International Recommendations for Screening and Preventative Practices for Long-Term Survivors of Transplantation and Cellular Therapy: A 2023 Update.

As hematopoietic cell transplantation (HCT) and cellular therapy expand to new indications and international access improves, the number of HCTs performed annually continues to rise. Parallel improvements in HCT techniques and supportive care entails more patients surviving long term, creating further emphasis on survivorship needs. Survivors are at risk for developing late complications secondary to pretransplantation, peritransplantation, and post-transplantation exposures and other underlying risk factors. Guidelines for screening and preventive practices for HCT survivors were originally published in 2006 and then updated in 2012. An international group of experts was convened to review the contemporary literature and update the recommendations while considering the changing practices of HCT and cellular therapy. This review provides updated pediatric and adult survivorship guidelines for HCT and cellular therapy. The contributory role of chronic graft-versus-host disease (cGVHD) to the development of late effects is discussed, but cGVHD management is not covered in detail. These guidelines emphasize the special needs of patients with distinct underlying HCT indications or comorbidities (eg, hemoglobinopathies, older adults) but do not replace more detailed group-, disease-, or condition-specific guidelines. Although these recommendations should be applicable to the vast majority of HCT recipients, resource constraints may limit their implementation in some settings.

International recommendations for screening and preventative practices for long-term survivors of transplantation and cellular therapy: a 2023 update.

As hematopoietic cell transplantation (HCT) and cellular therapy expand to new indications and international access improves, the volume of HCT performed annually continues to rise. Parallel improvements in HCT techniques and supportive care entails more patients surviving long-term, creating further emphasis on survivorship needs. Survivors are at risk for developing late complications secondary to pre-, peri- and post-transplant exposures and other underlying risk-factors. Guidelines for screening and preventive practices for HCT survivors were originally published in 2006 and updated in 2012. To review contemporary literature and update the recommendations while considering the changing practice of HCT and cellular therapy, an international group of experts was again convened. This review provides updated pediatric and adult survivorship guidelines for HCT and cellular therapy. The contributory role of chronic graft-versus-host disease (cGVHD) to the development of late effects is discussed but cGVHD management is not covered in detail. These guidelines emphasize special needs of patients with distinct underlying HCT indications or comorbidities (e.g., hemoglobinopathies, older adults) but do not replace more detailed group, disease, or condition specific guidelines. Although these recommendations should be applicable to the vast majority of HCT recipients, resource constraints may limit their implementation in some settings.

Current incidence, severity, and management of veno-occlusive disease/sinusoidal obstruction syndrome in adult allogeneic HSCT recipients: an EBMT Transplant Complications Working Party study.

The current incidence, diagnostic policy, management, and outcome of VOD/SOS at EBMT centers were studied. All centers that had performed allogeneic HSCTs in adult patients within one defined year were invited to the study. Seventy-one centers participated with a total of 2886 allogeneic transplantations and 93 cases of VOD/SOS in 2018. The cumulative incidence of VOD/SOS at day 21 was 1.8% and at day 100 2.4%. Of 67 cases with detailed data, 52 were classical and 15 (22%) late onset (>day 21). According to the EBMT criteria, 65/67 patients had at least two VOD/SOS risk factors. The severity grades were: mild 0, moderate 3, severe 29, very severe 35. Fifty-four patients were treated with defibrotide. VOD/SOS resolved in 58% of the patients, 3/3 with moderate, 22/28 with severe, and 12/33 with very severe grade (p < 0.001). By day 100, 57% of the patients were alive; 3/3 with moderate, 22/29 with severe, and 13/35 with very severe VOD/SOS (p = 0.002). In conclusion, the incidence of VOD/SOS was low. Severe and very severe grades dominated. Very severe grade predicted poor outcome compared to severe grade further supporting the concept of early diagnosis and treatment to avoid a dismal outcome.

Return to Work Among Young Adult Survivors of Allogeneic Hematopoietic Cell Transplantation in the United States.

