Children's Oncology Group Study Research Articles

Clinical Practice Guideline-Inconsistent Management of Fertility Preservation in Pediatric Cancer Patients in Community Settings: A Children's Oncology Group Study.

Background: The primary objective was to measure adherence to clinical practice guideline (CPG) recommendations for fertility preservation (FP) in pediatric cancer patients treated in National Cancer Institute Community Oncology Research Program (NCORP) sites. Secondary objectives were to describe factors such as site size associated with CPG-inconsistent care delivery and cryopreservation completion. Methods: This retrospective, multicenter study included patients 15 to 21 years old with a first cancer diagnosis from January 2014 through December 2015 who were previously enrolled to a Children's Oncology Group (COG) study and received care at a participating NCORP site. Patients were randomly selected from a list generated by the COG for chart review by participating sites. Primary outcome was care delivery that was inconsistent with a strong CPG recommendation on FP, namely discussion and offering of FP options before cancer treatment initiation, as adjudicated centrally by a panel. Results: A total of 129 patients from 25 sites were included. Among these, 48% (62/129) received CPG-inconsistent care. Most CPG-inconsistent care was due to lack of FP discussion documentation (93.5%, 58/62). Small site size, treatment at a pediatric (vs mixed adult/pediatric) site, and female sex were associated with higher odds of CPG-inconsistent care delivery. Conclusions: Newly diagnosed pediatric cancer patients often received CPG-inconsistent care for FP, with disproportionate gaps noted for females, and those treated at smaller or pediatric NCORP sites. The primary reason for CPG-inconsistent care is lack of FP discussion from clinicians. Opportunities to improve FP CPG implementation are highlighted.

Clinical features and outcomes of young patients with low-grade non-rhabdomyosarcoma soft tissue sarcomas treated with a risk-based strategy: A report from Children's Oncology Group study ARST0332.

In retrospective analyses, the Pediatric Oncology Group [POG) and the Federation National des Centres de Lutte Contre le Cancer (FNCLCC) histologic grade predict outcome in pediatric non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), but prospective data on grading, clinical features, and outcomes of low-grade NRSTS are limited. We analyzed patients less than 30years of age enrolled on Children's Oncology Group (COG) study ARST0332 (NCT00346164) with POG grade 1 or 2 NRSTS. Low-risk patients were treated with surgery alone. Intermediate-/high-risk patients received ifosfamide/doxorubicin and radiotherapy, with definitive resection either before or after 12weeks of chemoradiotherapy. Estimated 5-year event-free and overall survival were 90% and 100% low risk (n=80), 55% and 78% intermediate risk (n=15), and 25% and 25% high risk (n=4). In low-risk patients, only local recurrence was seen in 10%; none with margins greater than 1mm recurred locally. Sixteen of 17 intermediate-/high-risk patients who completed neoadjuvant chemoradiotherapy underwent gross total tumor resection, 80% with negative margins. Intermediate-/high-risk group events included one local and seven metastatic recurrences. Had the FNCLCC grading system been used to direct treatment, 29% of low-risk (surgery alone) patients would have received radiotherapy ± chemotherapy. Most low-risk patients with completely resected POG low-grade NRSTS are successfully treated with surgery alone, and surgical margins greater than 1mm may be sufficient to prevent local recurrence. Patients with intermediate- and high-risk low-grade NRSTS have outcomes similar to patients with high-grade histology, and require more effective therapies. Use of the current FNCLCC grading system may result in overtreatment of low-risk NRSTS curable with surgery alone.

Bilateral Wilms tumor with anaplasia: A report from the Children's Oncology Group Study AREN0534.

The purpose of this study is to examine the outcomes in children with anaplastic bilateral Wilms tumor (BWT) from study AREN0534 in order to define potential prognostic factors and areas to target in future clinical trials. Demographic and clinical data from AREN0534 study patients with anaplasia (focal anaplasia [FA], or diffuse anaplasia [DA]) were compared. Event-free survival (EFS) and overall survival (OS) were reported using Kaplan-Meier estimation with 95% confidence bands, and differences in outcomes between FA and DA compared using log-rank tests. The impact of margin status was analyzed. Twenty-seven children who enrolled on AREN0534 had evidence of anaplasia (17 DA, 10 FA) in at least one kidney and were included in this analysis. Twenty-six (96%) had BWT. Nineteen percent had anaplastic histology in both kidneys (four of 17 DA, and one of 10 FA). Forty-six percent with BWT had bilateral nephron-sparing surgery (NSS); one child who went off protocol therapy, eventually required bilateral completion nephrectomies. Median follow-up for EFS and OS was 8.6 and 8.7years from enrollment. Four- and 8-year EFS was 53% [95% confidence interval (CI): 34%-83%] for DA; 4-year EFS was 80% [95% CI: 59%-100%], and 8-year EFS 70% [95% CI: 47%-100%] for FA. Three out of 10 children with FA and eight out of 17 children with DA had events. EFS did not differ statistically by margin status (p=.79; HR=0.88). Among the six children who died (five DA, one FA), all experienced prior relapse or progression within 18months. Events in children with DA/FA in the setting of BWT occurred early. Caution should be taken about interpreting the impact of margin status outcomes in the context of contemporary multimodal therapy. Future targeted investigations in children with BWT and DA/FA are needed.

Impact of Propofol Exposure on Neurocognitive Outcomes in Children With High-Risk B ALL: A Children's Oncology Group Study.

