Hematopoietic Cell Transplantation Survivors Research Articles

Serum anti-Müllerian hormone as a marker of ovarian reserve after cancer treatment and/or hematopoietic stem cell transplantation in childhood: proposal for a systematic approach to gonadal assessment.

Female patients treated with alkylating agents in childhood are at risk for ovarian impairment. We aimed at describing the pattern of residual ovarian function in a cohort of survivors of hematological malignancies and/or hematopoietic stem cell transplantation (HSCT) and assessing the relationship between cyclophosphamide equivalent dose (CED) and anti-Müllerian hormone (AMH). Gonadal health was clinically and biochemically assessed in 124 post-menarchal survivors who underwent treatment for pediatric hematological malignancies and/or HSCT between 1992 and 2019. Overt 'premature ovarian insufficiency' (POI) was detected in 72.1 and 3.7% of transplanted and non-transplanted patients, respectively; milder 'diminished ovarian reserve' (DOR) in 16.3 and 22.2%. In non-transplanted patients, increasing CED values were associated with lower AMH-SDS (P = 0.04), with the threshold of 7200 g/m2 being the best discriminator between DOR/POI and normal ovarian function (AUC: 0.75 on ROC analysis) and with an observed decrease of 0.14 AMH-SDS for each CED increase of 1 g/m2. In addition, age at diagnosis ≥10 years played a detrimental role on ovarian reserve (P = 0.003). In the HSCT group, irradiation was associated with a statistically significant reduction in AMH-SDS (P = 0.04). In non-transplanted patients, CED ≥ 7200 mg/m2 was associated with a DOR, while younger age at diagnosis played a protective role on ovarian reserve. As a result of the data collected, we propose a systematic algorithm to assess iatrogenic gonadal impairment in young female patients exposed to chemo-radiotherapy in childhood for hematological disorders.

Development and Implementation of an Advanced Practitioner-Led Survivorship Clinic for Patients Status Post Allogeneic Transplant.

Background:Survivor recovery from hematopoietic cell transplantation (HCT) is long term, with significant physical and psychological morbidities that impact quality of life and reentry into personal and social lives. The optimal timing of when and how to deliver comprehensive HCT survivorship care is not well defined.Purpose:The purpose of this study was to design, implement, and evaluate an advanced practitioner (AP)-led pilot survivorship clinic incorporating an individual and group format for patients post HCT at the 1-year transition period.Methods:A survey assessing physical, social, emotional, and spiritual needs and concerns was mailed to a sample of patients who underwent HCT between 2009 and 2014. This phase 1 survey was utilized in the phase 2 design of an AP-led pilot survivorship clinic for patients post allogeneic HCT. A total of 15 patients were approached, out of which 7 enrolled over a 12-month period in the pilot survivorship clinic.Results:The needs assessment survey noted the most prevalent moderate to high concerns were in the emotional domain, with 52% of respondents identifying fear of cancer returning and new cancer developing. The pilot survivorship clinic incorporating a group visit format with multiple sessions was not feasible for both patients and APs within the context of a small- to medium-sized HCT program.Conclusion:The needs assessment survey underscored the importance of addressing all four quality of life domains in cancer survivors. A hybrid survivorship clinic with one comprehensive group visit may be beneficial for HCT survivors at the 1-year transition for small- to medium-sized HCT programs.

A non-interventional study of microcirculation dynamics in allogeneic hematopoietic cell transplantation survivors compared to controls: evidence of impaired microvascular response regardless of conventional cardiovascular risk factors.

Allogeneic hematopoietic cell transplantation (alloHCT) survivors have been recently recognized as patients at increased cardiovascular risk. We hypothesized that vascular function remains impaired in alloHCT survivors free of graft-versus-host-disease or relapse. We enrolled consecutive adult alloHCT survivors and non-HCT control individuals (January 2019-March 2020), matched for traditional cardiovascular risk factors. Microvascular dysfunction was dynamically assessed in real time by Laser Speckle Contrast Analysis (LASCA). Carotid-femoral pulse-wave velocity (PWV) and carotid intima media thickness (IMT) were assessed as surrogate markers of cardiovascular disease. We studied 75 patients after a median of 3.2 (range 2.1-4.9) years from alloHCT, who had suffered from grade 2 to 3 acute (20%) and/or moderate/severe chronic GVHD (42%), and 75 controls. Although traditional cardiovascular risk factors and surrogate markers of cardiovascular disease did not differ between groups, alloHCT survivors showed significantly impaired microvascular function (baseline and peak flux, time to peak, base to peak and base to occlusion change). LASCA indices were also independently associated with alloHCT. Our study shows for the first-time impaired microcirculation dynamics in alloHCT survivors, independently of cardiovascular risk factors. Additional studies are needed to address the role of novel markers in cardiovascular risk prediction, along with effects of disease type, phase, and pre-transplant treatments.

Impact of chronic GVHD on QOL assessed by visual analogue scale in pediatric HSCT survivors and differences between raters: a cross-sectional observational study in Japan.

