Coronary artery calcium and cardiovascular outcomes in patients with lymphoma undergoing autologous hematopoietic cell transplantation.

BACKGROUND: Patients undergoing autologous hematopoietic cell transplantation (HCT) have a >2-fold risk of developing cardiovascular disease (CVD; heart failure, myocardial infarction, and stroke), compared to the general population. Coronary artery calcium (CAC) is predictive of CVD in nononcology patients but is not as well studied in patients who underwent HCT and survivors of HCT.The objective of this study was to examine the association between CAC and CVD risk and outcomes after HCT in patients with lymphoma. METHODS: This was a retrospective cohort study of 243 consecutive patients who underwent a first autologous HCT for lymphoma between 2009 and 2014. CAC (Agatston score) was determined from chest computed tomography obtained <60 days from HCT. Multivariable Cox regression analysis was used to calculate hazard ratio (HR) estimates and 95% confidence intervals (CIs), adjusted for covariates (age, conventional risk factors [e.g., hypertension and dyslipidemia], and cancer treatment). RESULTS: The median age at HCT was 55.7 years (range, 18.5-75.1 years), 59% were male, and 60% were non-Hispanic White. The prevalence of CAC was 37%. The 5-year CVD incidence for the cohort was 12%, and there was an incremental increase in the incidence according to CAC score: 0 (6%), 1-100 (20%), and >100 (32%) (p = .001). CAC was significantly associated with CVD risk (HR, 3.0; 95% CI, 1.2-7.5) and worse 5-year survival (77% vs. 50%; p < .001; HR, 2.0; 95% CI, 1.1-3.4), compared to those without CAC. CONCLUSIONS: CAC is independently associated with CVD and survival after HCT. This highlights the importance of integrating readily available imaging information in risk stratification and decision-making in patients undergoing HCT, which sets the stage for strategies to optimize outcomes after HCT.

Diabetes in childhood cancer survivors: emerging concepts in pathophysiology and future directions.

With advancements in cancer treatment and supportive care, there is a growing population of childhood cancer survivors who experience a substantial burden of comorbidities related to having received cancer treatment at a young age. Despite an overall reduction in the incidence of most chronic health conditions in childhood cancer survivors over the past several decades, the cumulative incidence of certain late effects, in particular diabetes mellitus (DM), has increased. The implications are significant, because DM is a key risk factor for cardiovascular disease, a leading cause of premature death in childhood cancer survivors. The underlying pathophysiology of DM in cancer survivors is multifactorial. DM develops at younger ages in survivors compared to controls, which may reflect an "accelerated aging" phenotype in these individuals. The treatment-related exposures (i.e., chemotherapy, radiation) that increase risk for DM in childhood cancer survivors may be more than additive with established DM risk factors (e.g., older age, obesity, race, and ethnicity). Emerging research also points to parallels in cellular processes implicated in aging- and cancer treatment-related DM. Still, there remains marked inter-individual variability regarding risk of DM that is not explained by demographic and therapeutic risk factors alone. Recent studies have highlighted the role of germline genetic risk factors and epigenetic modifications that are associated with risk of DM in both the general and oncology populations. This review summarizes our current understanding of recognized risk factors for DM in childhood cancer survivors to help inform targeted approaches for disease screening, prevention, and treatment. Furthermore, it highlights the existing scientific gaps in understanding the relative contributions of individual therapeutic exposures and the mechanisms by which they exert their effects that uniquely predispose this population to DM following cancer treatment.

Risk of Frailty in Survivors of Childhood Cancer: The Role of Socioenvironmental Factors.

The identification of frailty among relatively young survivors of childhood cancer has led to a growing body of work aimed at examining potential risk factors and interventions to decrease its burden in this population. In the accompanying article, Schwartz and colleagues present their findings regarding the association between neighborhood characteristics and frailty in survivors of childhood cancer and show that survivors living in resource poor neighborhoods had increased odds of frailty compared with those in resource-rich neighborhoods. This work further supports the need for focused educational initiatives and nutrition and exercise interventions to improve survivors' quality of health. See related article by Schwartz et al., p. 1021.

Imaging modalities for measuring body composition in patients with cancer: opportunities and challenges.

