. Results Patients with coGVHD had worse scores compared to patients without coGVHD. PROMs were highly correlated with each other. Diagnosis of coGVHD was a highly influential predictor for impairment in quality of life. No correlations between PROM scores and single clinical parameters were found. Conclusion This study confirms the importance of PROMs in patients with coGVHD. Quality of life (QOL) is clearly impaired in affected individuals compared to patients after alloHSCT without coGVHD. The entirety of all clinical features is the major influencing factor of QOL impairment whereas single parameters alone seem to have no measurable effect. SANDE showed comparable results to OSDI and is explicitly recommended in clinical routine.

Secondary autoimmune and inflammatory diseases (SAIDs) are underrecognized and poorly described after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The standardization of management is hindered by the scarcity of data on epidemiology, pathogenesis, and clinical outcomes. To improve the evidence base, we performed a retrospective multicenter EBMT database study of patients who underwent allo-HSCT between 2005 and 2019 for either hematological malignancy or severe aplastic anemia with available information on SAIDs. We included 129 cases of SAIDs and 14,617 controls. The 5-year incidence of SAIDs was 0.9% (95% confidence interval (CI): 0.7-1.1), and the 10-year incidence was 1.1% (95% CI: 0.9-1.3). The median time from allo-HSCT to the diagnosis of SAIDs was 442 days [interquartile range (IQR): 242-1082]. Overall survival after the onset of SAIDs was 83.4% (95% CI 74.6-89.3) at 2 years and 73.4% (95% CI: 62-82) at 5 years. In multivariate analysis, risk factors significantly associated with SAIDs were bone marrow failure (Hazard Ratio (HR): 3.41 [95% CI, 1.55-7.52], p = 0.002), female donor to male patient (HR 1.77 [95% CI, 1.15-2.73], p = 0.009), and the presence of chronic GvHD (HR 1.61 [95% CI, 1.04-2.51], p = 0.034). SAIDs after allo-HSCT are rare but clinically significant entities requiring further investigations, exploring treatment and prevention strategies, as well as improving diagnostic approaches.

Letermovir has demonstrated efficacy and tolerability as prophylaxis against clinically significant cytomegalovirus infection (csCMVi) in CMV-seropositive adult patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) compared to alternative antivirals. Despite these advantages, associated costs remain substantial. This study addresses the evidence gap by evaluating the health economic impact of CMV prophylaxis with letermovir in a real-world setting for alloHCT patients. This retrospective, multi-centre case-control study was conducted at six German tertiary care centres. A micro-costing approach evaluated hospitalisation and anti-CMV drug acquisition costs over a 48-week follow-up period post-alloHCT. The analysis included patients surviving at least 100 days following alloHCT, comparing individuals receiving letermovir prophylaxis (cases) with those who did not (controls) between January 2018 and April 2021. The incidence of csCMVi was significantly higher in the control than in the letermovir group (56

