Pediatric and Adolescent Hodgkin Lymphoma: Paving the Way for Standards of Care and Shared Decision Making.

Hodgkin lymphoma (HL) is a treatable cancer with an incidence peak in adolescent and young adult years. Treatment strategies have been developed to balance the intensity of therapy needed to maintain disease-free survival while simultaneously preserving overall survival. Risk-based, response-adapted frontline therapy has long used a combination of chemotherapy and radiotherapy (RT). Successive clinical trials over the past three decades have safely reduced cumulative alkylator, anthracycline, and RT exposures for many patients. The advent of checkpoint inhibitors and the CD30-targeted antibody drug conjugate, brentuximab vedotin, has provided new options for de-escalation of conventional therapies associated with late effects in survivors treated at a young age. The ability to evaluate novel agents has been accelerated in collaborative trials inclusive of children and adolescents within the US National Clinical Trials Network and between the Children's Oncology Group and the EuroNet Pediatric Hodgkin Lymphoma Consortium. With numerous treatment options, patients with HL and their clinicians have an opportunity for shared decision making from diagnosis, through cancer treatment, and into survivorship. Given excellent survival outcomes, decisions about treatment in classic HL should be collaborative and attention to long-term survivorship needs should remain a high priority. Patient-reported outcomes remain an important tool to aid clinicians working with survivors to optimize health status and related quality of life for decades after HL therapy.

Classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (HL) is rare disease, with an incidence of approximately 85,000 patients globally per year and a predilection for adolescents and young adults (ages 15-39). Since the introduction of combination chemotherapy in the 1960's and radiation dating back to the early 1900's, therapeutic options and by extension, clinical outcomes have improved dramatically with 5-year overall survival (OS) approaching 90% today. [1](#ref-0001) Advances in understanding HL biology have additionally facilitated development of targeted agents and immunotherapy which have further improved short and long-term outcomes. Despite continued improvements in up-front and salvage therapy, long-term survivors of HL experience several treatment-associated late toxicities, thus, along with efforts to improve therapeutic efficacy, efforts to reduce late effects remain a high-priority in the field.

Disparities in care and outcomes for adolescent and young adult lymphoma patients.

Though survival outcomes among adolescents and young adults (AYAs) with lymphoma have improved over the last three decades, socially vulnerable populations including non-White, low-income, and publicly insured groups continue to trail behind on survival curves. These disparities, while likely the result of both biological and non-biological factors, can be largely attributed to inequities in care over the full cancer continuum. Nationally representative studies have demonstrated that from diagnosis through therapy and into long-term survivorship, socially vulnerable AYAs with lymphoma face barriers to care that impact their short and long-term survival. Thus, improving outcomes for all AYAs with lymphoma requires dedicated study to understand, and then address the unique challenges faced by non-White and low-income lymphoma populations within this age group.

Children's Oncology Group's 2023 blueprint for research: Diversity and health disparities.

The Children's Oncology Group (COG) Diversity and Health Disparities Committee's (DHDC's) mission is to guarantee the highest standard of care for children and adolescents and young adults (AYA) with cancer regardless of ethnic, racial, gender, or socioeconomic background. We strive to identify and address issues of disparity within the existing scientific structure of COG and to support research across COG to improve survival by ensuring equitable access to COG-sponsored clinical trials. We are committed to advance COG-led research identifying mechanistic drivers of disparities and, concurrently, evaluating interventions to alleviate disparities in the COG trial setting. As trials identify the most promising therapies, diverse representation is critical to ensure that findings are relevant to everyone. Factors impacting clinical trial participation among vulnerable populations are complex, consisting of barriers at societal, systems, and individual levels. Recent efforts by investigators within DHDC demonstrated that trial-embedded collection of family-reported sociodemographic data and social determinants of health (SDoH) is feasible and acceptable in the context of COG. Diversity in the pediatric oncology workforce is essential and one potential approach to improving representation on clinical trials. To support and retain diverse oncology providers and researchers, a Minority Young Investigator Award (MYIA) was created to facilitate opportunities for graduating trainees and YIs with an interest in childhood cancer disparities research within COG. Although there are challenges to achieve the DHDC's priorities, only through collaboration and support for this work we will be able to elucidate mechanisms underlying inferior survival outcomes for historically marginalized children and AYA, and more importantly, implement interventional investigation to improve outcomes.

