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

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

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

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

Return to school practices after hematopoietic cell transplantation: a survey of transplant centers in the United States.

To understand transplant center recommendations on return-to-school timing and related support for hematopoietic cell transplant (HCT) survivors, we conducted a two-phase, cross-sectional, web-based survey: In Phase I, medical directors of pediatric HCT centers from the National Marrow Donor Program/ Be The Match Registry were asked regarding the availability of a return to school standardized operating procedure (SOP). In Phase II, HCT physician members of the Pediatric Transplantation and Cellular Therapy Consortium were approached to study inter-physician practice variability regarding return to school post-HCT, factors affecting their decision-making, and support provided by HCT centers for return to school. Out of 46 respondents in Phase I (55% response rate), 28 (61%) reported having a SOP. Wide variations in recommendations were noted in 12 received SOPs. In Phase II, 122 physicians (60 centers) responded (30.6% response rate). The majority (60%) recommended autologous HCT recipients return to school within 6 months post-HCT but 65% recommended allogeneic HCT recipients return to school after 6 months or once off immunosuppression. Our findings indicate a lack of consensus within and across HCT centers regarding recommended return to school timing and underscore need for a guideline to standardize this process to ensure patient safety and re-integration into school.

Impact of Hematopoietic Cell Transplantation on Cardiovascular Risk Factors and Insulin Sensitivity.

The use of hematopoietic cell transplantation (HCT) for treating malignant conditions in children has increased over the past five decades, leading to a growing population of long-term survivors.This population of childhood HCT survivors faces increased risks of adverse medical effects due to cancer treatments, including adverse cardiovascular disease (CVD) risk factors such as metabolic syndrome, insulin resistance. but the impact of exposure to HCT preparative conditioning regimen has not been clearly delineated. These risk factors, including obesity, dyslipidemia, hypertension, and insulin resistance (IR), are significant contributors to premature cardiovascular disease and represent a leading cause of non-relapse deaths in childhood cancer and HCT survivors. This study aimed to assess the early development of CVD risk factors and their relationship to insulin resistance in a large population of pediatric and young adult HCT survivors of childhood hematologic malignancies. The study compared their cardiovascular risk profiles, insulin resistance (measured by euglycemic hyperinsulinemic clamp studies), and body composition (determined by dual X-ray absorptiometry - DXA) with a cohort of sibling controls. We enrolled 151 HCT recipients (26.36 ±0.90 years at study enrollment; time since HCT of 2.6-31.5 years) and 92 sibling controls to complete at cardiovascular risk assessment including insulin sensitivity by hyperinsulinemic euglycemic clamp, anthropometry, body composition by dual X-ray absorptiometry, blood pressure, and serum biomarkers. We used linear models to test for mean differences in all continuous outcomes between survivors and siblings, accounting for intra-family correlations with generalized estimating equations. Recipients of HCT were found to have lower insulin sensitivity and more likely to have adverse CVD risk factors in comparison to their healthy siblings. Significantly higher percent fat mass and visceral adipose tissue, and significantly lower lean body mass were noted in HCT recipients than sibling controls despite having a similar body mass index between the two groups. Total body irradiation in the conditioning regimen was one of the strongest factors associated with lower insulin sensitivity, dyslipidemia and abnormal body composition leading to sarcopenic obesity. This study reveals that pediatric and young adult HCT survivors are more insulin resistant and have a higher prevalence of adverse cardiovascular risk factors compared to sibling controls. The presence of cardiovascular risk factors at a relatively young age raises concerns about an escalating trajectory of cardiovascular disease in this population. Therefore, regular monitoring of HCT survivors for cardiometabolic risk factors and early intervention will be crucial for preventing cardiovascular-related complications in the future. The findings underscore the importance of survivorship care for pediatric and young adult HCT survivors, with a focus on managing cardiovascular risk factors and promoting a healthy lifestyle to mitigate long-term adverse effects. Early identification and targeted interventions can significantly improve the long-term health outcomes of this vulnerable population, reducing the burden of cardiovascular disease and related complications.

