Haptoglobin Gene Expression and Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors: A COG-ALTE03N1 Report

Article describes how anthracycline-related cardiomyopathy is a leading cause of premature death in childhood cancer survivors. The authors interrogated differentially expressed genes (DEGs) to identify genetic variants serving regulatory functions or genetic variants not easily identified when using genomewide array platforms

Feasibility of implementing a supervised telehealth exercise intervention in frail survivors of hematopoietic cell transplantation: a pilot randomized trial

Abstract Background Patients undergoing hematopoietic cell transplantation (HCT) are at high risk of chronic health complications, including frailty and physical dysfunction. Conventional exercise programs have been shown to improve frailty in other cancer populations, but these have largely been based out of rehabilitation facilities that may act as geographic and logistical barriers. There is a paucity of information on the feasibility of implementing telehealth exercise interventions in long-term HCT survivors. Methods We conducted a pilot randomized trial to assess the feasibility of an 8-week telehealth exercise intervention in 20 pre-frail or frail HCT survivors. Participants were randomized to either a telehealth exercise (N = 10) or delayed control (N = 10). We administered a remote physical function assessment at baseline, followed by an 8-week telehealth exercise intervention (30-60 min/session, 3 sessions/week), and post-intervention. The primary endpoint was feasibility as determined by 1) > 70% of participants completing all remote physical functional assessments, and 2) > 70% of participants in the exercise group completing > 70% (17/24) of the prescribed exercise sessions. Exploratory outcomes included changes in gait speed, handgrip strength, and short physical performance battery. Results The mean [standard deviation] age at study enrollment was 64.7 [9.1] years old. Twelve had undergone allogenic and 8 had undergone autologous HCT at an average of 17 years from study enrollment. Both feasibility criteria were achieved. Nineteen patients (95%) completed all remote study outcome assessments at baseline and post-intervention, and nine participants in the exercise group completed > 70% of prescribed exercise sessions. Overall, no significant group x time interaction was observed on handgrip strength, fatigue, body mass index, and short physical performance battery test (P < 0.05). However, there were significant within-group improvements in four-meter gait speed (+ 13.9%; P = 0.004) and 5-minute gait speed (+ 25.4%; P = 0.04) in the exercise group whereas non-significant changes in four-meter gait speed (-3.8%) and 5-minute gait speed (-5.8%) were observed after 8 weeks. Conclusion Implementing an 8-week telehealth exercise intervention for long-term HCT survivors was feasible. Our findings set the stage for innovative delivery of supervised exercise intervention that reduces the burden of frailty in HCT survivors as well as other at-risk cancer survivors. Trial registration The protocol and informed consent were approved by the institutional IRB (IRB#20731) and registered (ClinicalTrials.gov NCT04968119; date of registration: 20/07/2021)

Late Mortality after Allogeneic Bone Marrow Transplantation in Childhood for Bone Marrow Failure Syndromes and Severe Aplastic Anemia

Children with bone marrow failure syndromes and severe aplastic anemia (SAA) are treated with allogeneic blood or marrow transplantation (BMT). However, there is a paucity of studies examining late mortality risk after allogeneic BMT performed in childhood for bone marrow failure syndromes and SAA and evaluating how this risk differs between these diseases. We investigated cause-specific late mortality in 2-year survivors of allogeneic BMT for bone marrow failure syndromes and SAA performed before age 22 years between 1974 and 2010 at 2 US transplantation centers. Vital status information was collected from medical records, the National Death Index, and Accurint databases. Overall survival was calculated using Kaplan-Meier techniques. The standardized mortality ratio (SMR) was calculated using age- sex-, and calendar-specific mortality rates from the Centers for Disease Control and Prevention. Among the 2-year survivors of bone marrow failure syndromes (n = 120) and SAA (n = 147), there were 15 and 19 deaths, respectively, yielding an overall survival of 86.4% for bone marrow failure syndromes and 93.1% for SAA at 15 years post-BMT. Compared with the general population, patients with bone marrow failure syndromes were at a higher risk for premature death (SMR, 22.7; 95% CI, 13.1 to 36.2) compared with those with SAA (SMR, 4.5; 95% CI, 2.8 to 7.0) (P <.0001). The elevated relative risk persisted at ≥15 years after BMT for both diseases. The hazard of all-cause late mortality was 2.9-fold (95% CI, 1.1 to 7.3) higher in patients with bone marrow failure syndromes compared with those with SAA. The high late mortality risk in recipients of allogeneic BMT in childhood for bone marrow failure syndromes calls for intensified life-long follow-up