Body composition assessment (ie, the measurement of muscle and adiposity) impacts several cancer-related outcomes including treatment-related toxicities, treatment responses, complications, and prognosis. Traditional modalities for body composition measurement include body mass index, body circumference, skinfold thickness, and bioelectrical impedance analysis; advanced imaging modalities include dual energy x-ray absorptiometry, computerized tomography, magnetic resonance imaging, and positron emission tomography. Each modality has its advantages and disadvantages, thus requiring an individualized approach in identifying the most appropriate measure for specific clinical or research situations. Advancements in imaging approaches have led to an abundance of available data, however, the lack of standardized thresholds for classification of abnormal muscle mass or adiposity has been a barrier to adopting these measurements widely in research and clinical care. In this review, we discuss the different modalities in detail and provide guidance on their unique opportunities and challenges.

Association Between Pretreatment Skeletal Muscle and Outcomes After CAR T-Cell Therapy.

BACKGROUND: The purpose of this study was to examine the association between baseline skeletal muscle measurements, acute toxicity (immune effector cell-associated neurotoxicity syndrome [ICANS], cytokine release syndrome), and treatment efficacy in patients undergoing CAR T-cell therapy for B-lineage lymphoma. PATIENTS AND METHODS: Skeletal muscle measurements were obtained from automated CT measurements in 226 consecutive patients who received CAR T-cell therapy between 2015 and 2021. The Kaplan-Meier method was used to examine progression-free survival (PFS) and overall survival (OS) at 1-year. Multivariable regression was used to calculate the hazard ratio (HR) with 95% confidence intervals, adjusted for covariates. RESULTS: The median age of the cohort was 63.1 years (range, 18.5-82.4 years), and most patients were male (66%) and had primary refractory disease (58%). Patients with abnormally low skeletal muscle at baseline were at greater risk of ICANS (HR, 1.74; 95% CI, 1.05-2.87) and had longer length of hospitalization (mean 27.7 vs 22.9 days; P<.05) compared with those with normal muscle mass. Abnormal skeletal muscle was independently associated with risk of disease progression (HR, 1.70; 95% CI, 1.11-2.57) and worse survival (HR, 2.44; 95% CI, 1.49-4.00) at 1 year compared with normal skeletal muscle. Individuals who had abnormal skeletal muscle and high lactate dehydrogenase (LDH) levels at baseline had poor 1-year PFS (17%) and OS (12%) compared with those with normal skeletal muscle and LDH levels (72% and 82%, respectively; P<.001). Patients who had abnormal skeletal muscle and LDH levels had a 5-fold risk (HR, 5.34; 95% CI, 2.97-9.62) of disease progression and a 10-fold risk (HR, 9.73; 95% CI, 4.81-19.70) of death (reference: normal skeletal muscle, normal LDH), independent of prior lines of therapy, extent of residual disease at time of CAR T-cell therapy, functional status, or product. CONCLUSIONS: This information can be used for risk stratification prior to CAR T-cell therapy or to implement prehabilitation and nutritional optimization before lymphodepletion as well as thereafter. These efforts will be complementary to ongoing efforts toward sustained efficacy after CAR T-cell therapy.

Social Vulnerability and Risk of Nonrelapse Mortality After Allogeneic Hematopoietic Cell Transplantation.

BACKGROUND: Risk of nonrelapse mortality (NRM) after hematopoietic cell transplantation (HCT) is high. Patient-level clinical prediction models such as the HCT-comorbidity index (HCT-CI) help identify those at increased risk for NRM, but the independent contribution of social determinants of health on HCT outcomes is not well characterized. METHODS: This study included 1602 patients who underwent allogeneic HCT between 2013 and 2019 at City of Hope. Census tract-level social vulnerability was measured using the social vulnerability index (SVI). Fine-Gray multivariable regression evaluated the association between SVI and 1-year NRM. Subgroup analysis examined risk of NRM across combined SVI and HCT-CI categories and by race and ethnicity. RESULTS: Cumulative incidence of 1-year NRM after HCT was 15.3% (95% confidence interval [CI] = 13.6% to 17.1%). In multivariable analysis, patients in the highest SVI tertile (highest social vulnerability) had a 1.4-fold risk (subdistribution hazard ratio [sHR] = 1.36, 95% CI = 1.04 to 1.78) of NRM compared with individuals in the lower tertiles; patients in the highest SVI tertile who also had elevated (≥3) HCT-CI scores had the highest risk (sHR = 1.81, 95% CI = 1.26 to 2.58) of 1-year NRM (reference: lower SVI tertiles and HCT-CI < 3). High social vulnerability was associated with risk of 1-year NRM in Asian (sHR = 2.03, 95% CI = 1.09 to 3.78) and Hispanic (sHR = 1.63, 95% CI = 1.04 to 2.55) but not non-Hispanic White patients. CONCLUSIONS: High social vulnerability independently associated with 1-year NRM after HCT, specifically among minority populations and those with a high comorbidity burden at HCT. These findings may inform targeted approaches for needs assessment during and after HCT, allowing for timely interventions to improve health outcomes in at-risk patients.