A nationwide cross-sectional survey was conducted in long-term survivors of allogeneic hematopoietic stem cell transplantation (HSCT) in childhood to investigate the effect of chronic graft-versus-host disease (cGVHD) on quality of life (QOL) and differences in QOL assessments between raters. QOL was evaluated by a visual analogue scale (VAS). Assessments were compared between the survivor, guardian, and attending pediatrician for those aged 15years or younger, and between the survivor and attending pediatrician for those aged 16years or older. For cGVHD, severity scores were obtained by organ and their association with the VAS score was analyzed. The average pediatrician-rated VAS score was higher than that of other raters for both patient age groups (< 15years and > 16years). By organ, involvement of the skin, digestive organs, and joints in GVHD affected the VAS scores. A high joint score was associated with a low VAS score, and conversely, a high lung score was associated with a low pediatrician-rated VAS score. Our results indicate that differences between raters must be considered when evaluating QOL of HSCT survivors, because patients appeared to experience grater inconvenience and difficulties due to joint GVHD than their pediatricians perceived.

Cumulative incidence of subsequent malignancy after allo-HCT conditioned with or without low-dose total body irradiation

AbstractSubsequent malignancies (SMs) present a significant burden of morbidity and are a common cause of late mortality in survivors of allogeneic hematopoietic cell transplant (allo-HCT). Previous studies have described total body irradiation (TBI) as a risk factor for the development of SMs in allo-HCT survivors. However, most studies of the association between TBI and SM have examined high-dose TBI regimens (typically ≥600 cGy), and thus little is known about the association between low-dose TBI regimens and risk of SMs. Our goal, therefore, was to compare the cumulative incidence of SMs in patients of Alberta, Canada, who received busulfan/fludarabine alone vs busulfan/fludarabine plus 400 cGy TBI. Of the 674 included patients, 49 developed a total of 56 malignancies at a median of 5.9 years' posttransplant. The cumulative incidence of SMs at 15 years' post-HCT in the entire cohort was 11.5% (95% confidence interval [CI], 8.5-15.6): 13.4% (95% CI, 9.1-19.3) in the no-TBI group and 10.8% (95% CI, 6.6-17.4) in the TBI group. In the multivariable model, TBI was not associated with SMs, whereas there was an association with number of pre-HCT cycles of chemotherapy. The standardized incidence ratio for the entire cohort, compared with the age-, sex-, and calendar year–matched general population, was 1.75. allo-HCT conditioning that includes low-dose TBI does not seem to increase risk of SMs compared with chemotherapy-alone conditioning.

Resignation and return to work in patients receiving allogeneic hematopoietic cell transplantation close up.

To characterize the issues regarding work and employment specific to allogeneic hematopoietic cell transplantation (allo-HCT) survivors, we conducted a nationwide cross-sectional questionnaire survey. We targeted allo-HCT survivors employed at diagnosis, aged 20-64 at survey, and survived ≥2years without relapse. The questionnaire included the timing of and reasons for resignation (termination of employment contract), and patient-related, HCT-related, work-related, and HCT center-related factors. A total of 1048 eligible participants were included in the analysis (response rate, 60%). The median time after allo-HCT was 5years (range, 2-30) at the time of survey. After diagnosis, 41% of participants resigned from work throughout the course of treatment. The most frequent timing of the first resignation was "after discharge post-HCT" (46%), followed by "from diagnosis to initial treatment" (27%). Factors significantly associated with resignation included female gender, older age, and part-time employment. Favorable factors included the presence of occupational health staff at the workplace, employment of ≥10years, and self-employed/freelance. After resignation, the overall incidence of return to work with some accommodations was 76% at 5years after HCT, but it was 52% without any accommodation. Overall, the rate of resignation was 41%, and the most frequent timing of resignation was after discharge post-HCT, accounting for approximately half of the resignations (46%). Workplace accommodations increased the rate of return to work from 52% to 76%. Early detection of employment-related concerns and support throughout the treatment process are necessary for patients receiving allo-HCT.

Metabolic syndrome and cardiovascular disease after haematopoietic cell transplantation (HCT) in adults: an EBMT cross-sectional non-interventional study

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.

Feasibility and acceptability of a home-based resistance training intervention in adolescent and young adult hematopoietic cell transplant survivors.

Adolescent and young adult (AYA) hematopoietic cell transplantation (HCT) survivors are at increased risk of metabolic syndrome and lean body mass (LBM) deficits. Resistance training (RT) is a potential intervention to improve LBM, metabolic fitness, and reduce risk of cardiovascular disease. Eligible participants ages 13-39years, 80-120days post-HCT, transfusion independent, and prednisone dose ≤1mg/kg/day were approached. Baseline assessments of body composition (DXA), anthropometrics, and strength testing were completed and participants were taught a 12-week, home-based RT intervention with weekly remote coaching. Follow-up assessments were at day +200 (FU1) and +365 post-HCT (FU2). Feasibility targets were (a) 60% enrollment of approached patients, (b) 80% completion of weekly phone calls, and (c) 80% completion of the RT intervention and FU1 assessments. Acceptability was based on positive responses in qualitative interviews. Twenty of 31 (65%) eligible AYAs enrolled. Three participants failed to complete baseline measurements (2=scheduling barriers, 1=passive refusal) and four participants who completed baseline assessments did not receive the intervention (1=medical reasons, 2=no longer interested). Of those who completed baseline assessments, 13 received the intervention, completed 88.5% of coaching calls, and 11 (65%) completed FU1. LBM (kg) increased or remained unchanged in nine of nine participants with complete body composition data at FU1 (mean 1.1kg; 95%CI: 0.4, 1.9). All participants who completed FU1 reported they would recommend the intervention to an AYA HCT survivor. A home-based RT intervention in AYA HCT survivors early post HCT is both feasible and acceptable and may maintain or increase LBM.