Late Mortality after Allogeneic Blood or Marrow Transplantation for Inborn Errors of Metabolism : A Report from the Blood or Marrow Transplant Survivor Study-2 (BMTSS-2)

Allogeneic blood or marrow transplantation (BMT) is currently considered the standard of care for patients with specific inborn errors of metabolism (IEM). However, there is a paucity of studies describing long-term survival and cause-specific late mortality after BMT in these patients with individual types of IEM. We studied 273 patients who had survived ≥2 years after allogeneic BMT for IEM performed between 1974 and 2014. The most prevalent IEM in our cohort were X-linked adrenoleukodystrophy (ALD; 37.3%), Hurler syndrome (35.1%), and metachromatic leukodystrophy (MLD; 10.2%). Conditional on surviving ≥2 years after BMT, the overall survival for the entire cohort was 85.5 ± 2.4% at 10 years and 73.5 ± 3.7% at 20 years. The cohort had a 29-fold increased risk of late death compared with an age- and sex-matched cohort from the general US population (95% CI, 22- to 38-fold). The increased relative mortality was highest in the 2- to 5-year period after BMT (standardized mortality ratio [SMR], 207; 95% confidence interval [CI], 130 to 308) and declined with increasing time from BMT, but remained elevated for ≥21 years after BMT (SMR, 9; 95% CI, 4 to 18). Sequelae from the progression of primary disease were the most common causes of late mortality in this cohort (76%). The use of T cell-depleted grafts in patients with ALD and Hurler syndrome was a risk factor for late mortality. Younger age at BMT and use of busulfan and cyclosporine were protective in patients with Hurler syndrome. Our findings demonstrate relatively favorable overall survival in ≥2-year survivors of allogeneic BMT for IEM, although primary disease progression continues to be responsible for the majority of late deaths

Burden of Morbidity after Allogeneic Blood or Marrow Transplantation for Inborn Errors of Metabolism : A BMT Survivor Study Report

Survival after blood or marrow transplantation (BMT) for inborn errors of metabolism (IEM) is excellent; however, the burden of morbidity in long-term survivors of BMT for IEM remains understudied. This study examined the risk of chronic health conditions (CHC) in ≥2-year survivors of allogeneic BMT for IEM performed between 1974 and 2014 using the BMT Survivor Study. In this retrospective cohort study, participants (or their parents; n = 154) reported demographic data and CHCs (graded using Common Terminology Criteria for Adverse Events version 5), and transplantation characteristics were obtained from institutional databases. Unaffected siblings (n = 494) served as a comparison group. Logistic regression was used to estimated the odds of severe/life-threatening CHCs compared with siblings. Cox proportional hazards regression was used to estimate factors associated with severe/life-threatening/fatal CHCs in survivors of BMT for IEM. Survivors of allogeneic BMT for IEM (leukodystrophies, 43.5%; mucopolysaccharidoses, 41.0%) were at 12.5-fold higher odds of severe/life-threatening CHCs (95% confidence interval [CI], 5.4 to 28.9) compared with their siblings. The mean 10-year post-BMT cumulative incidence of grade 3-5 CHCs was 47.5 ± 4.0%. Reduced-intensity conditioning (RIC) was associated with a 2.7-fold higher risk (95% CI, 1.2 to 6.2; P = .02) of any grade 3-5 CHC, a 6.7-fold higher risk of grade 3-5 cardiopulmonary conditions (95% CI, 1.3 to 35.4), and a 3.0-fold higher risk of severe hearing/vision deficits (95% CI, 1.4 to 6.6). Older (age >26 years) BMT survivors were significantly less likely to graduate from college (odds ratio [OR], 0.3; 95% CI, 0.1 to 0.7) or marry (OR, 0.01; 95% CI, 0.004 to 0.07) compared with their siblings. Survivors of BMT for IEM carry a significant burden of morbidities, which affects their ability to attain adult milestones. Efforts to reduce chronic health conditions in this population are needed