Many children treated for ALL develop long-term neurocognitive impairments. Increased risk of these impairments is associated with treatment and demographic factors. Exposure to anesthesia is an additional possible risk factor. This study evaluated the impact of cumulative exposure to anesthesia on neurocognitive outcomes among a multicenter cohort of children with ALL. This study was embedded in AALL1131, a Children's Oncology Group phase III trial for patients with high-risk B-ALL. In consenting patients age 6-12 years, prospective uniform assessments of neurocognitive function were performed during and at 1 year after completion of therapy. Exposure to all episodes of anesthetic agents was abstracted. Multivariable linear regression models determined associations of cumulative anesthetic agents with the primary neurocognitive outcome reaction time/processing speed (age-normed) at 1 year off therapy, adjusting for baseline neurocognitive score, age, sex, race/ethnicity, insurance status (as a proxy for socioeconomic status), and leukemia risk group. One hundred and forty-four children, 76 (52.8%) males, mean age of 9.1 (min-max, 6.0-12.0) years at diagnosis, underwent a median of 27 anesthetic episodes (min-max, 1-37). Almost all patients were exposed to propofol (140/144, 97.2%), with a mean cumulative dose of 112.3 mg/kg. One year after therapy, the proportion of children with impairment (Z-score ≤-1.5) was significantly higher compared with a normative sample. In covariate-adjusted multivariable analysis, cumulative exposure to propofol was associated with a 0.05 Z-score decrease in reaction time/processing speed per each 10 mg/kg propofol exposure (P = .03). In a multicenter and uniformly treated cohort of children with B-ALL, cumulative exposure to propofol was an independent risk factor for impairment in reaction time/processing speed 1 year after therapy. Anesthesia exposure is a modifiable risk, and opportunities to minimize propofol use should be considered.

Embryonal sarcoma of the liver in pediatric and young adult patients: A report from Children's Oncology Group study ARST0332.

Embryonal sarcoma of the liver (ESL) is a rare mesenchymal tumor most common in childhood; the optimal treatment approach is uncertain. The clinical features and outcomes of patients with ESL enrolled in a Children's Oncology Group (COG) clinical trial that evaluated a risk-based strategy for treating soft tissue sarcomas in patients aged <30 years were evaluated. This subset analysis included patients with ESL enrolled in COG study ARST0332. Central review of records, pathology, and imaging confirmed the diagnosis, presenting features, and surgery extent and complications. All patients received dose-intensive ifosfamide/doxorubicin chemotherapy, with cycle timing dependent on surgery and radiotherapy. Tumor resection occurred before study entry or after four cycles of chemotherapy; radiotherapy for residual tumor was optional. Thirty-nine eligible/evaluable patients with ESL were analyzed. All tumors were >10 cm in diameter; four were metastatic. Tumor resection was performed upfront in 23 and delayed in 16. Positive surgical margins (n=6) and intraoperative tumor rupture (n=6) occurred only in upfront resections. Eight patients received radiotherapy. Estimated 5-year event-free and overall survival were 79% (95% confidence interval [CI], 65%-93%) and 95% (95% CI, 87%-100%), respectively. Positive margins increased the local recurrence risk. One of 13 patients with documented hemorrhagic ascites and/or tumor rupture developed extrahepatic intra-abdominal tumor recurrence. The treatment strategy used in ARST0332 achieved favorable outcomes for patients with ESL despite a substantial proportion having high-risk disease features. Deferring tumor resection until after neoadjuvant chemotherapy may decrease the risk of intraoperative tumor rupture and improve the likelihood of adequate surgical margins.

Fertility preservation in pediatric solid tumors: A report from the Children's Oncology Group.

Treatment for childhood solid tumors may lead to an increased risk for gonadal dysfunction/infertility. Discussion of risk should occur at diagnosis, any changes in therapy, and during survivorship. Gonadotoxic therapies were abstracted from 32 Children's Oncology Group (COG) phase III, frontline solid tumor protocols, in use from 2000 to 2022. Risk for gonadal dysfunction/infertility was assessed based on gonadotoxic therapies, sex, and pubertal status and assigned as minimal, significant, and high following the Oncofertility Consortium Pediatric Initiative Network (PIN) risk stratification. Most protocols (65.6%, 21/32) contained at least one therapeutic arm with a high level of increased risk. Solid tumor therapies present challenges in risk stratification due to response-adjusted therapy and the need to account for radiation field in the risk assessment. This guide hopes to serve as a tool to assist in standardizing gonadotoxic risk assessments across disciplines and improve referral for fertility services and reproductive health counseling for patients receiving COG-based solid tumor therapy. Internationally, many solid tumor therapies follow similar paradigms to COG studies, and risk stratifications may be generalizable to similar styles of therapy. In addition, this model may be applied to other international groups with the goal of standardizing fertility assessments.

Discussion.

Discussion.

Race and Ethnic Group Enrollment and Outcomes for Wilms Tumor: Analysis of the Current Era Children's Oncology Group Study, AREN03B2.

