Pediatric Hodgkin Lymphoma Research Articles

Radiotherapy Utilization and Outcomes on a Contemporary Trial for Pediatric High-Risk Hodgkin Lymphoma Study

Contemporary trials in pediatric Hodgkin lymphoma (cHL) evaluate strategies to reduce radiotherapy (RT) utilization while maintaining excellent progression-free survival (PFS). An alternative strategy is to irradiate selective sites at higher risk of relapse, and/or use proton therapy (PT) to minimize exposure to healthy tissue. We investigated the use of PT and photon therapy (XRT) and associated early outcomes among patients receiving involved site RT (ISRT) to high-risk sites on the Children's Oncology Group (COG) trial AHOD1331 (NCT021664643). This multicenter randomized, open-label phase 3 study enrolled patients 2-21 years (yrs) with previously untreated cHL: stages IIB + bulk, IIIB, IVA, IVB. Patients were randomized to 5 cycles of either ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide) or the brentuximab vedotin (BV) containing regimen BV-AVE-PC given every 21 days. ISRT to 21 Gy was given to bulky mediastinal adenopathy and slow responding lesions (SRL) defined by 5-point score 4 or 5 on PET-CT after 2 cycles. ISRT could be delivered as 3D conformal XRT (3D), intensity modulated XRT (IMRT), or proton therapy (PT). Utilization of RT was compared by mode and by study enrollment midpoint among irradiated patients. Severe acute toxicity assessment included any incident grade 3 or higher toxicity during the ISRT period, except for neuropathy. Among 587 eligible patients who were enrolled across 153 institutions between March 2015 and August 2019 with a median follow up of 43.1 months, the 3-yr PFS was 82.5% (90% CI, 78.3%-85.9%) with ABVE-PC and 92.5% (90% CI 89.5%-94.6%) with BV-AVE-PC (p = 0.0002). There was no difference in ISRT receipt or modality by study arm (p = 0.33). Among those who received RT 69.7% received it due to bulky mediastinal adenopathy, 6.6% due to SRL, and 23.7% for both. Overall, 317 (54.0%) patients received protocol RT of which 28.7% received 3D, 44.8% received IMRT, and 26.5% received PT. PT utilization increased over the course of the study from 21.5% among the first 50% of irradiated patients to 31.5% in the second half of irradiated patients (p = 0.045). The 3-yr progression-free survival rates overall by RT were comparable: PT (88.0%, 90% CI 80.6% - 92.7%%); XRT (87.1%, 90% CI 82.9%-90.4%) (p = 0.85). No difference in PFS was observed between 3D versus IMRT (p = 0.65). No differences were observed in severe acute toxicities (8.33% vs. 8.15%, p = 0.96) between PT and XRT. Selective use of RT results in excellent outcomes for pediatric patients with high-risk HL and combination chemotherapy inclusive of the novel agent BV. Over the course of the study, PT utilization increased as an RT modality. Early results suggest that PT does not compromise disease control and has similar acute toxicity as XRT. Long term follow-up (>10 years) is needed to evaluate for secondary malignancies and cardiac toxicity among the different RT modalities.

Response-Adapted Omission of Radiotherapy in Pediatric Patients with Intermediate- and High-Risk Hodgkin Lymphoma Treated per EuroNet-PHL-C1: A Single Institution Analysis of Outcomes and Patterns of Failure