Background:CNS disorders (CNSD) after haematopoietic stem cell transplantation (HSCT) are a significant complication, although there are few specific studies on it. The major objective of this prospective case-control observational study was to characterise infectious and non-infectious CNSD (iCNSD and niCNSD, respectively) after HSCT. Methods:Patients were eligible for the CNSD group if they underwent HSCT between January 2021 and December 2022 at 20 centres in 11 countries and developed either an iCNSD or a niCNSD at any time after the start of conditioning prior to HSCT, up to the study termination (June 2023). Data were collected by local investigators and sent to the EBMT Leiden Study Unit, Leiden, Netherlands. For each case, two controls surviving the same period after HSCT without CNSD as the respective case were selected. Primary endpoints of this study were (1) percentage of iCNSD and niCNSD, including different causes, (2) characteristics of CNSD (e.g., percentage of patients with an abnormal brain imaging pattern), and (3) the course (e.g., mortality and overall survival [OS] = at different time points). This study is registered at ClinicalTrials.gov (NCT04737785). Findings:237 patients (84 cases and 153 controls) were included, of whom 98 (41%) were female and 139 (59%) were male. The frequency of CNSD after HSCT was estimated at 2.9% (84 of 2910 transplanted patients, 95% CI 2.3-3.6%). Among cases, 21 (25%) had a proven/probable iCNSD, 47 (56%) had a proven/probable niCNSD, and 16 (19%) had a possible or unclassified CNSD. Human herpes virus-6 (meningo-)encephalitis was the most frequent proven/probable iCNSD (n = 9, 43%). In patients with proven/probable niCNSD, vascular pathologies were dominant (n = 15, 32%). In a multivariable Cox regression analysis, CNSD at the inclusion time point (HR 2.96, 95% CI 1.13-7.74, p = 0.027) remained the only significant predictor of inferior OS. Causes of death in the CNSD group were the CNSD (n = 15/36, 42%, eight with proven/probable iCNSD, five with proven/probable niCNSD and two with possible/unspecified CNSD), other HSCT-related causes (n = 7, 19%), relapse/progression (n = 5, 14%), or other (including multifactorial reasons, n = 9, 25%). Relapse/progression was the most frequent cause of death among controls (n = 17/25, 68%). Interpretation:CNSD represent a serious complication after HSCT with an estimated 2.9% frequency and non-infectious causes prevailing over CNS infections. Patients with a CNSD after HSCT have a reduced OS, with the CNSD itself being the main cause of death. Funding:None.

IntroductionExtracorporeal photopheresis (ECP) is a safe, effective treatment for steroid-refractory acute GVHD (SR-aGVHD). Endothelial damage is a pathological substrate of aGVHD. MethodsEndothelial damage biomarkers were measured in SR-aGVHD patients' plasma before (PRE) and 1-month after initiating ECP as second-line therapy to explore differences by treatment response. ECP-treated SR-aGVHD patients (n=35) were classified into good (GR; n=18) and poor (PR; n=17) responders. Endothelial activation biomarkers (soluble Vascular Cell Adhesion Molecule-1, sVCAM-1; von Willebrand Factor, VWF; thrombomodulin, TM; soluble TNF receptor 1, sTNFR1; angiopoietin 2; ANG2); GVHD markers (suppression tumorigenicity 2, ST2; regenerating islet-derived 3-alpha, REG3alpha; T-cell immunoglobulinmucin-3, TIM3); soluble C5b9 (sC5b9), for complement activation; and circulating dsDNA, for neutrophil extracellular traps (NETs), were analyzed. The endothelial activation and stress index (EASIX) and C-reactive protein were evaluated. ResultsBefore ECP, endothelial damage biomarkers were elevated in all patients, with no significant differences between GR and PR. After 1-month, increased levels of REG3alpha and sC5b9, and decreased levels of TIM3, were observed in samples from PR. A panel combining 5 biomarkers (ST2, VWF, NETs, TIM3, ANG2) could identify GR after 1-month on ECP (likelihood ratio 2.0) and predict ECP response.DiscussionWe propose a simplified endothelial damage biomarker panel capturing early biological signals associated with response to ECP in SR-aGVHD patients.

Background:Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) are life-threatening complications that often arise after CAR T-cell immunotherapy. Endothelial dysfunction is believed to play a central role in their development, leading to the interest in biomarker-based tools for diagnosis and differentiating these toxicities from sepsis. This study aimed to evaluate the Endothelial Activation Stress Index (EASIX) and its modified version (m-EASIX, which replaces creatinine with C-reactive protein [CRP] (mg/dL)) as early predictors of severe CRS and ICANS, as well as tools to distinguish CRS from sepsis. Methods:One hundred and nineteen patients treated with CAR T-cell therapy for CD19-positive hematologic malignancies (n=94) or multiple myeloma (n=23) were included. EASIX and m-EASIX scores were measured at various time points: before CAR T-cell infusion, 24-48 hours post-infusion, at CRS or ICANS onset, and after treatment for each toxicity. A comparator group of 129 sepsis patients, including 86 with hematologic malignancies, was also analyzed. Results:Both EASIX and m-EASIX correlated with biomarkers of endotheliopathy, with m-EASIX showing stronger predictive power for severe toxicities and ICU admission. Higher EASIX and m-EASIX values at early time points were associated with worse overall survival (OS). Furthermore, m-EASIX accurately distinguished CRS from sepsis at symptom onset. Conclusions:m-EASIX is a practical and accessible tool for the early prediction of severe CAR T-cell-related toxicities, risk stratification, and differential diagnosis from sepsis, offering potential to guide clinical decision-making and early intervention.

