Exposure-Response and Subgroup Analyses to Support Body Weight-Based Dosing of Brentuximab Vedotin in Children and Young Adults with Newly Diagnosed High-Risk Classical Hodgkin Lymphoma.

PURPOSE: To evaluate the relationships between brentuximab vedotin (BV) pharmacokinetics, age, and body weight (BW) with efficacy and safety in pediatric and young adult patients with previously untreated, high-risk classical Hodgkin lymphoma (cHL) in the phase 3 AHOD1331 study. PATIENTS AND METHODS: Overall, 296 patients (age 2-21 years) in the overall population were randomized to and received BV + chemotherapy; the pharmacokinetic subpopulation comprised 24 patients (age <13 years). Age- and/or BW-based (pharmacokinetic surrogates) subgroup analyses of efficacy and safety were conducted for the overall population. Exposure-response analyses were limited to the pharmacokinetic subpopulation. RESULTS: There were no visible trends in disease characteristics across pediatric age subgroups, while BW increased with age. Observed antibody-drug conjugate exposures in patients aged <12 years were lower than those in adults administered BV 1.8 mg/kg every 3 weeks (Q3W), as exposure increased with BW. Nevertheless, no detrimental impact on event-free survival (EFS) was seen in younger subgroups: 3-year EFS was 96.2% (2-<12-years) and 92.0% (12-<18-years), with no events observed in those aged <6 years. Neither early response nor lack of need for radiation therapy was associated with high pharmacokinetic exposure. No evidence of exposure-driven grade ≥2 or ≥3 peripheral neuropathy or grade ≥3 neutropenia was seen in exposure-safety and BW-based subgroup analyses; the incidence of these safety events was comparable across pediatric age subgroups, despite lower exposure in younger children. CONCLUSIONS: No further adjustments based on age or BW are required for the BV dose (1.8 mg/kg Q3W) approved in children.

Automatic Quantification of Serial PET/CT Images for Pediatric Hodgkin Lymphoma Patients Using a Longitudinally-Aware Segmentation Network.

Purpose: Automatic quantification of longitudinal changes in PET scans for lymphoma patients has proven challenging, as residual disease in interim-therapy scans is often subtle and difficult to detect. Our goal was to develop a longitudinally-aware segmentation network (LAS-Net) that can quantify serial PET/CT images for pediatric Hodgkin lymphoma patients. Materials and Methods: This retrospective study included baseline (PET1) and interim (PET2) PET/CT images from 297 patients enrolled in two Children's Oncology Group clinical trials (AHOD1331 and AHOD0831). LAS-Net incorporates longitudinal cross-attention, allowing relevant features from PET1 to inform the analysis of PET2. Model performance was evaluated using Dice coefficients for PET1 and detection F1 scores for PET2. Additionally, we extracted and compared quantitative PET metrics, including metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in PET1, as well as qPET and ΔSUVmax in PET2, against physician measurements. We quantified their agreement using Spearman's ρ correlations and employed bootstrap resampling for statistical analysis. Results: LAS-Net detected residual lymphoma in PET2 with an F1 score of 0.606 (precision/recall: 0.615/0.600), outperforming all comparator methods (P<0.01). For baseline segmentation, LAS-Net achieved a mean Dice score of 0.772. In PET quantification, LAS-Net's measurements of qPET, ΔSUVmax, MTV and TLG were strongly correlated with physician measurements, with Spearman's ρ of 0.78, 0.80, 0.93 and 0.96, respectively. The performance remained high, with a slight decrease, in an external testing cohort. Conclusion: LAS-Net achieved high performance in quantifying PET metrics across serial scans, highlighting the value of longitudinal awareness in evaluating multi-time-point imaging datasets.

Personalized Impression Generation for PET Reports Using Large Language Models.