Association Between Body Composition and Development of Glucose Intolerance after Allogeneic Hematopoietic Cell Transplantation.

BACKGROUND: Allogeneic hematopoietic cell transplantation (HCT) recipients have increased risk of developing glucose intolerance and diabetes mellitus (DM). The strongest risk factor for glucose intolerance is being overweight/obese, as determined by body mass index (BMI), which does not account for differences in body composition. We examined the association between body composition measures from pre-HCT CT and early-onset (≤30 days) de novo glucose intolerance after HCT, and determined its impact on nonrelapse mortality (NRM). METHODS: This study included 749 patients without pre-HCT DM. Skeletal muscle loss [abnormal skeletal muscle gauge (SMG)] and abnormal visceral adiposity (VA) were defined by sex-specific tertiles. Fine-Gray proportional subdistribution HR estimates and 95% confidence intervals (CI) were obtained to determine the association between muscle loss and VA and development of glucose intolerance. 1 year NRM was calculated for patients alive at day 30. RESULTS: Median age at HCT was 50.2 years. By day 30, 8.1% of patients developed glucose intolerance and 731 remained alive. In multivariable analysis, abnormal SMG was associated with increased risk of glucose intolerance in nonoverweight (BMI < 25 kg/m2) patients (HR = 3.00; 95% CI, 1.15-7.81; P = 0.024); abnormal VA was associated with increased risk of glucose intolerance in overweight/obese patients (HR = 2.26; 95% CI, 1.24-4.12; P = 0.008). Glucose intolerance was independently associated with NRM (HR = 1.88; 95% CI, 1.05-3.39; P = 0.035). CONCLUSIONS: Abnormal SMG and VA were associated with glucose intolerance in nonoverweight and overweight/obese patients, respectively, which contributed to increased risk of 1 year NRM. IMPACT: This information may guide personalized interventions to decrease the risk of adverse outcomes after HCT. See related commentary by Giri and Williams, p. 2002.

Exercise training and NR supplementation to improve muscle mass and fitness in adolescent and young adult hematopoietic cell transplant survivors: a randomized controlled trial {1}.

BACKGROUND: Advances in hematopoietic cell transplantation (HCT) have led to marked improvements in survival. However, adolescents and young adults (AYAs) who undergo HCT are at high risk of developing sarcopenia (loss of skeletal muscle mass) due to the impact of HCT-related exposures on the developing musculoskeletal system. HCT survivors who have sarcopenia also have excess lifetime risk of non-relapse mortality. Therefore, interventions that increase skeletal muscle mass, metabolism, strength, and function are needed to improve health in AYA HCT survivors. Skeletal muscle is highly reliant on mitochondrial energy production, as reflected by oxidative phosphorylation (OXPHOS) capacity. Exercise is one approach to target skeletal muscle mitochondrial OXPHOS, and in turn improve muscle function and strength. Another approach is to use "exercise enhancers", such as nicotinamide riboside (NR), a safe and well-tolerated precursor of nicotinamide adenine dinucleotide (NAD+), a cofactor that in turn impacts muscle energy production. Interventions combining exercise with exercise enhancers like NR hold promise, but have not yet been rigorously tested in AYA HCT survivors. METHODS/DESIGN: We will perform a randomized controlled trial testing 16 weeks of in-home aerobic and resistance exercise and NR in AYA HCT survivors, with a primary outcome of muscle strength via dynamometry and a key secondary outcome of cardiovascular fitness via cardiopulmonary exercise testing. We will also test the effects of these interventions on i) muscle mass via dual energy x-ray absorptiometry; ii) muscle mitochondrial OXPHOS via an innovative non-invasive MRI-based technique, and iii) circulating correlates of NAD+ metabolism via metabolomics. Eighty AYAs (ages 15-30y) will be recruited 6-24 months post-HCT and randomized to 1 of 4 arms: exercise + NR, exercise alone, NR alone, or control. Outcomes will be collected at baseline and after the 16-week intervention. DISCUSSION: We expect that exercise with NR will produce larger changes than exercise alone in key outcomes, and that changes will be mediated by increases in muscle OXPHOS. We will apply the insights gained from this trial to develop individualized, evidence-supported precision initiatives that will reduce chronic disease burden in high-risk cancer survivors. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05194397. Registered January 18, 2022, https://clinicaltrials.gov/ct2/show/NCT05194397 {2a}.

