Children's Oncology Group Trial Research Articles

Implications of Implementing Children's Oncology Group Risk Stratification to Patients With Rhabdomyosarcoma Treated on European Paediatric Soft Tissue Sarcoma Study Group Clinical Trial.

Prognostic factors are crucial in tailoring treatments for patients with rhabdomyosarcoma (RMS). The European paediatric Soft tissue sarcoma Study Group (EpSSG) and the Children's Oncology Group (COG) employ similar prognostic factors, but utilize them differently resulting in diverse stratification systems. This diversity may result in dissimilar treatment approaches for comparable patients and hinder the comparison of clinical trial results. We reclassified 1993 patients enrolled in the EpSSG RMS 2005 and MTS 2008 studies based on the risk stratification used in current EpSSG and COG trials, and compared the type and cumulative doses of chemotherapy recommended to the different risk groups. Alkylating agents were compared using the cyclophosphamide equivalent dose formula. Metastatic RMS with high-risk features were excluded because no standard recommended treatment exists. Patients were variably distributed across EpSSG and COG risk stratifications. Notably, 34.2% of EpSSG standard-risk patients fell into three different COG risk groups (very low, low, and intermediate), and 66.8% of the total population, classified as standard, high, and very high risk by EpSSG, would all be considered intermediate risk by COG. Consequently, only 57.3% of the study population would receive comparable intensive chemotherapy under both EpSSG and COG protocols. Disparities emerged, with 16.5% undergoing more intensive and 17.2% receiving less intensive treatment in COG protocols compared to EpSSG studies. Our study shows the complexities of the current RMS risk stratification systems, emphasizing the need for a global consensus. A unified approach would reduce the risk of disparate treatments for similar patients and facilitate more straightforward cross-study comparisons.

Late Events Occurring After 5Years in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group.

Rhabdomyosarcoma is the most common pediatric soft tissue sarcoma, and 5-year overall survival exceeds 70%. With more long-term survivors, it is critical to understand the frequency of late events, including recurrence, second malignant neoplasm, and death, occurring 5years after diagnosis, and the variables associated with these events. We report late events in patients enrolled on Intergroup Rhabdomyosarcoma Study Group and Children's Oncology Group trials from 1997 to 2013 including D9602, D9803, D9802, ARST0331, ARST0431, ARST0531, and ARST08P1. A late event occurred in 2.9% of 5-year event-free survivors supporting guidelines to limit surveillance for these events to 5years from diagnosis.

Characteristics of patients with liver tumors deemed ineligible for enrollment on Children's Oncology Group trial AHEP1531: An opportunity to expand inclusion criteria and improve outcome.

Specific patients with hepatoblastoma (HB) and hepatocellular carcinoma (HCC) do not meet eligibility criteria for Children's Oncology Group (COG) trials, limiting an understanding of how comorbidities affect the outcome. We define such a population for future-focused care improvements. A questionnaire was sent to COG institutional principal investigators to obtain anonymized data regarding patients with a liver tumor diagnosis not enrolled on AHEP1531 due to ineligibility by trial criteria or other reasons (excluding parent/patient preference). Responses received for 55 patients (38 HB, 4 HCC, and 13 not reported) included 12 excluded from further analysis due to various factors, including lack of additional information. Five patients were eligible but not enrolled due to pandemic-related staffing issues (n=1) or the best interest of the patient (physician preference, n=1; risk for poor tolerance of chemotherapy, n=1; not specified, n=2). The remaining 38 patients included 1 ineligible due to a prior malignancy, 9 due to performance status, and 4 due to timing requirements. Thirty-five of 38 patients were ineligible due to organ function criteria (pulmonary/oxygen requirement, n=25; renal, n=10; liver, n=4; cardiac, n=3). Seven patients were ineligible due to two or more organ function criteria. Twenty-five of 38 patients were reported to have a preexisting condition including 4 patients with trisomy 18. Patients with HB, and potentially HCC, who are ineligible for COG trials are primarily patients with an oxygen requirement and/or renal insufficiency, often associated with preexisting congenital conditions. Such patients would benefit from future studies to improve outcomes.

Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia.