EuroNet-PHL-C1 demonstrated that 40% of intermediate- and high-risk pediatric Hodgkin lymphoma (HL) patients treated with OEPA-COPDAC chemotherapy achieved adequate response (AR) at early response assessment (ERA), and thus were able to omit radiotherapy (RT). However, patterns of failure with this treatment paradigm, and specifically, whether or not all initial sites of disease require RT for those with inadequate response (IR) at ERA is unknown. The purpose of our study is to examine outcomes and patterns of failure for those treated per EuroNet-PHL-C1 at our institution. Our hypothesis is that limiting RT to only sites of IR at ERA does not result in increased failures. An IRB-approved retrospective review of all intermediate- and high-risk classical HL pediatric patients treated at our institution per EuroNet-PHL-C1 between 2015 and 2021 was performed. Patients were treated per protocol with radiation omitted for those with AR (Deauville 1-2 and >75% tumor shrinkage) at ERA (PET/CDT after 2 cycles of chemo). For those with IR who required RT, only sites of IR (Deauville 3-5) at ERA were treated using involved site radiation treatment (ISRT), instead of all initial sites of disease as on EuroNet-PHL-C1. Outcomes including overall survival (OS) and progression free survival (PFS) were calculated using Kaplan-Meier curves and patterns of failure were classified as either initial site only, new site only, or initial and new sites. A total of 35 patients were identified, of which 33 had evaluable follow up with median follow up of 33 months. The median age at diagnosis was 14 (range, 4-18) and 48% were female. Of the 33, 7 (21%) had IR at ERA and thus required RT, while 26 (79%) were spared RT. In the group who received RT, 4/7 (57%) had initial B-symptoms and 4/7 (57%) had initial bulky disease, compared to 9/26 (35%) and 20/26 (77%), respectively, in those who did not receive RT. For our entire cohort, 2-year PFS and OS were 91% and 100%, respectively. For those who had RT, 2-year PFS was 83% compared to 92% in those who did not need RT. There was a total of 3 relapses (9%) at last follow up with 1/7 (14%) in those who had RT vs. 2/26 (8%) in those without RT. For the patient who relapsed after RT, relapse occurred both at initial and new sites. For the 2 who relapsed who did not receive RT, 1 was both in initial and new sites, while the other was initial site only. At our institution, the majority of patients treated per EuroNet-PHL-C1 avoided RT with excellent outcomes. For those requiring RT, limiting RT to only sites of IR at ERA does not appear to adversely affect outcomes, though analysis is limited by the low number of failures.

Diagnostic Accuracy of 18F-FDG PET - CT Imaging in determining the bone marrow involvement (BMI) in pediatric Hodgkin's Lymphoma (HL).

To determine diagnostic accuracy of 18F-FDG PET - CT imaging in determining Bone marrow involvement in pediatric HL by taking bone marrow biopsy as standard. This descriptive cross-sectional study was conducted in the Department of Pediatric Hematology/Oncology, Indus Hospital and Health Network, Karachi from July 2021 to December 2022. Treatment naïve histologically proven pediatric HL patients of both gender and aged between two to 16 years with both 18F-FDG PET - CT and bone marrow biopsy imaging were included. Basic demographics such as age, gender, height, weight, as well as classification and staging of HL was obtained. Results were assessed by expert reviewers who were blinded to clinical outcome. Sensitivity, specificity, positive and negative predictive value, and diagnostic precision were assessed. The data was analyzed via SPSS 26.0. Total 131 participants were included with a male predominance i.e. 104 (79.6%). The mean (±SD) age was 8.7 ± 3.4 years. The present study reported PET/CT to have a sensitivity, specificity diagnostic accuracy, PPV and NPV of 94.1%, 92%, 92%, 64% and 99% respectively. Our findings support the idea that BMB should not be routinely conducted in all patients but rather can be reserved exclusively for patients with dubious 18F-FDG bone marrow findings, as this test has strong diagnostic potential for evaluating BMI involvement in HL.

The clinical utility of PET/CT scan and tissue biopsy in the management and follow-up of paediatric Hodgkin lymphoma in South Africa

The clinical utility of PET/CT scan and tissue biopsy in the management and follow-up of paediatric Hodgkin lymphoma in South Africa

HL-326 Disseminated Pediatric Hodgkin Lymphoma (HL): Concentric Study Within the Hematology Department at Ibn Rochd University Hospital

HL-326 Disseminated Pediatric Hodgkin Lymphoma (HL): Concentric Study Within the Hematology Department at Ibn Rochd University Hospital

HL-291 Pediatric Hodgkin Lymphoma: Experience of Hematology Department in Casablanca

HL-291 Pediatric Hodgkin Lymphoma: Experience of Hematology Department in Casablanca