Unfavorable transcriptome profiles and social disadvantage in hematopoietic cell transplantation: a CIBMTR analysis.

Patient-reported outcomes (PROs) capture subjective social determinants of health (SDOHs), which can affect health outcomes through the stress response pathway. The conserved transcriptional response to adversity (CTRA) is a stress-mediated proinflammatory transcriptomic pattern that has been linked to adverse hematopoietic cell transplant (HCT) outcomes. This study examined the association of pretransplant CTRA with patient-reported SDOHs in allogeneic HCT recipients. In this cross-sectional study, pre-HCT SDOH-related PROs included the 36-Item Short Form Health Survey and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT). CTRA was assessed by RNA sequencing of whole blood specimens, with mixed effects linear regression models relating CTRA expression to PRO scores while controlling for age, sex, race, disease, and performance status. Among 121 patients, the median age was 54 years, 42% were female, and 91% were White. CTRA was elevated in participants reporting lower scores on the FACT-BMT (P = .003), including the general (P = .003) and BMT-specific (P = .014) components. Effects were driven by the social well-being domain (P = .0001). This corresponded to an 8% to 15% difference in CTRA RNA expression across a 4 standard deviation range in patient-reported SDOHs. Ancillary bioinformatics analyses confirmed the association of well-being with reduced proinflammatory transcription pathway activity [cyclic AMP response element-binding protein, (CREB), NF-κB, and activating protein-1 (AP-1)]. In conclusion, HCT-treated patients who experience unfavorable social conditions show elevated CTRA expression in pretransplant blood samples. These data highlight the biologic sequelae of social well-being and community context and suggest a potential molecular mechanism for the impact of social gradients in HCT outcomes. Targeting this pathway could optimize outcomes in this high-risk population.

The presence of busulfan metabolites and pharmacometabolomics in plasma drawn immediately before allograft infusion in hematopoietic cell transplant recipients.

Busulfan is hepatically metabolized through glutathione (GSH) conjugation; in vitro, this process depletes hepatocyte GSH stores and generates the cytotoxic metabolite γ-glutamyldehydroalanylglycine, which is too unstable to be quantitated in vivo. We sought to evaluate if pre-graft (i.e., immediately before allograft infusion) concentrations of busulfan metabolites' and of endogenous metabolomic compounds (EMCs) representing the glutathione pathway were associated with clinical outcomes in hematopoietic cell transplant (HCT) recipients receiving busulfan. The clinical outcomes evaluated were relapse, acute graft versus host disease (GVHD), chronic GVHD, non-relapse mortality, and neutrophil nadir. In pre-graft samples obtained from patients immediately before allograft infusion, our objectives were to evaluate for: (1) the presence of busulfan and its metabolites tetrahydrothiophenium ion (THT+), tetrahydrothiophene 1-oxide, sulfolane, and 3-hydroxysulfolane (N = 124); (2) EMCs using a global metabolomics assay (N = 77); and (3) the association of the busulfan metabolites and the EMCs with clinical outcomes. In the pre-graft samples, busulfan and THT+ could not be detected. THT 1-oxide, sulfolane, and 3-hydroxysulfolane were quantitated in 9.6%, 26%, and 58% of pre-graft samples; their concentrations were not associated with clinical outcomes. Four pre-graft EMCs were statistically significantly associated with the neutrophil nadir. The pre-graft EMCs were not associated with the other clinical outcomes. In conclusion, busulfan's metabolites are present in patients' plasma immediately before allograft infusion; the neutrophil nadir is associated with pre-graft EMCs. Future research should investigate the association of clinical outcomes with the concentrations of busulfan's metabolites and EMCs in the pre-graft plasma from allogeneic HCT recipients.

NCCN Guidelines® Insights: Survivorship, Version 1.2023.

The NCCN Guidelines for Survivorship are intended to help healthcare professionals address the complex and varied needs of cancer survivors. The NCCN Guidelines provide screening, evaluation, and treatment recommendations for psychosocial and physical problems resulting from adult-onset cancer and its treatment; recommendations to help promote healthy behaviors and immunizations in survivors; and a framework for care coordination. These NCCN Guidelines Insights summarize recent guideline updates and panel discussions pertaining to sleep disorders, fatigue, and cognitive function in cancer survivors.