To review race and ethnic group enrollment and outcomes for Wilms tumor (WT) across all 4 risk-assigned therapeutic trials from the current era Children's Oncology Group Renal Tumor Biology and Risk Stratification Protocol, AREN03B2. For patients with WT enrolled in AREN03B2 (2006 to 2019), disease and biologic features, therapeutic study-specific enrollment, and event-free (EFS) and overall (OS) 4-year survival were compared between institutionally reported race and ethnic groups. Among 5,146 patients with WT, no statistically significant differences were detected between race and ethnic groups regarding subsequent risk-assigned therapeutic study enrollment, disease stage, histology, biologic factors, or overall EFS or OS, except the following variables: Black children were older and had larger tumors at enrollment, whereas Hispanic children had lower rates of diffuse anaplasia WT and loss of heterozygosity at 1p. The only significant difference in EFS or OS between race and ethnic groups was observed among the few children treated for diffuse anaplasia WT with regimen UH-1 and -2 on high-risk protocol, AREN0321. On this therapeutic arm only, Black children showed worse EFS (hazard ratio = 3.18) and OS (hazard ratio = 3.42). However, this finding was not replicated for patients treated with regimen UH-1 and -2 under AREN03B2 but not on AREN0321. Race and ethnic group enrollment appeared constant across AREN03B2 risk-assigned therapeutic trials. EFS and OS on these therapeutic trials when analyzed together were comparable regarding race and ethnicity. Black children may have experienced worse stage-specific survival when treated with regimen UH-1 and -2 on AREN0321, but this survival gap was not confirmed when analyzing additional high-risk AREN03B2 patients.

Treatment and outcomes of clear cell sarcoma of the kidney: A report from the Children's Oncology Group studies AREN0321 and AREN03B2.

On the fifth National Wilms Tumor Study, treatment for clear cell sarcoma of the kidney (CCSK) included combined vincristine, doxorubicin, cyclophosphamide, and etoposide (regimen I) plus radiation therapy (RT), yielding 5-year event-free survival (EFS) rates of 100%, 88%, 73%, and 29% for patients who had with stage I, II, III, and IV disease, respectively. In the Children's Oncology Group study AREN0321 of risk-adapted therapy, RT was omitted for stage I disease if lymph nodes were sampled, and carboplatin was added for stage IV disease (regimen UH-1). Patients who had stage II/III disease received regimen I with RT. Four-year EFS was analyzed for patients enrolled on AREN0321 and onthose enrolled on AREN03B2 who received AREN0321 stage-appropriate chemotherapy. Eighty-two patients with CCSK enrolled on AREN0321, 50 enrolled on AREN03B2 only. The 4-year EFS rate was 82.7% (95% confidence interval [CI], 74.8%-91.4%) for AREN0321 and 89.6% (95% CI, 81.3%-98.7%) for AREN03B2 only (p=.28). When combining studies, the 4-year EFS rates for patients who had stage I (n=10), II (n=47), III (n=65), and IV (n=10) disease were 90% (95% CI, 73.2%-100.0%), 93.4% (95% CI, 86.4%-100.0%), 82.8% (95% CI, 74.1%-92.6%), and 58.3% (95% CI, 34%-100.0%), respectively. There were no local recurrences among seven patients with stage I disease who were treated without RT. One stage I recurrence occurred in the brain, which was the most common site of relapse overall. Among patients with local stage III tumors, neither initial procedure type, margin status, nor lymph node involvement were prognostic. Patients with stage I CCSK had excellent outcomes without local recurrences when treated without RT. Patients with stage IV disease appeared to benefit from a carboplatin-containing regimen, although their outcomes remained unsatisfactory. Further research is needed to improve outcomes for patients withadvanced-stage disease (ClinicalTrials.gov identifiers NCT00335556 and NCT00898365).

Population-Based Data Linkage Describing Patterns of Cancer Clinical Trial Enrollment Among Children and Adolescents.

Database linkage between cancer registries and clinical trial consortia has the potential to elucidate referral patterns of children and adolescents with newly diagnosed cancer, including enrollment into cancer clinical trials. This study's primary objective was to assess the feasibility of this linkage approach. Patients younger than 20 years diagnosed with incident cancer during 2012-2017 in the Kentucky Cancer Registry (KCR) were linked with patients enrolled in a Children's Oncology Group (COG) study. Matched patients between databases were described by sex, age, race and ethnicity, geographical location when diagnosed, and cancer type. Logistic regression modeling identified factors associated with COG study enrollment. Timeliness of patient identification by KCR was reported through the Centers for Disease Control and Prevention's Early Case Capture (ECC) program. Of 1,357 patients reported to KCR, 47% were determined by matching to be enrolled in a COG study. Patients had greater odds of enrollment if they were age 0-4 years (v 15-19 years), reported from a COG-affiliated institution, and had renal cancer, neuroblastoma, or leukemia. Patients had lower odds of enrollment if Hispanic (v non-Hispanic White) or had epithelial (eg, thyroid, melanoma) cancer. Most (59%) patients were reported to KCR within 10 days of pathologic diagnosis. Linkage of clinical trial data with cancer registries is a feasible approach for tracking patient referral and clinical trial enrollment patterns. Adolescents had lower enrollment compared with younger age groups, independent of cancer type. Population-based early case capture could guide interventions designed to increase cancer clinical trial enrollment.