Variant histology of pediatric nodular lymphocyte-predominant Hodgkin lymphoma with IgD and CD30 expression.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), recently known as nodular lymphocyte-predominant B-cell lymphoma (NLPBL), accounts for 5%-10% of Hodgkin lymphoma (HL). Different morphologic patterns of NLPBL are identified and categorized as typical patterns (type A and B) and variant histologic patterns (types C, D, E, and F). We investigated different morphologic patterns, CD30 and IgD expression in pediatric patients with NLPBL diagnosed at the Children's Cancer Hospital Egypt. Forty-six (53%) of the patients exhibited a typical histologic pattern, whereas the remaining (47%) exhibited variant histologic pattern. Variant histology is associated with unfavorable clinical characteristics, such as advanced stages, B-symptoms, and extranodal involvements, particularly bone marrow and bone infiltration, with p-values of .06, .05, and 0.01%, respectively. Additionally, 39% of patients with variant histology experienced disease progression or relapse, compared to only 15.2% of patients with typical patterns (p=.009). Types C and D are related to decreased event-free survival (EFS), as shown by a p-value of .05. The 5-year EFS for patients with variant histology was 94.4% for the rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone (RCHOP) versus 33.3% for the adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). IgD expression in lymphocyte-predominant (LP) cells was detected in 44 (50%) patients, while CD30 expression in LP cells was found in 39 (44%) patients. Variant histology of NLPBL was associated with advanced disease stages and a poor prognosis, while expression of IgD and CD30 in LP cells was not. The poor outcome of variant histology improved with the RCHOP regimen.

Digital pathology in pediatric nodular lymphocyte-predominant Hodgkin lymphoma: correlation with treatment response

Early-stage pediatric nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can be treated effectively with low-intensity chemotherapy, most frequently cyclophosphamide in combination with vinblastine and prednisone (CVP). Descriptive histological risk factors based on the disease-defining lymphocyte predominant cells (LP cells) as used within the Fan classification, are less predictive in early-stage patients. We used deep learning-based cell detection and spatial analysis on digitized biopsy slides from 53 early-stage pediatric NLPHL patients to quantitatively assess LP cell histomorphometry. We found that poor responding patients had significantly fewer LP cells per cluster and lower LP cell density than good responding patients. In our exploratory analysis, we found no correlation between Fan classes or B cell pattern variables and therapy response. We hypothesize that the relationship between poor treatment response and decreased LP cell density may be explained by differences in LP cell proliferation.

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.

Pediatric Hodgkin's lymphoma presenting with nephrotic syndrome: a case report

Hodgkin's lymphoma (HL) is a common type of lymphoma in children and adolescents, and it typically presents with lymphadenopathy, fever, and weight loss. Nephrotic syndrome is a rare but reported complication of HL, and it is associated with a poor prognosis. We report a case of a 12-year-old boy who presented with nephrotic syndrome as the initial manifestation of HL. The diagnosis was confirmed by a biopsy of the lymph node, which showed the characteristic Reed-Sternberg cells. The patient was treated with chemotherapy and he achieved complete remission of both HL and nephrotic syndrome. This report aims to raise awareness of the potential association between HL and nephrotic syndrome in pediatric patients, which can aid in early detection and prompt management.

Outcome and toxicity of ifosfamide, carboplatin, and etoposide versus gemcitabine and vinorelbine regimen for pediatric patients with relapsed or refractory Hodgkin's lymphoma.