Children's Oncology Group's 2023 blueprint for research: Hodgkin lymphoma.

The goal of therapy in pediatric Hodgkin lymphoma (HL) is to maximize overall survival while minimizing the morbidity of curative therapy. Key findings from recent Children's Oncology Group (COG) trials include: (i) superior event-free survival with the addition of brentuximab vedotin (Bv) in frontline regimens for high-risk disease, (ii) successful reduction in myeloablative regimens with demonstrated safety and efficacy of Bv and checkpoint inhibitor therapy in relapsed disease, and (ii) the potential to select a population that can be salvaged after relapse without receiving a stem cell transplant. The COG HL committee will lead a National cancer Institute National Clinical Trials Network phase 3 trial to evaluate the combination of Bv/nivolumab in early-stage disease. Ongoing advances in technology and blood biomarkers are increasing the ability to deliver biologically driven, personalized treatment for HL.

Disparities in parental distress in a multicenter clinical trial for pediatric acute lymphoblastic leukemia.

BACKGROUND: Parent psychological distress during childhood cancer treatment has short- and long-term implications for parent, child, and family well-being. Identifying targetable predictors of parental distress is essential to inform interventions. We investigated the association between household material hardship (HMH), a modifiable poverty-exposure defined as housing, food, or utility insecurity, and severe psychological distress among parents of children aged 1-17 years with acute lymphoblastic leukemia (ALL) enrolled on the multicenter Dana-Farber ALL Consortium Trial 16-001. METHODS: This was a secondary analysis of parent-reported data. Parents completed an HMH survey within 32 days of clinical trial enrollment (T0) and again at 6 months into therapy (T1). The primary exposure was HMH at T0 and primary outcome was severe parental distress at T0 and T1, defined as a score greater than or equal to 13 on the Kessler-6 Psychological Distress Scale. Multivariable models were adjusted for ALL risk group and single parent status. RESULTS: Among 375 evaluable parents, one-third (32%; n = 120/375) reported HMH at T0. In multivariable analyses, T0 HMH was associated with over twice the odds of severe psychological distress at T0 and T1 HMH was associated with over 5 times the odds of severe distress at T1. CONCLUSIONS: Despite uniform clinical trial treatment of their children at well-resourced pediatric centers, HMH-exposed parents-compared with unexposed parents-experienced statistically significantly increased odds of severe psychological distress at the time of their child's leukemia diagnosis, which worsened 6 months into therapy. These data identify a high-risk parental population who may benefit from early psychosocial and HMH-targeted interventions to mitigate disparities in well-being.

Implementation of Systematic Financial Screening in an Outpatient Breast Oncology Setting.

PURPOSE: Implementation of routine financial screening is a critical step toward mitigating financial toxicity. We evaluated the feasibility, sustainability, and acceptability of systematic financial screening in the outpatient breast oncology clinic at a large, urban cancer center. METHODS: We developed and implemented a stakeholder-informed process to systematically screen for financial hardship and worry. A 2-item assessment in English or Spanish was administered to patients through the electronic medical record portal or using paper forms. We evaluated completion rates and mode of completion. Through feedback from patients, clinicians, and staff, we identified strategies to improve completion rates and acceptability. RESULTS: From March, 2021, to February, 2022, 3,500 patients were seen in the breast oncology clinic. Of them, 39% (n = 1,349) responded to the screening items, either by paper or portal, 12% (n = 437) preferred not to answer, and the remaining 49% (n = 1,714) did not have data in their electronic health record, meaning they were not offered screening or did not complete the paper forms. Young adults (18-39 years) were more likely to respond compared with patients 70 years or older (61% v 30%, P < .01). English-preferring patients were more likely to complete the screening compared with those who preferred Spanish (46% v 28%, P < .01). Non-Hispanic White patients were more likely to respond compared with Non-Hispanic Black patients and with Hispanic patients (46% v 39% v 32%, P < .01). Strategies to improve completion rates included partnering with staff to facilitate paper form administration, optimizing patient engagement with the portal, and clearly communicating the purpose of the screening. CONCLUSION: Systematic financial screening is feasible, and electronic data capture facilitates successful implementation. However, inclusive procedures that address language and technology preferences are needed to optimize screening.

