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Conditioning protocols for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) are being developed continuously to improve their anti-leukemic efficacy and reduce their toxicity. In this study, we compared the conditioning protocol of fludarabine with melphalan 140 mg/m 2 (FluMel) with conditioning protocols based on this same backbone but with an additional alkylating agent i.e., either fludarabine/BCNU (also known as carmustine)/melphalan (FBM), or fludarabine/thiotepa/melphalan (FTM) 110 mg/m 2 . We included 1272 adult patients (FluMel, n = 1002; FBM/FTM, n = 270) with acute myeloid leukemia (AML) with intermediate/poor cytogenetic risk in first complete remission (CR) from the registry of the EBMT Acute Leukemia Working Party. Despite patients in the FBM/FTM group were older (64.1 years vs. 59.8 years, p < 0.001) and had a worse Karnofsky performance score (KPS < 90, 33% vs. 24%, p = 0.003), they showed a better overall survival (OS) (2 y OS: 68.3% vs. 58.1%, p = 0.02) and less non-relapse mortality (NRM) (2 y NRM: 15.8% vs. 22.2%, p = 0.009) compared to patients treated with FluMel. No significant differences were observed in relapse incidence (RI) (2 y RI: 24.9% vs. 23.7%, p = 0.62). In conclusion, the addition of a second alkylating agent (BCNU/carmustine or thiotepa) to FluMel as FBM/FTM conditioning, improves OS in AML patients in first CR with intermediate/poor risk cytogenetics after allo-HCT., (© 2023. The Author(s).)

Hematopoietic stem cell transplantation is a high-risk procedure. Auditing and yearly outcome reviews help keep optimal quality of care and come with increased survival, but also has significant recurring costs. When data has been entered in a standardized registry, outcome analyses can be automated, which reduces work and increases standardization of performed analyses. To achieve this, we created the Yearly Outcome Review Tool (YORT), an offline, graphical tool that gets data from a single center EBMT registry export, allows the user to define filters and groups, and performs standardized analyses for overall survival, event-free survival, engraftment, relapse rate and non-relapse mortality, complications including acute and chronic Graft vs Host Disease (GvHD), and data completeness. YORT allows users to export data as analyzed to allow you to check data and perform manual analyses. We show the use of this tool on a two-year single-center pediatric cohort, demonstrating how the results for both overall and event-free survival and engraftment can be visualized. The current work demonstrates that using registry data, standardized tools can be made to analyze this data, which allows users to perform outcome reviews for local and accreditation purposes graphically with minimal effort, and help perform detailed standardized analyses. The tool is extensible to be able to accommodate future changes in outcome review and center-specific extensions., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

In recent years considerable variations in conditioning protocols for allogeneic hematopoietic cell transplantation (allo-HCT) protocols have been introduced for higher efficacy, lower toxicity, and better outcomes. To overcome the limitations of the classical definition of reduced intensity and myeloablative conditioning, a transplantation conditioning intensity (TCI) score had been developed. In this study, we compared outcome after two frequently used single alkylator-based conditioning protocols from the intermediate TCI score category, fludarabine/melphalan 140 mg/m 2 (FluMel) and fludarabine/treosulfan 42 g/m 2 (FluTreo) for patients with acute myeloid leukemia (AML) in complete remission (CR). This retrospective analysis from the registry of the Acute Leukemia Working Party (ALWP) of the European Society of Bone Marrow Transplantation (EBMT) database included 1427 adult patients (median age 58.2 years) receiving either Flu/Mel (n = 1005) or Flu/Treo (n = 422). Both groups showed similar 3-year overall survival (OS) (54% vs 51.2%, p value 0.49) for patients conditioned with FluMel and FluTreo, respectively. However, patients treated with FluMel showed a reduced 3-year relapse incidence (32.4% vs. 40.4%, p value < 0.001) and slightly increased non-relapse mortality (NRM) (25.7% vs. 20.2%, p value = 0.06) compared to patients treated with FluTreo. Our data may serve as a basis for further studies examining the role of additional agents/ intensifications in conditioning prior to allo-HCT., (© 2022. The Author(s).)

Male-specific late effects after hematopoietic cell transplantation (HCT) include genital chronic graft-versus-host disease (GvHD), hypogonadism, sexual dysfunction, infertility, and subsequent malignancies. They may be closely intertwined and cause prolonged morbidity and decreased quality of life after HCT. We provide a systematic review of male-specific late effects in a collaboration between transplant physicians, endocrinologists, urologists, dermatologists, and sexual health professionals through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research, and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. The systematic review summarizes incidence, risk factors, screening, prevention and treatment of these complications and provides consensus evidence-based recommendations for clinical practice and future research., (© 2022. The Author(s).)