Pediatric classical Hodgkin lymphoma (CHL) is a curable disease; however, the optimal salvage regimen is unclear for relapsed/refractory (R/R) disease. This study aimed to compare response rates, toxicity, event-free survival (EFS), and overall survival (OS) of ifosfamide, carboplatin, and etoposide (ICE) with gemcitabine and vinorelbine (GV) regimen after first-line doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) in pediatric patients with R/R CHL. This is a retrospective cohort study of 132 pediatric patients with R/R CHL treated from July 2012 to December 2020 with ICE (n = 82) or GV (n = 50). The median age at relapse was 13.9 years, and 68.2% were men. Rates of complete response, partial response, and progressive disease before consolidation were 50.6%, 3.7%, and 45.7% for ICE and 28.5%, 0%, and 71.5% for GV (P = 0.011). By multivariate analysis, regimen (P = 0.002), time to relapse (P = 0.0001), and B-symptoms (P = 0.002) were independent factors to lower response rates. Hematological toxicity, electrolyte disturbance, hemorrhagic cystitis, infectious complications, and hospital admission for fever neutropenia were statistically significant higher for the ICE regimen. Treatment-related mortalities were 2.4% for ICE and 2% for GV (P = 0.86). The 3-year EFS was 39.3% ± 11.4% for ICE and 24.9% ± 12.5% for GV (P = 0.0001), while 3-year OS was 69.3% ± 10.6% and 74% ± 12.9% (P = 0.3), respectively. By multivariate analysis, regimen (P = 0.0001), time to relapse (P = 0.011), B-symptoms (P = 0.001), and leukocytosis (P = 0.007) were significant for EFS, while anemia (P = 0.008), and progressive disease on early response evaluation (P = 0.022) were significant for OS. The ICE regimen had a better overall response rate and EFS, but higher toxicity, than GV; however, OS and mortality were similar.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Staging of lung lesions in pediatric Hodgkin lymphoma (HL) is a long standing, controversial issue. Consortium groups define lung involvement and its distinction from E-lesions differently. Application of these criteria to individual patients are technically challenging and require expertise. The SEARCH group, working to create harmonization across consortia for the staging of pediatric HL, has completed this task for lung lesions. Methods: A survey of 7 case vignettes was distributed to 26 world experts in pediatric HL, replicating the previously published survey by Connors et al in 1984. Experts were asked to stage each case as lung involvement, or an E-lesion. Similar to Connors findings, our results demonstrated that experts were greatly divided on several cases, indicating ongoing differences in interpretation. Accordingly, the SEARCH group performed a harmonization initiative for the contemporary staging criteria for lung lesions. Representatives from each major consortium group (Pediatric Hodgkin Consortium, EuroNet PHL, Children’s Oncology Group) provided their current definitions for lung involvement, and rationale for staging decisions for the lung cases presented. Based on these discussions, a Delphi survey was drafted containing 12 statements pertaining to the staging criteria for lung lesions and distributed electronically to members of the SEARCH committee representing each consortium. Consensus was defined as a score of 3.75 or greater on a 5-point Likert scale (strongly disagree [1] to strongly agree [5]). Delphi rounds continued until consensus was achieved for all statements, or until a decision was made to remove a statement. Responses were collected anonymously and scores were pooled and reviewed after each round. Extreme scores and all comments were reviewed on committee calls before proceeding to the next round. Results: 21 experts responded to the first Delphi round, including pediatric oncologists, nuclear medicine radiologists, and radiation oncologists. 8 of 12 statements met consensus in Round 1. Several statements were edited to improve clarity and 1 statement was added. A second Delphi round was completed with 20 responses. All statements met consensus with the exception of one which was ultimately removed for group consensus that further investigation was required. Final consensus statements are available in Figure 1. Keywords: Hodgkin lymphoma, non-Hodgkin (pediatric, adolescent, and young adult) No conflicts of interests pertinent to the abstract.

Adherence to surveillance guidelines in survivors of hodgkin lymphoma: A report from the Childhood Cancer Survivor Study (CCSS).

10047 Background: Pediatric Hodgkin lymphoma (HL) is a highly curable disease. However, survivors are at high risk for long-term complications of therapy. The impact of sociodemographic and clinical factors on adherence to late effects surveillance guidelines is unknown. Methods: The CCSS is a retrospective cohort with prospective follow-up of survivors diagnosed from 1970-1999. HL survivors enrolled in CCSS who responded to a 2017 questionnaire were included. We assessed adherence to the Children’s Oncology Group surveillance guidelines for cardiomyopathy, breast cancer, colorectal cancer, and skin cancer. Multivariate logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals (aOR [95% CI]) for sociodemographic and clinical risk factors associated with adherence. Estimates were adjusted for area deprivation index (ADI); chronic health conditions; recent (≤2 years) routine check-up, cancer center or survivorship clinic visit; and possession of a survivorship care plan (SCP). Results: 1,380 HL survivors (45.6% male; median age 43.6 years, range 21.6-65.9 years) responded, of whom 55.5% were at elevated risk for cardiac dysfunction, 71.0% for breast cancer, 83.5% for skin cancer, and 39.4% for colorectal cancer. Of those at elevated risk, 42.7%, 19.9%, 31.3% and 48.9% were adherent to the guidelines for cardiac, breast, skin, and colorectal screening, respectively. Predictors of adherence to cardiac dysfunction guidelines were male sex (aOR 1.7 [1.1-2.6]), having children (aOR 1.6 [1.1-2.4]), recent routine checkup (aOR 4.0 [1.3-13.1]), recent visit to a cancer center or survivorship clinic (aOR 6.2 [3.9-10.0]), and possession of a SCP (aOR 3.1 [1.9-5.0]). Adherence to breast cancer guidelines was higher in those who were unmarried (aOR 2.1 [1.0-4.1]), had a recent visit to a cancer center or survivorship clinic (aOR 3.7 [2.0-7.0]), and possessed a SCP (aOR 3.5 [1.5-8.3]). Adherence to skin cancer guidelines was higher in those > 14 years at diagnosis (aOR 1.8 [1.3-2.4]), living in a low deprivation area (ADI 1-24.9) compared to a high deprivation area (ADI 75-100) (aOR 3.4 [1.9-5.9]), employed (aOR 1.8 [1.1-2.9]), > 30 years from diagnosis (aOR 2.4 [1.6-3.6]), with a recent routine check-up (aOR 3.6 [1.1-12.5]), and recent cancer care (aOR 2.4 [1.6-3.5]). Adherence to colorectal cancer guidelines was higher in those with grade 3-4 chronic health conditions (aOR 1.9 [1.1-3.3]). Conclusions: Less than 50% of HL survivors are adherent to screening guidelines. Sociodemographic risk factors are significant predictors of non-adherence, particularly to skin cancer screening guidelines. This threatens to potentiate outcome disparities among HL survivors.

