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Hispanic children with acute lymphoblastic leukemia (ALL) have lower 6-mercaptopurine (6MP) adherence and greater hazard of relapse compared with non-Hispanic White children. We examined the association between Spanish language and 6MP adherence, and hazard of relapse. 6MP adherence was measured electronically over a 6-month period. Participants were grouped by the language of demographic questionnaire completion: Non-Hispanic White-English Speaking (ES, n = 159), Hispanic-Spanish Speaking (Hispanic-SS, n = 59), and Hispanic-ES (n = 109). Hispanic-ES had significantly lower fitted median 6MP adherence compared with non-Hispanic White-ES participants (88.3%, 95% CI = 84.7% to 91.2% vs 95.0%, 95% CI = 93.6% to 96.2%, P < .001). There was no difference in fitted median 6MP adherence between Hispanic-ES and Hispanic-SS participants (88.3%, 95% CI = 84.1% to 91.5% vs 88.3%, 95% CI = 84.7% to 91.2%, P = .9) or adjusted hazard of relapse for Hispanic-SS participants (HR = 0.9, 95%CI = 0.3 to 2.4, P = .8). Spanish language use among Hispanic patients with ALL is not associated with lower 6MP adherence or greater relapse risk. Factors related to Hispanic ethnicity, apart from language, appear to influence adherence., (© The Author(s) 2024. Published by Oxford University Press.)

The association between antimetabolite dose intensity (DI) and adverse events among children receiving maintenance therapy for acute lymphoblastic leukemia (ALL) remains unclear, especially in context of antimetabolite adherence. Using COG-AALL03N1 data, we examined the association between high DI during the first four study months and (i) treatment-related toxicities during the subsequent two study months; and (ii) relapse risk. Patients were classified into a high DI phenotype (either 6-mercaptopurine [6-MP] or methotrexate [MTX] DI ≥110% during the first four study months, or 6-MPDI or MTXDI 100%-110% at study enrollment and ≥25% increase over the four study months) and normal DI phenotype (all others). Only patients with wildtype TPMT and NUDT15 were included. 6-MP adherence data were available for 63.7% of study participants and used to stratify as adherent (median adherence ≥85%) and non-adherent (median adherence <85%) participants. Multivariable analyses were adjusted for sociodemographic and clinical prognosticators. Of the 644 patients, 29.3% were exposed to high DI. High DI was associated with a 2.1-fold greater odds of hematologic toxicity (95%CI=1.4-3.1; reference: normal DI) in the entire cohort and 2.9-fold higher among adherers (95%CI=1.6-5.1); odds were comparable among non-adherers (2.1-fold, 95%CI=0.4-10.1).. While high DI was not associated with relapse in the entire cohort (adjusted hazard ratio [aHR]=1.4, 95%CI=0.8-2.4), it was associated with a greater hazard of relapse among adherent participants (aHR=2.4, 95%CI=1.0-5.5) but not among non-adherent participants (aHR=0.9, 95%CI=0.2-3.8). Dose escalation above protocol doses during maintenance therapy for ALL should be done cautiously after assessing adherence to prescribed therapy., (Copyright © 2024 American Society of Hematology.)

Purpose: Childhood cancer survivors carry a high burden of late-occurring treatment-related morbidity. Long-term risk-based anticipatory surveillance allows for early detection and management of complications. We sought to examine demographic, clinical, and social characteristics associated with survivorship clinic attendance at the Taking on Life after Cancer (TLC) Clinic at the Children's Hospital of Alabama., Methods: The cohort included 1122 TLC-eligible patients diagnosed with cancer between 2000 and 2016. The outcome of interest was ≥1 TLC visit. Univariable logistic regression modeling assessed cancer type, treatment era, age, sex, race/ethnicity, payer type, rural/urban residency, and distance from clinic. Significant variables (P<0.1) were retained in multivariable modeling., Results: The median age at diagnosis was 7 years old (0-19); 47% were female, 69% non-Hispanic White, 25% African American; 45% leukemia or lymphoma, 53% solid or CNS tumor, 3% other. We found that among 1122 survivors eligible to attend a survivorship clinic in the Deep South, only 52% attended. Odds of attendance were lower among survivors diagnosed at an older age, those with cancers other than leukemia/lymphoma, those lacking private insurance, and those living farther from the clinic. Race/ethnicity and rurality were not associated with clinic attendance., Conclusion: Just over half of eligible survivors attended survivorship clinic. Factors associated with non-attendance can be used to guide development of intervention strategies to ensure that childhood cancer survivors receive optimal long-term follow-up care., Implications for Cancer Survivors: Measures of healthcare access (insurance status and distance to care) were identified as potential intervention targets to improve uptake of survivorship care., (© 2024. The Author(s).)

Purpose: Therapy-related myeloid neoplasm (t-MN) is a life-threatening complication of autologous peripheral blood stem cell (PBSC) transplantation for non-Hodgkin lymphoma (NHL). Previous studies report an association between clonal hematopoiesis (CH) in PBSC and risk of t-MN, but small samples precluded examination of risk within specific subpopulations., Methods: Targeted DNA sequencing was performed to identify CH mutations in PBSC from a retrospective cohort of 984 patients with NHL (median age at transplant, 57 years; range, 18-78). Fine-Gray proportional subdistribution hazard regression models estimated association between number of CH mutations and t-MN, adjusting for demographic, clinical, and therapeutic variables. Secondary analyses evaluated the association between CH and t-MN among males and females., Results: CH was identified in PBSC from 366 patients (37.2%). t-MN developed in 60 patients after a median follow-up of 5 years. Presence of ≥2 mutations conferred increased t-MN risk (adjusted hazard ratio [aHR], 2.10; 95% CI [1.08 to 4.11]; P = .029). CH was associated with increased t-MN risk among males (aHR, 1.83 [95% CI, 1.01 to 3.31]) but not females (aHR, 0.56 [95% CI, 0.15 to 2.09]). Although the prevalence and type of CH mutations in PBSC were comparable, the 8-year cumulative incidence of t-MN was higher among males vs. females with CH (12.4% v 3.6%) but was similar between males and females without CH (4.9% v 3.9%). Expansion of CH clones from PBSC to t-MN was seen only among males., Conclusion: presence of CH mutations in PBSC confers increased risk of t-MN after autologous transplantation in male but not female patients with NHL. Factors underlying sex-based differences in risk of CH progression to t-MN merit further investigation.

Background: Autologous peripheral blood stem cell transplantation (aPBSCT) is the standard of care for adults with relapsed lymphoma, yet recipients remain at risk of developing chronic health conditions (CHCs). It was hypothesized that body composition measurements of skeletal muscle and fat are associated with late-onset CHCs and nonrelapse mortality after aPBSCT., Methods: Leveraging the Blood or Marrow Transplant Survivor Study, we examined association between pre-aPBSCT body composition and new-onset grade 3-5 CHCs among 187 adults with lymphoma treated with aPBSCT (2011-2014) surviving ≥2 years after aPBSCT. Using computed tomography scans at the L3 level, skeletal muscle mass (skeletal muscle area and skeletal muscle density [SMD]) and body fat (subcutaneous adipose tissue and visceral adipose tissue) were measured and quantified as sex-specific z-scores. Competing risk models were built to study the impact of body composition on incident grade 3 through 5 CHCs and nonrelapse mortality (NRM) adjusting for confounders., Results: The study cohort had a median age at aPBSCT of 57 years with 63% males, 77% non-Hispanic Whites and 81% with non-Hodgkin lymphoma. The 5-year cumulative incidence of grade 3 through 5 CHCs was 47% (95% Confidence Interval, CI, 38%-56%). Each SD increase in SMD was associated with 30% reduced risk of grade 3 through 5 CHCs (95% CI, 0.50-0.96). The 10-year cumulative incidence of NRM was 16% (95% CI, 10-22). No body composition measure was associated with NRM., Conclusions: The association between SMD and grade 3 through 5 CHCs following aPBSCT could inform development of prognostic models to identify adults with lymphoma at greatest risk of morbidity following aPBSCT., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: Therapy-related myeloid neoplasm (t-MN) is a life-threatening complication of autologous peripheral blood stem cell transplantation (aPBSCT) for Hodgkin lymphoma (HL). Although previous studies have reported an association between clonal hematopoiesis (CH) in the infused PBSC product and subsequent post-aPBSCT risk of t-MN in patients with non-HL, information about patients with HL treated with aPBSCT is not available., Methods: We constructed a retrospective cohort of 321 patients with HL transplanted at a median age of 34 years (range, 18-71). Targeted DNA sequencing of PBSC products performed for CH-associated or myeloid malignancy-associated genes identified pathogenic mutations in these patients., Results: CH was identified in the PBSC product of 46 patients (14.3%) with most prominent representation of DNMT3A (n = 25), PPM1D (n = 7), TET2 (n = 7), and TP53 (n = 5) mutations. Presence of CH in the PBSC product was an independent predictor of t-MN (adjusted hazard ratio [aHR], 4.50 [95% CI, 1.54 to 13.19]). Notably all patients with TP53 mutations in the PBSC product developed t-MN, whereas none of the patients with DNMT3A mutations alone (without co-occurring TP53 or PPM1D mutations) did. Presence of TP53 and/or PPM1D mutations was associated with a 7.29-fold higher hazard of t-MN when compared with individuals carrying no CH mutations (95% CI, 1.72 to 30.94). The presence of TP53 and/or PPM1D mutations was also associated with a 4.17-fold higher hazard of nonrelapse mortality (95% CI, 1.25 to 13.87). There was no association between CH and relapse-related mortality., Conclusion: The presence of TP53 and/or PPM1D mutations in the PBSC product increases the risk of post-aPBSCT t-MN and nonrelapse mortality among patients with HL and may support alternative therapeutic strategies.