Large language models (LLMs) have shown promise in accelerating radiology reporting by summarizing clinical findings into impressions. However, automatic impression generation for whole-body PET reports presents unique challenges and has received little attention. Our study aimed to evaluate whether LLMs can create clinically useful impressions for PET reporting. To this end, we fine-tuned twelve open-source language models on a corpus of 37,370 retrospective PET reports collected from our institution. All models were trained using the teacher-forcing algorithm, with the report findings and patient information as input and the original clinical impressions as reference. An extra input token encoded the reading physician's identity, allowing models to learn physician-specific reporting styles. To compare the performances of different models, we computed various automatic evaluation metrics and benchmarked them against physician preferences, ultimately selecting PEGASUS as the top LLM. To evaluate its clinical utility, three nuclear medicine physicians assessed the PEGASUS-generated impressions and original clinical impressions across 6 quality dimensions (3-point scales) and an overall utility score (5-point scale). Each physician reviewed 12 of their own reports and 12 reports from other physicians. When physicians assessed LLM impressions generated in their own style, 89% were considered clinically acceptable, with a mean utility score of 4.08/5. On average, physicians rated these personalized impressions as comparable in overall utility to the impressions dictated by other physicians (4.03, P = 0.41). In summary, our study demonstrated that personalized impressions generated by PEGASUS were clinically useful in most cases, highlighting its potential to expedite PET reporting by automatically drafting impressions.

Accelerating pediatric Hodgkin lymphoma research: the Hodgkin Lymphoma Data Collaboration (NODAL).

Data commons have proven to be an indispensable avenue for advancing pediatric cancer research by serving as unified information technology platforms that, when coupled with data standards, facilitate data sharing. The Pediatric Cancer Data Commons, the flagship project of Data for the Common Good (D4CG), collaborates with disease-based consortia to facilitate development of clinical data standards, harmonization and pooling of clinical data from disparate sources, establishment of governance structure, and sharing of clinical data. In the interest of international collaboration, researchers developed the Hodgkin Lymphoma Data Collaboration and forged a relationship with the Pediatric Cancer Data Commons to establish a data commons for pediatric Hodgkin lymphoma. Herein, we describe the progress made in the formation of Hodgkin Lymphoma Data Collaboration and foundational goals to advance pediatric Hodgkin lymphoma research.

Late Cardiac Toxic Effects Associated With Treatment Protocols for Hodgkin Lymphoma in Children.

Importance: Contemporary North American trials for children with Hodgkin lymphoma (HL) have decreased radiation therapy (RT) use and increased pharmacologic cardioprotection but also increased the cumulative doxorubicin dose, making overall treatment consequences for late cardiac toxic effects uncertain. Objective: To estimate the risk of cardiac toxic effects associated with treatments used in modern pediatric HL clinical trials. Design, Setting, and Participants: For this cohort study, Fine and Gray models were fitted using survivors in the Childhood Cancer Survivor Study who were diagnosed with HL between January 1, 1970, and December 31, 1999, and were followed for a median of 23.5 (range, 5.0-46.3) years. These models were applied to the exposures in the study population to estimate the 30-year cumulative incidence of cardiac disease. The study population comprised patients with intermediate-risk or high-risk HL treated in 4 consecutive Children's Oncology Group clinical trials from September 2002 to October 2022: AHOD0031, AHOD0831, AHOD1331, and S1826. Data analysis was performed from April 2020 to February 2023. Exposures: All patients received chemotherapy including doxorubicin, and some patients received mediastinal RT, dexrazoxane, or mediastinal RT and dexrazoxane. Main Outcomes and Measures: Estimated 30-year cumulative incidence of grade 3 to 5 cardiac disease. Results: The study cohort comprised 2563 patients, with a median age at diagnosis of 15 (range, 1-22) years. More than half of the patients were male (1357 [52.9%]). All 2563 patients received doxorubicin, 1362 patients (53.1%) received mediastinal RT, and 307 patients (12.0%) received dexrazoxane. Radiation therapy use and the median mean heart dose among patients receiving RT decreased, whereas the planned cumulative dose of doxorubicin and use of dexrazoxane cardioprotection increased. For patients treated at age 15 years, the estimated 30-year cumulative incidence of severe or fatal cardiac disease was 9.6% (95% CI, 4.2%-16.4%) in the AHOD0031 standard treatment group (enrolled 2002-2009), 8.6% (95% CI, 3.8%-14.9%) in the AHOD0831 trial (enrolled 2009-2012), 8.2% (95% CI, 3.6%-14.3%) in the AHOD1331 trial (enrolled 2015-2019), and 6.2% (95% CI, 2.7%-10.9%) in the S1826 trial (enrolled 2019-2022), whereas the expected rate in an untreated population was 5.0% (95% CI, 2.1%-9.3%). Despite the estimated reduction in late cardiac morbidity, the frequency of recommended echocardiographic screening among survivors will increase based on current guidelines. Conclusions and Relevance: In this cohort study of sequential HL trials, reductions in the proportion of children receiving mediastinal RT and increases in dexrazoxane use were estimated to offset the increased doxorubicin dose and produce a net reduction in late cardiac disease. Further studies on dexrazoxane are warranted to confirm whether its role in reducing cardiac toxic effects is maintained long term. These findings suggest that survivorship follow-up guidelines should be refined to align with the risks associated with treatment.

