Post-transplant Inflammatory Bowel Disease Associated with Donor-Derived TIM-3 Deficiency.

Inflammatory bowel disease (IBD) occurring following allogeneic stem cell transplantation (aSCT) is a very rare condition. The underlying pathogenesis needs to be better defined. There is currently no systematic effort to exclude loss- or gain-of-function mutations in immune-related genes in stem cell donors. This is despite the fact that more than 100 inborn errors of immunity may cause or contribute to IBD. We have molecularly characterized a patient who developed fulminant inflammatory bowel disease following aSCT with stable 100% donor-derived hematopoiesis. A pathogenic c.A291G; p.I97M HAVCR2 mutation encoding the immune checkpoint protein TIM-3 was identified in the patient's blood-derived DNA, while being absent in DNA derived from the skin. TIM-3 expression was much decreased in the patient's serum, and in vitro-activated patient-derived T cells expressed reduced TIM-3 levels. In contrast, T cell-intrinsic CD25 expression and production of inflammatory cytokines were preserved. TIM-3 expression was barely detectable in the immune cells of the patient's intestinal mucosa, while being detected unambiguously in the inflamed and non-inflamed colon from unrelated individuals. In conclusion, we report the first case of acquired, "transplanted" insufficiency of the regulatory TIM-3 checkpoint linked to post-aSCT IBD.

Hematopoietic cell transplantation and cellular therapies in Switzerland. Evolution over 25 years. A report from the stem cell transplantation and cellular therapies working groups of the SBST 1997-2021.

The Swiss Blood Stem Cell Transplantation and Cellular Therapy Group (SBST) leads a mandatory national registry for all hematopoietic stem cell transplants (HCT) and cellular therapies. After 25 years, information was available for 11,226 patients receiving an HCT (4031 allogeneic and 7195 autologous), including 925 pediatric patients. We compared patient characteristics and outcome by quinquennia 1997-2001, 2002-2006, 2007-2011, 2012-2016, and 2017-2021. There were numerous changes over time. Allogeneic transplant recipients became older (median age 33.7 vs. 54.3) and had more frequently unrelated donors and reduced intensity conditioning in later quinquennia. Similarly, age increased for recipients of autologous HCT (median 48.3 vs. 59.9). We did not see a significant drop in transplant activity during the SARS-CoV-2 pandemic. Analysis of outcome showed overall survival (relative risk (RR) of death 0.664 (0.529-0.832) and progression free survival (RR 0.708 (0.577-0.870) being improved over time comparing the latest to the first quinquennium adjusting for risk factors. Non-relapse mortality decreased in recipients of allogeneic HCT (RR: 0.371 (0.270-0.509)) over time but relapse risks did not. Outcome of autologous HCT improved as well across quinquennia, this improvement was mainly due to decreased relapse risks (RR 0.681 (0.597-0.777)), possibly related to maintenance treatment or rescue treatment for relapse mainly in myeloma patients. Cellular therapies other than allogeneic or autologous HCT, particularly chimeric antigen receptor T-cells (CAR-T) treatment have started to increase after 2019, year of approval of the first commercial CAR-T product in Switzerland. Data on chimeric antigen receptor T-cell treatment are too early for comparative analyses. Detailed analyses of changes over time are presented. This study includes all HCTs, and cellular therapies, data useful for quality assurance programs, health care cost estimation and benchmarking. Between 50% and 60% of patients are long-term survivors after both types of HCT, indicating growing populations of surviving patients requiring long-term care.

Feasibility of electronic patient-reported outcome monitoring and self-management program in aplastic anemia and paroxysmal nocturnal hemoglobinuria-a pilot study (ePRO-AA-PNH).

INTRODUCTION: Electronic patient-reported outcomes (ePRO) are increasingly recognized in health care, as they have been demonstrated to improve patient outcomes in cancer, but have been less studied in rare hematological diseases. The aim of this study was to develop and test the feasibility of an ePRO system specifically customized for aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH). METHODS: After performing a user-centered design evaluation an ePRO system for AA and PNH patients could be customized and the application was tested by patients and their medical teams for 6 months. Symptom-reporting triggered self-management advice for patients and prompts them to contact clinicians in case of severe symptoms, while the medical team received alerts of severe symptoms for patient care. RESULTS: All nine included patients showed a high adherence rate to the weekly symptom-reporting (72%) and reported high satisfaction. The system was rated high for usage, comprehensibility, and integration into daily life. Most patients (78%) would continue and all would recommend the application to other AA/PNH patients. Technical performance was rarely a barrier and healthcare providers saw ePRO-AA-PNH as a useful supplement, but the lacking integration into the hospital information system was identified as a major barrier to usage. CONCLUSION: An ePRO system customized for AA and PNH was feasible in terms of adherence, satisfaction, and performance, showing a high potential for these rare conditions in terms of data collection and patient guidance. However, the integration into clinical workflows is crucial for further routine use. TRIAL REGISTRATION: ClinicalTrials.gov NCT04128943.