Oral Mercaptopurine Adherence in Pediatric Acute Lymphoblastic Leukemia: A Survey Study From the Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium.

Background: Oral chemotherapy nonadherence is a challenge in clinical oncology. During therapy for acute lymphoblastic leukemia (ALL), poor adherence to 6-mercaptopurine (6MP) increases relapse risk. Clinically significant nonadherence is reported in 30% of children treated for ALL on Children's Oncology Group (COG) trials. Whether nonadherence rates vary across regimens with different treatment schedules and modes of administration is unknown. Methods: We conducted an exploratory, cross-sectional survey study on parents of children (1-18 years) receiving continuation therapy on, or as per Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 11-001. Treatment required weekly visits to the clinic and 14 days of oral 6MP every 3 weeks. Survey assessed self-reported sociodemographics, medication-taking, chemotherapy comprehension, and 6MP adherence; adherence survey items were developed from published surveys. Patients were grouped as nonadherent if they endorsed missing one 6MP dose during the last cycle, or more than one dose during prior cycles, for nonmedical reasons. Results: Sixty-two families completed the surveys, all of whom had evaluable adherence data. In total, 25% of patients met the study definition of nonadherence. Twenty-three percent reported that it was "not easy" to follow administration guidelines around the dairy intake and 57% requested more teaching and educational resources. Conclusion: Self-reported nonadherence to oral 6MP in the DFCI ALL Consortium is high, with rates similar to those observed in the COG. This suggests that the additional contact during weekly infusions on the DFCI is insufficient to address barriers affecting oral chemotherapy adherence.

Feasibility of oncology clinical trial-embedded evaluation of social determinants of health.

Social determinants of health (SDoH) are associated with stark disparities in cancer outcomes, but systematic SDoH data collection is virtually absent from oncology clinical trials. Trial-based SDoH data are essential to ensure representation of marginalized populations, contextualize outcome disparities, and identify health-equity intervention opportunities. We report the feasibility of a pediatric oncology multicenter therapeutic trial-embedded SDoH investigation. Among 448 trial participants, 392 (87.5%) opted-in to the embedded SDoH study; 375 (95.7%) completed baseline surveys, with high longitudinal response rates (88.9-93.1%) over 24 months. Trial-embedded SDoH data collection is feasible and acceptable and must be consistently included within future oncology trials.

New persistent opioid use among adolescents and young adults with sarcoma.

BACKGROUND: Adolescents and young adults (AYA) with sarcoma experience both acute and chronic pain related to their disease and treatment. Studies in older adults have reported a high risk of persistent opioid use after cancer therapy among previously opioid-naive patients; however, few studies have evaluated posttreatment opioid use among AYAs. This article describes patterns of new persistent opioid use among AYAs in the year after treatment for sarcoma. METHODS: Opioid-naive patients who were 10 to 26 years old and diagnosed with sarcoma (2008-2016) were identified with the IBM Marketscan Database. Included subjects had an International Classification of Diseases code for sarcoma (ninth or tenth revision), received anticancer therapy (chemotherapy, surgery, and/or radiation) within 30 days of the first diagnosis code, and had continuous insurance coverage (commercial or Medicaid) for more than 12 months both before the diagnosis and after the last therapy. The primary outcome was new persistent opioid use, which was defined as at least 2 opioid prescriptions in the 12 months following treatment completion. Covariates included age, sex, insurance, tumor type, surgical procedure, mental health (MH) or substance use diagnoses before or during therapy, and concomitant lorazepam use. RESULTS: In total, 938 patients met the inclusion criteria; 521 (56%) were male, and 578 (62%) were younger than 18 years. In total, 727 (78%) had commercial insurance, and 273 (29%) had an MH diagnosis either before or during the treatment period. Of the total group, 464 (49%) used opioids during treatment only. Of those who used opioids during treatment, 135 (23%) received at least 2 prescriptions in the year after therapy. In a multivariable analysis, Medicaid versus commercial insurance (odds ratio [OR], 1.74; 95% confidence interval [CI], 1.15-2.64) and non-soft tissue sarcoma (OR for Ewing sarcoma, 3.23; 95% CI, 1.81-5.78; OR for osteosarcoma, 2.05; 95% CI, 1.36-3.09) conferred a higher likelihood of new persistent use. CONCLUSIONS: In this cohort of AYAs treated for sarcoma, 64% of the patients received opioid prescriptions during treatment, and 23% of these patients became new persistent users. Because of the risks associated with persistent opioid use, studies of novel pain management strategies along with age-appropriate education and anticipatory guidance are urgently needed. LAY SUMMARY: Using an insurance claims database, we conducted a study to determine the rate of new persistent opioid use among adolescents and young adults treated for sarcoma. We found that 64% of adolescents and young adults treated for sarcoma received opioid prescriptions during treatment, and 23% of these patients met the criteria for new persistent opioid use. These findings support the need for age-appropriate education and novel pain management strategies in this vulnerable population.

