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

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).; 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).; 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.; ClinicalTrials.gov. Identifier: NCT04789863 . Registered April 01, 2021

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

Haematopoietic cell transplantation in Switzerland, changes and results over 20 years: a report from the Swiss Blood Stem Cell Transplantation Working Group for Blood and Marrow Transplantation registry 1997-2016.

In 1997, the Swiss Blood Stem Cell Transplantation Group (SBST) initiated a mandatory national registry for all haematopoietic stem cell transplants (HCTs) in Switzerland. As of 2016, after 20 years, information was available for 7899 patients who had received an HCT (2781 allogeneic [35%] and 5118 autologous [65%]). As some patients had more than one transplant the total number of transplants was 3067 allogeneic and 6448 autologous. We compared patient characteristics and outcome of the first decade (1997-2006) and second decade (2007-2016) of the registry. There were numerous changes over time. For allogeneic HCT, transplant rates, and therefore use of HCT technology, increased from 14 to 21.8 HCTs per 1 million inhabitants per year from the first to the second decade. Likewise autologous HCTs increased from 24.8 to 37.2 annually corrected for population growth. Allogeneic transplant recipients were older (38.4 vs 48.3 years) and more frequently had unrelated donors in the second decade. Similarly, age increased for recipients of autologous HCT (50.8 vs 56.4 years). Analysis of outcome showed that the probabilities of overall and progression-free survival were stable over time, in spite of the treatment of older and higher risk patients. In multivariate analysis, nonrelapse mortality decreased in recipients of allogeneic HCT (relative risk 0.68, 95% confidence interval 0.52-0.87) over the two decades. Improvement in adjusted nonrelapse mortality compensated for the fact that higher risk patients were treated in more recent years, resulting in similar overall survival. Five-year survival probabilities were 56% (53-59%) in the first and 54% (51-57%) in the second decade for allogeneic HCT, and 59% (57-61%) in the first and 61% (59-63%) in the second decade for autologous HCT. Detailed analyses of changes over time are presented. This study included all HCTs performed in Switzerland during the period of observation and the data are useful for quality assurance programmes, healthcare cost estimation and healthcare planning. Between 50 and 60% of patients were long-term survivors after both types of HCT, indicating growing populations of surviving patients requiring long-term care and observation

Exploring stem cell transplanted patients' perspectives on medication self-management and electronic moni-toring devices measuring medication adherence: A qualitative sub-study of the Swiss SMILe implementa-tion 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

Evaluation of the pretransplantation workup before allogeneic transplantation

An extensive workup is generally performed before allogeneic transplantation. The extent of this workup varies substantially between centers because of a lack of guidelines. We analyzed 157 consecutive allogeneic transplant candidates to understand the significance of components of the pretransplant evaluation. Workup consisted of chest computed tomography (CT); magnetic resonance imaging of the head; dental, ears-nose-throat (ENT), ophthalmology, and gynecology evaluations; pulmonary function tests; echocardiography; cytomegalovirus PCR; urine culture; clinical evaluation; and disease staging. Results were categorized as "normal or minor finding" or "major finding" (having significant consequences such as further testing or therapy). Major findings were classified as incidental or related to history and symptoms. Components of the pretransplant workup with the highest rate of major findings were CT (22%), dental evaluation (13%), and ENT (12%, mostly symptomatic). All other components had a low rate of major findings. Although 126 transplants were performed as scheduled, 24 were delayed and 7 canceled at short notice. The main reasons for delaying or canceling transplantation were active infection and unexpected disease progression. A prospective evaluation of a more restricted, symptom-guided pretransplant evaluation appears to be warranted

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

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.; 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.; 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%).; 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

Synergistic effect of sorafenib and cGvHD in patients with high-risk FLT3-ITD+AML allows long-term disease control after allogeneic transplantation

The multikinase inhibitor sorafenib has shown a strong anti-leukemic effect in FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML); however, remission is often transient. To better understand the role of sorafenib, we performed a retrospective analysis of all patients who received sorafenib in combination with allogeneic hematopoietic stem cell transplantation (HSCT) at our center. Seventeen patients with FLT3-ITD positive AML were treated with sorafenib in combination with allogeneic HSCT. Seven patients received sorafenib therapy pre- and posttransplant, and 10 patients were given sorafenib only posttransplant. Median duration of sorafenib treatment was 13 months (range 1-42); median dose was 600 mg (range 100-1200). Fourteen patients (82 %) achieved a complete remission (CR), while 5 patients (29 %) eventually developed progressive disease. Developing chronic graft-versus-host disease (GvHD) had a strong protective influence on the risk of sorafenib resistance (p = 0.028, HR 0.08, 95 % CI 0.01-0.76). In a total of 8 patients, sorafenib had to be stopped, paused or dose-reduced due to toxicity. In 5 patients with pronounced toxicity, we switched to an alternating dosing schedule with 1 month on/1 month off sorafenib. These patients subsequently remained in sustained complete molecular remission, with a median follow-up of 20 months. Our data indicate that sorafenib can achieve high rates of sustained remission in high-risk patients treated in combination with HSCT

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

Gene-expression Profiling in Patients with Plasma Cell Myeloma Treated with Novel Agents

Novel agents such as thalidomide, lenalidomide and bortezomib have in part anti-angiogenic properties. In this study, we examined gene expression of angiogenic molecules in patients with plasma cell myeloma (PCM).; We included 93 patients with PCM treated with novel agents (immunomodulatory drugs (IMiDs), bortezomib or a combination of both). The mRNA levels of angiogenic molecules were measured using the Human Angiogenesis RT2 Profiler PCR Array. The response evaluation was performed after three cycles.; Regarding all 93 patients, gene expression of 15 out of 84 genes tested (pre- and post-treatment and changes in levels pre-treatment/post-treatment) were significantly different in responders compared to non-responders. Responders had a lower expression of pro-angiogenic factors and increased expression of antiangiogenic factors.; In the IMiD-treated groups we found significant changes of expression of angiogenic genes in responders compared to non-responders, whereas in the bortezomib-based group the difference in expression of angiogenic genes was not significant