Alemtuzumab and CXCL9 levels predict likelihood of sustained engraftment after reduced-intensity conditioning HCT.

Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peritransplantation alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from the Bone Marrow Transplant Clinical Trials Network 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism <5% after initial engraftment and/or requirement of cellular intervention). Thirty-three patients with hemophagocytic lymphohistiocytosis (n = 25) and other IEIs (n = 8) who underwent HCTs with T-cell-replete grafts were included. Patients with day 0 alemtuzumab levels ≤0.32 µg/mL had a markedly lower incidence of MC, 14.3%, vs 90.9% in patients with levels >0.32 µg/mL (P = .008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels >0.32 µg/mL (P = .08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day 14+ CXCL9 level ≤2394 pg/mL (day 14+ median) was 73.6% vs 0% in patients with a level >2394 pg/mL (P = .002). CXCL9 levels inversely correlated with alemtuzumab levels. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely affect sustained engraftment in the nonmyeloablative HCT setting. This trial was registered at www.clinicaltrials.gov as #NCT01998633.

Idiopathic Pneumonitis Syndrome After Total Body Irradiation in Pediatric Patients Undergoing Myeloablative Hematopoietic Stem Cell Transplantation: A PENTEC Comprehensive Review.

PURPOSE: Pulmonary complications, especially idiopathic pneumonitis syndrome (IPS), are potentially life altering or fatal sequelae of hematopoietic cell transplantation (HCT). Total body irradiation (TBI) as part of the conditioning regimen has been implicated in IPS. A comprehensive PENTEC (Pediatric Normal Tissues in the Clinic) review was performed to increase our understanding of the role of TBI in the development of acute, noninfectious IPS. METHODS AND MATERIALS: A systematic literature search was conducted using the MEDLINE, PubMed, and Cochrane library databases for articles describing pulmonary toxicity in children treated with HCT. Data pertaining to TBI and pulmonary endpoints were extracted. Risk of IPS was analyzed in relation to patient age, TBI dose, fractionation, dose rate, lung shielding, timing, and type of transplant, with the goal to better understand factors associated with this complication in children undergoing HCT. A logistic regression model was developed using a subset of studies with comparable transplant regimens and sufficient TBI data. RESULTS: Six studies met criteria for modeling of the correlation of TBI parameters with IPS; all consisted of pediatric patients undergoing allogeneic HCT with a cyclophosphamide-based chemotherapy regimen. IPS was variably defined, but all studies that reported IPS were included in this analysis. The mean incidence of post-HCT IPS was 16% (range, 4%-41%). Mortality from IPS, when it occurred, was high (median, 50%; range, 45%-100%). Fractionated TBI prescription doses encompassed a narrow range of 9 to 14 Gy. Many differing TBI methods were reported, and there was an absence of 3-dimensional dose analysis of lung blocking techniques. Thus, a univariate correlation between IPS and total TBI dose, dose fractionation, dose rate, or TBI technique could not be made. However, a model, built from these studies based on prescribed dose using a normalized dose parameter of equivalent dose in 2-Gy fractions (EQD2), adjusted for dose rate, suggested correlation with the development of IPS (P = .0004). The model-predicted odds ratio for IPS was 24.3 Gy-1 (95% confidence interval, 7.0-84.3). Use of TBI lung dose metrics (eg, midlung point dose) could not be successfully modeled, potentially because of dosimetric uncertainties in the actual delivered volumetric lung dose and imperfections in our modeling process. CONCLUSIONS: This PENTEC report is a comprehensive review of IPS in pediatric patients receiving fractionated TBI regimens for allogenic HCT. IPS was not clearly associated with 1 single TBI factor. Modeling using dose-rate adjusted EQD2 showed a response with IPS for allogeneic HCT using a cyclophosphamide-based chemotherapy regimen. Therefore, this model suggests IPS mitigation strategies can focus on not just the dose and dose per fraction but also the dose rate used in TBI. More data are needed to confirm this model and to determine the influence of chemotherapy regimens and contribution from graft-versus-host disease. The presence of confounding variables (eg, systemic chemotherapies) that affect risk, the narrow range of fractionated TBI doses found in the literature, and limitations of other reported data (eg, lung point dose) may have prevented a more straightforward link between IPS and total dose from being observed.