Thrombotic Microangiopathy Increases the Risk of Chronic Kidney Disease but Not Overall Mortality in Long-term Transplant Survivors

Thrombotic microangiopathy (TMA) after allogeneic hematopoietic cell transplant (HCT) is associated with acute kidney injury (AKI) and increased mortality. The impact of TMA on chronic kidney disease (CKD) and long-term mortality among HCT survivors has not been fully examined. To assess the risk of CKD and mortality in HCT survivors with and without history of TMA, we conducted a retrospective cohort study among adult allogeneic HCT recipients who survived to at least 1 year post-transplantation. We examined the association between the history of TMA within 1 year and the onset of CKD longitudinally for 5 years with generalized estimating equation (GEE) while adjusting for other key confounders. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 using the CKD-EPI formula with outpatient creatinine values collected during the annual long-term follow-up unit follow-up visits. Kaplan Meier curves landmarked at 1 year were used for survival analyses. Among 2091 adult patients who underwent allogeneic HCT, we identified 1151 patients who survived at least 1 year and had available long-term follow-up data. Among them, 57 patients developed TMA within 1 year and 1094 did not have TMA. There was no pretransplantation baseline difference in eGFR between groups. After adjusting for confounders, history of TMA was associated with an odds ratio of 2.83 (95% confidence interval 1.33-6.03) for CKD development over 5 years after transplantation. The conditional 5-year survival was 78% in the TMA survivors and 80% in the non-TMA survivors (log rank P = .122). HCT survivors with a history of TMA had increased risk of CKD development. Although TMA was associated with high risk of mortality within 1 year after transplantation, long-term survival was comparable with non-TMA survivors. Future therapeutic interventions should focus on not only short-term mortality outcomes, but also short- and long-term kidney outcomes for HCT patients with TMA.

Metabolic Syndrome in Male Survivors of Pediatric Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Total Body Irradiation, Low-Grade Inflammation, and Hypogonadism

Metabolic syndrome (MetS) is a growing concern in survivors of pediatric hematopoietic stem cell transplantation (HSCT), but little is known about the underlying mechanisms. This study aimed to determine the prevalence and clinical presentation of MetS in male long-term survivors of pediatric HSCT and to investigate predisposing factors, including low-grade inflammation, altered fat distribution, and low testosterone levels. We included 98 survivors age 19 to 47 years at a median follow-up of 18 years (range, 8 to 35 years) after pediatric HSCT. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria. The prevalence and clinical manifestations of MetS were compared between our cohort and a control group of males from the background population (n=4767). Fat distribution was assessed by android/gynoid ratio from a whole-body dual-energy X-ray absorptiometry scan. Systemic inflammation was evaluated by IL-6 and high-sensitivity C-reactive protein (hsCRP). Serum testosterone levels were measured in morning samples. The prevalence of MetS was 30%, corresponding to the prevalence in the 50- to 80-year-old males from the background population. In individuals with MetS, hyperglycemia was more frequent in the HSCT survivors compared with age-matched controls with MetS (76% versus 20%; P < .001), whereas hypertension was more dominant in the control group with MetS (69% versus 93%; P=.01). In addition, normal or low body mass index was more commonly observed among HSCT survivors with MetS compared with age-matched controls with MetS (41% versus 11%; P=.002). MetS was more often associated with total body irradiation (TBI) compared with chemotherapy regimens (odds ratio [OR], 4.3; 95% confidence interval [CI], 1.2 to 24.4; P=.02), lower testosterone levels (OR, 5.4; 95% CI, 1.3 to 23.6; P=.02), higher IL-6 levels (OR, 1.8; 95% CI, 1.2 to 2.8; P=.004), and higher hsCRP levels (OR, 1.8; 95% CI, 1.3 to 2.6; P < .001) (estimates per 2-fold increase). In addition, an increased android/gynoid (AG) fat ratio was strongly associated with MetS (OR, 2.1; 95% CI, 1.5 to 2.9; P < .001), even though only 7% of patients met the criteria for increased abdominal circumference. Our results indicate an increased risk of MetS in early adulthood after pediatric HSCT. The clinical manifestations differed from those seen in age-matched controls with MetS, indicating different pathophysiology driven by hyperglycemia, altered fat distribution (despite no clinical abdominal obesity), and low-grade inflammation. Risk factors included TBI-based conditioning and low testosterone levels. These results underline the importance of continuous clinical assessment of the cardiometabolic risk profile and stress the presence of important dissimilarities in the pathophysiology of MetS in HSCT survivors compared with the background population.