Background: Coagulopathy and associated bleeding and deep vein thrombosis (DVT) are major causes of morbidity and mortality in patients with acute leukemia. The underlying mechanisms of these complications have not been fully elucidated., Objectives: To evaluate the associations between biomarker levels and bleeding and DVT in acute leukemia patients., Methods: We examined plasma levels of activators, inhibitors, and biomarkers of the coagulation and fibrinolytic pathways in patients aged ≥18 years with newly diagnosed acute leukemia compared with those of normal controls. Multivariable regression models were used to examine the association of biomarkers with bleeding and DVT in acute leukemia patients. The study included 358 patients with acute leukemia (29 with acute promyelocytic leukemia [APL], 253 with non-APL acute myeloid leukemia, and 76 with acute lymphoblastic leukemia) and 30 normal controls., Results: Patients with acute leukemia had higher levels of extracellular vesicle tissue factor (EVTF) activity, phosphatidylserine-positive extracellular vesicles, plasminogen activator inhibitor-1, plasmin-antiplasmin complexes, and cell-free DNA and lower levels of citrullinated histone H3-DNA complexes compared with normal controls. APL patients had the highest levels of EVTF activity and the lowest levels of tissue plasminogen activator among acute leukemia patients. There were 41 bleeding and 23 DVT events in acute leukemia patients. High EVTF activity was associated with increased risk of bleeding (subdistribution hazard ratio, 2.30; 95% CI, 0.99-5.31), whereas high levels of plasminogen activator inhibitor-1 were associated with increased risk of DVT (subdistribution hazard ratio, 3.00; 95% CI, 0.95-9.47) in these patients., Conclusion: Our study shows alterations in several biomarkers in acute leukemia and identifies biomarkers associated with risk of bleeding and DVT., Competing Interests: Declaration of competing interests R.G. has served as a consultant for Advisory Boards for Alexion, Takeda, and Sanofi and received an honorarium for presenting a webinar from Sanofi. The other authors declare no competing financial interests., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

We examined the prevalence, risk factors, and association between pre-frailty and subsequent mortality after blood or marrow transplantation (BMT). Study participants were drawn from the BMT Survivor Study (BMTSS) and included 3346 individuals who underwent BMT between 1974 and 2014 at one of three transplant centers and survived ≥2 years post-BMT. Participants completed the BMTSS survey at a median of 9 years from BMT and were followed for subsequent mortality for a median of 5 years after survey completion. Closest-age and same-sex biological siblings also completed the survey. Previously published self-reported indices (exhaustion, weakness, low energy expenditure, slowness, unintentional weight loss) classified participants as non-frail (0-1 indices) or pre-frail (2 indices). National Death Index was used to determine vital status and cause of death. Overall, 626 (18.7%) BMT survivors were pre-frail. BMT survivors had a 3.2-fold higher odds of being pre-frail (95% CI = 1.9-5.3) compared to siblings. Compared to non-frail survivors, pre-frail survivors had higher hazards of all-cause mortality (adjusted hazard ratio [aHR] = 1.6, 95% CI = 1.4-2.0). Female sex, pre-BMT radiation, smoking, lack of exercise, anxiety, and severe/life-threatening chronic health conditions were associated with pre-frailty. The novel association between pre-frailty and subsequent mortality provides evidence for interventions as pre-frail individuals may transition back to their robust state., (© 2024. The Author(s).)

We determined the risk of late morbidity and mortality after autologous blood or marrow transplantation (BMT) for lymphoma performed before age 40. The cohort included autologous BMT recipients who had survived ≥2 years after transplantation (N = 583 [HL = 59.9%; NHL = 40.1%]) and a comparison cohort (N = 1070). Participants self-reported sociodemographics and chronic health conditions. A severity score (grade 3 [severe], 4 [life threatening] or 5 [fatal]) was assigned to the conditions using CTCAE v5.0. Logistic regression estimated the odds of grade 3-4 conditions in survivors vs. comparison subjects. Proportional subdistribution hazards models identified predictors of grade 3-5 conditions among BMT recipients. Median age at BMT was 30.0 years (range: 2.0-40.0) and median follow-up was 9.8 years (2.0-32.1). Survivors were at a 3-fold higher adjusted odds for grade 3-4 conditions (95% CI = 2.3-4.1) vs. comparison subjects. Factors associated with grade 3-5 conditions among BMT recipients included age at BMT (>30 years: adjusted hazard ratio [aHR] = 2.31; 95% CI = 1.27-4.19; reference: ≤21 years), pre-BMT radiation (aHR = 1.52; 95% CI = 1.13-2.03; reference: non-irradiated), and year of BMT (≥2000: aHR = 0.54; 95% CI = 0.34-0.85; reference: <1990). The 25 years cumulative incidence of relapse-related and non-relapse-related mortality was 18.2% and 25.9%, respectively. The high risk for late morbidity and mortality after autologous BMT for lymphoma performed at age <40 calls for long-term anticipatory risk-based follow-up., (© 2024. The Author(s).)

Background: Blood or marrow transplantation (BMT) survivors carry a high burden of morbidity, yet health care utilization by this vulnerable population remains understudied. Patterns and predictors of various domains of health care utilization in long-term BMT survivors were evaluated., Methods: Study participants were drawn from the Bone Marrow Transplant Survivor Study (BMTSS). Patients transplanted between 1974 and 2014 at one of three transplant centers who had survived ≥2 years after BMT and were aged ≥18 years at the time of the study were included. A BMTSS survey served as the source of data for health care utilization, sociodemographics, and chronic health conditions. Domains of health care utilization in the 2 years preceding study participation included routine checkups, BMT-related visits, transplant/cancer center visits, emergency room (ER) visits, hospitalizations, and high health care utilization (≥7 physician visits during the 2 years before the study). Clinical characteristics and therapeutic exposures were abstracted from medical records., Results: In this cohort of 3342 BMT survivors (52% allogeneic), the prevalence of health care utilization declined over time since BMT for both allogeneic and autologous BMT survivors, such that among those who had survived ≥20 years, only 49%-53% had undergone routine checkups, 37%-38% reported BMT-related visits, and 28%-29% reported transplant/cancer center visits. The presence of severe/life-threatening conditions and chronic graft-vs-host disease increased the odds of health care utilization across all domains. Lower education, lack of insurance, and Hispanic ethnicity were associated with a lower prevalence of routine checkups and/or transplant/cancer center visits. Lower income increased the odds of ER visits but reduced the odds of hospitalizations or high health care utilization., Conclusions: This study identified vulnerable populations of long-term BMT survivors who would benefit from specialized risk-based anticipatory care to reduce high health care utilization, ER visits, and hospitalizations., (© 2023 American Cancer Society.)

We examined the association between risky health behaviors (smoking, heavy alcohol consumption, and lack of vigorous physical activity) and all-cause and cause-specific late mortality after blood or marrow transplantation (BMT) to understand the role played by potentially modifiable risk factors. Study participants were drawn from the BMT Survivor Study (BMTSS) and included patients who received transplantation between 1974 and 2014, had survived ≥2 years after BMT, and were aged ≥18 years at study entry. Survivors provided information on sociodemographic characteristics, chronic health conditions, and health behaviors. National Death Index was used to determine survival and cause of death. Multivariable regression analyses determined the association between risky health behaviors and all-cause mortality (Cox regression) and nonrecurrence-related mortality (NRM; subdistribution hazard regression), after adjusting for relevant sociodemographic, clinical variables and therapeutic exposures. Overall, 3866 participants completed the BMTSS survey and were followed for a median of 5 years to death or 31 December 2021; and 856 participants (22.1%) died after survey completion. Risky health behaviors were associated with increased hazard of all-cause mortality (adjusted hazard ratio [aHR] former smoker, 1.2; aHR current smoker, 1.7; reference, nonsmoker; aHR heavy drinker, 1.4; reference, nonheavy drinker; and aHR no vigorous activity, 1.2; reference, vigorous activity) and NRM (aHR former smoker, 1.3; aHR current smoker, 1.6; reference, nonsmoker; aHR heavy drinker, 1.4; reference: nonheavy drinker; and aHR no vigorous activity, 1.2; reference, vigorous activity). The association between potentially modifiable risky health behaviors and late mortality offers opportunities for development of interventions to improve both the quality and quantity of life after BMT., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background Anthracycline-induced cardiomyopathy is a leading cause of premature death in childhood cancer survivors, presenting a need to understand the underlying pathogenesis. We sought to examine differential blood-based mRNA expression profiles in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Methods and Results We designed a matched case-control study (Children's Oncology Group-ALTE03N1) with mRNA sequencing on total RNA from peripheral blood in 40 anthracycline-exposed survivors with cardiomyopathy (cases) and 64 matched survivors without (controls). DESeq2 identified differentially expressed genes. Ingenuity Pathway Analyses (IPA) and Gene Set Enrichment Analyses determined the potential roles of altered genes in biological pathways. Functional validation was performed by gene knockout in human-induced pluripotent stem cell-derived cardiomyocytes using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) technology. Median age at primary cancer diagnosis for cases and controls was 8.2 and 9.7 years, respectively. Thirty-six differentially expressed genes with fold change ≥±2 were identified; 35 were upregulated. IPA identified "hepatic fibrosis" and "iron homeostasis" pathways to be significantly modulated by differentially expressed genes, including toxicology functions of myocardial infarction, cardiac damage, and cardiac dilation. Leading edge analysis from Gene Set Enrichment Analyses identified lactate dehydrogenase A ( LDHA ) and cluster of differentiation 36 ( CD36 ) genes to be significantly upregulated in cases. Interleukin 1 receptor type 1, 2 ( IL1R1 , IL1R2 ), and matrix metalloproteinase 8, 9 ( MMP8, MMP9 ) appeared in multiple canonical pathways. LDHA -knockout human-induced pluripotent stem cell-derived cardiomyocytes showed increased sensitivity to doxorubicin. Conclusions We identified differential mRNA expression profiles in peripheral blood of anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Upregulation of LDHA and CD36 genes suggests metabolic perturbations in a failing heart. Dysregulation of proinflammatory cytokine receptors IL1R1 and IL1R2 and matrix metalloproteinases, MMP8 and MMP9 indicates structural remodeling that accompanies the clinical manifestation of symptomatic cardiotoxicity.