Male-specific late effects after hematopoietic cell transplantation (HCT) include genital chronic graft-versus-host disease (GVHD), hypogonadism, sexual dysfunction, infertility, and subsequent malignancies, such as prostate, penile, and testicular cancer. These effects may be closely intertwined and cause prolonged morbidity and decreased quality of life after HCT. Here we provide a systematic review of male-specific late effects in a collaboration among transplantation physicians, endocrinologists, urologists, dermatologists, and sexual health professionals through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. We used a systematic review methodology to summarize incidence, risk factors, screening, prevention, and treatment of these complications and provide consensus evidence-based recommendations for clinical practice and future research. Most of the evidence regarding male GVHD is still based on limited data, precluding strong therapeutic recommendations. Therefore, we recommend systematic screening for male genital GVHD regularly and reporting of cases to large registries to allow for a better understanding. Future research also should address treatment, given the little published evidence currently available. Male-specific endocrine consequences of HCT include hypogonadism, which also may affect bone health. Given the scanty evidence, current recommendations for hormone substitution and/or bone health treatment are based on similar principles as for the general population. Following HCT, sexual health decreases, and this topic should be addressed at regular intervals. Future studies should focus on interventional strategies to address sexual dysfunction. Infertility remains prevalent in patients having undergone myeloablative conditioning, warranting the offer of sperm preservation for all HCT candidates. Most studies on fertility rely on descriptive registry analysis and surveys, underscoring the importance of reporting post-HCT conception data to large registries. Although the quality of evidence is low, the development of cancer in male genital organs does not seem more prevalent in HCT recipients compared with the general population; however, subsequent malignancies in general seem to be more prevalent in males than in females, and special attention should be given to skin and oral mucosa. Male-specific late effects, which likely are more underreported than female-specific complications, should be systematically considered during the regular follow-up visits of male survivors who have undergone HCT. Care of patients with male-specific late effects warrants close collaboration between transplantation physicians and specialists from other involved disciplines. Future research should be directed toward better data collection on male-specific late effects and on studies about the interrelationships among these late effects, to allow the development of evidence-based effective management practices., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative treatment for patients with myeloid/lymphoid neoplasm (MLN) with FGFR1 rearrangement, but data on overall results are limited. We report on the largest series of patients (n = 22) with FGFR1-rearranged MLN undergoing allo-HCT. Distribution according to cytogenetic subtype was: t(8;13) in 11 cases, t(8;22) in 7 cases, t(6;8) in 2 cases, and other (n = 2). Over a third of patients displayed a chronic myeloproliferative (MPN) phenotype, another third showed MPN features with concomitant lymphoma or acute leukemia, and the remaining ones presented as acute leukemia. After a median follow-up of 4.1 years from transplant, the estimated 5-year survival rate, progression-free survival, non-relapse mortality and relapse incidence was 74%, 63%, 14% and 23%, respectively. Causes of death were relapse/progression (n = 4), graft-versus-host disease (n = 2) and organ toxicity (n = 1). Six patients experienced disease relapse at a median of 6.1 months (range: 2.3-119.6). Two of them achieved complete remission with ponatinib or pemigatinib and were alive at 34.5 and 37 months from relapse, respectively. These data highlight the significant curative potential of allo-HCT in this aggressive disease. Maintenance with tyrosine kinase inhibitors may be a promising approach, at least in cases with detectable residual disease after transplant., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The optimal CD34 + cell dose in the setting of RIC allo-HCT for myelofibrosis (MF) remains unknown. We retrospectively analyzed 657 patients with primary or secondary MF transplanted with use of peripheral blood (PB) stem cells after fludarabine/melphalan or fludarabine/busulfan RIC regimen. Median patient age was 58 (range, 22-76) years. Donors were HLA-identical sibling (MSD) or unrelated (UD). Median follow-up was 46 (2-194) months. Patients transplanted with higher doses of CD34 + cells (>7.0 × 10 6 /kg), had an increased chance of achievement of both neutrophil (hazard ratio (HR), 1.46; P < 0.001) and platelet engraftment (HR, 1.43; P < 0.001). In a model with interaction, for patients transplanted from a MSD, higher CD34 + dose was associated with improved overall survival (HR, 0.63; P = 0.04) and relapse-free survival (HR, 0.61; P = 0.02), lower risk of non-relapse mortality (HR, 0.57; P = 0.04) and higher rate of platelet engraftment. The combined effect of higher cell dose and UD was apparent only for higher neutrophil and platelet recovery rate. We did not document any detrimental effect of high CD34 + dose on transplant outcomes. More bulky splenomegaly was an adverse factor for survival, engraftment and NRM. Our analysis suggests a potential benefit for MF patients undergoing RIC PB-allo-HCT receiving more than 7.0 × 10 6 /kg CD34 + cells., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Allogeneic hematopoietic cell transplantation (allo-HCT) remains a treatment option for patients with chronic myeloid leukemia (CML) who fail to respond to tyrosine kinase inhibitors (TKIs). While imatinib seems to have no adverse impact on outcomes after transplant, little is known on the effects of prior use of second-generation TKI (2GTKI). We present the results of a prospective non-interventional study performed by the EBMT on 383 consecutive CML patients previously treated with dasatinib or nilotinib undergoing allo-HCT from 2009 to 2013. The median age was 45 years (18-68). Disease status at transplant was CP1 in 139 patients (38%), AP or >CP1 in 163 (45%), and BC in 59 (16%). The choice of 2GTKI was: 40% dasatinib, 17% nilotinib, and 43% a sequential treatment of dasatinib and nilotinib with or without bosutinib/ponatinib. With a median follow-up of 37 months (1-77), 8% of patients developed either primary or secondary graft failure, 34% acute and 60% chronic GvHD. There were no differences in post-transplant complications between the three different 2GTKI subgroups. Non-relapse mortality was 18% and 24% at 12 months and at 5 years, respectively. Relapse incidence was 36%, overall survival 56% and relapse-free survival 40% at 5 years. No differences in post-transplant outcomes were found between the three different 2GTKI subgroups. This prospective study demonstrates the feasibility of allo-HCT in patients previously treated with 2GTKI with a post-transplant complications rate comparable to that of TKI-naive or imatinib-treated patients., (© 2021. The Author(s).)