Individualized Treatment Summaries and Survivorship Care Plans (SCPs) for Hematopoietic Cell Transplant (HCT) Survivors Reduces Cancer Treatment Distress in a Randomized, Multicenter Study

Purpose: As HCT recipients are at risk for late effects, SCPs are increasingly being used in clinical practice to facilitate survivor care despite the lack of high-quality data on their implementation or efficacy. We conducted a randomized study to evaluate the impact of SCPs on HCT survivors' confidence in survivorship information (CSI), with secondary analyses evaluating cancer treatment distress (CTXD), knowledge of transplant exposures, health behaviors, health care utilization (HCU) and health general self-efficacy.Methods: Adult (≥18 yrs at HCT) survivors who were 1-5 years post-transplant, proficient in English, and without relapse or second cancers were eligible. To enhance generalizability, recipients with any diagnosis, HCT/donor type, and conditioning regimen could participate. Treatment summaries were generated using patient-specific clinical data submitted by transplant centers to the Center for International Blood and Marrow Transplant Research (CIBMTR). Focus group feedback from patients/caregivers, HCT physicians/nurses/social workers and general hematologist-oncologists informed the design of paper-based SCPs. Individualized SCPs were developed based on patient risk-factors and treatment exposures (e.g., age, sex, HCT type, graft-versus-host disease [GVHD], and use of total body irradiation [TBI] or steroids) and published guidelines for long-term followup of HCT survivors (Majhail et al, BBMT 2012). A baseline phone survey was conducted after enrollment and included standardized patient-reported outcomes (PROs) related to the objectives listed above. Patients were then randomized to SCP or routine care (RC) per their transplant center. A phone survey 2 weeks later assessed health literacy for patients on both arms and asked questions related to use of SCP for patients on the intervention arm. End-of-study phone PRO surveys were then administered at 6 months. The study was powered to detect a standardized effect size of ≥0.3 for the intent-to-treat primary outcome of CSI.Results: A total of 495 patients were enrolled at 17 transplant centers, of whom 458 completed baseline survey and were randomized (SCP=231, RC=227); 201 (87%) SCP and 199 (88%) RC patients completed 6 month assessments. Patient and transplant characteristics (including health literacy scores) were well balanced between the two arms. Median age was 59 yrs in both arms; 96% (SCP) and 92% (RC) patients were White, 49% and 60% were male, 48% and 44% had received allogeneic HCT, 11% and 16% had received a previous HCT, and 21% and 20% had received TBI based conditioning, respectively. Among allogeneic HCT recipients, 63% and 67% had a history of acute GVHD and 60% and 66% had a history of chronic GVHD, respectively. Receiving a SCP was not associated with a change in CSI, but was significantly associated with reduction in CTXD after Bonferroni correction for multiple outcomes (Table). Decrease in CTXD score in the SCP arm was independent of sex, transplant type, GVHD status, diagnosis, and health literacy. Age was significantly associated with CTXD scores (with higher distress among younger patients), although not with the SCP effect size (no significant interaction). No SCP effect was observed on any of the other secondary outcomes.Summary: In this large multicenter randomized study, we demonstrate that SCPs generated automatically using a centralized clinical registry (CIBMTR) to individualize to patient risk-factors, without clinical contact to interpret or personalize the SCP, is feasible and can produce a tool that lowers CTXD scores at 6 months in HCT survivors. Our study supports further development and implementation of individualized SCPs in this population that is at significant risk for late morbidity and mortality from transplantation. [Display omitted] DisclosuresMajhail:Anthem, Inc.: Consultancy; Sanofi: Honoraria.

Allogeneic Hematopoietic Cell Transplantation Causes Accelerated Aging Both of the Hematopoietic and Somatic Systems

Recent reports suggest that survivors of hematopoietic cell transplantation (HCT) exhibit clinical features consistent with accelerated aging including increased incidence of endocrinological, pulmonary and cardiovascular morbidity, other severe chronic disorders and excess of secondary malignancies. In addition, high incidence of frailty - a physiologic measure of aging, was documented in childhood cancer survivors. Data from additional studies suggest that cytotoxic therapy triggers an acceleration of the aging process whose likely mechanism may be cellular senescence. In order to corroborate the physiological and epidemiological data, more accurate biological markers of senescence should be assessed. Indeed, several studies, including from our group, reported on telomere shortening after HCT. Other studies showed elevation of inflammatory biomarkers, those being associated with the aging process. The accuracy of these biological markers is disputable due to inherent problems in their interpretation. Recently, several more accurate biomarkers of cellular age have been reported. The most promising is the DNA methylation status of several genomic loci, which can determine the cellular age with accuracy of 1.5 to 3 years. Additional markers, such as p16ink4A and IL-6 concentrations in serum are also considered as reliable markers of age.The present study assessed the hematopoietic and non-hematopoietic systems aging trajectory after allogeneic HCT. We took advantage of being able to assess quantitatively the hematopoietic system comparing blood cells derived from one person (the donor) and residing in two different hosts (donor and recipient). The blood cells aging may be affected by replicative stress after HCT and therefore do not necessarily represent the whole body aging; therefore we measured the age of buccal epithelial cells of the transplant survivors as well. For cellular age determination we used DNA methylation in three sites, previously validated as an accurate age determination method, p16ink4A blood levels and serum IL-6 concentration. To the best of our knowledge, this is the first study employing these novel markers for assessment of accelerated aging in a clinical setting.26 survivors of allogeneic HCT (median age, 48 years; range, 28 to 71) were evaluated at a median of 3.6 (range, 2.2 to 9) years after HCT. The cellular age of donor blood cells residing in the recipient was compared with the age of the blood cells residing in the respective donor and the cellular age of the patients' buccal epithelial cells was compared with their chronological age.In 21 out of 26 patients the cellular age of donor blood cells residing in the patients was significantly higher than that of the respective cells residing in the donor as determined by DNA methylation. The mean excess aging of the cells was 8.3 (range -5 to 30) years and in most of the patients the cells were more than 10 years “older” than the donors' cells. The buccal epithelial cells predicted age was also significantly higher than the chronological age; the median excess of aging was 8.7 (range, -37 to 10.5) years. The two other biomarkers of aging: IL-6 and p16ink4A also demonstrated advanced age compared to the chronological age. There was no association between the magnitude of aging and previous chemotherapy or GVHD. Telomere length was not significantly shortened in the transplanted patients compared to their donors, consistent with previous reports demonstrating initial telomere shortening and eventual return to normal levels.In conclusion, allogeneic stem cell transplantation is associated with significant accelerated aging of both of the hematopoietic and somatic systems. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Lifestyle Factors and Subsequent Ischemic Heart Disease Risk after Hematopoietic Cell Transplantation