Immunosuppressive treatments are broadly used to prevent or treat graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (alloSCT). The resulting severe treatment-related immunodeficiency is the main contributor to high alloSCT-associated mortality, highlighting the medical need for non-immunosuppressive strategies to prevent GVHD. Angiogenesis represents an attractive target because its therapeutic inhibition leads to reduced inflammation without major negative effects on immunity. The major hurdle for translation is safety: current anti-angiogenic drugs lack specificity and disrupt physiological angiogenesis, which is required for repair and regeneration. In search for more specific targets, we identified carnitine palmitoyltransferase 2 (Cpt2), a key enzyme in mitochondrial long-chain fatty acid oxidation, which is selectively upregulated during acute GVHD (aGVHD)-associated pathological angiogenesis. Genetic and therapeutic inhibition of Cpt2 prevented inflammation-associated pathologic endothelial changes and preserved normal endothelial cell functions in vitro . In preclinical alloSCT models, endothelial-specific CPT2 knockout as well as therapeutic CPT2 inhibition with perhexiline reduced aGVHD-associated angiogenesis, mitigated aGVHD severity and promoted functional restoration of the endothelial phenotype. Importantly, CPT2 inhibition did not inhibit immune reconstitution, preserved the graft-versus-leukemia effect and reduced tumor growth in preclinical models. Our data indicate that Cpt2 contributes to endothelial processes driving pathological angiogenesis in aGVHD. The selective targeting of pathologic angiogenesis is a new non-immunosuppressive strategy to mitigate aGVHD.

In 2024, the EBMT activity survey surpassed one million HCTs reported since 1990, a major milestone in cellular therapy. That year, 47,204 HCTs (21,023 allogeneic, 26,181 autologous) were reported in 43,791 patients across 688 centres in 53 countries. Compared to 2023, HCT activity decreased (-1.1% overall, -3.9% autologous), while allogeneic increased ( + 2.6%) to the highest annual activity to date. CAR-T therapy reached 6,082 patients ( + 24.5% vs 2023), surpassing 20,000 since 2018. Main indications for allo-HCT were myeloid (62%), lymphoid malignancies (~24%), and non-malignant disorders (~17%). For auto-HCT were plasma cell disorders (59%), lymphomas (22%), and solid tumours (~6%). Unrelated donors (56%) increased ( + 5%), while HLA-identical siblings (25%) and haploidentical (19%) remained stable. Cord blood use continued decreasing (-6.2%). Paediatric HCT activity decreased slightly (-1.7%; -1.9% allogeneic, -1.1% autologous). CAR-T therapy expanded (lymphomas remaining the leading indication (70%), followed by multiple myeloma (18%,) and ALL (8%). Autoimmune diseases indications increased by 67%). Overall, transplant and CAR-T activity steadily increased, with pandemic-related declines mitigated by safety measures, reflecting systems resilience and variable country contributions. From 2025, the EBMT survey will capture adult and paediatric activity separately, establishing a comprehensive database to monitor trends, inform practice, define clinical needs and assess equitable access.