Safety and clinical efficacy of sintilimab in pediatric patients with advanced or recurrent malignancies in a phase I study.

e14601 Background: This is a first phase I study investigating the safety and efficacy of sintilimab in pediatric patients with advanced or recurrent malignancies. Methods: During dose escalation, patients received a single-dose intravenous infusion of sintilimab. The planned dosing groups were 1, 3 and 10 mg/kg. During dose expansion, patients received sintilimab every three weeks. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to sintilimab according to the Response Evaluation Criteria in Solid Tumours version 1.1. PD-L1 expression of tumor in subjects were identified by immunohistochemistry (DACO,22C3). Whole exome sequencing (WES) was performed in 15 patients to characterize the mutational landscape and CNV status. Results: 29 patients were enrolled, including 10 patients with Hodgkin lymphoma (HL), 19 patients with other tumor types. Some special pathological types, including thymoma, choroid plexus carcinoma, and NK-T cell lymphoma are included. Patients were pretreated with a median of 3 prior lines of systemic treatment. Sintilimab was well tolerated without dose-limiting toxicity. By the safety data cutoff date, all patients experienced treatment related adverse events (TRAE) with most adverse events being grade 1 or 2, and ≥ grade 3 TRAEs occurred in 10%. Among all 27 subjects evaluated, 4 confirmed complete response (2HL, 1 NK/T lymphoma, 1 anaplastic ependymoma), 7 confirmed partial responses (4 HL, 1 Ewing sarcoma, 1 diffuse large-B lymphoma and 1 thymoma), and 7 stable disease were observed, for an objective response rate of 40.7%, and a disease control rate of 66.7%. Subjects with PD-L1-positive expression benefited more from sintilimab treatment than PD-L1-negative subjects (66.7% ORR versus 33.3% ORR, p=0.314) although statistically insignificant. The genomic profiling of WES indicatedpatients with a specific genomic mutation type predict the response of PD-1 therapy. Conclusions: Sintilimab was well tolerated and demonstrated promising anti-tumor activity in pediatric HL. The completion of the current phase I study has led to the initiation of the first prospective anti-PD-1 registration trial in Asia focusing on pediatric patients and serve as the basis for its potential study in combinatorial regimens for childhood cancer. Clinical trial information: NCT04400851 . [Table: see text]

Correlation of mean apparent diffusion coefficient (ADC) and maximal standard uptake value (SUVmax) evaluated by diffusion-weighted MRI and 18F-FDG-PET/CT in children with Hodgkin lymphoma: a feasibility study.