Purpose: To evaluate whether modifiable cardiovascular risk conditions and lifestyle factors are associated with increased risk for subsequent ischemic heart disease (IHD) and overall mortality among hematopoietic cell transplant (HCT) survivors.Methods: Greater than one-year HCT survivors aged ≥20 years, treated from 1970-2010 (n=3,833) were surveyed in 2010-2011 about cardiovascular health and lifestyle factors. Respondents (n=2,360, 61.6%) were then followed longitudinally with annual surveys from 2011-2016 for development of IHD. A series of adjusted models evaluated the relationship (hazard ratio, HR) between conventional cardiovascular risk conditions (obesity, hypertension, dyslipidemia, and diabetes) and lifestyle factors (smoking, fruit/vegetable intake, and physical activity) present at the baseline survey with subsequent IHD and overall mortality.Results: Of the 2,360 HCT survivors (median age at baseline survey, 55.9 years; median time since transplant, 10.8 years), 162 (6.9%) had IHD at time of the baseline survey. Compared with HCT survivors without IHD at the baseline survey, those with IHD had higher rates of hypertension (55.6% vs. 25.8%), dyslipidemia (77.8% vs. 30.6%) and diabetes (34.0% vs. 12.8%), and were less physically active at baseline (54.0% vs. 66.4% met national activity recommendations); p<0.001 for all comparisons. The 5-year overall mortality was markedly higher in HCT survivors with existing IHD compared with those without (28.2% vs. 15.2%, p<0.001). Among those without IHD at time of the baseline survey (n=2,198), the 5-year cumulative incidence of subsequent IHD was 4.3%. Obesity, dyslipidemia, diabetes, and physical inactivity at baseline were all associated with an increased risk for subsequent IHD (Table 1). In contrast, greater physical activity and greater fruit/vegetable intake at baseline were both associated with subsequent reduced overall mortality. When jointly considered, each additional cardiovascular risk condition and each adverse lifestyle factor were independently associated with subsequent IHD (HRs 1.4 [95% CI 1.0-1.9] and 1.9 [95% CI 1.2-2.9], respectively), and adverse lifestyle factors remained associated with overall mortality (HR 1.8 [95% CI 1.5-2.3]). Among those free of IHD at the baseline survey, 492 (23.7%) had Framingham risk scores predicting ≥20% 10-year risk for a serious cardiovascular event, and as expected, those with higher risk scores were more likely to experience subsequent IHD and mortality (Table 1). Overall results remained similar even if HCT survivors who experienced post-HCT relapse were excluded (n=255).Conclusions: In HCT survivors, cardiovascular risk conditions and adverse lifestyle factors influence the subsequent risk of ischemic heart disease and overall mortality. These results support strong efforts to promote healthy lifestyle behaviors and to treat cardiovascular risk factors more aggressively in HCT survivors. Such efforts may reduce future IHD and overall mortality in this high-risk population. [Display omitted] DisclosuresFlowers:Pharmacyclics: Consultancy. Martin:Fresenius, Neovii: Research Funding; Pfizer: Consultancy; Procter and Gamble: Equity Ownership; Incyte: Consultancy. Lee:Kadmon: Other: One-time advisory board member; Mallinckrodt: Honoraria; Amgen: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member.

Increased Proportion of Sickle Cell Disease Patients Develop Cardiovascular Disease Risk Factors Following Successful Hematopoietic Cell Transplantation