Classic Hodgkin Lymphoma in Adolescents and Young Adults.

Hodgkin lymphoma (HL) represents one of the more common cancers occurring in adolescent and young adults (AYAs) age 15-39 years. Despite a generally high cure rate, age-related differences in HL biology and the optimal therapeutic approaches including supportive care and risks for long-term adverse effects in the AYA population remain understudied. After an overview of HL epidemiology and biology in the AYA population, this review will cover frontline pediatric and adult treatment approaches. Recently completed and ongoing studies will foster harmonization of risk group definition and trial eligibility criteria across the AYA spectrum, enabling more rapid progress. In addition to treatment approaches, an evolving holistic care approach to AYA HL will result in enhanced understanding of unique challenges, and continued improved short- and long-term outcome for these patients.

Performance of the FACT-GOG-Ntx to assess chemotherapy-induced peripheral neuropathy (CIPN) in pediatric high risk Hodgkin lymphoma: report from the Children's Oncology Group AHOD 1331 study.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is an under-recognized complication of several chemotherapy agents used as part of curative-intent therapy for Hodgkin Lymphoma (HL). In the absence of validated self- or proxy-report measures for children and adolescents, CIPN reporting has relied on clinician rating, with grading scales often restricted to severe manifestations. In a proof-of-concept study, we assessed the feasibility and psychometric performance of the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-Ntx), a unidimensional CIPN symptom scale widely used adults with CIPN, in pediatric HL at risk for CIPN. METHODS: Youth (11+ years) and parents of all children (5-17.9 years) with newly diagnosed high-risk HL enrolled on Children's Oncology Group AHOD1331 (NCT02166463) were invited to complete the FACT-GOG-Ntx and a health-related quality of life (HRQL) measure at pre-treatment (Time 1), and during cycles 2 (Time 2) and 5 (Time 3) of chemotherapy during the first half of study accrual. Clinical grading of CIPN by providers was also assessed using the Balis Pediatric Neuropathy Scale. We evaluated Cronbach's alpha, construct validity, and agreement between raters. Change in FACT-GOG-Ntx scores over time was assessed using a repeated measures model. RESULTS: 306 patients had at least one completed FACT-GOG-Ntx with time-specific completion rates of > 90% for both raters. Cronbach's alpha was > 0.7 for youth and parent-proxy report at all time points. Correlations between FACT-GOG-Ntx and HRQL scores were moderate (0.41-0.48) for youth and parent-proxy raters across all times. Youth and parent-proxy raters both reported worse FACT-GOG-Ntx scores at Time 3 for those who had clinically-reported CIPN compared to those who did not. Agreement between raters was moderate to high. Compared to baseline scores, those at Time 3 were significantly lower for youth (ß = - 2.83, p < 0.001) and parent-proxy raters (ß = - 1.99, p < 0.001). CONCLUSIONS: High completion rates at all time points indicated feasibility of eliciting youth and parent report. Psychometric performance of the FACT-GOG-Ntx revealed acceptable reliability, evidence of validity, and strong inter-rater agreement, supporting the use of this self- or proxy-reported measure of CIPN in youth with high-risk HL exposed to tubulin inhibitors, as part of a Phase 3 clinical trial. CLINICAL TRIAL INFORMATION: Clinical Trials Registry, NCT02166463. Registered 18 June 2014, https://clinicaltrials.gov/ct2/show/study/NCT02166463.

Automatic Personalized Impression Generation for PET Reports Using Large Language Models.