Patient-Reported Outcomes in Long-Term Survivors of Autologous Hematopoietic Cell Transplantation in Multiple Myeloma.

The overall survival in patients with transplantation-eligible multiple myeloma has tripled over the past 2 decades, leading to a growing population of myeloma survivors. However, there is a paucity of data on health-related quality of life (HRQoL), distress, and health behaviors in long-term myeloma survivors who are in stable remission after autologous hematopoietic cell transplantation (AHCT). In this cross-sectional study using data from 2 randomized controlled trials of survivorship care plans and internet-based self-management intervention in transplantation survivors, the primary objective was to measure HRQoL (using the Short Form-12, version 2.0 [SF-12 v2]), distress (using the Cancer- and Treatment-Related Distress [CTXD] instrument), and health behaviors of myeloma survivors in stable remission after AHCT. A total of 345 patients at a median of 4 years (range, 1.4 to 11 years) post-AHCT were included. The mean SF-12 v2 Physical Component Summary (PCS) score was 45.5 ± 10.5, and the mean Mental Component Summary (MCS) score was 51.3 ± 10.1, compared with US population norms of 50 ± 10 for both (P < .001 and P = .021 for PCS and MCS comparisons, respectively). Notably, neither reached the threshold for a minimal clinically important difference. Approximately one-third of the patients had clinically significant distress based on the CTXD total score, with distress reported by 53% of the patients in the Health Burden domain, by 46% in the Uncertainty domain, by 33% in the Finances domain, by 31% in the Family Strain domain, by 21% in the Identity domain, and by 15% in the Medical Demands domain. Preventive care guidelines were adhered to by 81% of the myeloma survivors; however, adherence to exercise and diet guidelines were relatively low, at 33% and 13%, respectively. Myeloma AHCT survivors in stable remission have no clinically meaningful worsening in physical functioning compared with the general population. Survivorship programs should address ongoing distress due to health burden, uncertainty, and finances in myeloma survivors, along with evidence-based targeted interventions for modifiable health behaviors, such as nutrition and exercise.

Socioeconomic Factors and Adherence to Health Care Recommendations in Adolescent and Young Adult Cancer Survivors.

Purpose: The majority of adolescent and young adult (AYA) cancer survivors do not receive recommended health care surveillance after therapy. We used cross-sectional survey data to evaluate the impact of income, education, marital status, and insurance on health care adherence among AYA survivors. Methods: Eligible survivors were 18-39 years at diagnosis with invasive malignancy, 1-5 years from therapy completion. Online surveys assessed sociodemographic factors and self-report of completion of recommended health care services. Diagnosis and treatment data were abstracted from medical records. Multivariable logistic regression calculated odds ratios (ORs) and 95% confidence intervals (CIs) for adherence in relation to socioeconomic status and support. Results: Of 344 participants, 36% were adherent to at least 80% of recommendations. Adherence varied by cancer type: 34% for breast cancer, 52% for leukemia/lymphoma, 23% for other tumors. Adherence rates were similar among White, Asian, and Hispanic/Latinx patients. Lower adherence was associated with lower education (OR: 0.43; 95% CI: 0.23-0.80 for <4-year college degree) and lower annual income (OR: 0.51; 95% CI: 0.28-0.95 for $41,000-$80,000; OR: 0.40; 95% CI: 0.19-0.86 for ≤$40,000). Adherence decreased with decreasing income levels among those who were 1 to less than 3 years after diagnosis (OR: 0.25; 95% CI: 0.07-0.93 for $81,000-$120,000; OR: 0.24; 95% CI: 0.07-0.84 for $41,000-$80,000; OR: 0.13; 95% CI: 0.03-0.60 for ≤$40,000). Conclusion: Risk of nonadherence to health care guidelines was associated with lower income and lower education among AYA cancer survivors. Identification of these risks and related barriers to adherence in AYA survivors will inform interventions designed to meet needs of these high-risk groups, particularly during the first years after diagnosis. Trial Registration: NCT02192333.