Ultra-High Dose Vitamin D in Pediatric Hematopoietic Stem Cell Transplantation: A Nonrandomized Controlled Trial.

Vitamin D is essential for bone health and has immunomodulatory properties. Most pediatric patients are vitamin D insufficient (<30 ng/mL) before hematopoietic stem cell transplantation (HSCT). Standard supplementation strategies fail to achieve vitamin D sufficiency in the acute post-transplantation period, and there are scarce data to support optimal vitamin D supplementation in this patient population. This study aimed to evaluate whether a single, oral, weight-based ultra-high dose of vitamin D (Stoss dosing) was more effective than standard supplementation to achieve pre-HSCT vitamin D sufficiency and reduce the incidence of HSCT-related complications (acute graft-versus-host disease, veno-occlusive disease, and/or transplant-associated thrombotic microangiopathy) that are associated with immune-mediated endothelial damage. Secondary endpoints examined the immunomodulatory properties of vitamin D. We conducted a nonrandomized controlled clinical trial of Stoss-dosed vitamin D in pediatric patients receiving HSCT. The study prospectively enrolled 33 patients, 29 of whom successfully received Stoss-dosed vitamin D and were compared to 136 patients in a historical control. Patient characteristics were compared using Fisher's exact test or t-test. The one-sided Fisher's exact test was used for cohort comparison of the primary endpoints. Logistic regression was used to examine the association between patient-specific factors and total 25-hydroxy vitamin D (25-OHD) levels and the compiled HSCT complications. In the Stoss cohort, 97% (n = 28/29) of patients achieved pre-HSCT vitamin D sufficiency compared to 67% (n = 10/15) of patients in the historical control who were on standard supplementation at the time the total 25-OHD level was assessed (P = .013). The mean total 25-OHD level in the Stoss cohort was significantly higher than patients in the historical control who received standard supplementation (72.2 ng/mL versus 35.8 ng/mL, P < .001). Nine patients in the Stoss cohort maintained vitamin D sufficiency throughout the first 100 days after HSCT, and the remaining 19 patients maintained sufficiency for a median of 63 days (range 6-105 days) from the Stoss dose. Patients receiving Stoss-dosed vitamin D developed a lower combined incidence of HSCT-related complications than the historical control (25% [n = 7/28] versus 42% [n = 57/136], P = .055). After Stoss dosing, immunophenotyping studies found a significant decrease in subsets of CD8+ T cells and mononuclear cells (P = .040 and.013, respectively), and, in a subset of cells, larger decreases in phosphoprotein expression were seen with greater increases in total 25-OHD levels. Inflammatory cytokines did not change significantly after Stoss dosing. Stoss dosing is therefore a safe and effective approach to maintain vitamin D sufficiency in the immediate post-HSCT period and may be associated with decreased HSCT-related complications. Randomized studies are warranted to further investigate the efficacy of Stoss-dosed vitamin D to improve bone health and reduce complications in pediatric patients receiving HSCT.

Prevalence and risk factors for vitamin D deficiency in long-term childhood cancer survivors.

BACKGROUND: Childhood cancer survivors (CCS) have increased risk of developing chronic health conditions, including musculoskeletal disorders. Little is known regarding vitamin D deficiency (VDD, <20 ng/ml) and its association with bone mineral density (BMD) in long-term CCS. We evaluated the prevalence and risk factors for VDD in a large, diverse population of long-term CCS, and examined the association between VDD and BMD in patients who underwent guideline-recommended dual-energy X-ray absorptiometry (DXA) screening. METHODS: This cross-sectional study included 446 consecutive CCS seen from March 2018 to September 2020. Univariate analyses examined associations between CCS demographics, socioeconomic status, and treatment exposures and VDD. Multivariable logistic regressions identified factors associated with odds of VDD and reduced BMD. RESULTS: Median age at evaluation was 27.5 years (range 7-67 years); median time from completing therapy was 14.2 years (range 2-65 years). Fifty percent were female, and 45% were Hispanic. Twenty-four percent had VDD. In multivariable analysis, overweight and obese BMI were associated with VDD (overweight: OR 1.78, 95% CI 1.03-3.07, p = 0.04; obese: OR 2.40, 95% CI 1.39-4.13, p < 0.01; reference: normal/underweight), as was Hispanic or black race/ethnicity (OR 2.40, 95% CI 1.41-4.09, p < 0.01; reference: non-Hispanic white). In the 118 CCS with DXA results, VDD was independently associated with reduced BMD (OR 3.58, 95%CI 1.33-9.59, p = 0.01). CONCLUSIONS: CCS have a high prevalence of VDD. High BMI and Hispanic or black race/ethnicity were associated with VDD. Survivors with VDD had a greater than threefold risk of reduced BMD. Risk-based screening may facilitate timely interventions to mitigate VDD and improve BMD in CCS.