Purpose: To determine if fine-tuned large language models (LLMs) can generate accurate, personalized impressions for whole-body PET reports. Materials and Methods: Twelve language models were trained on a corpus of PET reports using the teacher-forcing algorithm, with the report findings as input and the clinical impressions as reference. An extra input token encodes the reading physician's identity, allowing models to learn physician-specific reporting styles. Our corpus comprised 37,370 retrospective PET reports collected from our institution between 2010 and 2022. To identify the best LLM, 30 evaluation metrics were benchmarked against quality scores from two nuclear medicine (NM) physicians, with the most aligned metrics selecting the model for expert evaluation. In a subset of data, model-generated impressions and original clinical impressions were assessed by three NM physicians according to 6 quality dimensions (3-point scale) and an overall utility score (5-point scale). Each physician reviewed 12 of their own reports and 12 reports from other physicians. Bootstrap resampling was used for statistical analysis. Results: Of all evaluation metrics, domain-adapted BARTScore and PEGASUSScore showed the highest Spearman's ρ correlations (ρ=0.568 and 0.563) with physician preferences. Based on these metrics, the fine-tuned PEGASUS model was selected as the top LLM. When physicians reviewed PEGASUS-generated impressions in their own style, 89% were considered clinically acceptable, with a mean utility score of 4.08 out of 5. Physicians rated these personalized impressions as comparable in overall utility to the impressions dictated by other physicians (4.03, P=0.41). Conclusion: Personalized impressions generated by PEGASUS were clinically useful, highlighting its potential to expedite PET reporting.

Impairment of health-related quality of life for children with acute lymphoblastic leukemia over the first year of therapy: A report from the DFCI ALL Consortium.

BACKGROUND: Children treated for acute lymphoblastic leukemia (ALL) receive prolonged treatment, resulting in toxicities that affect health-related quality of life (HR-QoL). Longitudinal assessment of HR-QoL allows improved understanding of experiences with ALL. PROCEDURE: Parent-proxy and child self-report HR-QoL over the first year of chemotherapy were evaluated in the context of DFCI Protocol 05-001, a phase 3 therapeutic trial for childhood ALL. HR-QoL was assessed with the Pediatric Quality-of-Life inventory (PedsQL) domains for Pain and Hurt, Procedural Anxiety, Treatment Anxiety, Emotional Functioning, General Fatigue, and Sleep/Rest Fatigue. RESULTS: Total of 281 subjects participated, with 141 contributing at least one child report and 280 at least one parent report. Children with ALL experienced impairment in HR-QoL by both patient and parent report compared to the published PedsQL reference population at each time point on each subscale. Agreement between parent and child assessment of HR-QoL impairment was high, particularly among those for whom HR-QoL was not impaired. During the consolidation phase, which included intensive asparaginase administration, multivariable models demonstrated more impairment in Treatment Anxiety and Procedural Anxiety for children treated with intramuscular asparaginase than intravenous asparaginase, but randomized groups were otherwise similar in HR-QoL. Impairments in fatigue, both General and Sleep/Rest, were evident throughout and worse during intensive asparaginase therapy. CONCLUSIONS: This report examines HR-QoL for children with ALL during treatment longitudinally by parent and patient report across multiple domains. Children with ALL demonstrated substantial impairment in HR-QoL, particularly related to fatigue during intensive consolidation therapy including asparaginase.

Significance of E-lesions in Hodgkin lymphoma and the creation of a new consensus definition: a report from SEARCH.

The International Staging Evaluation and Response Criteria Harmonization for Childhood, Adolescent, and Young Adult Hodgkin Lymphoma (SEARCH for CAYAHL) seeks to provide an appropriate, universal differentiation between E-lesions and stage IV extranodal disease in Hodgkin lymphoma (HL). A literature search was performed through the PubMed and Google Scholar databases using the terms "Hodgkin disease," and "extranodal," "extralymphatic," "E lesions," "E stage," or "E disease." Publications were reviewed for the number of participants; median age and age range; diagnostic modalities used for staging; and the definition, incidence, and prognostic significance of E-lesions. Thirty-six articles describing 12 640 patients met the inclusion criteria. Most articles reported staging per the Ann Arbor (72%, 26/36) or Cotswolds modification of the Ann Arbor staging criteria (25%, 9/36), and articles rarely defined E-lesions or disambiguated "extranodal disease." The overall incidence of E-lesions for patients with stage I-III HL was 11.5% (1330/11 602 unique patients). Available stage-specific incidence analysis of 3888 patients showed a similar incidence of E-lesions in stage II (21.2%) and stage III (21.9%), with E-lesions rarely seen with stage I disease (1.1%). E-lesions likely remain predictive, but we cannot unequivocally conclude that identifying E-lesions in HL imparts prognostic value in the modern era of the more selective use of targeted radiation therapy. A harmonized E-lesion definition was reached based on the available evidence and the consensus of the SEARCH working group. We recommend that this definition of E-lesion be applied in future clinical trials with explicit reporting to confirm the prognostic value of E-lesions.

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.