Severe, life-threatening, and fatal chronic health conditions after allogeneic blood or marrow transplantation in childhood

Background: A comprehensive assessment of morbidity after allogeneic bone marrow transplantation (BMT) performed in childhood remains understudied. Methods: Seven hundred eighty-nine allogeneic BMT recipients who had survived ≥2 years after BMT performed between 1974 and 2014 at age <22 years and 690 siblings completed a 255-item survey self-reporting sociodemographics and chronic health conditions. A severity score (grade 3 [severe], 4 [life-threatening], or 5 [fatal]) was assigned to the conditions using Common Terminology Criteria for Adverse Events, version 5.0. For the BMT cohort, the cumulative incidence of chronic health conditions was calculated as a function of time from BMT. Proportional subdistribution hazards models were used to determine predictors of grade 3–5 conditions. Logistic regression was used to estimate the risk of grade 3–4 conditions in BMT recipients who were alive at the time of this study compared with siblings. Results: The median age at transplantation was 11.3 years (range, 0.4–22.0 years), and the median length of follow-up was 11.7 years (range, 2.0–45.3 years). The most prevalent primary diagnoses were acute lymphoblastic leukemia (30.7%), and acute myeloid leukemia/myelodysplastic syndrome (26.9%). At age 35 years, the cumulative incidence of a grade 3–4 condition was 53.8% (95% CI, 46.7%–60.3%). The adjusted odds ratio of a grade 3–4 condition was 15.1 in survivors (95% CI, 9.5–24.0) compared with siblings. The risk of a grade 3–5 condition increased with age at BMT (hazard ratio [HR], 1.03; 95% CI, 1.01–1.05) and was higher among females (HR, 1.27; 95% CI, 1.02–1.59), patients who received total body irradiation (HR, 1.71; 95% CI, 1.27–2.31), and those reporting chronic graft-versus-host disease (HR, 1.38; 95% CI, 1.09–1.74). Conclusions: Two-year survivors of allogeneic BMT in childhood have an increased risk of grade 3–4 chronic health conditions compared with siblings, suggesting the need for long-term follow-up

Late mortality after autologous blood or marrow transplantation in childhood : A Blood or Marrow Transplant Survivor Study-2 report

Autologous blood or marrow transplantation (BMT) is a curative option for several types of childhood cancer. However, there is little information regarding the risk of late mortality. We examined all-cause mortality, relapse-related mortality (RRM), and nonrelapse-related mortality (NRM) in 2-year survivors of autologous BMT performed before age 22 between 1980 and 2010 at 1 of 2 US transplant centers. Vital status information was collected using medical records, National Death Index, and Accurint databases. Overall survival was calculated using Kaplan-Meier techniques. Cumulative incidence of mortality used competing risk methods. Standardized mortality ratio (SMR) was calculated using age-, sex-, and calendar-specific mortality rates from Centers for Disease Control and Prevention. Cox regression analysis was used to determine predictors of all-cause late mortality. Among the 345 2-year survivors, 103 deaths were observed, yielding an overall survival of 70.3% 15 years post-BMT. The leading causes of death included primary disease (50.0%), subsequent neoplasm (21.4%), and infection (18.2%). Overall, the cohort was at a 22-fold increased risk of late mortality (SMR, 21.8; 95% CI, 17.9-26.3), compared with the general population. Mortality rates remained elevated among the 10-year survivors (SMR, 20.6; 95% CI, 9.9-37.2) but approached those of the general population ≥15 years post-BMT. The 10-year cumulative incidence of RRM (14.3%) exceeded that of NRM (10.4%). The 10-year cumulative mortality rate declined over time (<1990, 35.1%; 1990-1999, 25.6%; 2000-2010, 21.8%; P 5 .05). In conclusion, childhood autologous BMT recipients have an increased risk of late mortality, compared with the general population. The late mortality rates have declined over the past 3 decades