Development and validation of a promising 5-gene prognostic model for pediatric acute myeloid leukemia

Risk classification in pediatric acute myeloid leukemia (P-AML) is crucial for personalizing treatments. Thus, we aimed to establish a risk-stratification tool for P-AML patients and eventually guide individual treatment. A total of 256 P-AML patients with accredited mRNA-seq data from the TARGET database were divided into training and internal validation datasets. A gene-expression-based prognostic score was constructed for overall survival (OS), by using univariate Cox analysis, LASSO regression analysis, Kaplan–Meier (K-M) survival, and multivariate Cox analysis. A P-AML-5G prognostic score bioinformatically derived from expression levels of 5 genes (ZNF775, RNFT1, CRNDE, COL23A1, and TTC38), clustered P-AML patients in training dataset into high-risk group (above optimal cut-off) with shorter OS, and low-risk group (below optimal cut-off) with longer OS (p < 0.0001). Meanwhile, similar results were obtained in internal validation dataset (p = 0.005), combination dataset (p < 0.001), two treatment sub-groups (p < 0.05), intermediate-risk group defined with the Children's Oncology Group (COG) (p < 0.05) and an external Japanese P-AML dataset (p = 0.005). The model was further validated in the COG study AAML1031(p = 0.001), and based on transcriptomic analysis of 943 pediatric patients and 70 normal bone marrow samples from this dataset, two genes in the model demonstrated significant differential expression between the groups [all log2(foldchange) > 3, p < 0.001]. Independent of other prognostic factors, the P-AML-5G groups presented the highest concordance-index values in training dataset, chemo-therapy only treatment subgroups of the training and internal validation datasets, and whole genome-sequencing subgroup of the combined dataset, outperforming two Children's Oncology Group (COG) risk stratification systems, 2022 European LeukemiaNet (ELN) risk classification tool and two leukemic stem cell expression-based models. The 5-gene prognostic model generated by a single assay can further refine the current COG risk stratification system that relies on numerous tests and may have the potential for the risk judgment and identification of the high-risk pediatric AML patients receiving chemo-therapy only treatment.

Vorinostat, temozolomide or bevacizumab with irradiation and maintenance BEV/TMZ in pediatric high-grade glioma: A Children's Oncology Group Study.

Outcomes for children with high-grade gliomas (HGG) remain poor. This multicenter phase II trial evaluated whether concurrent use of vorinostat or bevacizumab with focal radiotherapy (RT) improved 1-year event-free survival (EFS) compared to temozolomide in children with newly diagnosed HGG who received maintenance temozolomide and bevacizumab. Patients ≥ 3 and < 22 years with localized, non-brainstem HGG were randomized to receive RT (dose 54-59.4Gy) with vorinostat, temozolomide, or bevacizumab followed by 12 cycles of bevacizumab and temozolomide maintenance therapy. Among 90 patients randomized, the 1-year EFS for concurrent bevacizumab, vorinostat, or temozolomide with RT was 43.8% (±8.8%), 41.4% (±9.2%), and 59.3% (±9.5%), respectively, with no significant difference among treatment arms. Three- and five-year EFS for the entire cohort was 14.8% and 13.4%, respectively, with no significant EFS difference among the chemoradiotherapy arms. IDH mutations were associated with more favorable EFS (P = .03), whereas H3.3 K27M mutations (P = .0045) and alterations in PIK3CA or PTEN (P = .025) were associated with worse outcomes. Patients with telomerase- and alternative lengthening of telomeres (ALT)-negative tumors (n = 4) had an EFS of 100%, significantly greater than those with ALT or telomerase, or both (P = .002). While there was no difference in outcomes based on TERT expression, high TERC expression was associated with inferior survival independent of the telomere maintenance mechanism (P = .0012). Chemoradiotherapy with vorinostat or bevacizumab is not superior to temozolomide in children with newly diagnosed HGG. Patients with telomerase- and ALT-negative tumors had higher EFS suggesting that, if reproduced, mechanism of telomere maintenance should be considered in molecular-risk stratification in future studies.

Role of non-chromosomal birth defects on the risk of developing childhood Hodgkin lymphoma: A Children's Oncology Group study.

Non-chromosomal birth defects are an important risk factor for several childhood cancers. However, these associations are less clear for Hodgkin lymphoma (HL). Therefore, we sought to more fully elucidate the association between non-chromosomal birth defects and HL risk. Information on cases (n=517) diagnosed with HL (ages of 0-14) at Children's Oncology Group Institutions for the period of 1989-2003 was obtained. Control children without a history of cancer (n=784) were identified using random digit dialing and individually matched to cases on sex, race/ethnicity, age, and geographic location. Parents completed comprehensive interviews and answered questions including whether their child had been born with a non-chromosomal birth defect. To test the association between birth defects and HL risk, conditional logistic regression was applied to generate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Children born with any non-chromosomal birth defect were not more likely to be diagnosed with HL at 0-14 years of age (aOR: 0.91; 95% CI: 0.69-1.21). No associations were detected between major or minor birth defects and HL (aOR: 1.34; 95% CI: 0.67-2.67 and aOR: 0.88; 95% CI: 0.57-1.34, respectively). Similarly, no association was observed for children born with any birth defect and EBV-positive HL (aOR: 0.57; 95% CI: 0.25-1.26). Previous assessments of HL in children with non-chromosomal birth defects have been limited. Using data from the largest case-control study of HL in those<15 years of age, we did not observe strong associations between being born with a birth defect and HL risk.

BRAF Exon 15 Mutations in the Evaluation of Well-Differentiated Epithelial Nephroblastic Neoplasms in Children: A Report From the Children's Oncology Group Study AREN03B2.