Background: Hematopoietic cell transplantation (HCT) is currently the only proven curative treatment for sickle cell disease (SCD), with >90% event-free survival using a matched related donor (MRD). Long-term follow up in patients transplanted for malignant disease demonstrates a 4-fold increase in risk of developing cardiovascular disease (CVD). Risk factors for CVD include obesity, hypertension, diabetes, and dyslipidemia, which are reported in a higher incidence in both survivors of HCT and childhood malignancy. While patients with SCD typically have lower weight and blood pressure (BP) for age, cure of SCD may lead to decreased metabolic demand as well as increased weight and BP, thus uniquely predisposing post-transplant SCD subjects to CVD risk. Further, because of premature mortality due to SCD, true risk of CVD in these patients may be unknown.Objective: To investigate the development of CVD risk factors in SCD subjects who underwent HCT with myeloablative conditioning.Methods: We performed a retrospective data collection on SCD subjects who underwent allogeneic HCT at Children's Healthcare of Atlanta (CHOA) and survived to ³1 year post-HCT. Data on baseline patient and transplant characteristics as well as CVD risk factors (body mass index [BMI], BP, and cholesterol) were collected. BMI was categorized per CDC definition as underweight (<5th%), healthy weight (5th% to <85th%), overweight (85th% to <95th%), or obese (≥95th%). BP was categorized as >50th% and >90th% for patients with SCD, as per Table 1 in Pegelow et al. Pre- and post-HCT values were compared using Wilcoxon signed-rank tests or McNemar's tests, with p-values <0.05 considered statistically significant.Results: Sixty-seven SCD subjects underwent allogeneic HSCT from December 1993 to March 2016 at CHOA, 63 of whom survived to ≥1 year post-transplant. Fourteen patients did not have pre- or post-HCT BMI data available, thus were excluded from the analyses. Majority had clinically severe SCD (77.8%) and received bone marrow (93.3%) from a matched sibling donor (91.1%). Conditioning was myeloablative in all, majority using a combination of busulfan, cyclophosphamide, and anti-thymocyte globulin ± fludarabine. Patients underwent HCT at a median age of 8.8 years (range 1.8-20.3), at which time 40 (88.9%) were healthy weight, while 3 of each (6.7%) were underweight, overweight, and obese (Table 1). At last follow up (median age 10.3 years; range, 3.8-21.8), 27 patients (60.0%) were healthy weight, while 6 (13.3%) were underweight, 5 (11.1%) overweight, and 7 (15.6%) obese. When pre- and post-transplant BMI categories were compared, 66.7% of patients had no change, whereas 17.8% increased and 15.6% decreased. Of the 8 patients whose BMI category increased, 6.7% became overweight and 11.1% obese. Of the 7 patients who BMI category decreased, 2 obese patients (28.6%) became overweight, 2 overweight patients (28.6%) became obese, and 3 normal weight patients (42.9%) became underweight. BMI significantly increased from a median of 16.2 kg/m2 pre- to 19.0 kg/m2 post-HCT (p<0.001). There was no increase in the proportion of patients exceeding either the 50th or 90th percentile for systolic BP post-HCT (Figure 1). The proportion with diastolic BP exceeding 50th or 90th percentile for age for SCD was increased post-HCT compared to baseline. Five patients were diagnosed with hypertension ≥6 months post-transplant, 4 of whom were receiving treatment for chronic graft-versus-host disease (GVHD; steroids, cyclosporine [CSA], or steroids plus CSA) and 1 of whom was overweight. Routine cholesterol testing was rare, consistent with a pediatric cohort, with only 2 patients having hypercholesterolemia, both of whom were receiving treatment for chronic GVHD. Two patients had mildly elevated hemoglobin A1c levels post-HCT and none were diagnosed with diabetes. Ten patients developed chronic GVHD (22.0%), 8 of whom remained in a stable BMI category, with 1 of each either increasing or decreasing.Discussion: Following successful HCT, patients with SCD developed relative diastolic hypertension and increased BMI, both of which are known risk factors for CVD. Patients who developed chronic GVHD were more likely to be diagnosed with hypertension and/or hypercholesterolemia, although BMI category was not impacted. These data provide the rationale for longer term follow up for CVD risk factors and CVD in patients with SCD following HCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Accelerated T Cell Senescence after Allogeneic Hematopoeitic Stem Cell Transplantation

