Pediatric Hodgkin Lymphoma Patients Research Articles

Single-cell RNA sequencing of pediatric Hodgkin lymphoma to study the inhibition of T cell subtypes.

Pediatric classic Hodgkin lymphoma (cHL) patients have a high survival rate but suffer from severe long-term side effects induced by chemo- and radiotherapy. cHL tumors are characterized by the low fraction (0.1%-10%) of malignant Hodgkin andReed-Sternberg (HRS) cells in the tumor. The HRS cells depend on the surrounding immune cells for survival and growth. This dependence is leveraged by current treatments that target the PD-1/PD-L1 axis in cHL tumors. The development of more targeted therapies that are specific for the tumor and are therefore less toxic for healthy tissue compared with conventional chemotherapy could improve the quality of life of pediatric cHL survivors. Here, we applied single-cell RNA sequencing (scRNA-seq) on isolated HRS cells and the immune cells from the same cHL tumors. Besides TNFRSF8 (CD30), we identified other genes of cell surface proteins that are consistently overexpressed in HRS cells, such as NRXN3 and LRP8, which can potentially be used as alternative targets for antibody-drug conjugates or CAR T cells. Finally, we identified potential interactions by which HRS cells inhibit T cells, among which are the galectin-1/CD69 and HLA-II/LAG3 interactions. RNAscope was used to validate the enrichment of CD69 and LAG3 expression on T cells near HRS cells and indicated large variability of the interaction strength with the corresponding ligands between patients and between tumor tissue regions. In conclusion, this study identifies new potential therapeutic targets for cHL and highlights the importance of studying heterogeneity when identifying therapy targets, specifically those that target tumor-immune cell interactions.

Expression of mGluR5 in Pediatric Hodgkin and Non-Hodgkin lymphoma-A Comparative Analysis of Immunohistochemical and Clinical Findings Regarding the Association between Tumor and Paraneoplastic Neurological Disease.

Autoantibodies targeting the neuronal antigen metabotropic glutamate receptor 5 (mGluR5) have been identified in patients with Ophelia syndrome, which describes a co-occurrence of paraneoplastic limbic encephalitis and Hodgkin lymphoma (HL). Little data exist regarding frequency and function of mGluR5 in HL and its potential role in causing seropositive paraneoplastic disease. We studied a representative cohort of pediatric HL and NHL patients (n = 57) using immunohistochemistry and fluorescence staining to investigate mGluR5 expression. All lymphoma tissues displayed positive mGluR5 staining, with focus on Hodgkin-Reed-Sternberg (H-RS) cells. We did not detect any mGluR5 staining in tumor-free lymph nodes, which is consistent with the absence of GRM5 transcripts in RNA-sequencing data from non-malignant B and T cells. The frequent presence in pediatric lymphoma falls in line with reports of mGluR5 expression and associated tumor progression in other malignancies. We tested for correlation with clinical features, focusing on disease progression and neurological symptoms. Low mGluR5 expression in H-RS cells correlated with young patient age (<15 years) and positive histology for EBV infection. Paraneoplastic or neurological symptoms were found exclusively in HL patients. While an impact of mGluR5 on HL severity remains possible, a prognostic value of mGluR5 expression levels requires further investigation.

Outcomes of Proton Therapy to Infradiaphragmatic Sites in Pediatric Hodgkin Lymphoma Patients