Young adult (YA) survivors of allogeneic hematopoietic cell transplantation (HCT) are at risk for late psychosocial challenges, including the inability to return to work post-HCT. Work-related outcomes in this population remain understudied, however. We conducted this study to assess the post-HCT work status of survivors of allogeneic HCT who underwent HCT as YAs and to analyze the patient-, disease-, and HCT-related factors associated with their work status at 1 year post-HCT. Using Center for International Blood and Marrow Transplant Research data, we evaluated the post-HCT work status (full-time, part-time work, unemployed, or medical disability) of 1365 YA HCT survivors who underwent HCT between 2008 and 2015. Percentages of work status categories were reported at 4 time points: 6 months, 1 year, 2 years, and 3 years post-HCT. Percentages of post-HCT work status categories at the 1-year time point were also described in relation to survivors' pre-HCT work status categories. Factors associated with 1-year post-HCT work status (full-time or part-time work) were examined using logistic regression. From 6 months to 3 years post-HCT, the percentage of survivors working full-time increased from 18.3% to 50.7% and the percentage working part-time increased from 6.9% to 10.5%. Of patients in full-time work pre-HCT, 50% were unemployed or on medical disability at 1 year post-HCT. Female sex (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.40 to 0.77), HCT Comorbidity Index score ≥3 (OR, 0.57; 95% CI, 0.39 to 0.82), pre-HCT unemployment (OR, 0.37; 95% CI, 0.24 to 0.56), medical disability (OR, 0.44; 95% CI, 0.28 to 0.70), development of grade III-IV acute graft-versus-host disease (OR, 0.52; 95% CI, 0.34 to 0.80), and relapse within 1 year post-HCT (OR, 0.34; 95% CI, 0.21 to 0.56) were associated with a lower likelihood of employment at 1 year post-HCT. Compared with myeloablative conditioning (MAC) with total body irradiation (TBI), MAC without TBI (OR, 1.71; 95% CI, 1.16 to 2.53) was associated with a greater likelihood of employment at 1 year post-HCT. Graduate school-level education (OR, 2.47; 95% CI, 1.49 to 4.10) was also associated with a greater likelihood of employment at 1 year post-HCT. Although the work status among YA HCT survivors continued to improve over time, a substantial subset became or remained unemployed or on medical disability. These findings underscore the need for effective interventions to support return to work in this population.

Investigation and Management of Bone Mineral Density Following Hematopoietic Cell Transplantation: A Survey of Current Practice by the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation.

Reduced bone mineral density (BMD) is a well-recognized complication of hematopoietic cell transplantation (HCT), with significant drops in BMD occurring within the first 12 months after HCT. Guidance on identifying and managing this complication is available in several published guidelines. In this study, we investigated current practices in the investigation and management of low BMD in centers registered with the European Society for Blood and Marrow Transplantation (EBMT). A questionnaire about bone health was sent to all registered centers, and responses were received from 99 centers in 25 countries (52%) currently registered with the EBMT. Our data highlight considerable heterogeneity in practices across European centers in relation to investigations, management, and use of guidelines. Our data demonstrate the need for better dissemination and implementation of existing guidelines and also for the development of multidisciplinary guidelines with input from all relevant stakeholders.

Gonadal Function after Busulfan Compared with Treosulfan in Children and Adolescents Undergoing Allogeneic Hematopoietic Stem Cell Transplant.

Gonadal impairment is an important late effect with a significant impact on quality of life of transplanted patients. The aim of this study was to compare gonadal function after busulfan (Bu) or treosulfan (Treo) conditioning regimens in pre- and postpubertal children. This retrospective, multicenter study included children transplanted in pediatric European Society for Blood and Marrow Transplantation (EBMT) centers between 1992 and 2012 who did not receive gonadotoxic chemoradiotherapy before the transplant. We evaluated 137 patients transplanted in 25 pediatric EBMT centers. Median age at transplant was 11.04 years (range, 5 to 18); 89 patients were boys and 48 girls. Eighty-nine patients were prepubertal at transplant and 48 postpubertal. One hundred eighteen children received Bu and 19 Treo. A higher proportion of girls treated with Treo in the prepubertal stage reached spontaneous puberty compared with those treated with Bu (P = .02). Spontaneous menarche was more frequent after Treo than after Bu (P < .001). Postpubertal boys and girls treated with Treo had significantly lower luteinizing hormone levels (P = .03 and P = .04, respectively) compared with the Bu group. Frequency of gonadal damage associated with Treo was significantly lower than that observed after Bu. These results need to be confirmed in a larger population.

Role of Physical Therapy before and after Hematopoietic Stem Cell Transplantation: White Paper Report.