Although cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 90%, ALL remains a leading cause of cancer death in children. Half of relapses arise in children initially classified with standard-risk (SR) disease. To identify genomic determinants of relapse in children with SR ALL, we performed genome and transcriptome sequencing of diagnostic and remission samples of children with SR (n = 1,381) or high-risk B-ALL with favorable cytogenetic features (n = 115) enrolled on Children's Oncology Group trials. We used a case-control study design analyzing 439 patients who relapsed and 1,057 who remained in complete remission for at least 5 years. Genomic subtype was associated with relapse, which occurred in approximately 50% of cases of PAX5-altered ALL (odds ratio [OR], 3.31 [95% CI, 2.17 to 5.03]; P = 3.18 × 10-8). Within high-hyperdiploid ALL, gain of chromosome 10 with disomy of chromosome 7 was associated with favorable outcome (OR, 0.27 [95% CI, 0.17 to 0.42]; P = 8.02 × 10-10; St Jude Children's Research Hospital validation cohort: OR, 0.22 [95% CI, 0.05 to 0.80]; P = .009), and disomy of chromosomes 10 and 17 with gain of chromosome 6 was associated with relapse (OR, 7.16 [95% CI, 2.63 to 21.51]; P = 2.19 × 10-5; validation cohort: OR, 21.32 [95% CI, 3.62 to 119.30]; P = .0004). Genomic alterations were associated with relapse in a subtype-dependent manner, including alterations of INO80 in ETV6::RUNX1 ALL, IKZF1, and CREBBP in high-hyperdiploid ALL and FHIT in BCR::ABL1-like ALL. Genomic alterations were also associated with the presence of minimal residual disease, including NRAS and CREBBP in high-hyperdiploid ALL. Genetic subtype, patterns of aneuploidy, and secondary genomic alterations determine risk of relapse in childhood ALL. Comprehensive genomic analysis is required for optimal risk stratification.

Impact of Genetic Ancestry on T-cell Acute Lymphoblastic Leukemia Outcomes.

The influence of genetic ancestry on biology, survival outcomes, and risk stratification in T-cell Acute Lymphoblastic Leukemia (T-ALL) has not been explored. Genetic ancestry was genomically-derived from DNA-based single nucleotide polymorphisms in children and young adults with T-ALL treated on Children's Oncology Group trial AALL0434. We determined associations of genetic ancestry, leukemia genomics and survival outcomes; co-primary outcomes were genomic subtype, pathway alteration, overall survival (OS), and event-free survival (EFS). Among 1309 patients, T-ALL molecular subtypes varied significantly by genetic ancestry, including increased frequency of genomically defined ETP-like, MLLT10, and BCL11B-activated subtypes in patients of African ancestry. In multivariable Cox models adjusting for high-risk subtype and pathways, patients of Admixed American ancestry had superior 5-year EFS/OS compared with European; EFS/OS for patients of African and European ancestry were similar. The prognostic value of five commonly altered T-ALL genes varied by ancestry - including NOTCH1 , which was associated with superior OS for patients of European and Admixed American ancestry but non-prognostic among patients of African ancestry. Furthermore, a published five-gene risk classifier accurately risk stratified patients of European ancestry, but misclassified patients of African ancestry. We developed a penalized Cox model which successfully risk stratified patients across ancestries. Overall, 80% of patients had a genomic alteration in at least one gene with differential prognostic impact by genetic ancestry. T-ALL genomics and prognostic associations of genomic alterations vary by genetic ancestry. These data demonstrate the importance of incorporating genetic ancestry into analyses of tumor biology for risk classification algorithms.

Incorporating intensity modulated total body irradiation into a Children's Oncology Group trial: Rationale, techniques, and safeguards.

Historically, total body irradiation (TBI) has been delivered using static, parallel opposed photon beams (2D-TBI). Recently, centers have increasingly used intensity-modulated radiation therapy (IMRT) techniques for TBI. Relative to 2D-TBI, IMRT can reduce doses to critical organs (i.e., lungs and kidneys) while delivering myeloablative doses to the rest of the body, so it may decrease the risk of toxicity while maintaining oncologic outcomes. Despite these potential benefits, delivering TBI using IMRT introduces new challenges in treatment planning and delivery. We describe the extensive experience with IMRT-based TBI at Stanford University and City of Hope Cancer Center. These groups, and others, have reported favorable clinical outcomes and have developed methods to optimize treatment planning and delivery. A critical next step is to evaluate the broader adoption of this approach. Therefore, IMRT-based TBI will be incorporated into a prospective, multi-institutional Children's Oncology Group study with careful procedures and safeguards in place.

Poverty, race, ethnicity, and survival in pediatric nonmetastatic osteosarcoma: a Children's Oncology Group report.