Long-term survivors of allogeneic hematopoietic stem cell transplantation (HSCT) remain susceptible to opportunistic infections, relapse of primary malignancy and development of secondary malignancy, features that are consistent with continued immune deficiency. Reconstitution of T cell populations following HSCT and the preceding conditioning regimens occurs via two main routes: a thymic-dependent generation of naive T cells from progenitors via thymopoeisis, and a thymic-independent peripheral expansion of adoptively transferred, mature T cells in the graft. We hypothesized that dependence on peripheral expansion for reconstitution in individuals over forty years old leads to T cell populations that are prematurely senescent. In this retrospective study of patients who underwent matched, related allogeneic transplantation, we compared PBMCS from a cohort of long-term (4-5 years) survivors of transplant and their original donor infusion products (n=13), evaluating the expession of markers of immunosenescence and aging (CD28, KLRG1, CD57 and PD-1) at each time point. Using multi-parameter flow cytometry, we determined that CD8 cells expressed significantly higher levels of markers of T cell terminal differentiation and senescence post-transplant. Both the frequency and absolute number of Effector Memory and TEMRA, as well as the incidence of cells expressing senescence markers increased. Although there was no significant change in frequency of CD8+ T-cells actively proliferating (% Ki-67+), TREC analysis revealed that the frequency of recent thymic emigrants in the peripheral T-cell pool was reduced long-term. Additionally, we assessed the telomere lengths of CD8+ T-cells using Flow-FISH and, in line with our hypothesis that reliance on peripheral expansion results in replicative senescence, found that they were significantly shorter post-transplant. In conclusion, our study suggests that a contributory factor underlying the disposition for opportunistic infections in long-term survivors of transplant may be premature T cell dysfunction resulting from immune reconstitution-related senescence.Figure Captions:Figure I. Immune reconstitution post-transplant(A) Absolute T, B, and NK cell counts were measured at the donor infusion and post-transplant time points in 13 donor-recipient pairs. Lines indicate median values for each time point. (B) Individual CD4+ and CD8+ T cell changes post-transplant relative to the donor infusion time point. (C) Inversion of the normal CD4:CD8 ratio at the post-transplant time point. (D) Median values for absolute CD4 and CD8 cell counts per uL for the patient cohort throughout the post-transplant time period.Figure II. Alterations in T cell subsets post-transplant(A) Frequencies of Naive (CCR7+ CD45RA+), Central Memory (CCR7+ CD45RA-), Effector Memory (CCR7- CD45RA-), and Effector Memory cells that re-express CD45RA (TEMRA; CCR7- CD45RA+) subsets for both CD4 and CD8 cells at the donor infusion and post-transplant time points. Boxes indicate the 25th quartile, median, and 75th quartile values; whiskers indicate the minimum and maximum values. (B) Absolute cell numbers per uL for each CD4 and CD8 T cell subset. (C) Ratio of absolute cell number for Naïve/Central Memory + Effector Memory populations at the donor infusion and post-transplant time points. (D) TREC analysis of the CD4 and CD8 populations assessing thymic generation of naive T cells at the donor infusion and post-transplant time points (n=6). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cognitive Function in Older Adults with Hematological Malignancies

Background: Mild cognitive impairment is common with increasing age and can contribute to an increased risk of cognitive deficits that impair function and independence. Comprehensive geriatric assessment (CGA) predict treatment toxicity and tolerance in hematological malignancies. We utilized CGA and neuropsychological testing to describe vulnerabilities in a group of older adults awaiting autologous and allogeneic hematopoietic cell transplant (HCT).Methods: From August 2016 to June 2017, 30 consecutive patients ≥ 60 years with hematological malignancies who were considered for HCT completed CGA and neuropsychological assessment at the University of Nebraska Medical Center. Measures of cognitive functioning included a standardized battery of neuropsychological tests [Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery-CERAD-NP)] and Montreal Cognitive Test (MOCA). Patients completed Geriatric Depression Scale-15 (GDS-15), and carepartners completed a Collateral Source version of the GDS.Results: Patients had a median age of 69 years (range 61-78). MOCA and CERAD-NP were completed in 29 and 26 patients, respectively. Twenty patients met criteria for cognitive impairment and 6 patients met criteria for moderate-severe impairment (Table 1). Patients primarily displayed impairment in language, verbal and non-verbal memory, and >20% showed moderate-severe impairment in attention, executive functioning and visuospatial/visuoconstruction. Patients report a median of 3 (range of 0-8) symptoms on the GDS-15. 15% met criteria for depression, whereas 30% met criteria for depression based on reports from carepartners. Over 45% of patients have both impaired physical functioning on the Short Physical Performance Battery (SPPB <8) and cognitive impairment. One fourth of the patients have both cognitive impairment and one or more impairments in instrumental activities of daily living (IADL). In a subset of patients with HCT-CI score of 0-2, 34.5% met criteria for cognitive impairment, 25% had SPPB <8 and 31% had 1 or more impairments in IADL.Conclusions: Older patients with hematological malignancies, including those with HCT-CI score of 0-2 have a high prevalence of cognitive and functional impairment. Impaired memory and executive functioning have implications for their ability to adhere to complex medication regimens after HCT. Carepartners report more depressive symptoms suggesting that patients may be minimizing depressive symptoms. One fourth of patients are at high risk for further cognitive decline and disability due to preexisting cognitive impairment and impairment in IADLs. Prospective longitudinal studies are needed to better understand the trajectory and profile of cognitive changes in older HCT survivors and the impact of these cognitive changes on life activities and quality of life. [Display omitted] DisclosuresWildes:Janssen: Consultancy; Carevive Systems Inc: Consultancy.

Female Sex Is Associated with Improved Long-Term Survival Following Allogeneic Hematopoietic Stem Cell Transplantation

Life expectancy for long-term survivors of allogeneic hematopoietic stem cell transplantation (alloHSCT), defined as those living ≥5 years post-transplantation, is significantly lower compared with that of the age-matched general population despite a relatively low primary disease relapse rate at >2 years post-transplantation. Among several factors, patient sex is increasingly recognized as a prognostic indicator of long-term survival. We examined the influence of patient sex and donor-recipient sex matching on overall survival (OS) in a landmark analysis of long-term survivors. Using our institutional database supplemented with individual patient record review, we retrospectively investigated the relative influence of recipient sex and donor-recipient sex matching on outcomes of long-term survivors of alloHSCT between 1994 and 2014. Over this 20-year period, 247 met inclusion criteria for analysis; males and females had similar demographic and treatment characteristics. However, significantly more deaths after the 5-year landmark occurred in male recipients. Interestingly, donor sex did not have a significant impact on OS in multivariate analysis, and differences in OS of donor-recipient sex pairs was driven by recipient sex. In addition to recipient sex, only chronic graft-versus-host disease (cGVHD) retained significance as a covariate with an impact on OS in multivariate analysis. Men experienced slightly higher, but statistically nonsignificant, rates and increased severity of cGVHD, and had higher cGVHD-related mortality compared with females. In this long-term survival analysis of adult alloHSCT recipients, one of the only to include follow-up to 15 years, our results show that women survive significantly longer than men irrespective of their age at transplantation. This outcome is independent of other common pretransplantation prognostic indicators, such as donor sex or performance status at transplantation. The inferior survival in males is consistent with survival outcomes described in the transplantation literature. Increasing evidence suggests a biological basis for long-term sex-determined outcomes, possibly owing to differing rates or severity of cGVHD or sustained alloimmune tolerance in females. Larger studies are warranted to validate these retrospective clinical results.