Background: Anthracyclines are highly effective in treating cancer, albeit with increased cardiomyopathy risk. Although risk is attributed to associations with single nucleotide polymorphisms (SNPs), multiple SNPs on a gene and their interactions remain unexamined., Objectives: This study examined gene-level associations with cardiomyopathy among cancer survivors using whole-exome sequencing data., Methods: For discovery, 278 childhood cancer survivors (129 cases; 149 matched control subjects) from the COG (Children's Oncology Group) study ALTE03N1 were included. Logic regression (machine learning) was used to identify gene-level SNP combinations for 7,212 genes and ordinal logistic regression to estimate gene-level associations with cardiomyopathy. Models were adjusted for primary cancer, age at cancer diagnosis, sex, race/ethnicity, cumulative anthracycline dose, chest radiation, cardiovascular risk factors, and 3 principal components. Statistical significance threshold of 6.93 × 10 -6 accounted for multiple testing. Three independent cancer survivor populations (COG study, BMTSS [Blood or Marrow Transplant Survivor Study] and CCSS [Childhood Cancer Survivor Study]) were used to replicate gene-level associations and examine SNP-level associations from discovery genes using ordinal logistic, conditional logistic, and Cox regression models, respectively., Results: Median age at cancer diagnosis for discovery cases and control subjects was 6 years and 8 years, respectively. Gene-level association for P2RX7 (OR: 0.10; 95% CI: 0.04-0.27; P  = 2.19 × 10 -6 ) was successfully replicated (HR: 0.65; 95% CI: 0.47-0.90; P  = 0.009) in the CCSS cohort. Additional signals were identified on TNIK , LRRK2 , MEFV , NOBOX , and FBN3 . Individual SNPs across all discovery genes, except FBN3 , were replicated., Conclusions: In our study, SNP sets having 1 or no copies of P2RX7 variant alleles were associated with reduced risk of cardiomyopathy, presenting a potential therapeutic target to mitigate cardiac outcomes in cancer survivors., Competing Interests: This study was supported in part by the National Institutes of Health grant R35CA220502 (Dr Bhatia), Leukemia Lymphoma Society TRP grant 6563-19 (Dr Bhatia), the V Foundation grant DT2019-010 (Dr Bhatia), Leukemia and Lymphoma Society Career Development Award LLS 3386-19 (Dr Sharafeldin), and National Marrow Donor Program Be The Match Foundation (Dr Sharafeldin). The Childhood Cancer Survivor Study was supported by the National Cancer Institute grant CA55727 (Dr Armstrong). Support to St. Jude Children’s Research Hospital also was provided by the Cancer Center Support grant CA21765 (Principal Investigator Charles Roberts) and the American Lebanese-Syrian Associated Charities. The Children’s Oncology Group study (Genetic Analysis in Identifying Late-Occurring Complications in Childhood Cancer Survivors; NCT00082745; grant COG-ALTE03N1 [Dr Bhatia]) reported here is supported by the National Clinical Trials Network (NCTN) Operations Center grant U10CA180886; Principal Investigator Doug Hawkins); the NCTN Statistics & Data Center grant U10CA180899 (Principal Investigator Todd Alonzo); the Children’s Oncology Group Chair’s grant U10CA098543 (Principal Investigator Peter Adamson); The COG Statistics & Data Center grant U10CA098413 (Principal Investigator Peter Anderson); the NCI Community Oncology Research Program (NCORP) grant UG1CA189955 (Principal Investigator Brad Pollock); and the Community Clinical Oncology Program (CCOP) grant U10CA095861 (Principal Investigator Brad Pollock), and the St Baldrick’s Foundation through an unrestricted grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Anthracycline-induced cardiomyopathy is a leading cause of late morbidity in childhood cancer survivors. Aberrant DNA methylation plays a role in de novo cardiovascular disease. Epigenetic processes could play a role in anthracycline-induced cardiomyopathy but remain unstudied. We sought to examine if genome-wide differential methylation at 'CpG' sites in peripheral blood DNA is associated with anthracycline-induced cardiomyopathy. This report used participants from a matched case-control study; 52 non-Hispanic White, anthracycline-exposed childhood cancer survivors with cardiomyopathy were matched 1:1 with 52 survivors with no cardiomyopathy. Paired ChAMP (Chip Analysis Methylation Pipeline) with integrated reference-based deconvolution of adult peripheral blood DNA methylation was used to analyze data from Illumina HumanMethylation EPIC BeadChip arrays. An epigenome-wide association study (EWAS) was performed, and the model was adjusted for GrimAge, sex, interaction terms of age at enrollment, chest radiation, age at diagnosis squared, and cardiovascular risk factors (CVRFs: diabetes, hypertension, dyslipidemia). Prioritized genes were functionally validated by gene knockout in human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) using CRISPR/Cas9 technology. DNA-methylation EPIC array analyses identified 32 differentially methylated probes (DMP: 15 hyper-methylated and 17 hypo-methylated probes) that overlap with 23 genes and 9 intergenic regions. Three hundred and fifty-four differential methylated regions (DMRs) were also identified. Several of these genes are associated with cardiac dysfunction. Knockout of genes EXO6CB, FCHSD2, NIPAL2, and SYNPO2 in hiPSC-CMs increased sensitivity to doxorubicin. In addition, EWAS analysis identified hypo-methylation of probe 'cg15939386' in gene RORA to be significantly associated with anthracycline-induced cardiomyopathy. In this genome-wide DNA methylation profile study, we observed significant differences in DNA methylation at the CpG level between anthracycline-exposed childhood cancer survivors with and without cardiomyopathy, implicating differential DNA methylation of certain genes could play a role in pathogenesis of anthracycline-induced cardiomyopathy., (© 2023. Springer Nature Limited.)

The association between individual-level poverty and relapse in children receiving maintenance treatment for acute lymphoblastic leukemia (ALL) remains unclear. In a secondary analysis of COG-AALL03N1, we used data from US Census Bureau to categorize patients living below year-specific federal poverty thresholds, calculated using self-reported annual household income and size of household. Participants with federal poverty thresholds above 120% of their yearly household income were categorized as living in extreme poverty. Hazard of relapse was estimated using multivariable proportional subdistributional hazards regression for patients living in extreme poverty while receiving ALL maintenance therapy after adjusting for relevant predictors. Among 592 patients in this analysis, 12.3% of the patients were living in extreme poverty. After a median follow-up of 7.9 years, the cumulative incidence of relapse at 3 years from study enrollment among those living in extreme poverty was significantly higher (14.3%) than those not living in extreme poverty (7.6%). Multivariable analysis demonstrated that children living in extreme poverty had a 1.95-fold greater hazard of relapse than those not living in extreme poverty; this association was mitigated after the inclusion of race/ethnicity in the model, likely because of collinearity between race/ethnicity and poverty. A greater proportion of children living in extreme poverty were nonadherent to mercaptopurine (57.1% vs 40.9%); however, poor adherence did not completely explain the association between poverty and relapse risk. Future studies need to understand the mechanisms underlying the association between extreme poverty and relapse risk. This trial was registered at www.clinicaltrials.gov as #NCT00268528., (© 2023 by The American Society of Hematology.)

There is limited information regarding COVID-19 in long-term blood or marrow transplant (BMT) survivors. We leveraged the BMT Survivor Study (BMTSS) to address this gap. BMTSS included patients who underwent BMT at 1 of 3 sites in the United States between 1974 and 2014 and survived ≥2 years after BMT. A sibling cohort serves as a non-BMT comparison group. Participants (2430 BMT survivors; 780 non-BMT participants) completed the BMTSS survey between October 2020 and November 2021 about COVID-19 testing, risk mitigation behaviors, morbidity, and health care use. Median age at BMT was 46 years (range, 0-78 years) and median follow-up since BMT was 14 years (6-46 years); 76% were non-Hispanic White, 54% had received allogeneic BMT. The risk of COVID-19 infection was comparable for BMT survivors vs non-BMT participants (15-month cumulative incidence, 6.5% vs 8.1%; adjusted odd ratio [aOR] = 0.93; 95% confidence interval [CI], 0.65-1.33; P = .68). Among survivors, being unemployed (aOR 1.90; 95% CI, 1.12-3.23; P = .02; reference: retired) increased the odds of infection; always wearing a mask in public was protective (aOR = 0.49; 95% CI, 0.31-0.77; P = .002; reference: not always masking). When compared with COVID-positive non-BMT participants, COVID-positive BMT survivors had higher odds of hospitalization (aOR = 2.23; 95% CI, 0.99-5.05; P = .05); however, the odds of emergency department visits were comparable (aOR = 1.60; 95% CI = 0.71-3.58; P = .25). COVID-19 infection status did not increase the odds of hospitalization among BMT survivors (aOR = 1.32; 95% CI = 0.89-1.95; P = .17) but did increase the odds of emergency department visits (aOR = 2.63; 95% CI, 1.74-3.98; P <.0001). These findings inform health care providers about the management of care for long-term BMT survivors during the ongoing pandemic., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: The long-term risk of coronary heart disease (CHD) and clinical models that predict this risk remain understudied in blood or marrow transplantation (BMT) recipients., Objectives: This study sought to examine the risk of CHD after BMT and identify the associated risk factors., Methods: Participants included patients transplanted between 1974 and 2014 at City of Hope, University of Minnesota, or University of Alabama at Birmingham and those who survived ≥2 years after BMT. Multivariable logistic regression models assessed CHD risk in BMT survivors compared with a sibling cohort. A self-reported questionnaire and medical records provided information regarding sociodemographics, comorbidities, and therapeutic exposures, which were used to develop a CHD risk prediction nomogram., Results: Overall, 6,677 BMT recipients participated; the mean age at BMT was 43.9 ± 17.7 years, 58.3% were male, and 73.3% were non-Hispanic Whites. The median length of follow-up was 6.9 years (range: 2-46.2 years) from BMT. CHD was reported in 249 participants, with a 20-year cumulative incidence of 5.45% ± 0.39%. BMT survivors had a 1.6-fold greater odds of CHD compared with a sibling cohort (95% CI: 1.09-2.40). A nomogram was then developed to predict the risk of CHD at 10 and 20 years after BMT including age at BMT (HR: 1.06/y; 95% CI: 1.04-1.08), male sex (HR: 1.89; 95% CI: 1.15-3.11), a history of smoking (HR: 1.61; 95% CI: 1.01-2.58), diabetes (HR: 2.45; 95% CI: 1.23-4.89), hypertension (HR: 2.02; 95% CI: 1.15-3.54), arrhythmia (HR: 1.90; 95% CI: 0.89-4.06), and pre-BMT chest radiation (yes vs no: HR: 2.83; 95% CI: 1.20-6.67; unknown vs no: HR: 0.88; 95% CI: 0.34-2.28). The C-statistic was 0.77 in the test set (95% CI: 0.70-0.83)., Conclusions: This study identified BMT recipients at high risk for CHD, informing targeted screening for early detection and aggressive control of risk factors., Competing Interests: This study was supported in part by grants from the National Cancer Institute (grants R01 CA078938 and U01 CA213140) (Dr Bhatia); the Leukemia and Lymphoma Society (grant R6502-16) (Dr Bhatia); National Center for Advancing Translational Sciences of the National Institutes of Health under award number KL2TR003097 (Dr Gangaraju); and the National Heart, Lung, and Blood Institute (grant K08 HL159290) (Dr Gangaraju). Dr Gangaraju has served as a consultant for Sanofi and Alexion. Dr Weisdorf has received research funding from Fate and Incyte. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

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)., (© 2023. The Author(s).)