Children living in poverty and those of marginalized race or ethnicity experience inferior disease outcomes across many cancers. Whether survival disparities exist in osteosarcoma is poorly defined. We investigated the association between race, ethnicity, and proxied poverty exposures and event-free and overall survival for children with nonmetastatic osteosarcoma receiving care on a cooperative group trial. We conducted a retrospective cohort study of US patients with nonmetastatic, osteosarcoma aged 5-21 years enrolled on the Children's Oncology Group trial AOST0331. Race and ethnicity were categorized to reflect historically marginalized populations, as Hispanic, non-Hispanic Black, non-Hispanic Other, and non-Hispanic White. Poverty was proxied at the household and neighborhood levels. Overall survival and event-free survival functions of time from trial enrollment were estimated using the Kaplan-Meier method. Hypotheses of associations between risks for event-free survival, death, and postrelapse death with race and ethnicity were assessed using log-rank tests. Among 758 patients, 25.6% were household-poverty and 28.5% neighborhood-poverty exposed. Of the patients, 21% of children identified as Hispanic, 15.4% non-Hispanic Black, 5.3% non-Hispanic Other, and 54.0% non-Hispanic White. Neither household or neighborhood poverty nor race and ethnicity were statistically significantly associated with risks for event-free survival or death. Postrelapse risk for death differed statistically significantly across race and ethnicity with non-Hispanic Black patients at greatest risk (4-year postrelapse survival 35.7% Hispanic vs 13.0% non-Hispanic Black vs 43.8% non-Hispanic Other vs 38.9% non-Hispanic White; P = .0046). Neither proxied poverty exposures or race and ethnicity were associated with event-free survival or overall survival, suggesting equitable outcomes following frontline osteosarcoma trial-delivered therapy. Non-Hispanic Black children experienced statistically significant inferior postrelapse survival. Investigation of mechanisms underlying postrelapse disparities are paramount.

Clinical trial recruitment of people who speak languages other than English: a Children's Oncology Group report.

Persons who speak languages other than English are underrepresented in clinical trials, likely in part because of inadequate multilevel resources. We conducted a survey of institutions affiliated with the Children's Oncology Group (COG) to characterize current research recruitment practices and resources regarding translation and interpretation services. In October 2022, a 20-item survey was distributed electronically to institutions affiliated with COG to assess consent practices and resources for recruiting participants who speak languages other than English to COG trials. Descriptive statistics were used to summarize responses; responses were compared by institution size and type as well as respondent role. The survey was sent to 230 institutions, and the response rate was 60% (n = 139). In total, 60% (n = 83) of those respondents had access to short-form consent forms. Full consent form translation was required at 50% of institutions, and 12% of institutional review boards restricted use of centrally translated consent forms. Forty-six percent (n = 64) of institutions reported insufficient funding to support translation costs; 19% (n = 26) had access to no-cost translation services. Forty-four percent (n = 61) were required to use in-person interpreters for consent discussions; the most frequently cited barrier (56%) to obtaining consent was lack of available in-person interpreters. Forty-seven percent (n = 65) reported that recruiting persons who speak languages other than English to clinical trials was somewhat or very difficult. Institutions affiliated with COG face resource-specific challenges that impede recruitment of participants who speak languages other than English for clinical trials. These findings indicate an urgent need to identify strategies aimed at reducing recruitment barriers to ensure equitable access to clinical trials.

Azacitidine as epigenetic priming for chemotherapy is safe and well-tolerated in infants with newly diagnosed KMT2A-rearranged acute lymphoblastic leukemia: Children's Oncology Group trial AALL15P1.

Infants less than 1 year old diagnosed with KMT2A-rearranged (KMT2A-r) acute lymphoblastic leukemia (ALL) are at high risk of remission failure, relapse, and death due to leukemia, despite intensive therapies. Infant KMT2A-r ALL blasts are characterized by DNA hypermethylation. Epigenetic priming with DNA methyltransferase inhibitors increases the cytotoxicity of chemotherapy in preclinical studies. The Children's Oncology Group trial AALL15P1 tested the safety and tolerability of five days of azacitidine immediately prior to the start of chemotherapy on day six, in four post-induction chemotherapy courses for infants with newly diagnosed KMT2A-r ALL. The treatment was welltolerated, with only two of 31 evaluable patients (6.5%) experiencing dose-limiting toxicity. Whole genome bisulfite sequencing of peripheral blood mononuclear cells (PBMCs) demonstrated decreased DNA methylation in 87% of samples tested following five days of azacitidine. Event-free survival was similar to prior studies of newly diagnosed infant ALL. Azacitidine is safe and results in decreased DNA methylation of PBMCs in infants with KMT2A-r ALL, but the incorporation of azacitidine to enhance cytotoxicity did not impact survival. Clinicaltrials.gov identifier: NCT02828358.