Hematopoietic stem cell transplantation (HSCT) patients can suffer from various musculoskeletal problems resulting in long-term functional incapacity. Physical therapy (PT), as a part of the healthcare team, has been historically advocated for regaining functional capacity and improving quality of life post-HSCT. Because of the nature of this condition and the burden of post-transplant complications, this patient group requires a unique approach toward their rehabilitation that takes into account their complex musculoskeletal presentation ranging from fascia, muscle, tendons, bones, and ligaments. However, to our knowledge there is no universal standardized PT protocol or pathway to help guide rehab specialists to achieve optimal gains for this patient group, and anecdotal evidence suggests that these patients do not always receive the PT care they require. Hence, in collaboration with the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation, the Survivorship Special Interest Group of the American Society of Blood and Marrow Transplantation, and the Quality of Life Committee of the Eastern Mediterranean Blood and Marrow Transplantation, herein the Physical Therapy Association for Graft Versus Host Disease provides a brief review on role of PT in mitigating musculoskeletal complications in HSCT patients and makes evidence-based recommendations for incorporation of PT into routine HSCT care.

European experience and risk factor analysis of donor cell-derived leukaemias/MDS following haematopoietic cell transplantation.

Donor cell leukaemia (DCL) is a rare complication of allogeneic haematopoietic cell transplantation (HCT). We have investigated the prevalence and outcome of donor cell haematology malignancies within centres registered with the European Society of Blood and Marrow transplantation (EBMT). We have sought to identify risk factors to shed light on the pathogenesis of DCL as a model for leukaemogenesis. DCL cases were identified by questionnaire and a follow-up questionnaire requested detailed data. Control subjects from the EBMT registry who had not developed DCL were used for a matched pair analysis to identify risk factors. We identified 38 patients with DCL; the estimated prevalence was 80.5/100,000 transplants. Patients were predominantly treated for haematological malignancy. A clone was retrospectively identified in 7/25 (28%) donors for whom data was available. Overall survival was poor with 29/38 patients dead a median of 11 (range 0-91) months after DCL diagnosis. Matched case-pair analysis identified three factors on multivariate analysis as significantly associated with an increased risk for DCL: use of growth factors within the first 100 days after transplantation, in vivo T-cell depletion and multiple allografts. The risk factors identified, support reduced immune surveillance and replicative stress as pathogenic in the development of DCL.

Evaluation of Second Solid Cancers After Hematopoietic Stem Cell Transplantation in European Patients.

Importance: Incidence and risk factors of second solid cancers (SSCs) that occur after hematopoietic stem cell transplantation (HSCT) are well documented. However, clinical outcome data of patients who developed an SSC after HSCT are limited. Objective: To assess the outcome of patients with an SSC occurring after HSCT from the time of SSC diagnosis. Design, Setting, and Participants: This cohort study used data of 4065 patients from 26 countries registered with the European Society for Blood and Marrow Transplantation, which has maintained clinical data since 1977 of patients who received a transplant. Information from all patients who underwent a transplant in Europe and had an SSC diagnosis between January 1, 2000, and December 31, 2014, was extracted. The cohort included patients with 18 different cancers. Data analysis was conducted from September 3, 2017, to March 17, 2018. Main Outcomes and Measures: Median and 5-year age-standardized overall survival, causes of death, risk factor multivariate analysis using a clustered Cox proportional hazard regression model, and standardized mortality ratio were calculated for each of the 18 types of SSC. Results: In total, 220 617 patients underwent a transplant, of whom only 4065 (1.8%) patients with a second solid cancer after HSCT were included in the study. Among the 4065 patients, 2321 (57.1%) were men and 1744 (42.9%) were women, with a mean (range) age of 59.1 (3.2-82.3) years at diagnosis of second solid cancer. The 5-year age-standardized overall survival was 47% (95% CI, 45%-49%). The 5-year overall survival rate after SSC diagnosis was poor for pancreas, lung, hepatobiliary, esophageal, brain, and gastric cancers, with a median survival between 0.6 and 1 year. The 5-year overall survival was intermediate for endometrial, colorectal, sarcomas, ovarian, bladder, oropharyngeal, and kidney cancers, with a median survival between 2 and 10 years. The 5-year overall survival was more favorable for melanoma, breast, prostate, cervix, and thyroid cancers, with a median survival of 10 or more years. Additional transplant-associated factors for mortality for patients treated with allogeneic HSCT were age at transplant, donor type, conditioning regimen, and graft-vs-host disease. In total, 1777 patients (43.7%) died, of which 1256 (74.8%) were from SSC, 344 (20.5%) from primary disease, and 79 (4.7%) from other causes. Standardized mortality ratio was higher, compared with de novo solid cancers, for melanoma, prostate, breast, kidney, bladder, colorectal, and endometrial cancers but not for the other cancers. Conclusions and Relevance: The outcome of SSC is mainly dependent on the type of second cancer; thus, future studies should investigate the reasons the standardized mortality ratio is higher for some cancers to identify whether patients with these cancers should be treated differently and to help in screening and counseling patients who developed an SSC after HSCT.