Association of body mass index with toxicity and survival in pediatric patients treated with cisplatin-containing regimens.

Malnutrition is associated with treatment-related toxicities (TRT) in adults with solid tumors and in children with leukemia. Few studies have assessed whether malnutrition in pediatric patients treated for solid tumors impacts risk for TRT, relapse, and/or survival. To address this knowledge gap, this retrospective study evaluated the association between body mass index (BMI) at diagnosis, and imputed BMI during therapy, on the prevalence of TRT, specific toxicities, relapse, and survival in pediatric patients with solid tumors treated with cisplatin-containing regimens. Kaplan-Meier curves and regression models evaluated the association between patient-specific characteristics (including BMI) and TRT, relapse, and survival. The cohort included 221 patients, of whom 22% were malnourished at diagnosis (10% were underweight and 12% were obese). Most patients (60%) experienced at least one severe TRT, and 30% developed more than one severe TRT. Most patients with obesity at diagnosis remained obese during therapy (62%). In multivariable analysis, obesity at diagnosis was significantly associated with a more than threefold greater risk for developing severe TRT (p = 0.037), specifically for acute or chronic kidney injury (p = 0.014). Obesity at diagnosis and adolescent and young adult age (≥15 years at diagnosis) were associated with worse event-free survival (hazard ratio [HR] 2.32, p = 0.024 and HR 2.28, p = 0.010, respectively) and overall survival (HR 3.69, p = 0.006 and HR 2.6, p = 0.012, respectively). Obese and older patients therefore constitute populations at risk for poorer outcomes. Prospective studies are warranted to gain further insight into the mechanism and role of obesity and adolescence in developing TRT and/or treatment failure.

Improving the Timeliness of Chemotherapy Administration in the Bone Marrow Transplant Unit.

Patients undergoing hematopoietic stem cell transplantation (HSCT) are often admitted to the hospital the day they are due to begin their conditioning regimen. Timely initiation of chemotherapy during regular work hours is important for patient safety, because during the night shift fewer physicians and pharmacists are available for urgent or unexpected matters. A review of the data at our institution from October 2017 to August 2018 showed that approximately one-third of our chemotherapy was started during the night shift (after 19:00), and the average time from admission to start of chemotherapy was over 8 hours. There are currently no well-defined benchmarks for timeliness of chemotherapy initiation. The aim of this quality improvement initiative was to increase the percentage of patients who start chemotherapy in the bone marrow transplant unit before 19:00 from 65% to >80% by March 31, 2019. We identified barriers to timely initiation of chemotherapy through process mapping and analysis of failures. The primary barriers were late admissions (after 12:00 pm) and time from admission to preparation of chemotherapy. We addressed mechanisms to mitigate these barriers through Plan-Do-Study-Act testing. Interventions included providing families specific admission times and their rationales and process for notifying pharmacy of admissions immediately on arrival. We used standardized control charts to measure the impact of the interventions on change. We also monitored medication errors before and during the intervention. From September 2018 to March 2019 the percentage of patients who started preparative chemotherapy before 19:00 increased from 65% to 85%, the percentage of patients who were admitted after 12:00 remained similar before (31%) and after the interventions (33%), and the average time from admission to start of chemotherapy decreased from 8.6 hours (513 minutes) to 6.4 hours (382 minutes). Medication errors were similar before (n = 50) and after the interventions (n = 43). Using standardized processes, we demonstrated a substantial decrease in the percentage of HSCT patients starting their preparative regimen after 19:00 without a concurrent increase in errors. We believe these interventions and measurements can be used in all transplant centers and have the potential to influence patient safety and outcomes.

Association between Vitamin D and Risk for Early and Late Post-Transplant Complications.