Acute graft-versus-host disease (aGvHD) is a major cause of non-relapse mortality following allogeneic hematopoietic stem cell transplantation (alloHSCT). While corticosteroids are the standard first-line therapy, approximately half of the patients become steroid-refractory or -dependent (SR/D). Fecal microbiota transplantation (FMT) has emerged as a therapeutic strategy targeting the underlying gut dysbiosis associated with aGvHD. This study presents retrospective data on FMT for SR/D-aGvHD. This retrospective, multicenter study was conducted by the Complications Working Party of the EBMT. Data were collected from 9 centers on patients who received FMT for the treatment of SR/D-aGvHD between 2014 and 2019. The primary endpoint was the overall response rate (ORR) at day 28 post-FMT. Forty-seven patients were analyzed. The primary indication for FMT was gastrointestinal aGvHD (GI-aGvHD). In this heavily pre-treated, ruxolitinib-naïve population, the ORR at day 28 was 60.5%, increasing to 69.2% by day 56. At last follow-up, 23 patients (64% of survivors) had no symptoms of aGvHD. Adverse events related to FMT were reported in 24 patients (51.1%). A clinically significant secondary benefit was the 54.5% decolonization rate of antibiotic-resistant bacteria. In this cohort FMT demonstrated efficacy for SR/D-aGvHD, with response rates comparable to those of modern targeted agents.

Central nervous system complications (CNSC) after allogeneic hematopoietic cell transplantation (allo-HCT) are relatively common and may have a major impact on patients´ outcomes. Neurological symptoms may occur at any point during the post-transplant course, although they are more common early after HCT, with a wide range of possible presentations. As many of CNSC symptoms are non-specific, the initial assessment is often difficult, and early decisions regarding the diagnostic work-up can influence the identification of the underlying cause. Blood tests, neuroimaging and cerebrospinal fluid (CSF) analyses are particularly important, as they frequently provide the first clues that help narrow the very wide differential diagnoses. In view of these challenges, an international EBMT working group composed of haematologists, infectious disease specialists, neurologists, a neuroradiologist, and a microbiologist developed symptom-based recommendations for the early evaluation of CNSC after allo-HCT. The work summarizes key aspects of the clinical presentation and outlines practical steps for the initial diagnostic approach. These recommendations are intended to support haematologists, who are usually the first to assess these patients, in promptly recognizing CNSC so to start timely appropriate management.

Background:Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of refractory hematological malignancies but is frequently complicated by immune effector cell-associated neurotoxicity syndrome (ICANS). Early clinical recognition remains challenging, as the commonly used Immune Effector Cell-Associated Encephalopathy (ICE) score lacks sensitivity for subtle deficits. Methods:In this prospective bicentric study, 100 patients treated with CAR T-cells at Hannover Medical School and Charité - Universitätsmedizin Berlin underwent systematic neurological assessments using both ICE and the newly developed Berlin-Hannover ICANS Severity Assessment (BHISA). Examinations were performed at baseline prior to CAR T-cell infusion, on day 6-7 (±1 day) post-infusion, and during ICANS episodes. Data on the clinical course, other toxicities, comorbidities, CAR T-cell products, and ICANS treatment were collected. Results:Thirty-seven patients (37%) developed ICANS, which was associated with preceding cytokine release syndrome and specific CAR T-cell products. While ICE scores clustered at maximum values both at baseline and follow-up, BHISA showed a broader distribution and higher sensitivity to subtle changes. Correlation analyses confirmed agreement between ICE and BHISA, but BHISA captured early cognitive decline more reliably. Receiver operating characteristic analyses demonstrated comparable diagnostic accuracy (BHISA: AUC = 0.783, ICE: AUC = 0,777), with consistently higher sensitivity of BHISA at matched specificity. (Specificity target = 0.7, BHISA sensitivity = 0.743, ICE sensitivity = 0.571; Specificity target = 0.8, BHISA sensitivity = 0.629, ICE sensitivity = 0.571). Conclusion:BHISA may provide a more sensitive and more differentiated screening tool for ICANS than ICE by incorporating additional cognitive and motor domains, while remaining easy to use. This may enable earlier and more nuanced detection of CAR T related neurotoxicity, potentially improving patient monitoring across a heterogeneous population.