Dexrazoxane and Long-Term Heart Function in Survivors of Childhood Cancer.

PURPOSE: For survivors of childhood cancer treated with doxorubicin, dexrazoxane is cardioprotective for at least 5 years. However, longer-term data are lacking. METHODS: Within the Children's Oncology Group and the Dana Farber Cancer Institute's Childhood Acute Lymphoblastic Leukemia Consortium, we evaluated four randomized trials of children with acute lymphoblastic leukemia or Hodgkin lymphoma, who received doxorubicin with or without dexrazoxane, and a nonrandomized trial of patients with osteosarcoma who all received doxorubicin with dexrazoxane. Cumulative doxorubicin doses ranged from 100 to 600 mg/m2 across these five trials, and dexrazoxane was administered uniformly (10:1 mg/m2 ratio) as an intravenous bolus before doxorubicin. Cardiac function was prospectively assessed in survivors from these trials, plus a matched group of survivors of osteosarcoma treated with doxorubicin without dexrazoxane. Two-dimensional echocardiograms and blood biomarkers were analyzed centrally in blinded fashion. Multivariate analyses adjusted for demographic characteristics, cumulative doxorubicin dose, and chest radiotherapy determined the differences and associations by dexrazoxane status. RESULTS: From 49 participating institutions, 195 participants were assessed at 18.1 ± 2.7 years since cancer diagnosis (51% dexrazoxane-exposed; cumulative doxorubicin dose 297 ± 91 mg/m2). Dexrazoxane administration was associated with superior left ventricular fractional shortening (absolute difference, +1.4% [95% CI, 0.3 to 2.5]) and ejection fraction (absolute difference, +1.6% [95% CI, 0.0 to 3.2]), and lower myocardial stress per B-type natriuretic peptide (-6.7 pg/mL [95% CI, -10.6 to -2.8]). Dexrazoxane was associated with a reduced risk of having lower left ventricular function (fractional shortening < 30% or ejection fraction < 50%; odds ratio, 0.24 [95% CI, 0.07 to 0.81]). This protective association was primarily seen in those treated with cumulative doxorubicin doses ≥ 250 mg/m2. CONCLUSION: Among young adult-aged survivors of childhood cancer, dexrazoxane was associated with a cardioprotective effect nearly 20 years after initial anthracycline exposure.

Feasibility of delivering survivorship care via lay health educators: A pilot randomized controlled trial among rural cancer survivors.

PURPOSE: We tested the feasibility of survivorship care plan (SCP) delivery with/without a lay health educator (LHE) telephone-delivered information session among rural cancer survivors, and their effects on health-related self-efficacy and knowledge of cancer history. METHODS: Randomized trial of cancer survivors from 3 rural oncology clinics featuring either SCP alone (control) or SCP plus LHE-delivered information session (intervention). Participants completed a questionnaire on health-related self-efficacy and knowledge of cancer-specific medical history. Responses were compared to medical records for accuracy. SCPs were then mailed to participants. Approximately 5 months later, participants completed a follow-up questionnaire. A subset of participants took part in subsequent qualitative interviews about their study experience. FINDINGS: Of 301 survivors approached, 72 (23.9%) were randomized (mean age 66.4 years; 3.1 years from diagnosis; 62.5% female), and 65 (90.3%) completed the study. Global mental and physical health or self-efficacy scores did not change significantly from baseline to follow-up for either group. In exploratory analyses, self-efficacy increased in participants with inadequate/marginal health literacy in the intervention arm (+0.7, 95% CI = 0.1-1.2; P = .01). Accuracy of knowledge did not improve but was high at baseline (mean 76.0±14.5%). 60.1% and 48.4% of control and intervention participants, respectively, found SCPs definitely/somewhat useful. Qualitative data (n = 20) suggested that SCPs were helpful to patients when primary and oncology care were less integrated. CONCLUSIONS: An LHE-delivered informational session was feasible but had limited benefit to rural cancer survivors versus delivery of SCP alone but may be of benefit to patients with low health literacy or with less integrated care.