Purpose: Interindividual variability in the dose-dependent association between anthracyclines and cardiomyopathy suggests a modifying role of genetic susceptibility. Few previous studies have examined gene-anthracycline interactions. We addressed this gap using the Childhood Cancer Survivor Study (discovery) and the Children's Oncology Group (COG) study COG-ALTE03N1 (replication)., Methods: A genome-wide association study (Illumina HumanOmni5Exome Array) in 1,866 anthracycline-exposed Childhood Cancer Survivor Study participants (126 with heart failure) was used to identify single-nucleotide polymorphisms (SNPs) with either main or gene-environment interaction effect on anthracycline-related cardiomyopathy that surpassed a prespecified genome-wide threshold for statistical significance. We attempted replication in a matched case-control set of anthracycline-exposed childhood cancer survivors with (n = 105) and without (n = 160) cardiomyopathy from COG-ALTE03N1., Results: Two SNPs (rs17736312 [ ROBO2 ]) and rs113230990 (near a CCCTC-binding factor insulator [< 750 base pair]) passed the significance cutoff for gene-anthracycline dose interaction in discovery. SNP rs17736312 was successfully replicated. Compared with the GG/AG genotypes on rs17736312 and anthracyclines ≤ 250 mg/m 2 , the AA genotype and anthracyclines > 250 mg/m 2 conferred a 2.2-fold (95% CI, 1.2 to 4.0) higher risk of heart failure in discovery and an 8.2-fold (95% CI, 2.0 to 34.4) higher risk in replication. ROBO2 encodes transmembrane Robo receptors that bind Slit ligands (SLIT). Slit-Robo signaling pathway promotes cardiac fibrosis by interfering with the transforming growth factor-β1/small mothers against decapentaplegic (Smad) pathway, resulting in disordered remodeling of the extracellular matrix and potentiating heart failure. We found significant gene-level associations with heart failure: main effect ( TGF-β1 , P = .007); gene*anthracycline interaction ( ROBO2 *anthracycline, P = .0003); and gene*gene*anthracycline interaction ( SLIT2 * TGF-β1* anthracycline, P = .009)., Conclusion: These findings suggest that high-dose anthracyclines combined with genetic variants involved in the profibrotic Slit-Robo signaling pathway promote cardiac fibrosis via the transforming growth factor-β1/Smad pathway, providing credence to the biologic plausibility of the association between SNP rs17736312 ( ROBO2 ) and anthracycline-related cardiomyopathy.

Importance: Survivors of blood or marrow transplant (BMT) are at increased risk of subsequent malignant neoplasms (SMNs). Cancers of the gastrointestinal (GI) system are of special interest because their clinical behavior is often aggressive, necessitating early detection by increasing awareness of high-risk populations., Objective: To describe the risk of SMNs in the GI tract after BMT., Design, Setting, and Participants: A cohort study of 6710 individuals who lived at least 2 years after BMT performed between January 1, 1974, and December 31, 2014, at City of Hope, University of Minnesota, or University of Alabama at Birmingham. End of follow-up was March 23, 2020. Data analysis was performed between September 1, 2022, and September 30, 2022., Exposures: Demographic and clinical factors; therapeutic exposures before or as part of BMT., Main Outcomes and Measures: Development of SMNs in the GI tract after BMT. Participants self-reported SMNs in the GI tract; these were confirmed with pathology reports, medical records, or both. For deceased patients, death records were used. Standardized incidence ratios determined excess risk of SMNs in the GI tract compared with that of the general population. Fine-Gray proportional subdistribution hazard models assessed the association between risk factors and SMNs in the GI tract., Results: The cohort of 6710 individuals included 3444 (51.3%) autologous and 3266 (48.7%) allogeneic BMT recipients. A total of 3917 individuals (58.4%) were male, and the median age at BMT was 46 years (range, 0-78 years). After 62 479 person-years of follow-up, 148 patients developed SMNs in the GI tract. The standardized incidence ratios for developing specific SMNs ranged from 2.1 for colorectal cancer (95% CI, 1.6-2.8; P < .001) to 7.8 for esophageal cancer (95% CI, 5.0-11.6; P < .001). Exposure to cytarabine for conditioning (subdistribution hazard ratio [SHR], 3.1; 95% CI, 1.5-6.6) was associated with subsequent colorectal cancer. Compared with autologous BMT recipients, allogeneic BMT recipients with chronic graft-vs-host disease were at increased risk for esophageal cancer (SHR, 9.9; 95% CI, 3.2-30.5). Conditioning with etoposide (SHR, 2.0; 95% CI, 1.1-3.5) and pre-BMT anthracycline exposure (SHR, 5.4; 95% CI, 1.3-23.4) were associated with an increased risk of liver cancer compared with no exposure to the respective agents., Conclusions and Relevance: The findings of this cohort study are relevant for oncologists and nononcologists who care for the growing number of survivors of transplant. Awareness of subgroups of survivors of BMT at high risk for specific types of SMNs in the GI tract may influence recommendations regarding modifiable risk factors, as well as individualized screening.

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., (© 2022 American Cancer Society.)

Living in a disadvantaged neighborhood is associated with poor health outcomes. Blood or Marrow Transplant (BMT) survivors remain at risk of chronic health conditions requiring anticipatory management. We hypothesized that among BMT survivors, neighborhood disadvantage was associated with poor self-reported routine health care utilization and health. We leveraged data from BMTSS - a retrospective cohort study examining long-term outcomes among individuals surviving ≥2 y following BMT at three institutions between 1974 and 2014. Participants in this analysis completed the BMTSS survey (sociodemographics; chronic health conditions; time since routine check-up; self-reported health). The Area Deprivation Index (ADI) represented neighborhood disadvantage; this composite indicator of 17 census measures is a percentile rank (0 = least deprived to 100 = most deprived). Multivariable ordered logit regression adjusted for clinical factors and individual-level sociodemographics, modeling associations between ADI, time since routine check-up, and self-reported health. Among 2,857 survivors, median ADI was 24 (interquartile range: 10-46). Adjusting for self-reported individual-level socioeconomic indicators and chronic health conditions, patients in more disadvantaged neighborhoods had higher odds of reporting longer intervals since routine check-up (ORADI&#95;continuous = 1.007, P < .001) and poorer health status (controlling for time since check-up; ORADI&#95;continuous = 1.005, P = .003). Compared with patients living in the least disadvantaged neighborhood (ADI = 1), patients in the most disadvantaged neighborhood (ADI = 100), had twice the odds (ORADI = 1.007^99 = 2.06) of reporting no routine visits and 1.65-times the odds of reporting poor health (ORADI = 1.005^99 = 1.65). In BMT survivors, access to health care and health status are associated with area disadvantage. These findings may inform strategies to address long-term care coordination and retention for vulnerable survivors., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: The financial burden experienced by blood or marrow transplant (BMT) survivors during the COVID-19 pandemic remains unstudied. We evaluated the risk for high out-of-pocket medical costs and associated financial burden experienced by BMT survivors and a sibling comparison group during the COVID-19 pandemic., Methods: This study included 2,370 BMT survivors and 750 siblings who completed the BMT Survivor Study survey during the pandemic. Participants reported employment status, out-of-pocket medical costs, and financial burden. Medical expenses ≥ 10% of the annual household income constituted high out-of-pocket medical costs. Logistic regression identified factors associated with high out-of-pocket medical costs and financial burden., Results: BMT survivors were more likely to incur high out-of-pocket medical costs (11.3% v 3.1%; adjusted odds ratio [aOR], 2.88; 95% CI, 1.84 to 4.50) than the siblings. Survivor characteristics associated with high out-of-pocket medical costs included younger age at study (aOR per&#95;year&#95;younger&#95;age , 1.02; 95% CI, 1.00 to 1.03), lower prepandemic annual household income and/or education (< $50,000 US dollars and/or < college graduate: aOR, 1.96; 95% CI, 1.42 to 2.69; reference: ≥ $50,000 in US dollars and ≥ college graduate), > 1 chronic health condition (aOR, 2.82; 95% CI, 2.00 to 3.98), ≥ 1 hospitalization during the pandemic (aOR, 2.11; 95% CI, 1.53 to 2.89), and being unemployed during the pandemic (aOR, 1.52; 95% CI, 1.06 to 2.17). Among BMT survivors, high out-of-pocket medical costs were significantly associated with problems in paying medical bills (aOR, 10.57; 95% CI, 7.39 to 15.11), deferring medical care (aOR, 4.93; 95% CI, 3.71 to 6.55), taking a smaller dose of medication than prescribed (aOR, 4.99; 95% CI, 3.23 to 7.70), and considering filing for bankruptcy (aOR, 3.80; 95% CI, 2.14 to 6.73)., Conclusion: BMT survivors report high out-of-pocket medical costs, which jeopardizes their health care and may affect health outcomes. Policies aimed at reducing financial burden in BMT survivors, such as expanding access to patient assistance programs, may mitigate the negative health consequences.

Background: Anthracycline-related cardiomyopathy is a leading cause of premature death in childhood cancer survivors. The high interindividual variability in risk suggests the need to understand the underlying pathogenesis., Objectives: 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. Using leads from DEGs, candidate copy number variants (CNVs) and single-nucleotide variants (SNVs) were genotyped., Methods: Messenger RNA sequencing was performed on total RNA from peripheral blood of 40 survivors with cardiomyopathy (cases) and 64 matched survivors without cardiomyopathy (control subjects). Conditional logistic regression analysis adjusting for sex, age at cancer diagnosis, anthracycline dose, and chest radiation was used to assess the associations between gene expression and cardiomyopathy and between CNVs and SNVs and cardiomyopathy., Results: Haptoglobin ( HP ) was identified as the top DEG. Participants with higher HP gene expression had 6-fold greater odds of developing cardiomyopathy (OR: 6.4; 95% CI: 1.4-28.6). The HP2 -specific allele among the HP genotypes (HP1-1, HP1-2, and HP2-2) had higher transcript levels, as did the G allele among SNVs previously reported to be associated with HP gene expression (rs35283911 and rs2000999). The HP1-2 and HP2-2 genotypes combined with the G/G genotype for rs35283911 and/or rs2000999 placed the survivors at 4-fold greater risk (OR: 3.9; 95% CI: 1.0-14.5) for developing cardiomyopathy., Conclusions: These findings provide evidence of a novel association between HP2 allele and cardiomyopathy. HP binds to free hemoglobin to form an HP-hemoglobin complex, thereby preventing oxidative damage from free heme iron, thus providing biological plausibility to the mechanistic basis of the present observation., Competing Interests: This research is supported by the National Cancer Institute (R35CA220502; principal investigator [PI], S. Bhatia), Leukemia and Lymphoma Society (6563-19; PI, S. Bhatia), and the V Foundation (DT2019-010; PI, S. Bhatia). The Children’s Oncology Group study (COG-ALTE03N1 [NCT00082745]; PI, S. Bhatia) reported here is supported by the National Clinical Trials Network Operations Center Grant (U10CA180886; PI, D.S. Hawkins), the National Clinical Trials Network Statistics & Data Center Grant (U10CA180899; PI, Alonzo), the Children’s Oncology Group Chair’s Grant (U10CA098543; PI, Adamson), the Children’s Oncology Group Statistics & Data Center Grant (U10CA098413; PI, Anderson), the National Cancer Institute Community Oncology Research Program Grant (UG1CA189955; PI, Pollock), and the Community Clinical Oncology Program Grant (U10CA095861; PI, Pollock), and the St. Baldrick’s Foundation through an unrestricted grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background: Blood or marrow transplantation (BMT) is increasingly offered to older individuals with hematologic malignancies. The high prevalence of chronic health conditions in such individuals necessitates use of multiple medications. Beers Criteria represent a list of potentially inappropriate medications (PIMs) shown to increase the risk of health problems in the elderly. We sought to determine the prevalence and predictors of PIM use in older BMT survivors and identify associations with health problems., Methods: Study participants were drawn from the BMT Survivor Study, a cohort study of patients transplanted at three US transplant centers between 1974 and 2014 and surviving ≥2 years. For this report, the survivors were aged ≥65 years. Siblings served as a comparison group. Participants self-reported sociodemographics, chronic health conditions, and medication use. Logistic regression analyses identified predictors of PIM use and associations with health problems., Results: Overall, PIM use was comparable between BMT survivors (49.4%) and siblings (49.3%) (odds ratio [OR] = 0.9; 95% CI, 0.7-1.2); however, BMT survivors were more likely to use >1 PIM (17.4% vs. 12.4%; OR = 1.5; 95% CI, 1.01-2.4) and central nervous system-related PIMs (8.3% vs. 4.3%; OR = 2.18; 95% CI, 1.17-4.09). Predictors of PIM use included presence of severe/life-threatening chronic health conditions (OR = 1.5; 95% CI, 1.1-2.0), and chronic graft versus host disease (OR = 1.7; 95% CI, 1.1-2.7). Survivors taking >1 PIM reported more issues with vertigo (OR = 2.3; 95% CI, 1.1-4.7), balance (OR = 2.6; 95% CI, 1.7-4.1), faintness/dizziness (OR = 2.8; 95% CI, 1.8-4.6), and personal care (OR = 4.5; 95% CI, 1.4-14.8)., Conclusions: This study shows the health problems associated with PIM use and identifies vulnerable populations at higher risk for PIM use, providing evidence for caution in using PIMs in high-risk populations., (© 2022 American Cancer Society.)