Therapeutic interventions for diseases such as leukemia and autoimmune disorders are increasingly designed to selectively target and deplete specific immune cell subsets over prolonged periods. This can disrupt the homeostasis of the adaptive immune system, with consequences not only for peripheral blood but also for the “cradle of the immune system”, the bone marrow. This study hypothesized that such immune imbalance due to immune cell depletion therapies impairs the differentiation capacity of mesenchymal stromal cells (MSCs), which are key progenitors of bone cells and are thus essential for maintaining bone health. To validate this hypothesis, a series of cell culture experiments were conducted in which MSCs were stimulated with immune-conditioned media derived from various immune cell subsets. A comprehensive analytical approach was employed to evaluate the differentiating MSCs, including their associated supernatants, deposited collagen, mineralized matrix, and lipid deposition at defined time points during their maturation. Therefore, fluorescence and nonfluorescent histological staining, enzyme-linked immunosorbent assays (ELISAs), and expression analyses with Ribonucleic acid (RNA) were performed. This study demonstrated that, compared with immune-conditioned media from T cells or peripheral blood mononuclear cells (PBMCs), B cell-immune-conditioned media enriched with interleukin 4, bone morphogenetic protein 2 and Dickkopf 1 enhanced the osteogenic differentiation of MSCs in vitro. This positive osteogenic effect is driven primarily by elevated cytokine secretion by stimulated B cells, which in vivo in turn potentially stimulate bone turnover and modulate immune system function. In summary, these data demonstrate an pro-osteogenic and pro-adipogenic influence of B cells on differentiating MSCs in vitro, suggesting that an imbalance in immune cells in the bone marrow perturbs bone homeostasis.

This multicenter real-world study identifies critical determinants of outcome for tisagenlecleucel (tisa-cel) in treating post-HSCT relapse in 220 children/young adults with B-ALL from 31 European centers. Median follow-up was 30.0 months, with a 43.6% 2-year event-free survival (EFS), 67.2% overall-survival (OS), and 57.1% incidence of CAR-T failure. CAR-T for relapse after transplant from a matched sibling donor (MSD) compared to alternative donors was associated with lower 2-year-OS (MSD 59.1%, mismatched donor MMD 80.2%, matched family/unrelated donor MFD/MUD 68.3%, p = 0.046). Two-year incidence of CAR-T failure was highest for MSD (MSD 73.8%, MFD/MUD 49.7%, MMD 52.2%, p = 0.006). Patients who had relapsed early (< 6 months post HSCT) showed inferior 2-year-EFS (23.7%) and OS (47.2%) compared to patients with late relapse, ≥ 6 months after HSCT (EFS 49.8%, p = 0.001; OS 73.9%, p < 0.001). Early relapse was associated with a higher incidence of CAR-T failure and relapse after tisa-cel, particularly CD19+ relapses. Outcomes correlated with disease burden at lymphodepletion: 2-year-OS was 81.7% for MRD-, 69.2% for MRD+, and 55.2% for patients in non-remission (p = 0.003), with incidence of CAR-T failure highest in non-remission. Prior transplant from an MSD, early post-HSCT relapse, and disease burden at lymphodepletion identify patients at increased risk of CAR-T failure after HSCT.

CNS complications (CNSC) may occur in a significant proportion of patients after allogeneic haematopoietic cell transplantation (allo-HCT). They can be differentiated into infectious and non-infectious CNSC, such as vascular pathologies (e.g., bleeding, stroke), drug-related abnormalities, and CNS relapse of the underlying malignancy. Initiation of prompt and adequate diagnostics - mainly neuroimaging and cerebrospinal fluid (CSF) analyses - and treatment are crucial to improve the prognosis. Here, we report on the epidemiology, outcome, and neuroimaging of CNSC after allo-HCT. We also provide an overview of the special considerations for children with these complications. These findings and recommendations were developed during a multidisciplinary EBMT harmonisation workshop. Novel diagnostics, such as CSF next-generation sequencing (NGS) and special MRI sequences, are emerging and may improve the accuracy of diagnosis for selected CNSC. The prognosis of post-transplant CNSC is heterogeneous, with drug-related CNSC mainly having a favourable prognosis, while the outcome of CNS bleeding, CNS leukaemia, and cerebral fungal disease is still frequently dismal. A high level of awareness is crucial in the clinical routine - especially in distinct subgroups such as paediatrics - besides the development of novel algorithms, diagnostics, and treatment approaches to improve the outcome.