The SMILe integrated care model in allogeneic SteM cell TransplantatIon faciLitated by eHealth: a protocol for a hybrid effectiveness-implementation randomised controlled trial.

BACKGROUND: While effectiveness outcomes of eHealth-facilitated integrated care models (eICMs) in transplant and oncological populations are promising, implementing and sustaining them in real-world settings remain challenging. Allogeneic stem cell transplant (alloSCT) patients could benefit from an eICM to enhance health outcomes. To combat health deterioration, integrating chronic illness management, including continuous symptom and health behaviour monitoring, can shorten reaction times. We will test the 1st-year post-alloSCT effectiveness and evaluate bundled implementation strategies to support the implementation of a newly developed and adapted eICM in allogeneic stem cell transplantation facilitated by eHealth (SMILe-ICM). SMILe-ICM has been designed by combining implementation, behavioural, and computer science methods. Adaptions were guided by FRAME and FRAME-IS. It consists of four modules: 1) monitoring & follow-up; 2) infection prevention; 3) physical activity; and 4) medication adherence, delivered via eHealth and a care coordinator (an Advanced Practice Nurse). The implementation was supported by contextually adapted implementation strategies (e.g., creating new clinical teams, informing local opinion leaders). METHODS: Using a hybrid effectiveness-implementation randomised controlled trial, we will include a consecutive sample of 80 adult alloSCT patients who were transplanted and followed by University Hospital Basel (Switzerland). Inclusion criteria are basic German proficiency; elementary computer literacy; internet access; and written informed consent. Patients will be excluded if their condition prevents the use of technology, or if they are followed up only at external centres. Patient-level (1:1) stratified randomisation into a usual care group and a SMILe-ICM group will take place 10 days pre-transplantation. To gauge the SMILe-ICM's effectiveness primary outcome (re-hospitalisation rate), secondary outcomes (healthcare utilization costs; length of inpatient re-hospitalizations, medication adherence; treatment and self-management burden; HRQoL; Graft-versus-Host Disease rate; survival; overall survival rate) and implementation outcomes (acceptability, appropriateness, feasibility, fidelity), we will use multi-method, multi-informant assessment (via questionnaires, interviews, electronic health record data, cost capture methods). DISCUSSION: The SMILe-ICM has major innovative potential for reengineering alloSCT follow-up care, particularly regarding short- and medium-term outcomes. Our dual focus on implementation and effectiveness will both inform optimization of the SMILe-ICM and provide insights regarding implementation strategies and pathway, understudied in eHealth-facilitated ICMs in chronically ill populations. TRIAL REGISTRATION: ClinicalTrials.gov. Identifier: NCT04789863 . Registered April 01, 2021.

Exploring Stem Cell Transplanted Patients' Perspectives on Medication Self-Management and Electronic Monitoring Devices Measuring Medication Adherence: A Qualitative Sub-Study of the Swiss SMILe Implementation Science Project.