The distinction between well-differentiated epithelial favorable-histology Wilms tumor (EFHWT) and metanephric adenoma (MA) in children has historically been determined by the required absence of both a fibrous pseudocapsule and mitotic activity in MA. More recently these features have been allowed in adult MA. Mutations in exon 15 of the BRAF gene are reported in up to 88% of MAs but have not been reported in EFHWTs. To clarify the pathologic and molecular features used to distinguish between pediatric MA and EFHWT. Stage I epithelial tumors classified as EFHWT on central review (36 patients) were identified from the Children's Oncology Group AREN03B2 study. Thirteen tumors had morphologic features overlapping those of MA and 23 lacked such features; 35 of 36 had tissue available for sequencing of BRAF. Patients with EFHWTs with MA features (13) were older (mean, 8.4 versus 1.9 years; P < .001), had smaller tumor diameters (mean, 6.0 versus 9.7 cm; P < .001), and had fewer mitoses (mean, 1 versus 48 mitoses per 10 high-power fields; P < .001) than patients with EFHWT lacking MA features (23). All EFHWTs with MA features contained at least a partial fibrous pseudocapsule; 7 of 12 (58%) had BRAF exon 15 mutation. No BRAF exon 15 mutations were identified in 23 EFHWTs lacking MA features. None of the 13 EFHWT patients with MA features have experienced relapse (median follow-up 5.9 years). Pediatric epithelial neoplasms with features of MA that show partial encapsulation and/or modest mitotic activity may be classified as MAs. Although BRAF mutation supports the diagnosis of MA, it is not required for the diagnosis.

High IL2RA/CD25 expression is a prognostic stem cell biomarker for pediatric acute myeloid leukemia without a core-binding factor.

CD25 is an aberrant marker expressed on the leukemic stem cell (LSC) surface and an immunotherapy target in acute myeloid leukemia (AML). However, the clinical prevalence and significance of CD25 expression in pediatric AML are unknown. High IL2RA/CD25 expression in pediatric AML showed a stem cell-like phenotype, and elevated CD25 expression was associated with lower overall survival (p<.001) and event-free survival (p<.001) in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. This finding was reproduced in AML without a core-binding factor in the Children's Oncology Group study cohort. High CD25 expression has prognostic significance in pediatric AML.

Rationale and design of the Children's Oncology Group study AAML1831 integrated cardiac substudies in pediatric acute myeloid leukemia therapy.

Pediatric acute myeloid leukemia (AML) therapy is associated with substantial short- and long-term treatment-related cardiotoxicity mainly due to high-dose anthracycline exposure. Early left ventricular systolic dysfunction (LVSD) compromises anthracycline delivery and is associated with inferior event-free and overall survival in de novo pediatric AML. Thus, effective cardioprotective strategies and cardiotoxicity risk predictors are critical to optimize cancer therapy delivery and enable early interventions to prevent progressive LVSD. While dexrazoxane-based cardioprotection reduces short-term cardiotoxicity without compromising cancer survival, liposomal anthracycline formulations have the potential to mitigate cardiotoxicity while improving antitumor efficacy. This overview summarizes the rationale and methodology of cardiac substudies within AAML1831, a randomized Children's Oncology Group Phase 3 study of CPX-351, a liposomal formulation of daunorubicin and cytarabine, in comparison with standard daunorubicin/cytarabine with dexrazoxane in the treatment of de novo pediatric AML. Children (age <22 years) with newly diagnosed AML were enrolled and randomized to CPX-351-containing induction 1 and 2 (Arm A) or standard daunorubicin and dexrazoxane-containing induction (Arm B). Embedded cardiac correlative studies aim to compare the efficacy of this liposomal anthracycline formulation to dexrazoxane for primary prevention of cardiotoxicity by detailed core lab analysis of standardized echocardiograms and serial cardiac biomarkers throughout AML therapy and in follow-up. In addition, AAML1831 will assess the ability of early changes in sensitive echo indices (e.g., global longitudinal strain) and cardiac biomarkers (e.g., troponin and natriuretic peptides) to predict subsequent LVSD. Finally, AAML1831 establishes expert consensus-based strategies in cardiac monitoring and anthracycline dose modification to balance the potentially competing priorities of cardiotoxicity reduction with optimal leukemia therapy. This study will inform diagnostic, prognostic, preventative, and treatment strategies regarding cardiotoxicity during pediatric AML therapy. Together, these measures have the potential to improve leukemia-free and overall survival and long-term cardiovascular health in children with AML. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT04293562.

Performance of Positron Emission Tomography at Diagnosis and Response Assessment in Low and Intermediate-Risk Nodular Lymphocyte Predominant Hodgkin Lymphoma