Second primary malignancy risk after Hodgkin lymphoma treatment among HIV-uninfected and HIV-infected survivors.

We compared secondary primary malignancy risk (SPM) in HIV-uninfected and HIV-infected Hodgkin lymphoma (HL) survivors. We used data from the California Cancer Registry on patients diagnosed with HL from 1990 to 2015 (all ages included), and standardized incidence ratios (SIRs) and multivariable competing risk models for analyses. Of 19,667 survivors, 735 were HIV-infected. Compared with the general population, the risk of SPM was increased by 2.66-fold in HIV-infected and 1.92-fold in HIV-uninfected survivors. Among HIV-infected survivors, median time to development of SPM was shorter (5.4 years) than in HIV-uninfected patients (8.1 years). Additionally, the highest risk of SPM was observed <2 years after diagnosis in HIV-infected survivors (SIR = 4.47), whereas risk was highest ≥20 years after diagnosis (SIR = 2.39) in HIV-uninfected survivors. The risk of SPMs persisted for decades and was higher among HIV-infected survivors, suggesting that these patients should benefit from long-term surveillance and cancer prevention practices.

Improving Health Equity and Reducing Pediatric Cancer Disparities: The Role of the Medical Home.

The advances in pediatric cancer outcomes over the last quarter century are some of the most successful in modern medicine. Improved diagnostics and novel therapies have led to continued increases in the survival rates of most patients; however, not all populations have benefitted equally. Compared to White children, Black, Indigenous, People of Color patients with cancer more often present with advanced stage illness, less frequently participate in clinical trials, and are more likely to be lost to follow-up once therapy is complete. Proposed hypotheses for these disparities include both biologic and nonbiologic factors, and a growing body of research suggests that barriers influencing care from diagnosis through survivorship are important. In this article, we consider how primary pediatricians can help reduce disparities over the cancer continuum by identifying vulnerable populations, considering potential diagnoses, referring to cancer centers, and following up with patients through survivorship in partnership with the oncology team. [Pediatr Ann. 2022;51(1):e22-e26.].

Survival by age in paediatric and adolescent patients with Hodgkin lymphoma: a retrospective pooled analysis of children's oncology group trials.