Purpose: Individuals diagnosed with cancer age between 15 and 39 years (adolescents and young adults [AYAs]) have not seen improvement in survival compared with children or older adults; clinical trial accrual correlates with survival. Unique unmet needs among AYAs related to psychosocial support and fertility preservation (FP) are associated with health-related quality of life., Methods: We enhanced existing structures and leveraged faculty/staff across pediatric/adult oncology to create novel teams focused on AYA (age 15-39 years) care at a single center, with minimal dedicated staff and no change to revenue streams. We aimed to influence domains shown to drive survival and health-related quality of life: clinical trial enrollment, physician/staff collaboration, psychosocial support, and FP. We captured metrics 3 months after patients presented to the institution and compared them before/after Program implementation using descriptive statistics., Results: Among 139 AYAs (age 15-39 years) from the pre-Program era (January 2016-February 2019: adult, n = 79; pediatric, n = 60), and 279 from the post-Program era (February 2019-March 2022: adult, n = 215; pediatric, n = 64), there was no change in clinical trial enrollment( P ≥ .3), whereas there was an increase in the proportion of AYAs referred for supportive care and psychology (pediatric: P ≤ .02; adult: P ≤ .001); whose oncologists discussed FP (pediatric: 15% v 52%, P < .0001; adult: 37% v 50%, P = .0004); and undergoing FP consults (pediatric: 8% v 39%, P < .0001; adult 23% v 38%, P = .02)., Conclusion: This team-based framework has effected change in most targeted domains. To affect all domains and design optimal interventions, it is crucial to understand patient-level and facility-level barriers/facilitators to FP and clinical trial enrollment.

Background: Obesity at diagnosis of childhood acute lymphoblastic leukemia (ALL) is associated with greater risk of relapse; whether this association extends to obesity during maintenance is unstudied., Methods: This study used data from AALL03N1 to calculate median body mass index (BMI) for 676 children over 6 consecutive months during maintenance therapy; BMI percentile (BMI%ile) were operationalized as normal/underweight (<85%ile), overweight/obese (85%-98%ile), and extreme obesity (≥99%ile). Hazard of relapse was estimated using multivariable proportional subdistributional hazards regression after adjusting for all relevant demographic and clinical predictors., Results: Median age at study enrollment was 6 years and median length of follow-up was 7.9 years. Overall, 43.3% of the cohort was underweight/normal weight, 44.8% was overweight/obese, and 11.8% had extreme obesity. Cumulative incidence of relapse at 4 years from study enrollment was higher among those with extreme obesity (13.6% ± 4.5%) compared to those with underweight/normal weight (9.0% ± 2.1%). Multivariable analysis revealed that children with extreme obesity had a 2.4-fold (95% confidence interval [CI], 1.1-5.0; p = .01) greater hazard of relapse compared to those who were underweight/normal weight. Overweight/obese patients were at comparable risk to those who were underweight/normal weight (hazard ratio, 0.8; 95% CI, 0.4-1.6). Erythrocyte thioguanine nucleotide (TGN) levels were significantly lower among children with extreme obesity compared to those with underweight/normal weight (141.6 vs. 168.8 pmol/8 × 10 8 erythrocytes; p = .0002), however, the difference in TGN levels did not explain the greater hazard of relapse among those with extreme obesity., Conclusions: Extreme obesity during maintenance therapy is associated with greater hazard of relapse in children with ALL. Underlying mechanisms of this association needs further investigation., Lay Summary: Findings from this study demonstrate that extreme obesity during maintenance therapy is associated with a greater hazard of relapse among children with acute lymphoblastic leukemia. We show that children with obesity have lower levels of erythrocyte thioguanine nucleotides even after adjusting for adherence to oral chemotherapy. However, these lower levels do not explain the greater hazard of relapse, paving the way for future studies to explore this association., (© 2022 American Cancer Society.)

Purpose: We determined trends in life expectancy and cause-specific late mortality after autologous blood or marrow transplantation (BMT) performed over a 30-year period, using the BMT Survivor Study., Methods: We constructed a cohort of 4,702 individuals with hematologic neoplasms who lived ≥ 2 years after autologous BMT performed between 1981 and 2014 at three transplant centers. The end of follow-up was April 19, 2021. The primary exposure variable was autologous BMT performed in four eras: 1981-1999; 2000-2005; 2006-2010; and 2011-2014. Vital status and cause of death were obtained from National Death Index Plus program and Accurinct databases., Results: The median age at BMT was 53 years (range, 0-78 years), 58.7% were male, 67.8% were non-Hispanic White, and 28.3% had undergone transplantation between 2011 and 2014. Autologous BMT recipients experienced a 7-year reduction in life expectancy. The adjusted hazard of 5-year all-cause mortality declined over the four eras (reference: 1981-1999; hazard ratio [HR] 2000-2005 = 0.77; 95% CI, 0.62 to 0.94; HR 2006-2010 = 0.64; 95% CI, 0.51 to 0.79; HR 2011-2014 = 0.56; 95% CI, 0.45 to 0.71; P trend < .001), as did years of life lost (5.0 years to 1.6 years). The reduction in all-cause mortality was most pronounced among those transplanted for Hodgkin lymphoma or plasma cell dyscrasias, but was not observed among those transplanted for non-Hodgkin lymphoma or those conditioned with total-body irradiation. We also observed a decline in late deaths because of infection ( P trend < .0001; primarily for BMTs before 2006) and subsequent neoplasms ( P trend = .03; confined to decline in therapy-related myeloid neoplasm-related mortality) but not because of cardiovascular or renal disease., Conclusion: Late mortality among autologous BMT recipients has declined over a 30-year period. However, ongoing efforts are needed to mitigate development of infections, subsequent neoplasms, and cardiovascular and renal disease to further reduce late mortality., Competing Interests: Smita BhatiaThis author is an Associate Editor for Journal of Clinical Oncology. Journal policy recused the author from having any role in the peer review of this manuscript. Wendy LandierResearch Funding: Merck Sharp & Dohme (Inst) Stephen J. FormanStock and Other Ownership Interests: MustangBio, Lixte BiotechnologyConsulting or Advisory Role: Alimera Sciences, Lixte Biotechnology, MustangBioResearch Funding: MustangBioPatents, Royalties, Other Intellectual Property: MustangBio Daniel J. WeisdorfConsulting or Advisory Role: Incyte, Fate TherapeuticsResearch Funding: Incyte Mukta AroraConsulting or Advisory Role: Fate TherapeuticsResearch Funding: Syndax (Inst), Kadmon (Inst), Pharmacyclics (Inst)No other potential conflicts of interest were reported.

We examine the impact of conditioning intensity (low intensity: nonmyeloablative/reduced intensity vs high intensity: myeloablative) and total body irradiation (TBI) on the probability of live birth after blood or marrow transplantation (BMT). Study participants were drawn from the BMT Survivor Study (BMTSS) and included 1607 transplant survivors between 1974 and 2014 at age ≤45 years, with survival ≥2 years post-BMT and age at study ≥18 years. Closest-age, same-sex biologic siblings (n = 172) were 1:1 matched with 172 survivors. Survivors and siblings self-reported information on sociodemographic, chronic health conditions, and pregnancies. Within survivor analysis: the association between the primary exposure variable (no TBI/low-intensity conditioning; 200 to 800 cGy TBI/low-intensity conditioning; no TBI/high-intensity conditioning; >800 cGy TBI/high-intensity conditioning) and the odds of no post-BMT live birth were examined using multivariable logistic regression, adjusting for clinical and demographic variables. Median age at BMT was 31 years (IQR, 0 to 45), and median length of follow-up was 14.3 years (IQR, 2.4 to 41.4); 39.3% were autologous BMT recipients, and 46.6% were female. Overall, 120 (8.7%) survivors reported post-BMT live births. Receipt of >800 cGy TBI/high-intensity conditioning (odds ratio [OR], 3.7; 95% CI, 1.9-7.0; ref: no TBI/low-intensity conditioning) was associated with higher odds of reporting no live birth post-BMT. In contrast, 200 to 800 cGy TBI/low-intensity conditioning (OR, 1.3; 95% CI, 0.5-3.3), and no TBI/high-intensity conditioning (OR, 0.9; 95% CI, 0.5-1.7) were at similar risk of reporting post-BMT live birth as no TBI/low-intensity conditioning. Comparison with biologic siblings: Using conditional logistic regression, we found that BMT survivors were more likely to report no live birth (OR, 2.0; 95% CI, 1.2-3.3) compared with siblings. These findings could inform conditioning intensity options for patients wishing to preserve fertility post-BMT., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