PURPOSE: Little is known about allogeneic stem cell transplant (alloSCT) patients' medication adherence strategies. Acceptability and preferences regarding electronic monitoring (EM) systems to assess all three phases of medication adherence (ie, initiation, implementation, persistence) are crucial to allow their successful implementation in clinical or research settings but have not yet been evaluated. We therefore aimed to explore: 1) alloSCT patients' medication adherence and self-management strategies; and 2) their acceptability and preferences of three different EM systems (MEMS Cap, Helping Hand, Button) as part of the Swiss SMILe study. PATIENTS AND METHODS: Respecting anti-pandemic measures, we used a purposive sample of six adult alloSCT patients from the University Hospital Basel, Switzerland (USB)-6 weeks to 2 years post-alloSCT-to conduct three focus group sessions with two patients each. Using a semi-structured outline, we explored 1) patients' medication adherence strategies and medication self-management; and 2) their acceptance and preferences regarding EM use. The three tested EM systems were available for testing during each session. Discussions were audio-recorded, visualized using mind-mapping and analyzed using Mayring's qualitative content analysis. RESULTS: Patients (33% females; mean age 54.6±16.3 years; 10.4±8.4 months post-alloSCT) used medication adherence enhancing strategies (eg, preparing pillbox, linking intake to a habit). Still, they indicated that post-alloSCT medication management was challenging (eg, frequent schedule changes). All participants preferred the MEMS Button. Participants said its small size and the possibility to combine it with existing pillboxes (eg, putting it into/next to them) made them more confident about implementing it in their daily lives. CONCLUSION: Regarding EM systems for medication adherence, end-user preferences and acceptability influence adoption and fidelity. Of the three systems tested, our sample found the MEMS Button most acceptable and most preferable. Therefore, we will use it for our USB SMILe study.

Context-specific adaptation of an eHealth-facilitated, integrated care model and tailoring its implementation strategies-A mixed-methods study as a part of the SMILe implementation science project.

Background: Contextually adapting complex interventions and tailoring their implementation strategies is key to a successful and sustainable implementation. While reporting guidelines for adaptations and tailoring exist, less is known about how to conduct context-specific adaptations of complex health care interventions. Aims: To describe in methodological terms how the merging of contextual analysis results (step 1) with stakeholder involvement, and considering overarching regulations (step 2) informed our adaptation of an Integrated Care Model (ICM) for SteM cell transplantatIon faciLitated by eHealth (SMILe) and the tailoring of its implementation strategies (step 3). Methods: Step 1: We used a mixed-methods design at University Hospital Basel, guided by the Basel Approach for coNtextual ANAlysis (BANANA). Step 2: Adaptations of the SMILe-ICM and tailoring of implementation strategies were discussed with an interdisciplinary team (n = 28) by considering setting specific and higher-level regulatory scenarios. Usability tests were conducted with patients (n = 5) and clinicians (n = 4). Step 3: Adaptations were conducted by merging our results from steps 1 and 2 using the Framework for Reporting Adaptations and Modifications-Enhanced (FRAME). We tailored implementation strategies according to the Expert Recommendations for Implementing Change (ERIC) compilation. Results: Step 1: Current clinical practice was mostly acute-care-driven. Patients and clinicians valued eHealth-facilitated ICMs to support trustful patient-clinician relationships and the fitting of eHealth components to context-specific needs. Step 2: Based on information from project group meetings, adaptations were necessary on the organizational level (e.g., delivery of self-management information). Regulations informed the tailoring of SMILe-ICM`s visit timepoints and content; data protection management was adapted following Swiss regulations; and steering group meetings supported infrastructure access. The usability tests informed further adaptation of technology components. Step 3: Following FRAME and ERIC, SMILe-ICM and its implementation strategies were contextually adapted and tailored to setting-specific needs. Discussion: This study provides a context-driven methodological approach on how to conduct intervention adaptation including the tailoring of its implementation strategies. The revealed meso-, and macro-level differences of the contextual analysis suggest a more targeted approach to enable an in-depth adaptation process. A theory-guided adaptation phase is an important first step and should be sufficiently incorporated and budgeted in implementation science projects.

Medication adherence interventions in transplantation lack information on how to implement findings from randomized controlled trials in real-world settings: A systematic review.

BACKGROUND: Growing numbers of randomized controlled trials (RCTs) are showing the effectiveness of interventions to improve medication adherence in transplantation recipients. However, real-world implementation is still a major challenge. This systematic review assesses the range of information available in RCTs supporting these interventions' clinical adoption in adult transplant populations. METHODS: We included RCTs of interventions that a) targeted any phase of medication adherence in solid organ or allogeneic stem cell transplantation recipients and b) were published between January 2015 and November 2020. We excluded study protocols, conference abstracts and studies focusing only on pediatric populations. We identified relevant database and trial registries as well as traced references backward and citations forward. Implementation-relevant information was evaluated using adapted versions of Peters' ten criteria: 1. healthcare/organizational context; 2. social/economic/policy context; 3. patient involvement; 4. other stakeholder involvement; 5. sample representativeness; 6. trial conducted in a real-world-setting; 7. presence of feasibility study; 8. implementation strategy; 9. process evaluation; 10. implementation outcomes, using a stoplight color-rating system. RESULTS: Screening 17'004 titles/abstracts resulted in 23 eligible RCTs, including 2'339 patients (n = 19-209/study). All included studies focused on the implementation phase of medication adherence. The best-reported criteria were feasibility study (43%), representative sample (17%) and conducted in a real-world-setting (17%). Least reported were context (9%), implementation strategies (4%), process evaluation (4%). CONCLUSIONS: RCTs testing medication adherence interventions tend to report limited implementation-relevant information. This hinders their translation to real-world transplant settings. Integrating implementation science principles early in the conceptualization of RCTs would fuel real-world-translation, reducing research waste.