Prognostic value of chest x-ray- and CT-defined large mediastinal adenopathy in high-risk pediatric Hodgkin lymphoma: A report from the Children's Oncology Group Study AHOD0831.

PURPOSE/OBJECTIVE: We compared the prognostic value of chest radiograph (CXR)- and computed tomography (CT)-derived definition of large mediastinal adenopathy (LMA) in pediatric Hodgkin lymphoma (HL). MATERIALS/METHODS: Total 143 patients treated for stage IIIB/IVB HL on COG AHOD0831 were included in this study. Six definitions of LMA were investigated: (i) mediastinal mass ratio on CXR (MRCXR ) > 1/3; (ii) mediastinal mass ratio on CT (MRCT ) > 1/3; (iii) mediastinal mass volume on CT (MVCT ) > 200 mL; (iv) normalized mediastinal mass volume (MVCT /thoracic diameter [TD]) > 1 mL/mm; (v) mediastinal mass diameter on CT (MDCT ) > 10 cm; and (vi) normalized mediastinal mass diameter (MDCT /TD) > 1/3. RESULTS: Median age at diagnosis was 15.8 years (range: 5.2-21.3 years). In patients with a slow early response (SER) to chemotherapy, MVCT  > 200 mL, MDCT  > 10 cm, and MDCT /TD > 1/3 were associated with worse relapse-free survival (RFS) on MVA, while MRCXR  > 1/3, MRCT  > 1/3, and MVCT /TD > 1 mL/mm trended toward worse RFS; MDCT /TD was the most strongly prognostic for inferior RFS, with a hazard ratio of 6.41 for MDCT /TD > 1/3 versus ≤1/3 on MVA (p = .02). CONCLUSION: LMA according to MVCT  > 200 mL, MDCT  > 10 cm, and MDCT /TD > 1/3 is associated with poor prognosis in advanced-stage HL patients with SER. The normalized mediastinal diameter, MDCT /TD > 1/3 appears to be the strongest predictor of inferior RFS.

An institutional review of genomic sequencing in pediatric solid tumors.

BACKGROUND: Although tumor genomic profiling has aided the advancement of targeted genetic therapy, its clinical integration remains a challenge in pediatric cancers due to lower mutation frequency and less available targeted drugs. There have been multiple novel studies examining molecular sequencing in pediatrics; however, many of these studies primarily utilized large-scale, genome-wide screening applications that limit applicable use due to the availability of testing. This study examined the institutional use of a targeted, clinically available approach to tumor genomic sequencing. METHODS: A retrospective chart review was performed on pediatric patients with solid tumors who were managed at Roswell Park Comprehensive Cancer Center and underwent molecular testing of their tumor biopsy via OmniSeq from August 2016 to July 2021. Results were reviewed for mutations considered to be "actionable" by targeted therapy. Patients with actionable mutations were further examined to evaluate treatment course, receival of targeted therapy, and clinical outcomes. RESULTS: We identified 64 pediatric patients consisting of 20 (31%) with CNS tumors and 44 (69%) with non-CNS tumors, ranging in age from 9 months to 21 years. Thirty-five total actionable mutations were identified amongst 27 patients (42%). Of these 27, 12 patients (44%) received at least 1 targeted drug against a respective actionable mutation, of which 6 patients (50%) achieved clinical benefit to therapy, including 1 complete response. CONCLUSIONS: The use of a clinically focused and readily available targeted molecular sequencing panel identified actionable mutations at a comparable rate to the large-scale, less readily available sequencing panels utilized in other studies. Half of our patients who received targeted therapy achieved a complete response or clinical benefit from therapy. Although targeted therapy has a role in pediatric cancer treatment, many newer drugs require further research on their safety and efficacy.

Symptom management care pathway adaptation process and specific adaptation decisions.