Outcome of children and young adults with localized extremity rhabdomyosarcoma treated on Children's Oncology Group trials.

10006 Background: Extremity rhabdomyosarcoma (RMS) accounts for 15-20% of patients with localized RMS. The long-term survival and associated prognostic factors of extremity RMS patients treated on the contemporary Children’s Oncology Group (COG) trials have not been reported. Methods: Patients with localized extremity RMS enrolled on the D9602, D9803, ARST0331 and ARST0531 COG trials were analyzed. The Kaplan-Meyer method estimated event-free (EFS) and overall survival (OS). The Log-rank test and Cox regression were used to estimate the prognostic significance of age at diagnosis, sex, race, tumor site & size, IRS group, stage, histology, FOXO1 fusion status, anaplasia, lymph node involvement, delayed primary excision (DPE) and radiation on survival. Results: We identified 159 patients with localized extremity RMS; 108 (68%) were < 10 years at diagnosis, 84(53%) had primary tumor > 5 cm, and 35 (22%) and 98 (62%) had IRS group II and III disease. Histology was alveolar in 106 (67%), and 43 (27%) had regional lymph node involvement on imaging or pathology. Seventeen were treated on low-risk (LR) studies D9602 (N = 10) and ARST0331 (N = 7), whereas 142 were treated on intermediate-risk (IR) trials D9803 (N = 85) and ARST0531 (N = 57). Eighty patients (50%) underwent primary surgical excision and 121 (76%) received radiotherapy. DPE was attempted in 60 patients (38%), resulting in an R0 (microscopically negative) margin in 48 (80%). Relapse/progression occurred in 52 patients: metastatic 26 (50%), local 22 (42%), and combined 3(6%). The 5-year EFS and OS of the whole cohort were 62.6% (95% CI: 54%-71.2%) and 78.7%% (95%CI: 71.4%-85.9%). LR patients treated on D9602 and ARST0331 trials had comparable 5-year EFS (70% vs. 71.4%, p-0.90) and OS (90% vs. 85.7%, p-0.54), respectively, while IR patients had significantly better 5-year EFS (68.9% vs. 51%, p-0.023) and OS (86.2% vs. 64.4%, p-0.007) on D9803 trial than ARST0531 trial. The 5-year EFS and OS of IRS group III patients with DPE with R0 margins were comparable to IRS group II patients (70.4% vs. 66.6%) & (86.5% vs. 84.6%), respectively. On univariable analysis, age at diagnosis and sex were associated with EFS, while age at diagnosis, sex, tumor size, IRS group, stage and fusion status were associated with OS (p < 0.05). None of the analyzed factors demonstrated independent statistical association with EFS, whereas female sex was the only factor independently associated with OS [Hazard ratio (HR): 0.4, 95% CI 0.20-0.85)]. Conclusions: IR localized extremity RMS patients treated on ARST0531 had suboptimal outcome. Survival of IRS group III patients with R0 DPE was comparable to IRS group II patients. Females with localized extremity RMS had better OS than males. Clinical trial information: NCT00354835 ; NCT00003958 ; NCT00075582 ; NCT00002995 .

Chemotherapy in pediatric low-grade gliomas (PLGG).

Pediatric low-grade gliomas (PLGG) are commonly treated with a combination of surgery, radiotherapy, and chemotherapy. Recent trends prioritize reducing long-term morbidities, particularly in younger patients. While historically chemotherapy was reserved for cases progressing after radiotherapy, evolving recommendations now advocate for its early use, particularly in younger age groups. The carboplatin and vincristine (CV) combination stands as a standard systemic therapy for PLGG, varying in dosage and administration between North America and Europe. Clinical trials have shown promising response rates, albeit with varying toxicity profiles. Vinblastine has emerged as another effective regimen with minimal toxicity. TPCV, a regimen combining thioguanine, procarbazine, lomustine, and vincristine, was compared to CV in a Children's Oncology Group trial, showing comparable outcomes, but more toxicity. Vinorelbine, temozolomide, and metronomic chemotherapy have also been explored, with varied success rates and toxicity profiles. Around 40-50% of PLGG patients require subsequent chemotherapy lines. Studies have shown varied efficacy in subsequent lines, with NF1 patients generally exhibiting better outcomes. The identification of molecular drivers like BRAF mutations has led to targeted therapies' development, showing promise in specific molecular subgroups. Trials comparing targeted therapy to conventional chemotherapy aim to delineate optimal treatment strategies based on molecular profiles. The landscape of chemotherapy in PLGG is evolving, with a growing focus on molecular subtyping and targeted therapies. Understanding the role of chemotherapy in conjunction with novel treatments is crucial for optimizing outcomes in pediatric patients with low-grade gliomas.