Health-Related Quality of Life Outcomes in Older Hematopoietic Cell Transplantation Survivors.

The use of hematopoietic cell transplantation (HCT) has been increasing in older patients. However, the levels if distress, psychosocial functioning, and health-related quality of life (HRQOL) among older HCT survivors remains largely unknown. In this secondary analysis using data from 2 randomized controlled trials, we analyzed baseline Cancer and Treatment Distress (CTXD) and Confidence In Survivorship Information (CSI) surveys of HCT survivors who were age ≥60 years at the time of transplantation and alive and disease-free ≥1 year post-autologous or -allogeneic HCT. We analyzed associations of these parameters with the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores of the 12-Item Short Form Survey (SF-12) and a healthcare adherence (HCA) scale, after adjusting for transplantation and patient demographic factors. A total of 567 patients were included. The median patient age at HCT was 65 years, and 68% of the patients underwent autologous HCT. The median CTXD score was .7 (mild), and the greatest distress was reported in the "health burden" subscale. The median CSI score was 1.4 (moderate-high), with the lowest confidence reported in the "late effects" subscale. We found negative Spearman correlations between CTXD score and SF-12 PCS (P = -.59) and MCS (P = -.54) and positive Spearman correlations between CSI score and SF-12 PCS (P = .23) and MCS (P = .30). The median HCA scale score was high at .8. Male sex, autologous HCT, increased distress level, and worse CSI score were associated with lower use of preventive care. Older survivors experienced a low level of distress and moderate-high level of CSI at ≥1 year post-HCT. As lower distress and higher CSI were associated with improved HRQOL and optimized preventive HCA, CTXD/CSI measures can be used to individualize the care of older adult HCT survivors.

Prediction of Busulfan Clearance by Predose Plasma Metabolomic Profiling.

Intravenous busulfan doses are often personalized to a target plasma exposure (targeted busulfan) using an individual's busulfan clearance (BuCL). We evaluated whether BuCL could be predicted by a predose plasma panel of 841 endogenous metabolomic compounds (EMCs). In this prospective cohort of 132 hematopoietic cell transplantation (HCT) patients, all had samples collected immediately before busulfan administration (preBU) and 96 had samples collected 2 weeks before busulfan (2-week-preBU). BuCL was significantly associated with 37 EMCs after univariate linear regression analysis and controlling for false discovery (< 0.05) in the 132 preBU samples. In parallel, with preBU samples, we included all 841 EMCs in a least absolute shrinkage and selection operator-penalized regression which selected 13 EMCs as predominantly associated with BuCL. Then, we constructed a prediction model by estimating coefficients for these 13 EMCs, along with sex, using ordinary least-squares. When the resulting linear prediction model was applied to the 2-week-preBU samples, it explained 40% of the variation in BuCL (adjusted R2  = 0.40). Pathway enrichment analysis revealed 18 pathways associated with BuCL. Lysine degradation followed by steroid biosynthesis, which aligned with the univariate analysis, were the top two pathways. BuCL can be predicted before busulfan administration with a linear regression model of 13 EMCs. This pharmacometabolomics method should be prioritized over use of a busulfan test dose or pharmacogenomics to guide busulfan dosing. These results highlight the potential of pharmacometabolomics as a precision medicine tool to improve or replace pharmacokinetics to personalize busulfan doses.

NCCN Guidelines® Insights: Survivorship, Version 1.2022.

The NCCN Guidelines for Survivorship are intended to help healthcare professionals who work with survivors to ensure that the survivors' complex and varied needs are addressed. The NCCN Guidelines provide screening, evaluation, and treatment recommendations for the consequences of adult-onset cancer and its treatment; recommendations to help promote physical activity, weight management, and immunizations in survivors; and a framework for care coordination. This article summarizes updates to the NCCN Guidelines pertaining to preventive health for cancer survivors, including recommendations about alcohol consumption and vaccinations.