Purpose: When treating pediatric patients with radiotherapy (RT), an important area of optimization is reducing integral dose with the goal of minimizing toxicity. As a result, proton radiation (PT) is a well-established RT modality for certain clinical indications within pediatrics. However, there is limited data on outcomes of PT in pediatric patients with Hodgkin lymphoma who receive RT to infradiaphragmatic targets. We report on radiation planning details, doses achieved to organs at risk (OARs), and outcomes for this population, and additionally provide comparative dosimetric data between photon and proton plans for a patient subset. Methods: This is a single-institution retrospective study of pediatric patients with Hodgkin lymphoma who received curative intent PT to infradiaphragmatic targets between 2011-2022. Demographic and clinical factors were collected from the electronic medical record, and toxicity was reported using CTCAE version 5.0. Dosimetric and clinical factors associated with toxicity and oncologic outcomes were assessed via Cox regression, while the paired t-test or Wilcoxon signed rank sum test was used for dosimetric analyses. Photon comparison plans were generated for a subset of 10 patients who received PT to a range of infradiaphragmatic subsites, and doses to key OARs were compared across modalities via the Wilcoxon signed rank sum test. Results: Twenty-one patients comprising 22 PT courses were included. Median follow-up was 4.8 years. Mean age at the time of RT was 14.2 years (range 4-22 years) and 48% were male. Median dose was 21 Gray equivalent (GyE) over 14 fractions. 50% of patients received PT to multiple subdiaphragmatic sites, and top locations treated in single-target PT courses included spleen (32%), retroperitoneum (14%), and pelvis (3%). Most common acute grade 1 (G1) toxicities were fatigue (59%) and anorexia (36%). Rates of acute G2 and G3+ toxicity were 18% and 0%, respectively. The average maximum dose (Dmax) to the spinal cord was 15.3 Gy and bowel bag (BB) was 19.9 Gy. Multiple BB metrics were significantly different between patients who developed nausea and those who did not: V5 Gy (median 42% vs. 2%, p=.0068), V15 Gy (median 30% vs. 1%, p=.0056), V20 Gy (median 26% vs. 0%, p=.0038), mean (median 949 vs. 35 cGy, p=.0063), and Dmax (median 2295 vs. 2184 cGy, p=.0301). Rectum Dmax also significantly varied between those who did or did not develop abdominal discomfort (median 119 vs. 0 cGy, p=.0071). No other OAR metrics were significantly different based on acute toxicity. Following PT, two patients developed persistent gastrointestinal issues of unclear etiology, and one patient developed chronic kidney disease (CKD). No statistically significant differences in doses to BB (V5 Gy, V15 Gy, V20 Gy, Dmax, or mean) or kidney (mean or V5 Gy) were detected between these patients and those without chronic abdominopelvic sequelae. Kidney V18 Gy and V20 Gy for the patient with subsequent CKD was 2% and 0%, respectively. No patients developed a second malignancy after PT, and 0% experienced progression of disease (POD) after final course of PT. In our 10 patient subset with photon comparison plans, protons achieved numerically lower averages for all OARs assessed with the exception of spinal cord Dmax (889 vs. 851 cGy), although these differences were not statistically significant (all p&amp;gt;0.05). Conclusions: PT is well-tolerated when utilized to target single or multiple infradiaphragmatic locations in pediatric Hodgkin lymphoma patients and leads to excellent oncologic and toxicity outcomes with long-term follow-up. PT may confer dosimetric advantages when compared to photons, although larger patient subsets are needed.

Longitudinal Differences By Treatment Arm in Health-Related Quality of Life Among High Risk Pediatric Hodgkin's Lymphoma Patients Treated on the Children's Oncology Group Ahod 1331 Study

Introduction: Brentuximab vendotin (BV) with AVE-PC demonstrated superior efficacy to ABVE-PC for pediatric patients with high-risk HL in the AHOD 1331 trial. However, there are no data regarding the impact on health-related quality of life (HRQoL) with the addition of BV into the treatment of pediatric HL. Methods: Eligibility for AHOD 1331 (NCT 02166463) included previously untreated HL with high risk disease, defined as stage IIB +bulk, IIIB, IVA, or IVB classic HL. Participants were randomized to either BV-AVE-PC (“BV” arm) or ABVE-PC (standard arm). Among the first 309 participants enrolled in a prespecified longitudinal patient-reported outcomes sub study, 280 were age 11+ years and eligible to self-report HRQoL using the seven-item Child Health Ratings Inventories (CHRIs)-Global scale. HRQoL was assessed prior to treatment (T1), at cycle 2 (T2), at cycle 5 (T3), and at the end of treatment (T4). A clinically meaningful increase in HRQoL was considered a change of 7 points in the CHRIs-Global score (CHRIs), translating to a 1/3 standard deviation. Multivariable linear regression estimated the association between demographic/clinical variables and HRQoL at T1. Linear mixed models estimated the change in HRQoL relative to T1 with a time*treatment arm interaction to estimate differences in the change in HRQoL across treatment arm. This model was adjusted for age, sex, race/ethnicity, stage, large mediastinal adenopathy (LMA), B-symptoms at diagnosis, and a time-varying covariate for involved site radiation prior to T4. Results: Participant and disease characteristics were balanced by treatment arm; mean age at enrollment was 15.6 years (SD= 1.9), 52% were female, 60.4% had LMA, and 58% were stage IV. 93% of participants completed the CHRIs at T1, 92% at T2, 89% at T3, and 74% at T4. At T1, female sex (mean (SD) 64.1 (20.2) vs 71.3 (23.3) p=0.004) and fever (60.8 (23.0) vs. 71.9 (20.4) p=0.024) were associated with worse HRQoL. At each time point after pre-treatment (T1), HRQoL was higher, on average, in the BV arm compared to the standard arm (Figure 1). By T2, participants in the BV arm experienced a statistically and clinically significant increase in HRQoL compared to pre-treatment (T1) (Table 1; β=7.3 95%CI 3.2, 11.4; p≤0.001), which was greater than the change experienced in the standard arm (difference in change β=5.1 95%CI -0.2, 10.3; p=0.057). At T3 and T4 the BV arm continued to experience statistically significant improvements in HRQoL relative to T1 (T3 β=5.3 95%CI 0.8, 9.9; p=0.022; T4 β=14.6 95%CI 10.3, 18.9; p≤0.001). The standard arm did not experience a statistically or clinically significant increase in HRQoL from T1 until T4 (β=9.3 95%CI 4.7, 11.5; p&amp;lt;0.001). Conclusion: Patients with high-risk pediatric HL treated with BV-AVE-PC experienced more rapid and sustained improvement in HRQoL compared to patients treated with ABVE-PC. These data also demonstrate the feasibility and importance of incorporating HRQoL assessments into pediatric clinical trials.