Background: Nodular lymphocyte predominant Hodgkin lymphoma (nLPHL) has different histology, clinical presentation, and outcomes than classical Hodgkin Lymphoma (cHL). Positron Emission Tomography (PET) plays an important role in staging and response assessment in cHL, but little is published about the use of PET to guide treatment in nLPHL. A better understanding of the clinical significance of PET response in nLPHL is critical for incorporating PET into prospective trials. Methods: Children's Oncology Group study AHOD03P1 (NCT00107198) enrolled patients with low-risk nLPHL and AHOD0031 (NCT00025259) enrolled patients with intermediate-risk cHL and nLPHL &amp;lt;22 years of age. AHOD03P1 patients with stage IA and &amp;gt;1 lymph node or stage IIA nLPHL were treated with 3 cycles of doxorubicin, vincristine, prednisone, and cyclophosphamide (AV-PC) chemotherapy, given every 21 days. Patients with a complete response (CR) based on anatomic response and qualitative reading (&amp;lt;mediastinal blood pool) of negative PET on central review did not receive radiation therapy while patients with &amp;lt;CR received 21-Gy involved field radiation therapy (IFRT). AHOD0031 patients with stages IB, IAE, IIB, IIAE, IIIA, IVA with or without bulk disease, and IA or IIA with bulk disease received 2 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE-PC) followed by response evaluation. Slow early responders were randomized to an additional 2 cycles of ABVE-PC with or without 2 cycles of dexamethasone, etoposide, cisplatin and cytarabine (DECA) and all received IFRT. Rapid early responders (RERs) received 2 additional cycles of ABVE-PC. RERs with CR were randomized to IFRT or no further therapy. RER/non-CRs were non-randomly assigned to IFRT. PET scans from both trials available in the Imaging and Radiation Oncology Core (IROC) were retrospectively reviewed and assigned a score of 1-5 on the Deauville 5-point scale (5PS). Patients who did not have evaluable imaging due to either scans not performed, on CD-ROM and inaccessible, or poor quality, were excluded from this analysis. Three-year event-free survival (EFS) was analyzed by 5PS at end of therapy using the Kaplan Meier method. Results: AHOD03P1 enrolled 135 patients with low-risk nLPHL who received chemotherapy and AHOD0031 enrolled 96 patients with intermediate-risk nLPHL. PET imaging available for review at diagnosis in 99 low-risk patients, 92% 5PS=5, and 55 intermediate-risk patients, 98% 5PS=5. Median age 13.4 years (range 16.5), 84.9% male, 29.9% Stage I, 49.8% Stage II, 18.6% Stage III, and 1.7% Stage IV. After 3 cycles of chemotherapy, 106 low-risk patients had available PET scans, 5PS 1 n=50, 5PS 2 n=35, 5PS 3 n=11, 5PS 4 n=7, and 5PS 5 n=3. Three-year EFS for patients with end of chemotherapy 5PS was: 5PS 1 89.9% (95% CI 77.3-95.7%), 5PS 2 97.1% (95% CI 81.4-99.6%), 5PS 3 90.9% (95% CI 50.8-98.7%), 5PS 4 28.6% (95% CI 1.0-71.1%), 5PS 5 66.7% (95% CI 5.4-94.5%) p=0.0081. When categorized as PET negative (5PS 1-3) and PET positive (5PS 4-5), 3-year EFS was 92.6% (95% CI 85.2-96.4%) for PET negative and 45.0% (95% CI 10.6-75.3%) for PET positive patients, p=0.0036 (Figure 1A). Forty-nine intermediate-risk patients had available PET scans after 2 cycles of chemotherapy, 5PS 1 n=9, 5PS 2 n=26, 5PS 3 n=10, 5PS 4 n=3, and 5PS 5 n=1. Three-year EFS by interim response was: 5PS 1 88.9% (95% CI 43.3-98.4%), 5PS 2 96.0% (95% CI 74.8-99.4%), 5PS 3 100%, 5PS 4 100%, 5PS 5 0%, p&amp;lt;0.0001. Thirty-six patients had available PET scans after 4 cycles of chemotherapy, 5PS 1 n=20, 5PS 2 n=11, 5PS 3 n=3, 5PS 4 n=1, and 5PS 5 n=1. Three-year EFS by response after 4 cycles of chemotherapy: 5PS 1 95.0% (95% CI 69.5-99.3%), 5PS 2 100%, 5PS 3 100%, 5PS 4 100%, 5PS 5 0% p&amp;lt;0.0001. When divided into PET negative (5PS 1-3) and PET positive (5PS 4-5), 3-year EFS 97.0% (95% CI 80.4-99.6%) for PET negative and 50.0% (95% CI 0.6-91.0%) for PET positive patients after 4 cycles of chemotherapy, p=0.1449 (Figure 1B). Conclusions: At diagnosis, low and intermediate-risk nLPHL lesions are almost always PET avid with 5PS=5. PET response following 3 cycles of AV-PC chemotherapy is highly predictive of outcome in pediatric patients with low-risk nLPHL when considering 5PS=3 as PET negative. Intermediate-risk patients with negative PET following ABVE-PC achieved excellent outcomes. Whether PET maintains prognostic significance in patients with nLPHL treated with rituximab needs to be studied.

Patients with Down Syndrome and High-Risk B-Acute Lymphoblastic Leukemia Demonstrate Improved Outcomes on a Modified Chemotherapy Regimen: A Report from Children's Oncology Group Study AALL1131