Feasibility and efficacy of salvage allogeneic stem cell transplantation in AML patients relapsing after autologous stem cell transplantation.

Autologous hematopoietic cell transplantation (HCT) is suitable for consolidation of favorable-/intermediate-risk AML patients in CR1. However, ~50% of AML patients relapse after autologous HCT, and efficacy of subsequent salvage strategies including allogeneic HCT remains unclear. We studied 123 consecutive patients with newly diagnosed AML undergoing high-dose chemotherapy (HDCT)/autologous HCT in CR1. In relapsing patients afterwards, we analyzed salvage treatments and outcomes focusing particularly on salvage allogeneic HCT. Of 123 patients, 64 (52%) relapsed after autologous HCT. Subsequently, 13 (21%) received palliative therapy, whereas 51 (79%) proceeded to salvage therapy with a curative intent. Of the 47 patients with a curative intent and who did not proceed directly to allogeneic HCT, 23 (49%) achieved CR2 or had ongoing hematologic CR1 despite molecular relapse. Finally, 30 patients (47%) received allogeneic HCT with estimated 3-year leukemia-free and overall survival rates of 33% and 43%. Hematologic remission at allogeneic HCT and lack of acute GvHD had a positive impact on OS and LFS (p < 0.05). Our study suggests that almost 80% of AML patients can undergo salvage therapy following relapse after front-line HDCT/autologous HCT. Allogeneic HCT can provide cure in one third of patients relapsing after front-line HDCT/autologous HCT.

Management of transthyretin amyloidosis.

Transthyretin amyloidosis (ATTR amyloidosis) is a disease caused by deposition of transthyretin fibrils in organs and tissues, which causes their dysfunction. The clinical heterogeneity of ATTR amyloidosis and the variable presentation of symptoms at early disease stages, historically meant treatment delays. Diagnostic tools and therapy options of ATTR amyloidosis have markedly improved in recent years. The first Swiss Amyloidosis Network (SAN) meeting (Zurich, Switzerland, January 2020) aimed to define a consensus statement regarding the diagnostic work-up and treatment for systemic amyloidosis, tailored to the Swiss healthcare system. A consortium of 45 clinicians and researchers from all Swiss regions and universities was selected by the SAN committee to represent all sub-specialty groups involved in care of patients with amyloidosis. A steering committee conducted the literature search and analysis, wrote the critical synthesis and elaborated a list of statements that were evaluated by all the participants. These recommendations will improve outcomes and quality of life for patients with ATTR amyloidosis. A global review of these guidelines is planned every 3 years with a formal meeting of all the involved experts.

Development of an integrated model of care for allogeneic stem cell transplantation facilitated by eHealth-the SMILe study.

PURPOSE: Allogeneic stem cell transplantation would benefit from re-engineering care towards an integrated eHealth-facilitated care model. With this paper we aim to: (1) describe the development of an integrated care model (ICM) in allogeneic SteM-cell-transplantatIon faciLitated by eHealth (SMILe) by combining implementation, behavioral, and computer science methods (e.g., contextual analysis, Behavior Change Wheel, and user-centered design combined with agile software development); and (2) describe that model's characteristics and its application in clinical practice. METHODS: The SMILe intervention's development consisted of four steps, with implementation science methods informing each: (1) planning its set-up within a theoretical foundation; (2) using behavioral science methods to develop the content; (3) choosing and developing its delivery method (human/technology) using behavioral and computer science methods; and (4) describing its characteristics and application in clinical practice. RESULTS: The SMILe intervention is embedded within the eHealth enhanced Chronic Care Model, entailing four self-management intervention modules, targeting monitoring and follow-up of important medical and symptom-related parameters, infection prevention, medication adherence, and physical activity. Interventions are delivered partly face-to-face by a care coordinator embedded within the transplant team, and partly via the SMILeApp that connects patients to the transplant team, who can monitor and rapidly respond to any relevant changes within 1 year post-transplant. CONCLUSION: This paper provides stepwise guidance on how implementation, behavioral, and computer science methods can be used to develop interventions aiming to improve care for stem cell transplant patients in real-world clinical settings. This new care model is currently being tested in a hybrid I effectiveness-implementation trial.