Health-care professionals' perspective on discussing sexual issues in adult patients after haematopoietic cell transplantation.

The majority of adult patients have sexual concerns after post-haematopoietic cell transplantation. Even so, health-care professionals (HCP) do not routinely discuss these problems. We, therefore, surveyed all the members of the European Society for Blood and Marrow Transplantation to evaluate the barriers and facilitators to discussing sexual issues. The 73-item web-survey was completed by 166 registered nurses (RNs) and 126 medical doctors (MDs). Sixty-eight percent reported that they seldom discussed sexual issues. Younger MDs (p < 0.001) and those who work in non-western European countries (p = 0.003), RNs with probably less sexual education themselves (p = 0.002), MDs and RNs who have limited knowledge about sexual complications (p < 0.001) and MDs and RNs who feel uncomfortable discussing sexual issues (p < 0.001) are all less likely to discuss these matters. The major perceived barriers were that patients might be embarrassed if sexual issues were discussed in the presence of a relative (60% RNs, 67% MDs) and that professionals prefer patients to raise sexual issues themselves (54% RNs, 44% MDs). The most important perceived facilitator was for the patient to initiate discussion (≥ 90% for RNs and MDs). Overall, haematopoietic cell transplantation survivors may not be receiving the support on sexual issues they probably need.

A systematic review of clinical prediction scores for deep vein thrombosis.

Objective Diagnosis of deep vein thrombosis remains a challenging problem. Various clinical prediction rules have been developed in order to improve diagnosis and decision making in relation to deep vein thrombosis. The purpose of this review is to summarise the available clinical scores and describe their applicability and limitations. Methods A systematic search of PubMed, MEDLINE and EMBASE databases was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance using the keywords: clinical score, clinical prediction rule, risk assessment, clinical probability, pretest probability, diagnostic score and medical Subject Heading terms: 'Venous Thromboembolism/diagnosis' OR 'Venous Thrombosis/diagnosis'. Both development and validation studies were eligible for inclusion. Results The search strategy returned a total of 2036 articles, of which 102 articles met a priori criteria for inclusion. Eight different diagnostic scores were identified. The development of these scores differs in respect of the population included (hospital inpatients, hospital outpatients or primary care patients), the exclusion criteria, the inclusion of distal deep vein thrombosis and the use of D-dimer. The reliability and applicability of the scores in the context of specific subgroups (inpatients, cancer patients, elderly patients and those with recurrent deep vein thrombosis) remains controversial. Conclusion Detailed knowledge of the development of the various clinical prediction scores for deep vein thrombosis is essential in understanding the power, generalisability and limitations of these clinical tools.

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Cardiovascular Disease and Associated Risk Factors Working Group Report.

A number of studies have shown that autologous and allogeneic hematopoietic cell transplantation (HCT) contribute to an increased incidence of cardiovascular disease (CVD) and worsening of cardiovascular risk factors that could contribute to further CVD over time. These observations, combined with a notable increase in the number of survivors after HCT in recent years, highlight the need for studies aimed at modifying risk or preventing these outcomes by changing specific approaches and/or post-HCT interventions. To address these issues, the National Heart, Lung and Blood Institute and National Cancer Institute co-sponsored an international initiative on late effects after HCT. This report summarizes the major gaps in knowledge along with detailed recommendations regarding study priorities from the Cardiovascular Disease and Associated Risk Factors Committee, a multidisciplinary panel of international experts. The committee calls for specific studies aimed at understanding and preventing arterial disease and cardiac dysfunction (heart failure, valvular disease, and arrhythmias), as well as decreasing cardiovascular risk factors (hypertension, hyperglycemia, dyslipidemia, and sarcopenic obesity) after HCT.

Recommended screening and preventive evaluation practices of adult candidates for hematopoietic stem cell transplantation.