Vitamin D (VD) deficiency is a well-described phenomenon in pediatric patients undergoing hematopoietic stem cell transplant (HSCT). VD modulates inflammation, and deficiency pre-HSCT and at day +100 has been associated with graft-versus-host disease (GVHD) and poorer survival. However, a paucity of data has specifically described the association between VD status and immune-mediated complications including GVHD and veno-occlusive disease (VOD). Additionally, data to guide recommendations for VD monitoring and supplementation during HSCT are scarce. Our primary objective was to evaluate the association between VD and post-HSCT complications. The key secondary aim was to evaluate the routine use and efficacy of VD monitoring and supplementation practices. To our knowledge, this is the largest study of its kind in the pediatric population. This retrospective study evaluated VD level (VDL) before and 1 year after HSCT, VD supplementation practices, and their association with acute GVHD, VOD, and survival in pediatric patients who received autologous and allogeneic HSCT for both malignant and nonmalignant diseases from January 2013 to April 2018. Of 314 HSCTs, 43% of patients (n = 136) had VDL measured before HSCT; 61% of this cohort had pre-HSCT VD insufficiency (<30 ng/mL). Neither pre-HSCT nor follow-up VDL was associated with the incidence of GVHD or VOD. Supplementation did not result in significantly different post-HSCT VDL.VDL was correlated with overall survival; every 10-ng/mL increase in VDL was associated with a 28% decreased risk of death (P = .01). Current accepted VD supplementation regimens for pediatric HSCT do not achieve sufficient VDL in most patients after HSCT. VD status was associated with all-cause mortality but not with individual comorbidities; prospective studies are required to establish the connection between VD status, inflammatory-mediated HSCT complications, and potential benefit of VD supplementation before and after HSCT. These studies are needed to inform evidence-based guidelines for monitoring and supplementing VD during HSCT.

Awareness of cord blood collection and the impact on banking.

BACKGROUND: Umbilical cord blood (UCB) is an important source of hematopoietic stem cells for transplantation especially in minority populations with limited chances of finding a histocompatible volunteer donor in the registry. UCB has the advantages of early availability, successful outcomes despite some histocompatibility mismatch, and low incidence of chronic graft-versus-host disease. Public cord blood banks that disseminate UCB products for transplant depend on voluntary donation at participating hospitals and obstetrical providers for collection. PROCEDURE: Using survey questionnaires, we evaluated attitudes toward UCB donation, the frequency of donation, and provider opinions on UCB collection in the greater St. Louis metropolitan area that caters to minority ethnicities in significant numbers. RESULTS: Our data suggest that nervousness and lack of information regarding the donation and utility of the product were ubiquitous reasons for not donating. Additionally, irrespective of age or level of education, women relied on healthcare providers for information regarding UCB donation. Providers reported primarily time constraints to discussing UCB donation at prenatal visits (54%). Of the interviewees, 62% donated UCB. Fallout due to refusal or preferring private banking was miniscule. CONCLUSIONS: These results suggest that dedicated personnel focused on disseminating information, obtaining consent, and collecting the UCB product at major hospitals can enrich cord blood banks especially with minority cords. Sustained and focused efforts could improve upon a relatively high wastage rate and ensure a robust supply of UCB products at local public banks.

Interventions to Improve HPV Vaccine Uptake: A Systematic Review.

CONTEXT: The human papillomavirus (HPV) vaccine is a safe, effective cancer prevention method that is underutilized in the United States. Despite increased understanding of barriers to vaccination, rates remain low. Globally, developed and developing nations have achieved high rates of vaccination. OBJECTIVE: Identification of effective strategies is necessary to optimize uptake of the HPV vaccine. We systematically reviewed the literature for national and international interventions that have successfully increased HPV vaccine uptake. DATA SOURCES: We used a standardized protocol to search for articles published between January 1, 2006, and April 30, 2015, in 3 electronic databases: PubMed, Scopus, and Embase. STUDY SELECTION: We identified interventions designed to increase HPV vaccine uptake among adolescents and young adults aged 11 to 26 years. All study designs were acceptable. Only articles that included postintervention vaccination rates were included. DATA EXTRACTION: Two authors independently reviewed each article for data extraction and quality assessment. Interventions were classified according to the Community Preventive Service Task Force guide. RESULTS: Results were reported according to the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework. Fifty-one articles met eligibility criteria: 2 informational interventions, 18 behavioral interventions, and 31 environmental interventions. Factors associated with HPV vaccine uptake were increased vaccine availability, decreased financial barriers, and interventions targeting both providers and patients. LIMITATIONS: Lack of consistent RE-AIM metric reporting, limiting our ability to assess intervention validity and quality. CONCLUSIONS: Population-based vaccination strategies that increased vaccine availability reached the greatest number of adolescents and were most successful in achieving high rates of vaccination.