Introduction: Children with Down syndrome (DS) have a 20-fold increased risk of developing B-acute lymphoblastic leukemia (B-ALL), and demonstrate an increased risk of both relapse and treatment-related mortality (TRM). The Children's Oncology Group (COG) High-Risk (HR) B-ALL trial AALL0232 was permanently closed to DS HR patients due to excessive TRM, primarily due to overwhelming sepsis during times of severe neutropenia. On the successor HR B-ALL trial AALL1131, a primary objective for DS patients was therefore to reduce TRM by enhancing supportive care and modifying some elements of therapy. Methods: DS HR patients were treated on a single non-randomized stratum, with several modifications compared to non-DS HR patients. The majority of DS HR patients received a three-drug Induction, with only slow early responders (M2/M3 marrow at Induction day 15) receiving a single dose of anthracycline (daunorubicin 50 mg/m 2). Interim Maintenance 1 (IM-1) consisted of four IV courses of intermediate dose (ID; 2,000 mg/m 2) rather than high-dose methotrexate (HD MTX; 5,000 mg/m 2), with leucovorin rescue beginning earlier, at hour 30 and advancing if tolerated to hour 36, rather than at hour 42. Maintenance modifications included administration of vincristine/steroid pulses every 12 instead of every 4 weeks, and equal duration of therapy for boys and girls. Results: Patient characteristics (Table 1) were similar among the 280 DS HR patients and 5,612 non-DS HR patients except for more frequent bone marrow minimal residual disease (BM MRD) &amp;gt;0.01% in DS vs non-DS patients both at end of Induction (EOI; 54.1% vs 34.9%, p &amp;lt;0.0001) and at end of consolidation (EOC; 23.9% vs 12.0%, p=0.001). DS HR patients were also less likely to have favorable or unfavorable cytogenetics (p &amp;lt;0.0001). In terms of tolerability of the modified IM-1 phase, the duration was significantly longer in DS vs non-DS patients (mean 80.0 ± 16.6 days vs 74.0 ± 14 days, p &amp;lt;0.0001), and delays over 14 days were significantly more frequent (9.7% vs 4.7%, p=0.001). Nevertheless severe toxicities during IM-1 were low, with only 2 DS HR cases of grade 4 mucositis, 2 grade 4 infections, and 1 grade 5 event (sudden death, not otherwise specified). AALL1131 successfully achieved an induction death rate &amp;lt;10% in DS HR patients, although the rate remained significantly higher than in non-DS patients (3.6% vs 1.7%, p=0.035). Event-free survival (EFS) and overall survival (OS) in DS HR patients were improved compared to outcomes on older trials but remained significantly lower than non-DS patients (Figure 1), with 5-year EFS 69.1 ± 3.1% vs 79.5 ± 0.6% (p &amp;lt;0.0001), and 5-year OS 83.3 ± 2.5% vs 88.4 ± 0.5% (p=0.0005). Among DS HR patients, outcomes were particularly poor among those with EOC MRD &amp;gt;0.01% compared to those with EOC MRD &amp;lt;0.01% (5-year EFS 25.8 + 9.9% vs 62.2 + 6.6%, p &amp;lt;0.0021; 5-year OS 54.0 + 12.2% vs 88.1 + 4.5%, p &amp;lt;0.0003). Conclusion: AALL1131 achieved the goal of decreasing induction mortality for DS HR patients, and the modified IM-1 phase utilizing ID MTX with early leucovorin rescue was well-tolerated, with minimal grade 4-5 toxicities, despite a longer mean duration and more frequent treatment delays compared to non-DS patients receiving HD MTX. DS HR patients continued to demonstrate disparities in EOI and EOC MRD levels, as well as in 5-year EFS and OS. Innovative strategies utilizing targeted therapies and immunotherapy are needed to further improve outcomes for patients with DS HR ALL.

Impact of Treatment with Inotuzumab Ozogamicin before or after Chimeric Antigen Receptor T-Cell Therapy in Children with Relapsed/Refractory Acute Lymphoblastic Leukemia

Background: Inotuzumab (InO), a monoclonal antibody targeting CD22 conjugated to calicheamicin, is widely used for relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) with good salvage rates (O'Brien, JCO 2022, Bhojwani, Leukemia 2019). Feasibility data on its use as a bridge to Chimeric Antigen Receptor T-cell therapy (CART) or as salvage therapy post CART is limited. Concern has been raised that InO given prior to leukapheresis might impact the quality of T-cell collection and, when used for bridging therapy prior to CART, could result in insufficient B-cell antigen load at the time of CART infusion, therefore reducing efficacy. Methods: Data of patients who received InO monotherapy on Children's Oncology Group study AALL1621 Cohort 1 and who received any form of CART prior to study enrollment or within 1 year of coming off protocol therapy, irrespective of other anti-leukemic treatments, were collected retrospectively using a standardized Case Report Form. Results: Forty-eight patients received InO on AALL1621; 3-year overall survival (OS) rate was 35.4±6.9%. Thirteen received InO prior to CART and thirteen received InO post CART including 1 patient who received CD19 CART prior to InO and CD22 CART post InO (Table 1). InO prior to CART (11 CD19 CART, 1 CD22 CART, 1 unknown): Seven patients went directly to CART post InO, 5 received intervening chemotherapy, and 1 had an intervening transplant with relapse post. Nine patients received tisagenlecleucel and 3 received an investigational CART. Patients were infused CART 1-150 days (median 45 days) after coming off protocol therapy. At CART infusion, 10 patients had detectable ALL, only 2 had no CD19 expressing cells at infusion (ALL or normal B-cells) and 1 unknown. At post CART bone marrow evaluation on day 28, 7/12 (58.3%) were in a minimal residual disease (MRD) negative (&amp;lt;0.01%) remission, 1 had MRD=0.021%, 1 had unknown response. Three had residual disease including the single patient who received CD22-targeted CART. Four MRD negative patients who received CART post-InO are alive without relapse at a median of 3.8 years post CART and 1 is alive with a subsequent relapse. At 3 years post CART infusion OS is 53.9±13.8%. T-cells were collected immediately following 3-9 doses of InO in 8/13 (61.5%) patients (1-6 months from date of enrollment on the study), 2 were collected prior to InO and three had unknown collection dates. All had a CART product manufactured successfully. Post CART 7/13 patients did not develop thrombocytopenia (&amp;lt; 50,000/uL); 5 who developed thrombocytopenia had measurable ALL at day 28 post CART or soon after. One other patient went to planned transplant post CART and remained with low platelets and ANC. Almost all patients (11/13) had ANC &amp;lt; 500/uL post CART, of whom 3 did not recover including two with persistent ALL. InO Post CART (11 CD19-targeted CART, 2 CD22-targeted CART): Of the 13 patients who received InO post CART therapy, 7/13 (53.8%) achieved an MRD-negative complete remission (CR) to CART but then developed detectable disease 2-36 months post CART. Five did not have a CR post-CART, 4 of whom enrolled on AALL1621 within one month; 1 received intervening chemotherapy. One had an unknown response. On univariate analysis CR rate with InO therapy was no different for those who received CART prior to InO than those who did not. As well, risk of a dose limiting toxicity event (DLT) or developing sinusoidal obstructive syndrome (SOS) during InO therapy or during subsequent transplant after InO was not different in patients with CART exposure prior to AALL1621 enrollment. Conclusion: The ability to collect and manufacture CART cells was feasible within weeks of receiving InO. Response to CART post InO was lower than retrospective cohorts (Ceolin, Leukemia 2022) but 3-year OS post CART was consistent with published CD19-targeted CART trials at 53.9% (Maude, NEJM 2018; Pasquini, Blood Adv 2020). InO did not appear to impact durability of remission in those who attained an MRD negative remission with CART. Given most patients had a CD19 target due to disease presence at the time of CART infusion, differential response to CART based upon antigen could not be analyzed. Prior InO exposure did not appear to worsen cytopenias post CART when compared to published CART trials and was associated with a comparable 3-year OS. As well, CART exposure prior to InO did not appear to effect response or increase the risk of DLT or SOS during subsequent InO therapy.