Busulfan-cyclophosphamide versus cyclophosphamide-busulfan as conditioning regimen before allogeneic hematopoietic cell transplantation: a prospective randomized trial.

Busulfan and cyclophosphamide (BuCy) is a frequently used myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT). Theoretical considerations and pharmacological data indicate that application of busulfan prior to subsequent cyclophosphamide (BuCy) may trigger liver toxicity. Reversing the order of application to cyclophosphamide-busulfan (CyBu) might be preferable, a hypothesis supported by animal data and retrospective studies. We performed a prospective randomized trial to determine impact of order of application of Bu and Cy before allo-HCT in 70 patients with hematological malignancy, 33 patients received BuCy and 37 CyBu for conditioning. In the short term, there were minimal differences in liver toxicity favoring CyBu over BuCy, significant only for alanine amino transferase at day 30 (p = 0.03). With longer follow-up at 4 years, non-relapse mortality (6% versus 27%, p = 0.05) was lower and survival (63% versus 43%, p = 0.06) was higher with CyBu compared to BuCy. Other outcomes, such as engraftment (p = 0.21), acute and chronic graft-versus-host disease (p = 0.40; 0.36), and relapse (p = 0.79), were similar in both groups. We prospectively show evidence that the order of application of Cy and Bu in myeloablative conditioning in allo-HCT patients has impact on outcome.

Cellular immunotherapy with multiple infusions of in vitro-expanded haploidentical natural killer cells after autologous transplantation for patients with plasma cell myeloma.

BACKGROUND AIMS: To investigate the feasibility and safety of haploidentical natural killer (NK) cell infusions as consolidation immunotherapy after autologous stem cell transplant (ASCT) in patients with plasma cell myeloma. METHODS: Ten patients (median age, 59 years) received induction treatment followed by high-dose melphalan (200 mg/m2) at day -1, ASCT at day 0 and increasing NK cell doses (1.5 × 106, 1.5 × 107 and multiple doses of 1.0 × 108 cells/kg body weight) from day +1 to day +30 after ASCT. NK cells were harvested and purified from peripheral blood of haploidentical donors and expanded for 19 days with interleukin (IL)-2 and IL-15 under Good Manufacturing Practice conditions. RESULTS: NK cell numbers increased 56.0-fold (37.4- to 75.5-fold). Patients received a median of 3.8 × 108 (0.9-5.7 × 108) NK cells/kg body weight in six (three to eight) infusions. Multiparametric mass cytometry analysis demonstrated an altered surface receptor repertoire of expanded NK cells with increased degranulation and cytokine production activities but diminished expression of perforin. Donor NK cells were detectable in the peripheral blood, peaking 1 h after each dose (up to 90% donor NK cells). The treatment was safe and well tolerated, without evidence of graft-versus-host disease. Comparison with a control patient population receiving ASCT without NK cell infusions showed no significant difference in relapse, progression-free survival and overall survival. CONCLUSIONS: This study demonstrates reliable manufacturing of high numbers of activated NK cells for multiple-dose infusions and safe administration of these cellular products. The trial was registered at ClinicalTrials.gov (identifier no. NCT01040026).

Patient preferences for allogeneic haematopoietic stem cell transplantation: how much benefit is worthwhile from the patient's perspective?