The objective was to analyse if magnetic resonance imaging (MRI) can act as a non-radiation exposure surrogate for (18)F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in children with histologically confirmed Hodgkin lymphoma (HL) before treatment. This was done by analysing a potential correlation between apparent diffusion coefficient (ADC) in MRI and the maximum standardized uptake value (SUVmax) in FDG-PET/CT. Seventeen patients (six female, eleven male, median age: 16 years, range: 12-20 years) with histologically confirmed HL were retrospectively analysed. The patients underwent both MRI and (18)F-FDG PET/CT before the start of treatment. (18)F-FDG PET/CT data and correlating ADC maps in MRI were collected. For each HL-lesion two readers independently evaluated the SUVmax and correlating meanADC. The seventeen patients had a total of 72 evaluable lesions of HL and there was no significant difference in the number of lesions between male and female patients (median male: 15, range: 12-19 years, median female: 17 range: 12-18 years, p = 0.021). The mean duration between MRI and PET/CT was 5.9 ± 5.3 days. The inter-reader agreement as assessed by the intraclass correlation coefficient (ICC) was excellent (ICC = 0.98, 95% CI: 0.97-0.99). The correlated SUVmax and meanADC of all 17 patients (ROIs n = 72) showed a strong negative correlation of -0.75 (95% CI: -0.84, - -0.63, p = 0.001). Analysis revealed a difference in the correlations of the examination fields. The correlated SUVmax and meanADC showed a strong correlation at neck and thoracal examinations (neck: -0.83, 95% CI: -0.93, - -0.63, p < 0.0001, thoracal: -0.82, 95% CI: -0.91, - -0.64, p < 0.0001) and a fair correlation at abdominal examinations of -0.62 (95% CI: -0.83, - -0.28, p = 0.001). SUVmax and meanADC showed a strong negative correlation in paediatric HL lesions. The assessment seemed robust according to inter-reader agreements. Our results suggest that ADC maps and meanADC have the potential to replace PET/CT in the analysis of disease activity in paediatric Hodgkin lymphoma patients. This may help reduce the number of PET/CT examinations and decrease radiation exposure to children.

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.

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). 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 )>200mL; (iv) normalized mediastinal mass volume (MVCT /thoracic diameter [TD])>1mL/mm; (v) mediastinal mass diameter on CT (MDCT )>10cm; and (vi) normalized mediastinal mass diameter (MDCT /TD)>1/3. Median age at diagnosis was 15.8years (range: 5.2-21.3years). In patients with a slow early response (SER) to chemotherapy, MVCT >200mL, MDCT >10cm, 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>1mL/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). LMA according to MVCT >200mL, MDCT >10cm, 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.

Differentiation between rebound thymic hyperplasia and thymic relapse after chemotherapy in pediatric Hodgkin lymphoma.

Rebound thymic hyperplasia (RTH) is a common phenomenon caused by stress factors such as chemotherapy (CTX) or radiotherapy, with an incidence between 44% and 67.7% in pediatric lymphoma. Misinterpretation of RTH and thymic lymphoma relapse (LR) may lead to unnecessary diagnostic procedures including invasive biopsies or treatment intensification. The aim of this study was to identify parameters that differentiate between RTH and thymic LR in the anterior mediastinum. After completion of CTX, we analyzed computed tomographies (CTs) and magnetic resonance images (MRIs) of 291 patients with classical Hodgkin lymphoma (CHL) and adequate imaging available from the European Network for Pediatric Hodgkin lymphoma C1 trial. In all patients with biopsy-proven LR, an additional fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT was assessed. Structure and morphologic configuration in addition to calcifications and presence of multiple masses in the thymic region and signs of extrathymic LR were evaluated. After CTX, a significant volume increase of new or growing masses in the thymic space occurred in 133 of 291 patients. Without biopsy, only 98 patients could be identified as RTH or LR. No single finding related to thymic regrowth allowed differentiation between RTH and LR. However, the vast majority of cases with thymic LR presented with additional increasing tumor masses (33/34). All RTH patients (64/64) presented with isolated thymic growth. Isolated thymic LR is very uncommon. CHL relapse should be suspected when increasing tumor masses are present in distant sites outside of the thymic area. Conversely, if regrowth of lymphoma in other sites can be excluded, isolated thymic mass after CTX likely represents RTH.

The Pediatric Proton and Photon Therapy Comparison Cohort: Study Design for a Multicenter Retrospective Cohort to Investigate Subsequent Cancers After Pediatric Radiation Therapy