Distance to Care Predicts Clinical Trial Enrollment on COG ALL Clinical Trials: A Report from the Children's Oncology Group

Introduction: Equitable participation in clinical trials for all populations is essential to ensure the generalizability of clinical trial results. Historical data suggest that the majority of pediatric patients are enrolled on a trial when treated at a cooperative group institution and minoritized patients are proportionally represented. We proposed to evaluate clinical trial enrollment on Children's Oncology Group (COG) acute lymphoblastic leukemia (ALL) studies to determine if among those who participate in registry studies, there are disparities in participation in therapeutic clinical trials. We hypothesized that minoritized children, those living in disadvantaged neighborhoods, and those living distant from trial sites are less likely to enroll on therapeutic ALL studies. Methods: This study leverages the Childhood Cancer Research Network (CCRN), a childhood cancer case recruitment protocol that enrolled patients between 2008 and 2015. Within the CCRN registry cohort, we evaluated predictors of therapeutic and non-therapeutic clinical trial enrollment for patients with ALL. Patients &amp;gt;21 years at diagnosis and those without race or ethnicity reported were excluded. Enrollment on an upfront therapeutic trial (that overlapped with the timeframe during which the CCRN protocol was active) was defined as participation on one of the following 10 ALL trials: AALL0232, AALL0331, AALL0433, AALL0434, AALL0631, AALL0932, AALL1131, AALL1231, AALL1331, AALL1621. Enrollment on a non-therapeutic trial was defined as participation in any biology repository (including AALL03B1, AALL05B1, AALL08B1), supportive care, or late effects COG study. Potential predictors of interest included a composite of self-reported race and ethnicity, age at diagnosis, neighborhood socioeconomic status (SES) as measured by the Yost Index at the census tract, and distance to care (calculated as distance from home address to COG hospital). Poisson regression with log link and robust error variance was used to estimate adjusted risk ratios (aRR) and corresponding 95% confidence intervals (CI) for enrollment on a COG therapeutic clinical trial. Results: Of the 13,392 patients with ALL enrolled in the CCRN registry, 65% (n=8650) enrolled on a therapeutic COG clinical trial, 9% (1199) enrolled on a non-therapeutic trial without enrolling on a therapeutic trial, and 26% (3543) enrolled in the registry, but no other COG clinical trial. The majority of patient were between 1-9 years old and 58% were non-Hispanic (NH) White, 26% were Hispanic, and 7.2% were NH Black. Almost 11% of patients lived more than 100 miles from the COG center where they received treatment. Neither race nor ethnicity was associated with participation on a clinical trial (as shown in Table 1). Similarly, neighborhood SES was not associated with clinical trial participation. In multivariable models, age and distance to care were both meaningful predictors of therapeutic COG clinical trial enrollment with infants (aRR 0.64, 95%CI 0.57, 0.72) and adolescents (aRR 0.76, 95%CI 0.73, 0.80) less likely to enroll. Those that lived 100-250 miles from their COG center were 8% less likely to enroll (aRR 0.92, 95%CI 0.87, 0.97) and those that lived &amp;gt;250 miles from their COG center were 26% less likely to enroll (aRR 0.74, 95%CI 0.67, 0.81). Age was also a predictor of enrollment on non-therapeutic trials, but distance to care was not associated with enrollment on non-therapeutic trials. Conclusion: Among those who enroll on COG registry trials (which previous data suggests accounts for 55% of patients with ALL), race, ethnicity, and neighborhood SES are not associated with participation in therapeutic or non-therapeutic clinical trials. While age impacts risk stratification in ALL and thus may have impacted eligibility for various therapeutic trials, greater distance to care emerged as a relevant barrier to enrollment on therapeutic clinical trials. This novel finding in pediatric oncology suggests that interventions focused on ensuring access to clinical trials among those that live more than 100 miles from a COG site should be implemented. Approaches to address this disparity could include allowing study labs to be drawn locally and study visits to be conducted by telehealth when feasible.