Oncological studies have shown that patients consider small benefits sufficient to make adjuvant chemotherapy worthwhile. We sought to determine the minimal survival benefits that patients considered enough to legitimate allogeneic haematopoietic stem cell transplantation (HCT) and the factors associated with patient preferences. One hundred eighty-four patients having previously received allogeneic HCT at our centre were included and completed a questionnaire exploring patient expectations elicited by time trade-off scenarios as well as quality of life (QoL), symptoms of graft-versus host disease (GvHD) and sociodemographic characteristics. The majority of patients considered a minimal survival benefit of at least 5 (38.6%) or 10 years (41.9%) sufficient to justify HCT, with less than 5% considering survival < 1 year sufficient to warrant HCT. In terms of minimal cure rate, a cumulative 14.8% of patients accepted cure rates below 30% and 30.6% rates below 50%. Likelihood-ratio tests were significant for the effect of age at transplant on expected minimal survival (p = 0.007) and cure rates (p = 0.0001); that is, younger patients at HCT were more likely to accept smaller survival and cure rates. Pre-transplant risk score, QoL, GvHD score and sociological factors did not seem to influence patients' expectations. In conclusion, patient expectations of treatment were much higher than what had been reported in oncological studies. Patients who experienced HCT considered a survival superior to 1 year and cure rates above 50% sufficient to make it worthwhile. Younger patients were more likely to accept smaller benefits; no other predictors for preferences could be detected.

Expert recommendation from the Swiss Amyloidosis Network (SAN) for systemic AL-amyloidosis.

Systemic amyloidosis is a heterogeneous group of diseases associated with protein misfolding into insoluble beta-sheet rich structures that deposit extracellularly in different organs, eventually compromising their function. There are more than 30 different proteins, known to be amyloidogenic with “light chain” (AL)-amyloidosis being the most common type, followed by transthyretin (ATTR)-, and amyloid protein A (AA)-amyloidosis. Systemic amyloidosis is a rare disease with an incidence of around 10 patients in 1 million inhabitants. Recently several new therapeutic options have been developed for subgroups of amyloidosis patients, and the introduction of novel therapies for plasma cell myeloma has led to an increase in the therapeutic armamentarium for plasma cell disorders, including AL amyloidosis. Among them, proteasome inhibitors, immunomodulatory agents (-imids), and monoclonal antibodies have been successfully introduced into clinical practice. Still, high-quality data from randomised controlled trials regarding the benefit of these cost-intensive drugs in AL amyloidosis are widely lacking, and due to the rarity of the disease many physicians will not gain routine experience in the management of these frail patients. The diagnosis of AL amyloidosis relies on a close collaboration between clinicians, pathologists, imaging experts, and sometimes geneticists. Diagnosis and treatment options in this complex disorder should be discussed in dedicated multidisciplinary boards. In January 2020, the first meeting of the Swiss Amyloidosis Network took place in Zurich, Switzerland. One aim of this meeting was to establish a consensus guideline regarding the diagnostic work-up and the treatment recommendations for systemic amyloidosis tailored to the Swiss health care system. Forty-five participants from different fields in medicine discussed many aspects of amyloidosis. These are the Swiss Amyloidosis Network recommendations which focus on diagnostic work-up and treatment of AL-amyloidosis.

New-onset Post-transplant Diabetes and Therapy in Long-term Survivors After Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has increased but so have long-term sequelae. New-onset post-transplant diabetes mellitus (PTDM) occurs frequently following allo-HSCT. PATIENTS AND METHODS: Study endpoints were incidence and risk factors of PDTM. We studied 599 adult patients suffering from either acute myeloid leukemia n=220), acute lymphoblastic leukemia (n=79), chronic myeloid leukemia (n=22), myelodysplastic syndrome/myeloproliferative neoplasm (n=105), chronic lymphocytic leukemia (n=37), lymphoma/myeloma (n=116, or non-malignant disorders (e.g. bone marrow failure, hemoglobinopathies) (n=20) who underwent myeloablative (466; 77.8%) or non-myeloablative (131; 21.9%) allo-HSCT between 2006 and 2016. RESULTS: Altogether, 39 patients (6.5%) developed PTDM. In a competing-risk analysis, time to PTDM was associated with acute grade 2-4 graft-versus-host-disease (p=0.017). Further cardiovascular risk factors were hypertension (n=145; 24.2%), coronary artery disease (n=36, 6%), dyslipidemia (n=139; 23.3%), and stroke (n=12; 2%). CONCLUSION: After allo-HSCT, a significant number of patients developed PTDM and patients with acute graft-versus-host-disease were found to have a higher risk for PTDM. Long-term and continuous follow-up for diabetes and cardiovascular risk factors after HSCT is important in order to be able to provide timely and appropriate treatment.