Metabolic syndrome (MetS) is associated with cardiovascular disease in the general population and is also a potential cardiovascular risk factor in survivors of haematopoietic cell transplantation (HCT). We report an EBMT cross-sectional, multi-centre, non-interventional study of 453 adult HCT patients surviving a minimum of 2 years post-transplant attending routine follow-up HCT and/or late effects clinics in 9 centres. The overall prevalence of MetS was 37.5% rising to 53% in patients >50 years of age at follow-up. There were no differences in rates of MetS between autologous and allogeneic HCT survivors, nor any association with graft-versus-host disease (GvHD) or current immunosuppressant therapy. Notably, there was a significantly higher occurrence of cardiovascular events (CVE, defined as cerebrovascular accident, coronary heart disease or peripheral vascular disease) in those with MetS than in those without MetS (26.7% versus 9%, p < 0.001, OR 3.69, 95% CI 2.09-6.54, p < 0.001), and, as expected, MetS and CVE were age-related. Unexpectedly, CVE were associated with occurrence of second malignancy. Screening for and management of MetS should be integrated within routine HCT long-term follow-up care for both allogeneic and autologous HCT survivors. Further research is warranted, including randomised controlled trials of interventional strategies and mechanistic studies of cardiovascular risk in HCT survivors., (© 2021. The Author(s).)

Secondary autoimmune diseases (2ndADs), most frequently autoimmune cytopenias (AICs), were first described after allogeneic hematopoietic stem cell transplantation (HSCT) undertaken for malignant and hematological indications, occurred at a prevalence of ~5-6.5%, and were attributed to allogeneic immune imbalances in the context of graft versus host disease, viral infections, and chronic immunosuppression. Subsequently, 2ndADs were reported to complicate roughly 2-14% of autologous HSCTs performed for an autoimmune disease. Alemtuzumab in the conditioning regimen has been identified as a risk for development of 2ndADs after either allogeneic or autologous HSCT and is consistent with the high rates of 2ndADs when using alemtuzumab as monotherapy. Due to the significant consequences but variable incidence, depending on conditioning regimen, of 2ndADs and similarity in known immune reconstitution kinetics after autologous HSCT for autoimmune diseases and after alemtuzumab monotherapy, we propose that an imbalance between B and T lineage regeneration early after HSCT may underlie the pathogenesis of 2ndADs.