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., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Importance: The past 4 decades have seen substantial changes in allogeneic blood or marrow transplantation (BMT) practice, with the overarching goal of expanding the eligible patient pool while optimizing disease-free survival., Objective: To determine trends in life expectancy and cause-specific late mortality after allogeneic BMT performed over a 40-year period., Design, Setting, and Participants: A retrospective cohort study of 4741 individuals who lived 2 or more years after allogeneic BMT performed between January 1, 1974, and December 31, 2014, was conducted at City of Hope, University of Minnesota, or University of Alabama at Birmingham. The end of follow-up was March 23, 2020., Exposures: Allogeneic BMT performed in 3 eras: 1974-1989, 1990-2004, and 2005-2014., Main Outcomes and Measures: All-cause, recurrence-related, and nonrecurrence-related mortality and projected reduction in life expectancy. Information regarding vital status and cause of death was obtained from the National Death Index Plus and Accurint databases., Results: Of the 4741 individuals included in the study, 2735 (57.7%) were male; median age at BMT was 33 years (range, 0-75 years). The cumulative incidence of recurrence-related mortality plateaued at 10 years, reaching 12.2% (95% CI, 11.0%-13.4%) at 30 years from BMT. In contrast, the incidence of nonrecurrence-related mortality continued to increase and was 22.3% (95% CI, 20.4%-24.3%) at 30 years. Leading causes of nonrecurrence-related mortality included infection (30-year cumulative incidence, 10.7%; standardized mortality ratio [SMR], 52.0), subsequent malignant neoplasms (30-year cumulative incidence, 7.0%; SMR, 4.8), cardiovascular disease (30-year cumulative incidence, 4.6%; SMR, 4.1), and pulmonary disease (30-year cumulative incidence, 2.7%; SMR, 13.9). Compared with the general population, the relative mortality remained higher at 30 or more years after BMT (SMR, 5.4; 95% CI, 4.0-7.1). The cohort experienced a 20.8% reduction in life expectancy (8.7 years of life lost). Compared with 1974-1989 (reference), the adjusted 10-year hazard ratio (HR) of all-cause mortality declined over the 3 eras (1990-2004: HR, 0.67; 95% CI, 0.53-0.85; 2005-2014: HR, 0.52; 95% CI, 0.39-0.69; P < .001 for trend), as did years of life lost (1974-1989: 9.9 years [reference]; 1990-2004: 6.5 years; and 2005-2014: 4.2 years). The reduction in late mortality was most pronounced among individuals who underwent transplantation at ages younger than 18 years (1990-2004: HR, 0.62; 95% CI, 0.40-0.96; 2005-2014: HR, 0.30; 95% CI, 0.16-0.54; reference: 1974-1989; P < .001 for trend) and those who received bone marrow (1990-2004: HR, 0.70; 95% CI, 0.54-0.90; 2005-2014: HR, 0.45; 95% CI, 0.29-0.69; reference: 1974-1989; P < .001 for trend)., Conclusions and Relevance: This cohort study noted that late mortality among recipients of allogeneic BMT has decreased over the past 40 years; however, life expectancy was not restored to expected rates compared with the general US population. Furthermore, the reduction in risk of late mortality appeared to be confined to those who underwent transplantation at a younger age or those who received bone marrow. Further efforts to mitigate disease recurrence, infections, subsequent neoplasms, cardiovascular disease, and pulmonary disease may be useful in this population.

Allogeneic blood or marrow transplant (BMT) recipients are at risk for venous thromboembolism (VTE) because of high-intensity therapeutic exposures, comorbidities, and a proinflammatory state due to chronic graft-versus-host disease (GVHD). The long-term risk of VTE in allogeneic BMT survivors remains unstudied. Participants were drawn from the Blood or Marrow Transplant Survivor Study (BMTSS), a retrospective cohort study that included patients who underwent transplantation between 1974 and 2014 and survived ≥2 years after BMT. We analyzed the risk of VTE in 1554 2-year survivors of allogeneic BMT compared with 907 siblings. Using backward variable selection guided by minimizing Akaike information criterion, we created a prediction model for risk of late-occurring VTE. Allogeneic BMT survivors had a 7.3-fold higher risk of VTE compared with siblings (95% CI, 4.69-11.46; P < .0001). After a median follow-up of 11 years, conditional on surviving the first 2 years after BMT, the cumulative incidence of late-occurring VTE was 2.4% at 5 years, 4.9% at 10 years, and 7.1% at 20 years after BMT. The final model for VTE risk at 2 years post-BMT included History of stroke, chronic GVHD, Hypertension, Sex (male vs female) and Stem cell source (peripheral blood stem cells vs other) ("HiGHS2") (corrected C-statistics: 0.73; 95% CI = 0.67-0.79). This model was able to classify patients at high and low VTE risk (10-year cumulative incidence, 9.3% vs 2.4% respectively; P < .0001). The BMTSS HiGHS2 risk model when applied at 2 years post-BMT can be used to inform targeted prevention strategies for patients at high risk for late-occurring VTE., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Poor mercaptopurine (6MP) adherence (mean adherence rate < 90%) increases the relapse risk among children with acute lymphoblastic leukemia (ALL). 6MP adherence remains difficult to measure in real time. Easily measured patient-level factors could identify patients at risk for poor adherence., Methods: The authors measured 6MP adherence via electronic monitoring for 6 months per patient. Using data from month 3, they created a risk prediction model for 6MP nonadherence in 407 children with ALL (mean age, 7.7 ± 4.4 years); they used receiver operating characteristic analyses in the training set (n = 250) and replicated this in the test set (n = 157)., Results: Age, race/ethnicity, 6MP dose intensity, absolute neutrophil count, 6MP ingestion patterns, and household structure were retained in the prediction model. The model yielded areas under the receiver operating characteristic curve (AUCs) of 0.79 (95% confidence interval [CI], 0.71-0.85) and 0.74 (95% CI, 0.63-0.85) in the training and test sets, respectively. The model performed better for those who were ≥12 years old (AUC, 0.79; 95% CI, 0.59-0.99) than those <12 years old (AUC, 0.70; 95% CI, 0.58-0.81). Using the predicted probability of nonadherence based on receiver operating characteristic analysis, the authors developed a binary risk classifier to classify patients with a high or low probability of nonadherence. The sensitivity and specificity of the binary risk classifier were 71% and 76%, respectively. Adjusted for clinical prognosticators, the risk of relapse was 2.2-fold higher (95% CI, 0.94-5.1; P = .07) among patients with a high probability of nonadherence in comparison with those with a low probability, as identified by the risk prediction model., Conclusions: The risk prediction model identified patients with a high probability of nonadherence and could be used in real time to personalize recommendations and interventions in the clinic., Lay Summary: The vast majority of children with acute lymphoblastic leukemia, the most common childhood cancer, are cured. The treatment of acute lymphoblastic leukemia includes taking an oral chemotherapy medicine (mercaptopurine) for approximately 2 years. Children who miss doses of this medicine (specifically children who take the medicine less than 90% of the time that it is prescribed) are more likely to suffer leukemia relapse. The authors of this article have measured mercaptopurine adherence with electronic bottle caps to determine characteristics of patients that predict nonadherence, and they have created a prediction tool that could allow physicians to identify and intervene with patients at high risk of nonadherence., (© 2021 American Cancer Society.)

Therapeutic practices for multiple myeloma (MM) have evolved, such that novel-agent-based therapy and autologous peripheral blood stem cell transplantation (aPBSCT) is the current standard. Whether cause-specific mortality has changed with time remains unclear. We examined late cause-specific mortality among patients with MM receiving aPBSCT from 1989 to 2014. We conducted a prospective cohort study using participants enrolled in the enrolled in the Blood or Marrow Transplant Survivor Study. We created 3 eras to reflect changing MM therapy: <2000 (pre-thalidomide); 2000-2005 (thalidomide); 2006-2014 (lenalidomide). We used Kaplan-Meier techniques and Cox regression for examining all-cause mortality, and subdistribution hazards models for cause-specific mortality. In total, 1906 patients were followed up for a median of 9.2 years. Conditional on surviving 2 years, the 10-year overall survival was 45%. The 10-year cumulative incidence of myeloma- and non-myeloma-related mortality was 33% and 13%, respectively. Multivariable analysis showed declining MM-specific mortality (subdistribution hazard ratio [SHR] 2000-2005  = 0.80, 95% confidence interval [CI], 0.60-1.07; SHR 2006-2014  = 0.46, 95% CI, 0.34-0.62; referent group: <2000), infection-related mortality (SHR 2000-2005  = 0.50, 95% CI, 0.29-0.85; SHR 2006-2014  = 0.35, 95%CI 0.21-0.60; referent group: <2000) and cardiovascular disease-related mortality (SHR 2000-2005  = 0.45, 95% CI 0.20-0.99; SHR 2006-2014  = 0.41, 95% CI 0.18-0.93; referent group: <2000). Although primary disease remains the major cause of late mortality, we observed a significant temporal decline in myeloma-, infection-, and cardiac-related late mortality over the past 25 years., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Blood or bone marrow transplantation (BMT) survivors with frailty are at a higher risk of subsequent mortality. Longitudinal trends in the frailty state are not known and could help identify vulnerable subpopulations at risk of subsequent adverse events., Methods: This study included a cohort of 470 autologous and allogeneic BMT recipients who had survived ≥2 years after BMT and completed a baseline questionnaire (t1) at a median of 7.3 years after BMT and a follow-up questionnaire (t2) 13.2 years after t1. The main outcome was change in frailty state between t1 and t2. Frailty phenotype was defined as exhibiting ≥3 of the following characteristics: clinically underweight, exhaustion, low energy expenditure, slow walking speed, and muscle weakness. The following categories of change in frailty state were evaluated: worsened, improved, and stable., Results: Of the 470 participants, 36.4% were aged ≥60 years at t1, and 50.6% were men. The prevalence of frailty increased from 4.8% at t1 to 9.6% at t2. Worsening was observed in 18.8% of patients, and improvement was reported in 9.7%. Pre-BMT exposure to vincristine (odds ratio [OR], 2.1; 95% CI, 1.3-3.39) was associated with worsening. Female sex (OR, 1.5; 95% CI, 0.93-2.4) was associated with a trend toward worsening. Pre-BMT exposure to vincristine (OR, 2.79; 95% CI, 1.44-5.43), a history of chronic graft-versus-host disease (OR, 2.58; 95% CI, 1.2-5.5), and grade 3 and 4 chronic health conditions at t1 (OR, 2.1; 95% CI, 1.08-4.33) were associated with frailty at t2., Conclusions: In a cohort of BMT survivors who were followed longitudinally for a median of 20.6 years from BMT, the frailty status worsened for approximately20% over a 13-year timespan. BMT survivors who are at risk for worsening frailty could benefit from targeted interventions., (© 2020 American Cancer Society.)