INTRODUCTION: Hematopoietic stem cell transplantation (HSCT) is associated with a substantial risk of morbidity and mortality. Better selection of HSCT patients for intensive treatment, and consequently reduction of non-beneficial care, may improve the therapeutic outcome. AREAS COVERED: This manuscript provides a systematic review which examines t he current criteria for selection of HSCT patients. EXPERT OPINION: Identifying patients who may benefit from HSCT involves many factors, including overall health, prior therapies, age, disease, and stage. The decision regarding transplant eligibility should be made on a case by case basis, based on a risk-benefit assessment. The advent of the comorbidity index as a measure of health status at the time of HSCT has facilitated the incorporation of comorbidities into the pre-transplant assessment of patients. Many HSCT protocols are still age-dependent, with criteria limited to patients either younger or older than arbitrary age cut-offs.The prognostic role of age in the transplant setting has never been consistent. As physicians and researchers continue improving the HSCT process and outcomes, optimization of the delivery of a comprehensive treatment plan should become an important component of overall patient management.

Metabolic Syndrome and Cardiovascular Disease after Hematopoietic Cell Transplantation: Screening and Preventive Practice Recommendations from the CIBMTR and EBMT.

Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors that increases the risk of cardiovascular disease, diabetes mellitus, and all-cause mortality. Long-term survivors of hematopoietic cell transplantation (HCT) have a substantial risk of developing MetS and cardiovascular disease, with an estimated prevalence of MetS of 31% to 49% among HCT recipients. Although MetS has not yet been proven to impact cardiovascular risk after HCT, an understanding of the incidence and risk factors for MetS in HCT recipients can provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal to review literature and recommend practices appropriate to HCT recipients. Here we deliver consensus recommendations to help clinicians provide screening and preventive care for MetS and cardiovascular disease among HCT recipients. All HCT survivors should be advised of the risks of MetS and encouraged to undergo recommended screening based on their predisposition and ongoing risk factors.

Teaching skills training for medical students.

BACKGROUND: The UK General Medical Council has recommended that medical students be taught how to teach; however, the current state of teaching skills training in England has not yet been investigated. AIMS: To explore the current state of undergraduate teaching skills training at medical schools in England. METHODS: A questionnaire survey was sent to all 24 medical schools in England, enquiring about the basic structure, content areas, staffing, delivery and assessment methods of compulsory courses. RESULTS: A response rate of 22/24 (92%) was achieved, and 18/22 (82%) of the responding institutions offered some form of teaching skills training. The most frequently covered content areas were small group facilitation skills, large group teaching skills and use of effective feedback. Teaching was delivered by a combination of hospital doctors, non-physician educators or general practitioner educators in the majority of courses. Six of the nine (67%) compulsory courses featured student assessments. The main barriers to implementing these courses were staffing limitations, insufficient time and lack of student engagement. CONCLUSIONS: Our study demonstrates both the similarities and variation between undergraduate teaching skills courses across England. However, further research will be necessary to determine whether the long-term impact of such training will result in better educators, and ultimately in improved patient care.

Ongoing graft-versus-host disease is a risk factor for azoospermia after allogeneic hematopoietic stem cell transplantation: a survey of the Late Effects Working Party of the European Group for Blood and Marrow Transplantation.

The aim of this study was to assess the degree of spermatogenesis defects in sperm analysis in long-term male survivors after allogeneic hematopoietic stem cell transplantation in order to identify the risk factors related to potential infertility after hematopoietic stem cell transplantation and to provide data on longitudinal sperm recovery after hematopoietic stem cell transplantation. Here, the Late Effects Working Party of the European Group for Blood and Marrow Transplantation reports data of sperm analysis from 224 males who underwent hematopoietic stem cell transplantation. Median time between transplantation and sperm analysis was 63 months (8-275 months). At last sperm analysis, presence of any degree of spermatozoa was reported in 70 (31%) and complete azoospermia in 154 (69%) patients. In multivariate analysis, being conditioned with total body irradiation (RR 7.1; 95% CI: 3.4-14.8) and age over 25 years at transplantation (RR 2.4; 95% CI: 1.09-5.2) were significantly associated with higher risk for azoospermia. In patients not conditioned with total body irradiation, ongoing chronic graft-versus-host disease is the main adverse factor for sperm recovery (RR of 3.11; 95% CI: 1.02-9.47; P=0.045). Already established risk factors, such as total body irradiation and age older than 25 years at hematopoietic stem cell transplantation, were seen to be the most relevant adverse risk factor for sperm production after hematopoietic stem cell transplantation. Furthermore, for the first time, ongoing graft-versus-host disease has been shown to be the most relevant adverse factor for sperm recovery, particularly in patients conditioned without total body irradiation. We also introduce a useful scoring system to predict the probability of male long-term survivors' azoospermia.