The physical properties of protons lower doses to surrounding normal tissues compared with photons, potentially reducing acute and long-term adverse effects, including subsequent cancers. The magnitude of benefit is uncertain, however, and currently based largely on modeling studies. Despite the paucity of directly comparative data, the number of proton centers and patients are expanding exponentially. Direct studies of the potential risks and benefits are needed in children, who have the highest risk of radiation-related subsequent cancers. The Pediatric Proton and Photon Therapy Comparison Cohort aims to meet this need. We are developing a record-linkage cohort of 10,000 proton and 10,000 photon therapy patients treated from 2007 to 2022 in the United States and Canada for pediatric central nervous system tumors, sarcomas, Hodgkin lymphoma, or neuroblastoma, the pediatric tumors most frequently treated with protons. Exposure assessment will be based on state-of-the-art dosimetry facilitated by collection of electronic radiation records for all eligible patients. Subsequent cancers and mortality will be ascertained by linkage to state and provincial cancer registries in the United States and Canada, respectively. The primary analysis will examine subsequent cancer risk after proton therapy compared with photon therapy, adjusting for potential confounders and accounting for competing risks. For the primary aim comparing overall subsequent cancer rates between proton and photon therapy, we estimated that with 10,000 patients in each treatment group there would be 80% power to detect a relative risk of 0.8 assuming a cumulative incidence of subsequent cancers of 2.5% by 15 years after diagnosis. To date, 9 institutions have joined the cohort and initiated data collection; additional centers will be added in the coming year(s). Our findings will affect clinical practice for pediatric patients with cancer by providing the first large-scale systematic comparison of the risk of subsequent cancers from proton compared with photon therapy.

Pharmacokinetics and safety of bendamustine in the BEABOVP regimen for the treatment of pediatric patients with Hodgkin lymphoma.

The Stanford V chemotherapy regimen has been used to treat Hodgkin lymphoma (HL) patients since 2002 with excellent cure rates; however, mechlorethamine is no longer available. Bendamustine, a drug structurally similar to alkylating agents and nitrogen mustard, is being substituted for mechlorethamine in combination therapy in a frontline trial for low- and intermediate-risk pediatric HL patients, forming a new backbone of BEABOVP (bendamustine, etoposide, doxorubicin, bleomycin, vincristine, vinblastine, and prednisone). This study evaluated the pharmacokinetics and tolerability of a 180mg/m2 dose of bendamustine every 28days to determine factors that may explain this variability. Bendamustine plasma concentrations were measured in 118 samples from 20 pediatric patients with low- and intermediate-risk HL who received a single-day dose of 180mg/m2 of bendamustine. A pharmacokinetic model was fit to the data using nonlinear mixed-effects modeling. Bendamustine concentration vs time demonstrated a trend toward decreasing clearance with increasing age (p = 0.074) and age explained 23% of the inter-individual variability in clearance. The median (range) AUC was 12,415 (8,539, 18,642)µg hr/L and the median (range) maximum concentration was 11,708 (8034, 15,741)µg/L. Bendamustine was well tolerated with no grade 3 toxicities resulting in treatment delays of more than 7days. A single-day dose of 180mg/m2 of bendamustine every 28days was safe and well tolerated in pediatric patients. While age accounted for 23% of inter-individual variability observed in bendamustine clearance, the differences did not affect the safety and tolerability of bendamustine in our patient population.

Therapy results in pediatric Hodgkin lymphoma — does less mean better? Experience from a single children’s oncology center

Therapy results in pediatric Hodgkin lymphoma reflect remarkable progress in pediatric oncology. In the last decade, relevant development of new therapeutic options for children with refractory or relapsed disease has been made. In this study, we retrospectively analyzed therapy results and risk factors in children treated in a single oncology center according to five therapeutic protocols. Data from 114 children treated by a single institution between 1997 and 2022 were analyzed. Classic Hodgkin lymphoma therapy results were divided into four therapeutic periods: 1997–2009, 2009–2014, 2014–2019, and 2019–2022. For nodular lymphocyte-predominant Hodgkin lymphoma, data from one therapeutic protocol was analyzed. For the entire group, the 5-year probability of overall survival was 93.5%. There were no statistically significant differences between therapeutic periods. The occurrence of B symptoms at diagnosis and incidence of relapse were risk factors for death (p = 0.018 and p < 0.001). Relapse occurred in 5 cases. The 5-year probability of relapse-free survival for the entire group was 95.2%, without significant differences between groups. Patients treated between 1997 and 2009 had over a sixfold higher risk for events, defined as primary progression, relapse, death, or incidence of secondary malignancies (OR = 6.25, p = 0.086). The 5-year probability of event-free survival for all patients was 91.3%. Five patients died, and the most common cause of death was relapse. Modern therapeutic protocols in pediatric Hodgkin lymphoma are marked by excellent outcomes. Patients with disease relapses have a notably high risk of death, and the development of new therapeutic options for this group remains one of the main goals of current trials.