Purpose: Low-dose tamoxifen reduces breast cancer risk, but remains untested in chest-irradiated cancer survivors-a population with breast cancer risk comparable with BRCA mutation carriers. We hypothesized that low-dose tamoxifen would be safe and efficacious in reducing radiation-related breast cancer risk., Patients and Methods: We conducted an investigator-initiated, randomized, phase IIb, double-blinded, placebo-controlled trial (FDA IND107367) between 2010 and 2016 at 15 U.S. sites. Eligibility included ≥12 Gy of chest radiation by age 40 years and age at enrollment ≥25 years. Patients were randomized 1:1 to low-dose tamoxifen (5 mg/day) or identical placebo tablets for 2 years. The primary endpoint was mammographic dense area at baseline, 1 and 2 years. IGF-1 plays a role in breast carcinogenesis; circulating IGF-1 and IGF-BP3 levels at baseline, 1 and 2 years served as secondary endpoints., Results: Seventy-two participants (low-dose tamoxifen: n = 34, placebo: n = 38) enrolled at a median age of 43.8 years (35-49) were evaluable. They had received chest radiation at a median dose of 30.3 Gy. Compared with the placebo arm, the low-dose tamoxifen arm participants had significantly lower mammographic dense area ( P = 0.02) and IGF1 levels ( P < 0.0001), and higher IGFBP-3 levels ( P = 0.02). There was no difference in toxicity biomarkers (serum bone-specific alkaline phosphatase, lipids, and antithrombin III; urine N-telopeptide cross-links) between the treatment arms. We did not identify any grade 3-4 adverse events related to low-dose tamoxifen., Conclusions: In this randomized trial in chest-irradiated cancer survivors, we find that low-dose tamoxifen is effective in reducing established biomarkers of breast cancer risk and could serve as a risk-reduction strategy., (©2020 American Association for Cancer Research.)

Background: Anthracycline-related cardiomyopathy is a leading cause of late morbidity in childhood cancer survivors. Glutathione S-transferases (GSTs) are a class of phase II detoxification enzymes that facilitate the elimination of anthracyclines. As free-radical scavengers, GSTs could play a role in oxidative damage-induced cardiomyopathy. Associations between the GSTμ1 (GSTM1) null genotype and iron-overload-related cardiomyopathy have been reported in patients with thalassemia., Methods: The authors sought to identify an association between the GSTM1 null genotype and anthracycline-related cardiomyopathy in childhood cancer survivors and to corroborate the association by examining GSTM1 gene expression in peripheral blood and human-induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) from survivors with and without cardiomyopathy. GSTM1 gene deletion was examined by polymerase chain reaction in 75 survivors who had clinically validated cardiomyopathy (cases) and in 92 matched survivors without cardiomyopathy (controls). Conditional logistic regression analysis adjusting for sex, age at cancer diagnosis, chest radiation, and anthracycline dose was used to assess the association between genotype and cardiomyopathy. Proprietary bead array technology and quantitative real-time polymerase chain reaction were used to measure GSTM1 expression levels in samples from 20 cases and 20 matched controls. hiPSC-CMs from childhood cancer survivors (3 with cardiomyopathy, 3 without cardiomyopathy) also were examined for GSTM1 gene expression levels., Results: A significant association was observed between the risk of cardiomyopathy and the GSTM1 null genotype (odds ratio, 2.7; 95% CI, 1.3-5.9; P = .007). There was significant downregulation of GSTM1 expression in cases compared with controls (average relative expression, 0.67 ± 0.57 vs 1.33 ± 1.33, respectively; P = .049). hiPSC-CMs from patients who had cardiomyopathy revealed reduced GSTM1 expression (P = .007)., Conclusions: The current findings could facilitate the identification of childhood cancer survivors who are at risk for anthracycline-related cardiomyopathy., (© 2020 American Cancer Society.)

Purpose: To examine the association between total body irradiation (TBI) and subsequent breast cancer in women treated with blood or marrow transplantation (BMT) for hematologic malignancies., Patients and Methods: Participants were drawn from the BMT Survivor Study (BMTSS), a retrospective cohort study that included patients who underwent transplantation between 1974 and 2014 and survived for ≥ 2 years after BMT. Patients with pre-BMT chest radiation or a history of breast cancer were excluded. Participants completed the BMTSS survey, which included details regarding breast cancer diagnosis. Subsequent breast cancer was confirmed by pathology report review or physician notes. Cox proportional hazards models assessed the association between TBI and subsequent breast cancer. Standardized incidence ratios were calculated to determine the excess risk of subsequent breast cancer compared with that in the general population., Results: A total of 1,464 female BMT survivors (allogeneic: n = 788; autologous: n = 676) participated, with a median follow-up of 9.3 years from BMT. TBI was used in 660 patients (46%). Thirty-seven women developed subsequent breast cancer (allogeneic: n = 19; autologous: n = 18). Multivariable analysis revealed that exposure to TBI was associated with an increased risk of subsequent breast cancer among allogeneic BMT survivors (hazard ratio [HR], 3.7 [95% CI, 1.2 to 11.8]; P = .03) and autologous BMT survivors (HR, 2.6 [95% CI, 1.0 to 6.8]; P = .048). Pre-BMT exposure to alkylating agents was associated with an increased risk of subsequent breast cancer among autologous BMT survivors (HR, 3.3 [95% CI, 1.0 to 9.0]; P = .05). Compared with that in the general population, exposure to TBI at age < 30 years was associated with a 4.4-fold higher risk of subsequent breast cancer in allogeneic BMT survivors and a 4.6-fold higher risk in autologous BMT survivors., Conclusion: The association between TBI and subsequent breast cancer, especially among those exposed at a young age, as well as pre-BMT exposure to alkylating agents, should inform breast cancer screening for early detection.

Importance: Suboptimal adherence to oral mercaptopurine treatment in children with acute lymphoblastic leukemia (ALL) increases the risk of relapse. A frequently expressed barrier to adherence is forgetfulness, which is often overcome by parental vigilance., Objective: To determine whether a multicomponent intervention, compared with education alone, will result in a higher proportion of patients with ALL who have mercaptopurine adherence rates 95% or higher, for all study participants and among patients younger than 12 years and vs those aged 12 years and older., Design, Setting, and Participants: The adherence intervention trial was an investigator-initiated, multi-institutional, parallel-group, unblinded, randomized clinical trial conducted between July 16, 2012, and August 8, 2018, at 59 Children's Oncology Group institutions in the US, enrolling patients with ALL diagnosed through age 21 years and receiving mercaptopurine for maintenance. The date of final follow-up was January 2, 2019. Data analysis was performed from February to October 2019., Interventions: Patients were randomized 1:1 to education alone or the intervention package, which consisted of education and personalized text message reminders daily to prompt directly supervised therapy. Four weeks of baseline adherence monitoring were followed with a 16-week intervention., Main Outcomes and Measures: The primary end point was the proportion of patients with adherence rates 95% or higher over the duration of the intervention for all study participants, and for those younger than 12 years vs those aged 12 years and older., Results: There were 444 evaluable patients (median age, 8.1 years; interquartile range, 5.3-14.3 years), including 230 in the intervention group and 214 in the education group. Three hundred two patients (68.0%) were boys, 180 (40.5%) were non-Hispanic White, 170 (38.3%) were Hispanic, 43 (9.7%) were African American, and 51 (11.5%) were Asian or of mixed race/ethnicity. The proportion of patients with adherence rates 95% or higher did not differ between the intervention vs education groups (65% vs 59%; odds ratio, 1.33; 95% CI, 1.0-2.0; P = .08). Exploratory analyses showed that among patients aged 12 years and older, those in the intervention group had higher mean (SE) adherence rates than those in the education group (93.1% [1.1%] vs 90.0% [1.3%]; difference, 3.1%; 95% CI, 0.1%-6.0%; P = .04). In particular, among patients aged 12 years and older with baseline adherence less than 90%, those in the intervention group had higher mean (SE) adherence rates than those in the education group (83.4% [2.5%] vs 74.6% [3.4%]; difference, 8.8%; 95% CI, 2.2%-15.4%; P = .008). No safety concerns were identified., Conclusions and Relevance: Although this multicomponent intervention did not result in an increase in the proportion of patients with ALL who had mercaptopurine adherence rates 95% or higher, it did identify a high-risk subpopulation to target for future adherence intervention strategies: adolescents with low baseline adherence., Trial Registration: ClinicalTrials.gov Identifier: NCT01503632.

Background: Autologous blood or bone marrow transplantation (aBMT) is considered the standard of care for patients with multiple myeloma (MM). Significantly improved survival necessitates an understanding of the morbidity burden borne by the growing survivor population., Methods: The authors evaluated severe and/or life-threatening chronic health conditions (CHCs) and subsequent neoplasms (SNs) in patients with MM who were treated with aBMT using the Bone Marrow Transplant Survivor Study. A total of 630 study participants had undergone aBMT for MM at 1 of 3 BMT centers, had survived ≥2 years after aBMT, and were aged ≥18 years at the time of survey completion. Survivors of aBMT identified 289 nearest-age siblings to constitute an unaffected comparison group. Scoring of CHCs was based on version 5 of the National Cancer Institute Common Terminology Criteria for Adverse Events to determine severity (with grade 3 indicating serious and grade 4 indicating life-threatening)., Results: The 10-year cumulative incidence of any grade 3 to 4 CHC among survivors of aBMT was 57.6 ± 3.2%. Survivors of MM were found to be at 40% higher odds of developing grade 3 to 4 CHCs when compared with siblings (95% confidence interval [95% CI], 1.0-1.9). Among SNs, 96% were solid tumors, yielding a 10-year cumulative incidence of 13.6% ± 2.5%. Pre-aBMT exposure to cyclophosphamide (hazard ratio [HR], 3.5; 95% CI, 1.5-8.1) and immunomodulatory drugs (HR, 3.9; 95% CI, 1.5-10.1) were associated with an increased risk of solid tumors. Melanoma (10-year cumulative incidence: 3.3% ± 1.2%) and squamous cell carcinoma (10-year cumulative incidence: 5.1% ± 1.8%), were the most common SNs. Pre-aBMT exposure to cyclophosphamide (HR, 6.02; 95% CI, 1.4-26.1) and immunomodulatory drugs (HR, 7.9; 95% CI, 0.9-68.5) was associated with an increased risk of melanoma., Conclusions: The 10-year cumulative incidence of severe and/or life-threatening CHCs was found to approach 60% in long-term survivors of MM, with solid SNs constituting a large morbidity burden. The current study has provided evidence supporting the close monitoring of survivors to manage morbidity., (© 2020 American Cancer Society.)