Long-term neurocognitive and quality of life outcomes in survivors of pediatric hematopoietic cell transplant.

Pediatric patients who undergo hematopoietic cell transplant (HCT) are at risk for neurocognitive impairments, which can impact quality of life. Given limited long-term studies, we aimed to characterize the late neurocognitive outcomes in a cohort of pediatric HCT survivors. Eligible survivors (HCT at age < 21 year and ≥ 1 year post-HCT) completed a 60-question survey of neurocognitive function and quality of life, which included the Childhood Cancer Survivor Study Neurocognitive Questionnaire (CCSS-NCQ) and the Neuro-Quality of Life Cognitive Function Short Form (Neuro-QoL). Analyses of risk factors included univariate comparisons and multivariable logistic regression. Participants (n = 199, 50.3% female, 53.3% acute leukemia, 87.9% allogeneic transplants) were surveyed at median age of 37.8 years (interquartile range [IQR] 28.5-48.8) at survey and median 27.6 years (IQR 17.0-34.0) from transplant. On the CCSS-NCQ, 18.9-32.5% of survivors reported impairments (Z score > 1.28) in task efficiency, memory, emotional regulation, or organization, compared with expected 10% in the general population (all p < 0.01). In contrast, survivors reported average Neuro-QoL (T score 49.6±0.7) compared with population normative value of 50 (p = 0.52). In multivariable regression, impaired Neuro-QoL (T score < 40) was independently associated with hearing issues (OR 4.97, 95% CI 1.96-12.6), history of stroke or seizure (OR 4.46, 95% CI 1.44-13.8), and sleep disturbances (OR 6.95, 95% CI 2.53-19.1). Although long-term survivors of pediatric HCT reported higher rates of impairment in specific neurocognitive domains, cognitive quality of life was perceived as similar to the general population. Subsets of survivors with certain co-morbidities had substantially worse neurocognitive outcomes. While the long-term impact of pediatric HCT can include neurocognitive deficits, survivors report average cognitive quality of life.

Development of a survivorship screening tool in survivors of hematopoietic cell transplant.

This study describes the development of a screening measure focused on the potential needs of hematopoietic cell transplant (HCT) survivors at least 1-year post-transplant. A multidisciplinary team met regularly to develop a screening measure to better understand the ongoing medical and clinical symptoms experienced by survivors of HCT. This measure was given to 299 patients presenting to an HCT survivorship clinic, with referrals offered for any issues reaching clinical threshold. A factor analysis was performed to examine the underlying factor structure of the measure. Analyses indicated a 3-factor underlying structure, including physical, emotional, and practical concerns. Areas most consistently endorsed as ongoing areas of concern included fatigue, financial concerns, and worry about their future. Interestingly, while many patients were interested in referrals for these issues, some patients did not wish to have their symptoms managed at our center. Survivors of hematopoietic cell transplant continue to experience symptoms well after their treatment has ended, including issues related to the emotional, physical, and practical impact of their illness and treatment regimen. It is vital that their providers understand the frequency of these concerns as well as patients' preference for intervention. While HCT has become increasingly successful in treating hematologic cancers, many survivors experience a range of issues post-transplant. Survivorship care for these patients must include ongoing thorough assessment related to the practical, emotional, and medical symptoms experienced post-transplant, with appropriate intervention provided in-house where possible or in the community according to patient preference.

Evaluation of fatigue and related factors in survivors of pediatric cancer and hematopoietic stem cell transplant.

This study sought to better understand specific factors contributing to fatigue in survivors of pediatric cancer and hematopoietic stem cell transplant (HSCT). As part of a larger study evaluating long-term psychosocial functioning of pediatric cancer survivors, N = 87 participants completed measures assessing fatigue and emotional and behavioral functioning. Chart abstraction was used to catalog diagnosis, treatments received, treatment intensity, and late effects. Results suggest clinically significant fatigue in n = 4 (4.6%) of survivors participating in this study. Fatigue was greater for participants with more recent diagnoses and who were more recently off treatment and was positively associated with parent and self-report of internalizing (emotional) and externalizing (behavioral) symptoms. Participants with more severe late effects suffered greater fatigue; however, fatigue was not associated with treatment intensity or therapy type. Fatigue is an important variable to consider in evaluating the social, emotional, behavioral, and physical well-being of cancer and HSCT survivors. Interventions are needed to address fatigue directly, while also addressing both contributing factors to fatigue and potential negative outcomes that result from fatigue in survivorship.