BACKGROUND: There is substantial heterogeneity in symptom management provided to pediatric patients with cancer. The primary objective was to describe the adaptation process and specific adaptation decisions related to symptom management care pathways based on clinical practice guidelines. The secondary objective evaluated if institutional factors were associated with adaptation decisions. METHODS: Fourteen previously developed symptom management care pathway templates were reviewed by an institutional adaptation team composed of two clinicians at each of 10 institutions. They worked through each statement for all care pathway templates sequentially. The institutional adaptation team made the decision to adopt, adapt or reject each statement, resulting in institution-specific symptom management care pathway drafts. Institutional adaption teams distributed the 14 care pathway drafts to their respective teams; their feedback led to care pathway modifications. RESULTS: Initial care pathway adaptation decision making was completed over a median of 4.2 (interquartile range 2.0-5.3) weeks per institution. Across all institutions and among 1350 statements, 551 (40.8%) were adopted, 657 (48.7%) were adapted, 86 (6.4%) were rejected and 56 (4.1%) were no longer applicable because of a previous decision. Most commonly, the reason for rejection was not agreeing with the statement (70/86, 81.4%). Institutional-level factors were not significantly associated with statement rejection. CONCLUSIONS: Acceptability of the 14 care pathways was evident by most statements being adopted or adapted. The adaptation process was accomplished over a relatively short timeframe. Future work should focus on evaluation of care pathway compliance and determination of the impact of care pathway-consistent care on patient outcomes. TRIAL REGISTRATION: clinicaltrials.gov, NCT04614662. Registered 04/11/2020, https://clinicaltrials.gov/ct2/show/NCT04614662?term=NCT04614662&draw=2&rank=1 .

Importance of Central Imaging Review in a Pediatric Hodgkin Lymphoma Trial Using Positron Emission Tomography Response Adapted Radiation Therapy.

PURPOSE: We investigated the effects of central review of the interim fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan response (iPET) assessment on treatment allocation in the risk-based, response-adapted, Children's Oncology Group study AHOD1331 (ClinicalTrials.gov identifier: NCT02166463) for pediatric patients with high-risk Hodgkin lymphoma. METHODS AND MATERIALS: Per protocol, after 2 cycles of systemic therapy, patients underwent iPET, with visual response assessment by 5-point Deauville score (DS) at their treating institution and a real-time central review, with the latter considered the reference standard. An area of disease with a DS of 1 to 3 was considered a rapid-responding lesion, whereas a DS of 4 to 5 was considered a slow-responding lesion (SRL). Patients with 1 or more SRLs were considered iPET positive, whereas patients with only rapid-responding lesions were considered iPET negative. We conducted a predefined exploratory evaluation of concordance in iPET response assessment between institutional and central reviews of 573 patients. The concordance rate was evaluated using the Cohen κ statistic (κ > 0.80 was considered very good agreement and κ > 0.60-0.80, good agreement). RESULTS: The concordance rate (514 of 573 [89.7%]) had a κ of 0.685 (95% CI, 0.610-0.759), consistent with good agreement. In terms of the direction of discordance, among the 126 patients who were considered iPET positive by institutional review, 38 (30.2%) were categorized as iPET negative by central review, preventing overtreatment with radiation therapy. Conversely, among the 447 patients who were considered iPET negative by institutional review, 21 patients (4.7%) were categorized as iPET positive by the central review and would have been undertreated without radiation therapy. CONCLUSIONS: Central review is integral to PET response-adapted clinical trials for children with Hodgkin lymphoma. Continued support of central imaging review and education about DS are needed.

Baseline metabolic tumour burden improves risk stratification in Hodgkin lymphoma: A Children's Oncology Group study.

The Children's Oncology Group AHOD0831 study used a positron emission tomography (PET) response-adapted approach in high-risk Hodgkin lymphoma, whereby slow early responders (SERs) received more intensive therapy than rapid early responders (RERs). We explored if baseline PET-based characteristics would improve risk stratification. Of 166 patients enrolled in the COG AHOD0831 study, 94 (57%) had baseline PET scans evaluable for quantitative analysis. For these patients, total body metabolic tumour volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake value (SUVmax ) and peak SUV (SUVpeak ) were obtained. MTV/TLG thresholds were an SUV of 2.5 (MTV2.5 /TLG2.5 ) and 40% of the tumour SUVmax (MTV40% /TLG40% ). TLG2.5 was associated with event-free survival (EFS) in the complete cohort (p = 0.04) and in RERs (p = 0.01), but not in SERs (p = 0.8). The Youden index cut-off for TLG2.5 was 1841. Four-year EFS was 92% for RER/TLG2.5  up to 1841, 60% for RER/TLG2.5  greater than 1841, 74% for SER/TLG2.5  up to 1841 and 79% for SER/TLG2.5  greater than 1841. Second EFS for RER/TLG2.5  up to 1841 was 100%. Thus, RERs with a low baseline TLG2.5 experienced excellent EFS with less intensive therapy, whereas RERs with a high baseline TLG2.5 experienced poor EFS. These findings suggest that patients with a high upfront tumour burden may benefit from intensified therapy, even if they achieve a RER.