Background: Blood or marrow transplantation (BMT) is increasingly offered to older adults with hematologic malignancies; however, their risk for severe pain is poorly understood. Using the Bone Marrow Transplant Survivor Study, the current study investigated the prevalence and predictors of pain after BMT (allogeneic or autologous) as well as its association with physical performance impairments and frailty., Methods: The cohort included 736 patients with hematologic malignancies who underwent BMT at an age ≥ 60 years at 1 of 3 transplant centers between 1974 and 2014 and survived ≥2 years after BMT; 183 unaffected siblings also participated. Study participants reported on 4 pain domains (nonminor everyday pain, moderate to severe bodily pain, prolonged pain, and moderate to extreme pain interference), and the presence of 1 or more domains was indicative of a severe and/or life-interfering pain composite variable., Results: Overall, 39.4% of the BMT survivors reported severe pain with 2.6-fold greater odds of reporting pain in comparison with sibling controls. Among BMT recipients, those with less education, lower incomes, and active chronic graft-versus-host disease had higher odds of reporting pain. In multivariable analyses, BMT survivors with pain were more likely to have impaired physical performance and were more likely to meet the frailty criteria. BMT survivors reported higher use of pain medications (17.8% vs 9.3%) and opioid pain medications (6.5% vs 2.2%) in comparison with sibling controls., Conclusions: Nearly 40% of older BMT survivors who were followed for a median of 5 years after BMT reported pain, and BMT survivors had 2.6-fold higher odds of reporting severe, nonminor or life-interfering pain in comparison with siblings., (© 2020 American Cancer Society.)

Background: Patients with non-Hodgkin lymphoma (NHL) have an increased risk of venous thromboembolism (VTE), particularly when they are receiving treatment. Blood or marrow transplantation (BMT) is recommended for relapsed/refractory NHL, and the risk of VTE after these patients undergo BMT is uncertain., Methods: Patients with NHL who survived 2 years or longer after BMT were surveyed for long-term health outcomes, including VTE. The median follow-up was 8.1 years (interquartile range, 5.6-12.9 years). The risk of VTE in 734 patients with NHL versus 897 siblings without a history of cancer and the risk factors associated with VTE were analyzed., Results: BMT survivors of NHL were at increased risk for VTE in comparison with siblings (odds ratio for allogeneic BMT survivors, 4.61; P < .0001; odds ratio for autologous BMT survivors, 1.75; P = .035). The cumulative incidence of VTE was 6.3% ± 0.9% at 5 years after BMT and 8.1% ± 1.1% at 10 years after BMT. In allogeneic BMT recipients, an increased body mass index (BMI; hazard ratio [HR] for BMI of 25-30 kg/m 2 , 3.52; 95% confidence interval [CI], 1.43-8.64; P = .006; HR for BMI > 30 kg/m 2 , 3.44; 95% CI, 1.15-10.23; P = .027) and a history of chronic graft-versus-host disease (HR, 3.33; 95% CI, 1.59-6.97; P = .001) were associated with an increased risk of VTE. Among autologous BMT recipients, a diagnosis of coronary artery disease (HR, 5.94; 95% CI, 1.7-20.71; P = .005) and prior treatment with carmustine (HR, 4.91; 95% CI, 1.66-14.51; P = .004) were associated with increased VTE risk., Conclusions: Patients with NHL who survive BMT are at risk for developing late occurring VTE, and ongoing vigilance for this complication is required. Future studies assessing the role of thromboprophylaxis in high-risk patients with NHL are needed., (© 2019 American Cancer Society.)

Background: Late mortality was investigated in patients with chronic myelogenous leukemia (CML) who underwent blood or bone marrow transplant (BMT) with or without prior tyrosine kinase inhibitor (TKI) therapy., Methods: By using data from the Blood or Marrow Transplant Survivor Study, the authors examined late mortality in 447 patients with CML who underwent BMT between 1974 and 2010, conditional on surviving ≥2 years post-BMT. For vital status information, the medical records, the National Death Index, and the Accurint database were used. Standardized mortality ratios (SMRs) were calculated using general population age-specific, sex-specific, and calendar-specific mortality rates. Kaplan-Meier techniques and Cox regression were used for all-cause mortality analyses. Cumulative incidence and proportional subdistribution hazards models for competing risks were used for cause-specific mortality analyses., Results: The 10-year overall survival rate was 65.7% and 73% for those who underwent transplant with and without pre-BMT exposure to TKI therapy, respectively. Patients who underwent transplant with and without pre-BMT TKI experienced SMRs of 6.4 and 6.4, respectively (P = .8); and the SMRs were 11.6 and 8.1, respectively, for those with high-risk disease (P = .2). Independent predictors of non-CML-related mortality included chronic graft-versus-host disease (hazard ratio [HR], 2.8; 95% CI, 1.8-4.4) and busulfan/cyclophosphamide conditioning (HR, 0.5; 95% CI, 0.3-0.9; reference, total body irradiation/cyclophosphamide conditioning). The 20-year cumulative incidence of CML-related and non-CML-related mortality was 6% and 36%, respectively, for the entire cohort. Both CML-related mortality (HR, 1.0; 95% CI, 0.1-12.6) and non-CML-related mortality (HR, 1.3; 95% CI, 0.6-3.1) were comparable for those with and without pre-BMT TKI therapy., Conclusions: The similar late mortality experienced by patients with CML who undergo transplantation with or without pre-BMT TKIs suggests that allogeneic BMT can be considered in the context of TKI intolerance or nonadherence. The prevention of post-BMT non-CML-related mortality could favorably affect long-term survival., (© 2019 American Cancer Society.)

Purpose: Fundamental gaps in knowledge regarding the risk of subsequent neoplasms (SNs) in children with pathogenic neurofibromatosis type 1 (NF1) variants exposed to radiation and/or alkylator chemotherapy have limited the use of these agents., Methods: We addressed these gaps by determining the SN risk in 167 NF1-affected versus 1,541 non-NF1-affected 5-year childhood cancer survivors from the Childhood Cancer Survivor Study and 176 nonoverlapping NF1-affected individuals with primary tumors from University of Alabama at Birmingham and Children's Hospital of Philadelphia exposed to radiation and/or chemotherapy. Proportional subdistribution hazards multivariable regression analysis was used to examine risk factors, adjusting for type and age at primary tumor diagnosis and therapeutic exposures., Results: In the Childhood Cancer Survivor Study cohort, the 20-year cumulative incidence of SNs in NF1 childhood cancer survivors was 7.3%, compared with 2.9% in the non-NF1 childhood cancer survivors ( P = .003), yielding a 2.4-fold higher risk of SN (95% CI, 1.3 to 4.3; P = .005) in the NF1-affected individuals. In the University of Alabama at Birmingham and Children's Hospital of Philadelphia cohort, among NF1-affected individuals with a primary tumor, the risk of SNs was 2.8-fold higher in patients with irradiated NF1 (95% CI, 1.3 to 6.0; P = .009). In contrast, the risk of SNs was not significantly elevated after exposure to alkylating agents (hazard ratio, 1.27; 95% CI, 0.3 to 3.0; P = .9)., Conclusion: Children with NF1 who develop a primary tumor are at increased risk of SN when compared with non-NF1 childhood cancer survivors. Among NF1-affected children with a primary tumor, therapeutic radiation, but not alkylating agents, confer an increased risk of SNs. These findings can inform evidence-based clinical management of primary tumors in NF1-affected children.

Hemostatic complications are commonly encountered in blood or marrow transplantation (BMT) recipients, increasing their morbidity and mortality and are well described in the immediate post-transplantation period. The risk of venous thromboembolism (VTE) in long-term survivors of autologous BMT has not been studied previously. Patients who underwent autologous BMT between January 1, 1974, and December 31, 2010 for a hematologic malignancy, lived 2 years or more after transplantation, and were age ≥18 years were surveyed for long-term outcomes. The median duration of follow-up was 9.8 years (interquartile range, 6.4 to 14.3 years). We analyzed the risk of VTE in 820 autologous BMT recipients who survived for ≥2 years, compared with 644 siblings. BMT survivors were at a 2.6-fold higher risk of VTE compared with siblings (95% confidence interval [CI], 1.6 to 4.4; P =.0004), after adjusting for sociodemographic characteristics. Conditional on surviving for ≥2 years after BMT, the mean cumulative incidence of VTE was 3.9 ± .8% at 5 years and 6.1 ± 1.1% at 10 years. A diagnosis of plasma cell disorder (hazard ratio [HR], 2.37; 95% CI, 1.3 to 4.2; P = .004) and annual household income ≤$50,000 (HR, 2.02; 95% CI, 1.2 to 3.6; P = .015) were associated with increased VTE risk. Our data indicate that autologous BMT survivors are at elevated risk for developing late-occurring VTE. The development of risk prediction models to identify autologous BMT survivors at greatest risk for VTE and thromboprophylaxis may help decrease the morbidity and mortality associated with VTE., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

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 22years 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 15years 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 ≥15years 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., (Copyright © 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2018. Published by Elsevier Inc.)

Importance: Allogeneic blood or marrow transplantation (BMT) is a curative option for malignant and nonmalignant diseases of childhood. However, little is known about trends in cause-specific late mortality in this population during the past 3 decades., Objectives: To examine cause-specific late mortality among individuals who have lived 2 years or more after allogeneic BMT performed in childhood and whether rates of late mortality have changed over time., Design, Setting, and Participants: A retrospective cohort study was conducted of individuals who lived 2 years or more after undergoing allogeneic BMT performed in childhood between January 1, 1974, and December 31, 2010. The end of follow-up was December 31, 2016., Exposure: Allogeneic BMT performed in childhood., Main Outcomes and Measures: All-cause mortality, relapse-related mortality, and non-relapse-related mortality. Data on vital status and causes of death were collected using medical records, the National Death Index Plus Program, and Accurint databases., Results: Among 1388 individuals (559 females and 829 males) who lived 2 years or more after allogeneic BMT performed in childhood, the median age at transplantation was 14.6 years (range, 0-21 years). In this cohort, there was a total of 295 deaths, yielding an overall survival rate of 79.3% at 20 years after BMT. The leading causes of death were infection and/or chronic graft-vs-host disease (121 of 244 [49.6%]), primary disease (60 of 244 [24.6%]), and subsequent malignant neoplasms (45 of 244 [18.4%]). Overall, the cohort had a 14.4-fold increased risk for death (95% CI, 12.8-16.1) compared with the general population (292 deaths observed; 20.3 deaths expected). Relative mortality remained elevated at 25 years or more after BMT (standardized mortality ratio, 2.9; 95% CI, 2.0-4.1). The absolute excess risk for death from any cause was 12.0 per 1000 person-years (95% CI, 10.5-13.5). The cumulative incidence of non-relapse-related mortality exceeded that of relapse-related mortality throughout follow-up. The 10-year cumulative incidence of late mortality decreased over time (before 1990, 18.9%; 1990-1999, 12.8%; 2000-2010, 10.9%; P = .002); this decrease remained statistically significant after adjusting for demographic and clinical factors (referent group: <1990; 1990-1999: hazard ratio, 0.64; 95% CI, 0.47-0.89; P = .007; 2000-2010: hazard ratio, 0.49; 95% CI, 0.31-0.76; P = .002; P < .001 for trend)., Conclusions and Relevance: Late mortality among children undergoing allogeneic BMT has decreased during the past 3 decades. However, these patients remain at an elevated risk of late mortality even 25 years or more after transplantation when compared with the general population, necessitating lifelong follow-up.