Risk Factors for Development of Pneumatosis Intestinalis after Pediatric Hematopoietic Stem Cell Transplantation: A Single-Center Case-Control Study.

The significance of pneumatosis intestinalis (PI) in pediatric patients following hematopoietic stem cell transplantation (HSCT) is poorly understood. A knowledge gap remains with respect to the etiology, risk factors, and evidence-based treatment of these patients. As a result, management is frequently based on each center's clinical practice, without standardization across treatment centers. In this single-center trial, we aimed to validate both previously proposed and additional risk factors for the development of PI and to examine our management and outcomes for these patients. We performed a retrospective case-control study examining risk factors for the development of PI in pediatric HSCT patients at a single tertiary referral children's hospital. We used univariate and multivariable conditional logistic regression analysis to explore differences in pharmacologic and other transplantation-specific risk factors. Between 2012 and 2019, PI was diagnosed in 212 patients at our pediatric hospital, of whom 42 were HSCT recipients. The majority of patients (88%; n = 37 of 42) with PI were diagnosed by X-ray. Eighteen patients (43%) were asymptomatic and diagnosed incidentally after imaging was obtained for standard post-transplantation surveillance or other nonrelated indications. All patients with PI were hospitalized and placed on strict bowel rest while receiving parenteral nutrition and antibiotics. Recurrence of PI occurred in 4 patients (10%) following their initial diagnosis. Increased doses of steroid exposure within 30 days of PI diagnosis (odds ratio [OR], 5.7; 95% confidence interval [CI], 2.1 to 15.3; P = .0006), presence of grade II-IV gastrointestinal acute graft-versus-host disease (GVHD) (OR, 5.3; 95% CI, 1.0 to 28.1; P = .05), and receipt of >50% of total daily nutrition by nasogastric (NG) tube feeds (OR, 22.0; 95% CI, 1.3 to 370.2; P = .03) were identified as independent risk factors for the development of PI. Intensity of the conditioning regimen, exposure to total body irradiation, stem cell source, donor type, HLA matching, use of mycophenolate mofetil, and presence of bacterial or viral infection at the time of PI diagnosis were not demonstrably associated with the development of PI in our study. We conclude that development of asymptomatic PI is a benign condition following HSCT, and that the risk for PI is increased in patients with gastrointestinal GVHD, patients receiving steroid therapy, and patients relying on supplemental NG tube feeds for at least one-half of their total daily nutrition.

Health-Related Quality of Life in Young Adult Survivors of Hematopoietic Cell Transplantation.

Young adults (YA), age 18 to 39 years, are at a stage of life that may make them more vulnerable than older adults to impairments in health-related quality of life (HRQOL) during and after hematopoietic cell transplantation (HCT). Health self-efficacy (HSE), the belief that one can implement strategies to produce a desired health outcome, has been associated with health outcomes in oncology research. Little is known about HRQOL or HSE in YA HCT survivors compared with older HCT survivors. Given the age-specific psychosocial challenges facing YA HCT recipients and research on non-transplant YA cancer survivors, we hypothesized that YA survivors would have worse post-HCT HRQOL compared with older adults, and that among YA HCT survivors, higher levels of HSE would be associated with higher levels of HRQOL and lower levels of cancer-related distress. This was a cross-sectional secondary analysis of 2 combined baseline datasets from multicenter studies of HCT survivors approached for participation in clinical trials of survivorship interventions. Participants from 20 transplantation centers in the United States were at 1 to 10 years post-HCT and age ≥18 years at the time of study enrollment, had no evidence of disease relapse/progression or subsequent malignancies, and could read English adequately to consent for and complete assessments. Medical record and patient-reported data were obtained for demographics and HCT-related clinical factors and complications (eg, total body irradiation, chronic graft-versus-host disease [cGVHD]). Participants completed surveys on HRQOL, including the Short-Form [SF]-12, HSE, and Cancer and Treatment Distress (CTXD), which includes 6 subscales and reports an overall mean score. On the SF-12, both the Mental Component Score (MCS) and Physical Component Score (PCS) were calculated. Two cohorts were compared: YAs (age 18 to 39 years at transplantation) and older adults (age ≥40 years at transplantation). Multiple linear regression analyses identified factors associated with HSE, PCS, MCS, and CTXD in YAs. In this analysis of 979 survivors, compared with the older adults, the YA participants had lower median mental health scores (SF-12 MCS: 48.40 versus 50.23; P = .04) and higher cancer-related distress (CTXD: .96 versus .85; P = .04), but better physical health (SF-12 PCS: 48.99 versus 47.18; P = .049). Greater overall cancer-related distress was driven by higher levels of uncertainty, financial concern, and medical demand subscales for YAs compared with older adults. Young adults also had lower HSE (2.93 versus 3.08; P = .0004). In a multivariate model, HSE was strongly associated with age group (P = .0005) after adjusting for multiple other transplantation-related factors. Among YAs, HSE was associated with the SF-12 MCS and PCS and the CTXD, and HSE remained significant after adjusting for other transplantation-related factors. Overall, the YA HCT survivors had lower mental health, increased cancer-related distress, and lower levels of HSE compared with the older adults. Although the direction of these effects cannot be determined with these data, the strong association between HSE and HRQOL among YAs suggests that targeting interventions to improve HSE may have broad impact on health outcomes.