We assessed the incidence and outcome of early candidemia after hematopoietic stem cell transplant (HSCT). The analysis included all first HSCTs performed from 2000 to 2015 in adult and pediatric patients with a non-leukemic disease and recorded in the EBMT registry. Overall survival (OS), non-relapse mortality (NRM), and relapse mortality (RM) were evaluated. Candidemia was diagnosed in 420 of 49,852 patients at a median time of 17 days post HSCT (range 0-100), the cumulative incidence being 0.85%. In 65.5% of episodes, candidemia occurred by day 30 after HSCT. The mortality rate by day 7 was 6.2%, whereas 100-day NRM was higher (HR 3.47, p < 0.0001), and 100-day OS was lower (HR 3.22, p < 0.0001) than that of patients without candidemia. After a median follow-up of 4.3 years, 5-year OS, NRM, and RM for patients with and without candidemia were 50.5% vs. 60.8%, p < 0.0001, 28.2% vs.18.8%, p < 0.0001, and 25.3% vs. 27.2%, p = 0.4, respectively. In conclusion, in non-leukemic transplant patients, the occurrence of an early episode of candidemia is rare but it is still associated with a negative effect on the outcome.

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.

Complications involving the central nervous system (CNS) occur in 9-14% of patients following allogeneic hematopoietic stem cell transplantation (HSCT), including stroke-like episodes, demyelination, encephalitis, and nonspecific neurological symptoms. Here we report a case of multiple sclerosis (MS) like relapsing remitting encephalomyelitis following allogeneic HSCT, which did not respond to disease modifying therapies (DMTs) and "domino" autologous HSCT. A 53-year-old male was treated with allogeneic HSCT for lymphoid blast transformation of chronic myeloid leukemia. Ten months later he presented with confusion, slurred speech, left sided facial weakness and ataxia. A magnetic resonance imaging brain scan showed multiple enhancing tumefactive lesions. Neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) antibodies were negative. After extensive investigations for infections, autoimmune disorders and recurrence of malignancy, he underwent brain biopsy, which showed a macrophage rich lesion with severe myelin loss but axonal preservation indicating a demyelinating pathology. Although his symptoms improved with corticosteroids, he relapsed five months later. In the absence of any systemic features suggesting graft versus host disease (GvHD), his presentation was thought to be compatible with MS. The illness followed an aggressive course that did not respond to glatiramer acetate and natalizumab. He was therefore treated with "domino" autologous HSCT, which also failed to induce long-term remission. Despite further treatment with ocrelizumab, he died of progressive disease. An autopsy limited to the examination of brain revealed multifocal destructive leukoencephalopathy with severe myelin and axonal loss. Immunohistochemistry showed macrophage located in the perivascular area, with no T or B lymphocytes. The appearance was unusual and not typical for chronic MS plaques. Reported cases of CNS demyelination following allogeneic HSCT are very limited in the literature, especially in relation to histopathological examination. Although the clinical disease course of our patient following allogeneic HSCT resembled an "MS-like" relapsing remitting encephalomyelitis, the autopsy examination did not show any evidence of active inflammation. The impact of DMTs and HSCT on the histological appearance of "MS-like" CNS pathologies is unknown. Therefore, reporting this and similar cases will improve our awareness and understanding of underlying disease mechanisms., (Copyright © 2020 Das, Gill, Lo, Chan-Lam, Price, Wharton, Jessop, Sharrack and Snowden.)