BACKGROUND: Adolescents with Hodgkin lymphoma have worse disease outcomes than children. Whether these differences persist within clinical trials is unknown. We examined survival, by age, in patients receiving response-adapted therapy for Hodgkin lymphoma on Children's Oncology Group (COG) trials. METHODS: Patients (aged 1-21 years) diagnosed with classical Hodgkin lymphoma and enrolled between Sept 23, 2002, and Jan 19, 2012, on one of three phase 3 COG trials in the USA and Canada were eligible for inclusion. The three COG trials were defined by risk group according to Ann Arbor stage, B-symptoms, and bulk (AHOD0431 [low risk; NCT00302003], AHOD0031 [intermediate risk; NCT00025259], or AHOD0831 [high risk; NCT01026220]). The outcomes of this study were event-free survival (death, relapse, or subsequent neoplasm) and overall survival. Cox proportional hazards models estimated survival, adjusting for disease and treatment factors both overall and in patients with mixed cellularity or non-mixed cellularity (nodular sclerosing and not-otherwise-specified) disease. FINDINGS: Of 2155 patients enrolled on the three trials, 1907 (88·4%; 968 [50·8%] male and 939 [49·2%] female; 1227 [64·3%] non-Hispanic White) were included in this analysis. After a median follow-up of 7·4 years (IQR 4·3-10·2), older patients (aged ≥15 years) had worse unadjusted 5-year event-free survival (80% [95% CI 78-83]) than did younger patients (aged <15 years; 86% [83-88]; HR 1·38 [1·11-1·71]; p=0·0038). Older patients also had worse unadjusted 5-year overall survival than did younger patients (96% [95% CI 95-97] vs 99% [98-99]; HR 2·50 [1·41-4·45]; p=0·0012). In patients with non-mixed cellularity histology, older patients had a significantly increased risk of having an event than did younger patients with the same histology (HR 1·32 [1·03-1·68]; p=0·027). Older patients with mixed cellularity had significantly worse 5-year event-free survival than did younger patients in unadjusted (77% [95% CI 65-86] for older patients vs 94% [88-97] for younger patients; HR 2·93 [1·37-6·29]; p=0·0039) and multivariable models (HR 3·72 [1·56-8·91]; p=0·0032). Overall, older patients were more likely to die than younger patients (HR 3·08 [1·49-6·39]; p=0·0025). INTERPRETATION: Adolescents (≥15 years) treated on COG Hodgkin lymphoma trials had worse event-free survival and increased risk of death compared with children (<15 years). Our findings highlight the need for prospective studies to examine tumour and host biology, and to test novel therapies across the age spectrum. FUNDING: National Institutes of Health, St Baldrick's Foundation, and Lymphoma Research Foundation.

Racial Disparities in Children, Adolescents, and Young Adults with Hodgkin Lymphoma Enrolled in the New York State Medicaid Program.

Background: We examined the impact of race/ethnicity and age on survival in a publicly insured cohort of children and adolescent/young adults (AYA; 15-39 years) with Hodgkin lymphoma, adjusting for chemotherapy using linked Medicaid claims. Materials and Methods: We identified 1231 Medicaid-insured patients <1-39 years diagnosed with classical Hodgkin lymphoma between 2005 and 2015, in the New York State Cancer Registry. Chemotherapy regimens were based on contemporary therapeutic regimens. Cox proportional hazards regression models quantified associations of patient, disease, and treatment variables with overall survival (OS) and disease-specific survival (DSS), and are presented as hazard ratios (HR) with confidence intervals (95% CIs). Results: At median follow-up of 6.6 years, N = 1108 (90%) patients were alive; 5-year OS was 92% in children <15 years. In multivariable models, Black (vs. White) patients had 1.6-fold increased risk of death (HR: 1.58, 95% CI: 1.02-2.46; p = 0.042). Stage III/IV (vs. I/II) was associated with 1.9-fold increased risk of death (HR: 1.86, 95% CI: 1.25-2.78; p = 0.002) and treatment at a non-National Cancer Institute (NCI) affiliate was associated with worse DSS (HR: 2.71, 95% CI: 1.47-4.98; p = 0.001). Conclusions: In this Medicaid-insured cohort of children and AYAs with Hodgkin lymphoma, Black race/ethnicity remained associated with inferior OS in multivariable models adjusted for disease, demographic, and treatment data. Further work is needed to identify dimensions of health care access not mediated by insurance, as findings suggest additional factors are contributing to observed cancer disparities in vulnerable pediatric and AYA populations.

Use of Communication Technology to Improve Clinical Trial Participation in Adolescents and Young Adults With Cancer: Consensus Statement From the Children's Oncology Group Adolescent and Young Adult Responsible Investigator Network.

Adolescents and young adults (AYAs; age 15-39 years) with cancer are under-represented in cancer clinical trials because of patient, provider, and institutional barriers. Health care technology is increasingly available to and highly used among AYAs and has the potential to improve cancer care delivery. The COVID-19 pandemic forced institutions to rapidly adopt novel approaches for enrollment and monitoring of patients on cancer clinical trials, many of which have the potential for improving AYA trial participation overall. This consensus statement from the Children's Oncology Group AYA Oncology Discipline Committee reviews opportunities to use technology to optimize AYA trial enrollment and study conduct, as well as considerations for widespread implementation of these practices. The use of remote patient eligibility screening, electronic informed consent, virtual tumor boards, remote study visits, and remote patient monitoring are recommended to increase AYA access to trials and decrease the burden of participation. Widespread adoption of these strategies will require new policies focusing on reimbursement for telehealth, license portability, facile communication between electronic health record systems and advanced safeguards to maintain patient privacy and security. Studies are needed to determine optimal approaches to further incorporate technology at every stage of the clinical trial process, from enrollment through study completion.