Outcomes after hematopoietic cell transplantation among non-English- compared to English-speaking recipients.

Multiple studies have documented that racial/ethnic minority patients are less likely to undergo hematopoietic cell transplantation (HCT) in the United States (US), and if they do, they often have worse outcomes. No studies to our knowledge have compared the outcomes of English-speakers to non-English speakers undergoing HCT in the US. To test our hypothesis that non-English speakers have worse outcomes than English speakers after HCT, all transplants performed between 2015 and 2019 at Fred Hutchinson Cancer Research Center in Seattle, WA, USA were analyzed. Cox proportional hazards models were used to test our hypothesis, adjusting for significant clinical covariates. Out of 2051 patients, 106 (5%) were documented to be non-English speakers. Mortality for non-English speakers was not different than English speakers (adjusted HR 1.02, 95% CI 0.63-1.63, p = 0.95). When the analysis was limited to the allogeneic population, the results were similar to the total population (adjusted HR 1.10, 0.64-1.88, p = 0.73). The risk of grade II-IV acute graft-versus-host disease (GVHD) was higher in the non-English speaking subset: adjusted OR 2.01, 95% CI, 1.02-3.98, p = 0.04. These data suggest that non-English speakers have similar survival compared to English speakers following HCT although they have more acute GVHD.

The Role of Follicle-stimulating Hormone in Vascular Dysfunction Observed in Hematopoietic Cell Transplant Recipients.

Childhood cancer survivors who receive a hematopoietic cell transplantation (HCT) are at increased risk for follicle-stimulating hormone (FSH) abnormalities, which may have a substantial negative impact on vascular function. The purpose of this study was to examine the association of vascular function with FSH in HCT recipients, non-HCT recipients and healthy controls. The study included childhood cancer survivors who were HCT recipients (n=24) and non-HCT recipients (n=308), and a control group of healthy siblings (n=211) all between 9 and 18 years old. Vascular measures of carotid artery structure and function (compliance and distensibility), brachial artery flow-mediated dilation and endothelial-independent dilation were measured using ultrasound imaging. A fasting blood sample was collected to measure hormone levels. FSH was significantly higher in HCT recipients compared with non-HCT recipients and healthy controls (P<0.01). Carotid compliance and distensibility were significantly lower in HCT and non-HCT recipients compared with healthy controls (P<0.05). Higher FSH was associated with decreased carotid compliance (P<0.05). This study's results suggest that higher levels of FSH in HCT recipients may result in significant reductions in vascular function compared with non-HCT recipients and healthy controls. Therefore, gonadotropin endocrine dysfunction, particularly abnormal FSH levels, may be an underlying mechanism of vascular dysfunction.