Incidence of CMV Replication and the Role of Letermovir Primary/Secondary Prophylaxis in the Early Phase After Allogeneic Hematopoietic Stem Cell Transplantation - A Single Centre Study.

BACKGROUND/AIM: Cytomegalovirus (CMV) replication may cause life-threatening complications after allogeneic haematopoietic stem cell transplantation (allo-HSCT). The aim of the study was to characterize CMV events, and the outcome of letermovir (LTV) CMV prophylaxis. PATIENTS AND METHODS: In this retrospective analysis of patients treated with an allo-HSCT between 2010 and 2020, we determined plasma CMV events, as well as associated risk factors. RESULTS: We identified 423 patients who had undergone allo-HSCT between 2010 and 2020. CMV DNAemia was found in 130/423 (30.7%) of patients. CMV reactivation rate was significantly higher in patients with acute graft-versus-host disease, HLA mismatch, and CMV IgG seropositivity of donors and recipients. Among 42 patients receiving LTV prophylaxis those, 5 (11.9%) showed CMV DNAemia under LTV versus 87/353 (24.6%) in a control group. CONCLUSION: Despite the development of better approaches with weekly monitoring and early treatment initiation, CMV reactivations play an important role after allo-HSCT.

Development of a patient-reported outcome questionnaire for aplastic anemia and paroxysmal nocturnal hemoglobinuria (PRO-AA/PNH).

BACKGROUND: The introduction of new therapy modalities has significantly improved the outcome of aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) patients. However, relatively little is known about the exact disease burden of AA/PNH since standardized assessments of symptoms including health-related quality of life (HRQoL) are frequently missing or inadequately designed for this rare patient group. We aimed to develop AA/PNH-specific questionnaires for self-reporting of symptoms, which could be included in electronic platforms for data collection and patient care. METHODS: By scoping review, we extracted any reported symptoms in AA/PNH and their prevalence from the literature (Phase I). Consensus rounds with patients and medical experts were conducted to identify core symptoms reported in the literature and to add missing items (Phase II). Ultimately, AA/PNH-specific patient-reported outcome (PRO) questionnaires including the selected measures were designed (Phase III). RESULTS: AA symptoms from 62 and PNH symptoms from 45 observational studies were extracted from the literature. Twenty-four patients and seven medical experts identified 11 core symptoms including HRQoL issues after three consensus rounds. Significant differences in the symptom ranking of patients versus medical experts could be observed. Therefore, patient- as well as expert-centered PRO questionnaires in AA and PNH were created following the concepts of validated instruments. CONCLUSION: The development of symptom self-reporting questionnaires for AA and PNH was feasible and the disease-specific PRO questionnaires can now be validated within a web-based workflow in a subsequent feasibility study.

Very long-term follow-up of aplastic anemia treated with immunosuppressive therapy or allogeneic hematopoietic cell transplantation.

INTRODUCTION: Since the 1970s outcome of aplastic anemia (AA) patients has improved significantly due to the introduction of immunosuppressive therapy (IST) and allogeneic hematopoietic transplantation (HCT). However, patients may suffer from persistent disease, relapse, clonal evolution, graft-versus-host disease and other late effects. Here, we analyse very long-term outcome of all AA patients at our institution comparing not only survival, but also response status and complications. METHODS: Patient charts of all 302 AA patients treated between 1973 and 2017 at the University Hospital Basel, Switzerland, were retrospectively analysed. RESULTS: First line treatment was IST in 226 (75%) and HCT in 76 (25%) patients. Overall survival at 30 years was similar in patients treated initially by HCT and IST (44% (±14%), and 40% (± 9%) respectively, with better results in more recent years. Partial and no response occurred more frequently after IST, relapse incidence after IST was 24 %, whereas non-engraftment and graft failure was documented in 15 patients (19 %) after HCT. Clonal evolution to myelodysplastic syndrome / acute myeloid leukemia was 16 % at 25 years in IST patients, 1.3 % in HCT patients, iron overload (18 versus 4 %, p = 0.002) and cardiovascular events (11 versus 1 %, p=0.011) occured significantly more often in IST than HCT treated patients. The majority of long-term survivors, 96% of those alive at 25 years, were in complete remission at last follow up, irrespective of the initial treatment modality. CONCLUSION: Very long term survivors after AA are those with stable hematopoietic recovery.