Outcome of patients with relapsed or refractory nonrhabdomyosarcoma soft tissue sarcomas enrolled in phase 2 cooperative group clinical trials: A report from the Children's Oncology Group.

The aim of this study was to estimate the event-free survival (EFS) of children and young adults with relapsed or refractory nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) treated in nonrandomized phase 2 studies conducted by the Children's Oncology Group (COG) and predecessor groups to establish a benchmark EFS for future phase 2 NRSTS trials evaluating the activity of novel agents. A retrospective analysis of patients with recurrent or refractory NRSTS prospectively enrolled in nonrandomized phase 2 COG and predecessor group trials between 1994 and 2015 was conducted. EFS was defined as disease progression/relapse or death and calculated via the Kaplan-Meier method. The log-rank test and relative risk regression were used to compare EFS distribution by age at enrollment, sex, race, NRSTS histology, prior lines of therapy, calendar year of trial, and type of radiographic response. In total, 137 patients were enrolled in 13 phase 2 trials. All trials used radiographic response rate as a primary outcome, and none of the agents used were considered active on the basis of trial-specified thresholds. The estimated median EFS and 6-month EFS of the entire study cohort was 1.5 months (95% confidence interval [CI], 1.3-1.8 months) and 19.4% (95% CI, 12.7%-26%), respectively. No difference in EFS was observed by age at enrollment, sex, race, NRSTS histology subtype, prior lines of therapies, and trial initiation year. EFS significantly differed by radiographic response. The EFS for children and young adults with relapsed or refractory NRSTS remains suboptimal. Established EFS can be referenced as a benchmark for future single-agent phase 2 trials incorporating potentially active novel agents in this population.

Identifying Tumor-Specific Immune Response and Biomarkers of High-Risk Hodgkin Lymphoma Patients Treated with and without Brentuximab on Children's Oncology Group Trial AHOD1331

Introduction: There is an unmet need to examine anti-tumor immune responses and predictive biomarkers in the peripheral blood to guide effective combination immunotherapies in classic Hodgkin Lymphoma (cHL). We hypothesized that treatment with the anti-CD30 antibody drug conjugate brentuximab vedotin (Bv) in combination with chemotherapy will have dual therapeutic effects in HL, with direct antiproliferative effects and a restoration of favorable tumor specific cytotoxic T cell immune response. We evaluated tumor-specific cytotoxic T cell response, cytokine and chemokine milieu in the peripheral blood of pediatric patients with HL before and after treatment with either standard chemotherapy or chemotherapy + Bv. Methods: Children's Oncology Group clinical trial AHOD1331 was a randomized phase III trial for newly diagnosed high risk cHL ages ≥2 to 22 years which compared standard chemotherapy with doxorubicin, bleomycin, etoposide, prednisone and cyclophosphamide (ABVE-PC) to Bv + AVE-PC with response adapted radiation. Peripheral blood samples were collected at diagnosis (pre) and following completion of treatment (post). Peripheral blood mononuclear cells and plasma were isolated using Ficoll Density gradient. Plasma was cryopreserved for batch testing of Th1/Th2 cytokines, sCD30, sCD163 and TARC by Luminex assay. Cytotoxic T cell responses to non-EBV HL specific tumor associated antigens (TAAs) MAGEA4, PRAME, and survivin pre and post treatment were tested using the interferon-γ ELISPOT assay after ex vivo expansion. TAA-T cell specificity was reported as spot forming count (SFC per 10 5 T cells). Changes in cytokine levels and T cell responses pre versus post treatment were compared using paired t-tests and blinded to treatment arm.Levels of sCD30, sCD163 and TARC were compared both pre and post treatment. Thecox model was used to evaluate association between levels and event free survival (EFS) across both arms. Results There was no difference in patient or disease characteristics between the entire study cohort (n=587) and patients analyzed (n=216). There were 184 patients with pre and post cytokine data, 71 patients with pre and post ELISPOT-T cell data, 147 patients with pre and post sCD30/sCD163 data, and 146 with pre and post TARC data. Compared to pre-treatment levels, there was a significant reduction in the immunosuppressive cytokines IL-13 (p=0.004) and increase in pro-inflammatory cytokines IL17a (p=0.03), Interferon-γ (p=0.0008), GCSF(p=0.0012) and MCP1(p=0.02). This change in cytokine levels from baseline to post-treatment was similar for both treatment arms except a higher increase in IL17a(p=0.015) was noted in the standard chemotherapy arm compared to the Bv arm (Table 1). Among 147 paired samples evaluated, sCD30, sCD163 and TARC all were significantly lower post treatment (Figure 1), but did not differ across arms. Pre treatment sCD163 and TARC values were significantly associated with EFS (p = 0.005 and 0.045), as was the degree of change in sCD163 post-treatment levels as compared to pre-treatment levels (p = 0.0156). Among 71 patients with pre and post ELISPOT-T cell data, there was a significant increase in the T cell responses specific to PRAME(p=0.04) post treatment and a trend for increased MAGEA4, but no association with EFS. Conclusions Treatment results in an increased T cell response to HL-specific antigen PRAME post therapy in both treatment arms suggesting that recovery post anti-HL treatment can promote tumor antigen specific T cell immunity in vivo. Further, reduction in immunosuppressive cytokines IL-13 and changes in proinflammatory cytokines Interferon-γ following treatment suggest a favorable milieu for T cell expansion. Pre-treatment levels of soluble CD163 and TARC are associated with EFS and may present a potential predictive biomarker, as well as degree of change of CD163 post treatment, irrespective of addition of immunotherapy. Our results have implications for identifying immune markers of response to guide future immunotherapies and cytotoxic T cell therapy in cHL. (NCT02166463)