This retrospective study explored the incidence of autoimmune cytopenia (AIC) in 530 paediatric and adult patients with acquired aplastic anaemia (aAA) who underwent first allogeneic HSCT between 2002 and 2012. AIC was a rare complication with a cumulative incidence of AIC at 1, 3, 5 and 10 years post HSCT of 2.5% (1.2-3.9 95% CI), 4.4% (2.6-6.2 95% CI), 4.6% (2.8-6.5 95% CI) and 5.1% (3.1-7.2 95% CI). Overall survival at 5 years after diagnosis of AIC was 85.9% (71-100 95% CI). Twenty-five patients were diagnosed with AIC at a median of 10.6 (2.6-91.5) months post HSCT. Eight (32%) patients were diagnosed with immune thrombocytopenia (ITP), seven (28%) with autoimmune haemolytic anaemia (AIHA), seven (24%) with Evans syndrome and four (16%) with autoimmune neutropenia (AIN). Treatment strategies were heterogeneous. Complete responses were seen in 12 of 25 patients, with death in three patients. In multivariable Cox analysis of a subgroup of 475 patients, peripheral blood stem cell (PBSC) transplant was associated with higher risk of AIC compared with bone marrow (BM) when conditioning regimens contained fludarabine and/or alemtuzumab (2.81 [1.06-7.49 95% CI]; p = 0.038), or anti-thymocyte globulin (ATG) (2.86 [1.11-7.37 95% CI]; p = 0.029). Myeloablative conditioning was associated with a lower risk of AIC compared with reduced intensity conditioning (RIC) in fludarabine and/or alemtuzumab (0.34 [0.12-0.98 95% CI]; p = 0.046) and ATG containing regimens (0.34 [0.12-0.95 95% CI]; p = 0.04). These findings provide clinically useful information regarding the incidence of a rare and potentially life-threatening complication of allogeneic HSCT for aAA, and further support for BM as the preferred stem cell source for transplant of patients with aAA.

As the use of hematopoietic stem cell transplantation (HSCT) has become a more widespread and effective treatment for hematological malignant and non-malignant conditions, the need to minimize the harmful effects of graft- vs.-host disease (GvHD) has become more important in achieving good outcomes. With diagnosis of GvHD reliant on its clinical manifestations, research into biomarkers for the diagnosis, progression, and even for the prediction of disease, is imperative to combating the high levels of morbidity and mortality post-HSCT. Despite the development of novel treatment approaches to GvHD, corticosteroids remain the standard first-line treatment, with immunosuppressant therapies as second-line options. These strategies however have significant limitations and associated complications. Extracorporeal Photopheresis (ECP) has shown to be effective and safe in treating patients with symptomatic GvHD. ECP has been shown to have varied effects on multiple parts of the immune system and does not appear to increase the risk of relapse or infection in the post HSCT setting. Even so, ECP can be logistically more complex to organize and requires patients to be sufficiently stable. This review aims to summarize the potential role of biomarkers to help guide individualized treatment decisions in patients with acute and chronic GvHD. In relation to ECP, robust biomarkers of GvHD will be highly useful in informing patient selection, intensity and duration of the ECP schedule, monitoring of response and other treatment decisions alongside the concurrent administration of other GvHD therapies. Further research is warranted to establish how GvHD biomarkers are best incorporated into ECP treatment pathways with the goal of tailoring ECP to the needs of individual patients and maximizing benefit., (Copyright © 2020 Mankarious, Matthews, Snowden and Alfred.)

Background: This retrospective study assessed the use and long-term outcome of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with severe autoimmune diseases (ADs), reported to the European Society for Blood and Marrow Transplantation (EBMT) registry. Methods: Between 1997 and 2014, 128 patients received allogeneic HSCT for various hematological ( n = 49) and non-hematological ( n = 79) refractory ADs. The median age was 12.7 years (0.2-62.2). Donors were syngeneic for seven, matched related for 46, unrelated for 51, haploidentical for 15, and cord blood for nine patients. Results: The incidence of grades II-IV acute graft-vs.-host disease (GvHD) was 20.8% at 100 days. Cumulative incidence of chronic GvHD was 27.8% at 5-years. Non-relapse mortality (NRM) was 12.7% at 100-days. Overall survival (OS) and Progression-Free Survival (PFS) were 70.2 and 59.4% at 5-years, respectively. By multivariate analysis, age <18 years, males, and more recent year of transplant were found to be significantly associated with improved PFS. Reduced conditioning intensity was associated with a lower NRM. On a subgroup of 64 patients with detailed information a complete clinical response was obtained in 67% of patients at 1-year. Conclusions: This large EBMT survey suggests the potential of allogeneic HSCT to induce long-term disease control in a large proportion of refractory ADs, with acceptable toxicities and NRM, especially in younger patients.

Mesenchymal stromal cells (MSCs) have been successfully used for the treatment of steroid-resistant graft-versus-host-disease (GvHD). However, the lack of early predictors of clinical responses impacts on the time at which to add further treatment and consequently the design of informative clinical trials. Here, we present the UK experience of one of the largest cohorts of GvHD patients undergoing MSC infusions so far reported. We show that clinical responses assessed as early as 1 week after MSC infusion predict patients' overall survival. In our cohort, cell dose, patients' age and type of organ involvement are crucial factors associated with clinical responses., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)