Whole-transcriptome analysis in acute lymphoblastic leukemia: a report from the DFCI ALL Consortium Protocol 16-001.

The molecular hallmark of childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent, prognostic genetic alterations, many of which are cryptic by conventional cytogenetics. RNA sequencing (RNA-seq) is a powerful next-generation sequencing technology that can simultaneously identify cryptic gene rearrangements, sequence mutations and gene expression profiles in a single assay. We examined the feasibility and utility of incorporating RNA-seq into a prospective multicenter phase 3 clinical trial for children with newly diagnosed ALL. The Dana-Farber Cancer Institute ALL Consortium Protocol 16-001 enrolled 173 patients with ALL who consented to optional studies and had samples available for RNA-seq. RNA-seq identified at least 1 alteration in 157 patients (91%). Fusion detection was 100% concordant with results obtained from conventional cytogenetic analyses. An additional 56 gene fusions were identified by RNA-seq, many of which confer prognostic or therapeutic significance. Gene expression profiling enabled further molecular classification into the following B-cell ALL (B-ALL) subgroups: high hyperdiploid (n = 36), ETV6-RUNX1/-like (n = 31), TCF3-PBX1 (n = 7), KMT2A-rearranged (KMT2A-R; n = 5), intrachromosomal amplification of chromosome 21 (iAMP21) (n = 1), hypodiploid (n = 1), Philadelphia chromosome (Ph)-positive/Ph-like (n = 16), DUX4-R (n = 11), PAX5 alterations (PAX5 alt; n = 11), PAX5 P80R (n = 1), ZNF384-R (n = 4), NUTM1-R (n = 1), MEF2D-R (n = 1), and others (n = 10). RNA-seq identified 141 nonsynonymous mutations in 93 patients (54%); the most frequent were RAS-MAPK pathway mutations. Among 79 patients with both low-density array and RNA-seq data for the Philadelphia chromosome-like gene signature prediction, results were concordant in 74 patients (94%). In conclusion, RNA-seq identified several clinically relevant genetic alterations not detected by conventional methods, which supports the integration of this technology into front-line pediatric ALL trials. This trial was registered at www.clinicaltrials.gov as #NCT03020030.

Initial cancer treatment and survival in children, adolescents, and young adults with Hodgkin lymphoma: A population-based study.

BACKGROUND: Hodgkin lymphoma (HL) is a treatable tumor affecting children, adolescents and young adults (AYAs; 15-39 years old). Population-based studies report worse survival for non-White children and AYAs but have limited data on individual therapeutic exposures. This study examined overall and HL-specific survival in a population-based cohort of patients while adjusting for sociodemographic factors and treatment. METHODS: Data for 4807 patients younger than 40 years with HL (2007-2017) were obtained from the California Cancer Registry. Individual treatment information was extracted from text fields; chemotherapy regimens were defined by standard approaches for pediatric and adult HL. Multivariable Cox models examined the influence of patient and treatment factors on survival. RESULTS: At a median follow-up of 4.4 years, 95% of the patients were alive. Chemotherapy differed by age, with 70% of 22- to 39-year-olds and 41% of <22-year-olds receiving doxorubicin, bleomycin, vinblastine, and dacarbazine (P < .001). In multivariable models, older patients (22-39 vs < 21 y; hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11-2.10), Black (vs White patients); HR, 1.90; 95% CI, 1.25-2.88), and Hispanic patients (HR, 1.45; 95% CI, 1.06-1.99) experienced worse survival; among those < 21 y, Black race was associated with a 3.3-fold increased risk of death (HR, 3.26; 95% CI, 1.43-7.42). CONCLUSIONS: In children and AYAs with HL, older age and non-White race/ethnicity predicted worse survival after adjustments for treatment data. Further work is needed to identify the biological and nonbiological factors driving disparities in these at-risk populations.