Oral Chemotherapy Adherence in Pediatric Acute Lymphoblastic Leukemia (ALL): A Report from the Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 16-001

Background: Successful treatment of pediatric acute lymphoblastic leukemia (ALL) requires 2 years of risk-directed therapy, much of which is built on a backbone of oral chemotherapy including 6-mercaptopurine (6MP) and dexamethasone (DEX). Studies conducted in the Children's Oncology Group (COG) demonstrate that poor adherence to 6MP during the maintenance phase confers increased relapse risk; however, little is known about the rates of 6MP adherence in non-COG ALL regimens. DFCI ALL Consortium protocols utilize 3-week cycles including 14-day pulses of 6MP with weekly intravenous or intramuscular methotrexate. This treatment approach requires more frequent contact between families and healthcare providers and reduces the number of oral chemotherapy agents prescribed. Whether this higher-touch regimen might reduce the frequency of non-adherence as compared to published COG data is not known. Additionally, there remains a paucity of data investigating incidence of non-adherence to DEX, 6MP, and to any medications during the first year of therapy. Methods: Oral chemotherapy adherence was prospectively evaluated as an embedded ancillary study on the DFCI ALL Consortium Protocol 16-001. Eligible participants included English-, Spanish-, or French-speaking caregivers of patients (<22 years) receiving 6MP and DEX (both liquid and tablet formations) and did not utilize a pillbox. Adherence to 6MP and DEX were measured using Medication Event Monitoring Systems (MEMS) caps, which record the date and time of medicine bottle opening. MEMS caps were used to measure adherence for three consecutive cycles during the first year of therapy, and again for three consecutive cycles during the second year of therapy. Caregivers completed surveys reporting sociodemographic determinants of health (SDOH), medication-taking behaviors, and chemotherapy comprehension. MEMS-based medication adherence rates were calculated as a percentage based upon the ratio of the number of days with MEMS cap openings to the number of days 6MP and/or DEX were prescribed. Adherent patients were defined as those with ≥95% adherence based on prior COG trials that observed an excess risk of relapse below this threshold (Bhatia JAMA Onc 2015). Results: Between 2018 - 2022, 252/429 (59%) eligible patients consented to study participation, and adherence data was successfully collected for 207 (82%). Sixty-six (26%) participants were enrolled from Canadian hospital centers, and 186 (74%) participants were enrolled from US hospital centers. Participant age included 159 (77%) <10 years of age, 31 (15%) 10 - 14 years, and 17 (8%) 15 - 21 years (see Table 1). Thirty-four (16%) patients identified as Hispanic, 13 (6%) non-Hispanic Black, 18 (9%) non-Hispanic Other, and 142 (69%) non-Hispanic White. 57 (31%) patients relied on public insurance at time of diagnosis, 61 (34%) patients reported a primary household language other than English, and 36 (20%) patients lived in lone-parent households. A third, 61 (34%) and 62 (34%), of caregivers reported being unsure of what would happen if their child stopped taking 6MP or DEX, respectively. Over the course of six cycles, MEMS-measured adherence rates to 6MP (N = 180) and DEX (N = 195) were 73% (range 21 - 100) and 86% (range 10 - 100), respectively. Preliminary data suggest that adherence rates to 6MP improved during year 2 of treatment (cycles 4-6 of monitoring) (Table 2). In unadjusted analyses, there was a non-significant association between patient age and likelihood of adherence to oral medication: adherence to 6MP was 71% in those <10 years, 80% in those 10 - 14 years, and 71% in those 15 years or older (Jonckheere-Terpstra test p = 0.66). Conclusion: Among a diverse cohort of patients treated with a DFCI ALL Consortium regimen, adherence to oral chemotherapy is suboptimal with rates of 73% to 6MP and 86% to DEX. This finding recapitulates published data from COG ALL trials, suggesting more frequent contact with healthcare providers in the DFCI Consortium protocol does not mitigate non-adherence. Numerical differences between age groups suggest patients ages 10 - 14 years (N=31) have higher adherence compared to patients both younger and older. These preliminary findings suggest that there may be a behavioral component when it comes to medication adherence - with barriers among young children differing from those in both younger and older adolescents.

Association of the social disorganization index with time to first septic shock event in children with acute myeloid leukemia.

Pediatric acute myeloid leukemia (AML) chemotherapy increases the risk of life-threatening complications, including septic shock (SS). An area-based measure of social determinants of health, the social disorganization index (SDI), was hypothesized to be associated with SS and SS-associated death (SS-death). Children treated for de novo AML on two Children's Oncology Group trials at institutions contributing to the Pediatric Health Information System (PHIS) database were included. The SDI was calculated via residential zip code data from the US Census Bureau. SS was identified via PHIS resource utilization codes. SS-death was defined as death within 2weeks of an antecedent SS event. Patients were followed from 7days after the start of chemotherapy until the first of end of front-line therapy, death, relapse, or removal from study. Multivariable-adjusted Cox regressions estimated hazard ratios (HRs) comparing time to first SS by SDI group. The assembled cohort included 700 patients, with 207 (29.6%) sustaining at least one SS event. There were 233 (33%) in the SDI-5 group (highest disorganization). Adjusted time to incident SS did not statistically significantly differ by SDI (reference,SDI-1; SDI-2: HR, 0.84 [95% confidence interval (CI), 0.51-1.41]; SDI-3: HR, 0.70 [95% CI, 0.42-1.16]; SDI-4: HR, 0.97 [95% CI, 0.61-1.53]; SDI-5: HR, 0.72 [95% CI, 0.45-1.14]). Nine patients (4.4%) with SS experienced SS-death; seven of these patients (78%) were in SDI-4 or SDI-5. In a large, nationally representative cohort of trial-enrolled pediatric patients with AML, there was no significant association between the SDI and time to SS.

Outcomes in Children, Adolescents, and Young Adults With Down Syndrome and ALL: A Report From the Children's Oncology Group.

Patients with Down syndrome (DS) and B-ALL experience increased rates of relapse, toxicity, and death. We report results for patients with DS B-ALL enrolled on Children's Oncology Group trials between 2003 and 2019. We analyzed data for DS (n = 743) and non-DS (n = 20,067) patients age 1-30 years on four B-ALL standard-risk (SR) and high-risk trials. Patients with DS exhibited more frequent minimal residual disease (MRD) ≥0.01% at end induction (30.8% v 21.5%; P < .001). This difference persisted at end consolidation only in National Cancer Institute (NCI) high-risk patients (34.0% v 11.7%; P < .0001). Five-year event-free survival (EFS) and overall survival (OS) were significantly poorer for DS versus non-DS patients overall (EFS, 79.2% ± 1.6% v 87.5% ± 0.3%; P < .0001; OS, 86.8% ± 1.4% v 93.6% ± 0.2%; P < .0001), and within NCI SR and high-risk subgroups. Multivariable Cox regression analysis of the DS cohort for risk factors associated with inferior EFS identified age >10 years, white blood count >50 × 103/μL, and end-induction MRD ≥0.01%, but not cytogenetics or CRLF2 overexpression. Patients with DS demonstrated higher 5-year cumulative incidence of relapse (11.5% ± 1.2% v 9.1% ± 0.2%; P = .0008), death in remission (4.9% ± 0.8% v 1.7% ± 0.1%; P < .0001), and induction death (3.4% v 0.8%; P < .0001). Mucositis, infections, and hyperglycemia were significantly more frequent in all patients with DS, while seizures were more frequent in patients with DS on high-risk trials (4.1% v 1.8%; P = .005). Patients with DS-ALL exhibit an increased rate of relapse and particularly of treatment-related mortality. Novel, less-toxic therapeutic strategies are needed to improve outcomes.

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 blueprint for research: Acute lymphoblastic leukemia.

Cure rates for acute lymphoblastic leukemia (ALL), the most common childhood cancer have steadily improved over the past five decades. This is due to intensifying systemic therapy, recognizing and treating the central nervous system as a sanctuary site, and implementing modern risk stratification to deliver varying intensities of therapy based on age, presenting white blood count, sentinel somatic genetics, and therapy response. Recently, numerous Children's Oncology Group trials have demonstrated the lack of benefit of intensifying traditional chemotherapy, providing evidence that new approaches are needed to cure the patients for whom cure has been elusive. Distinguishing those who require intensive or novel therapeutic approaches from others who will be cured with minimal therapy is key for future trials. Incorporating new genomic biomarkers and more sensitive measures of minimal/measurable residual disease provide opportunities to achieve these goals.

Children's Oncology Group 2023 blueprint: Nursing discipline.

In contrast to other Children's Oncology Group (COG) committees, the COG nursing discipline is unique in that it provides the infrastructure necessary for nurses to support COG clinical trials and implements a research agenda aimed at scientific discovery. This hybrid focus of the discipline reflects the varied roles and expertise within pediatric oncology clinical trials nursing that encompass clinical care, leadership, and research. Nurses are broadly represented across COG disease, domain, and administrative committees, and are assigned to all clinically focused protocols. Equally important is the provision of clinical trials-specific education and training for nurses caring for patients on COG trials. Nurses involved in the discipline's evidence-based practice initiative have published a wide array of systematic reviews on topics of clinical importance to the discipline. Nurses also develop and lead research studies within COG, including stand-alone studies and aims embedded in disease/ treatment trials. Additionally, the nursing discipline is charged with responsibility for developing patient/family educational resources within COG. Looking to the future, the nursing discipline will continue to support COG clinical trials through a multifaceted approach, with a particular focus on patient-reported outcomes and health equity/disparities, and development of interventions to better understand and address illness-related distress in children with cancer.

Feasibility and acceptability of social determinants of health data collection in the context of a Children’s Oncology Group trial.

10010 Background: Children who are Black, Hispanic or of proxied low socioeconomic status experience inferior survival outcomes despite receipt of uniform treatment on Children’s Oncology Group (COG) trials. Investigation of mechanisms underlying these disparities and evaluation of interventions to address them has been limited by inadequate data. Prior COG trials have collected child race, ethnicity, insurance and zip code—non-modifiable data elements that are prone to misclassification bias—as proxies for exposure to adverse social determinants of health (SDOH). Collection of parent-reported SDOH data provides key information not previously assessed in COG trials, including modifiable exposures such as household material hardship (HMH): food, housing, utility or transportation insecurity. We report the preliminary feasibility and acceptability of the first COG trial to prospectively embed SDOH data collection. Methods: ANBL1531 (NCT03126916), the current frontline, groupwide COG trial for patients with high-risk neuroblastoma, was amended in September 2019 to include an opt-in, correlative aim to evaluate parent-reported SDOH. Parents of patients &lt; 18 years could opt-in during initial ANBL1531 consent to complete a brief, single-timepoint survey at their enrolling site during Induction Cycle 1. Survey domains included parent-reported demographics, HMH, household income, and social support. Paper/pencil surveys available in English, Spanish or French were self-completed or read-aloud by site personnel and could be administered in any language with an interpreter. Surveys were submitted to a central disparities study team for data cleaning and entry into an electronic database. Results: As of December 31, 2022, 360/413 eligible participants opted-in to the embedded SDOH aim across 101 COG sites (87.2% consent rate). Among participants, 316 surveys (87.8%) were completed a median of 11 days post-enrollment. Four (1.1%) parents declined survey completion (3 withdrew consent). Reasons for non-completed surveys included: survey still pending within protocol-specified window (n = 10), institutional COVID-19 restrictions (n = 6), site scheduling issues (n = 6), patient came off ANBL1531 protocol (n = 5) and unknown (n = 13). Data missingness for HMH, the primary SDOH of interest, was 0.8%. Surveys were administered in English, Spanish, French, Vietnamese, Arabic, Mandarin and Tamil. Conclusions: Collection of parent-reported SDOH data as an optional, embedded component of a groupwide COG trial is feasible and acceptable, as demonstrated by remarkable willingness to participate and infrequency of missing data. Incorporation of this approach in future National Clinical Trials Network trials is essential to inform impactful health equity research, including the development and evaluation of targeted interventions to address outcome disparities.