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.

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.

Are Semiquantitative Methods Superior to Deauville Scoring in the Monitoring Therapy Response for Pediatric Hodgkin Lymphoma?

Tailoring treatment in patients with Hodgkin lymphoma (HL) is paramount to maximize outcomes while avoiding unnecessary toxicity. We aimed to compare the performance of SUVmax reduction (ΔSUVmax%) and the PET ratio (rPET) versus the Deauville score (DS) for assessing the chemotherapy response in pediatric HL patients undergoing 18F-FDG PET-CT. Fifty-two patients with biopsy-proven HL (aged 8-16 years) were enrolled at baseline, interim (after the second or third chemotherapy round) and post-therapy (on completion of first-line chemotherapy). Interim and post-therapy DS, ΔSUVmax% and rPET were compared as response predictors. Patients were classified as responders or non-responders based on a 24-month clinical follow-up. Interim DS showed a sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy of 100%, 80.4%, 100%, 40% and 82.7%, respectively, in predicting the therapy response. Post-therapy DS showed a sensitivity, specificity, PPV, NPV and accuracy of 66.7%, 97.8%, 95.7%, 80% and 94.2%, repsectively. Interim ΔSUVmax% showed a sensitivity, specificity, PPV, NPV and accuracy of 83.3%, 82.6%, 97.4%, 38.5% and 82.7%, respectively, with a 56.3% cutoff. Post-therapy ΔSUVmax% showed a sensitivity, specificity, PPV, NPV and accuracy of 83.3%, 84.8%, 97.5%, 41.7% and 84.6%, respectively, with a 76.8% cutoff. Compared to ΔSUVmax%, DS showed a significantly higher sensitivity, specificity (p < 0.05) and NPV (p < 0.01). The sensitivity, specificity, PPV, NPV and accuracy of rPET in predicting the therapy response at 24 months were 76.1%, 100%, 100%, 35.3% and 78.8%, respectively, with a cut-off of 1.31. DS and rPET showed comparable predictive performance (p > 0.58). In conclusion, DS is an easier method with better performance than ΔSUVmax% and rPET in predicting the chemotherapy response in pediatric HL patients.

Optimized Whole-Body PET MRI Sequence Workflow in Pediatric Hodgkin Lymphoma Patients.

18F-FDG PET/MRI might be the diagnostic method of choice for Hodgkin lymphoma patients, as it combines significant metabolic information from PET with excellent soft-tissue contrast from MRI and avoids radiation exposure from CT. However, a major issue is longer examination times than for PET/CT, especially for younger children needing anesthesia. Thus, a targeted selection of suitable whole-body MRI sequences is important to optimize the PET/MRI workflow. Methods: The initial PET/MRI scans of 84 EuroNet-PHL-C2 study patients from 13 international PET centers were evaluated. In each available MRI sequence, 5 PET-positive lymph nodes were assessed. If extranodal involvement occurred, 2 splenic lesions, 2 skeletal lesions, and 2 lung lesions were also assessed. A detection rate was calculated dividing the number of visible, anatomically assignable, and measurable lesions in the respective MRI sequence by the total number of lesions. Results: Relaxation time-weighted (T2w) transverse sequences with fat saturation (fs) yielded the best result, with detection rates of 95% for nodal lesions, 62% for splenic lesions, 94% for skeletal lesions, and 83% for lung lesions, followed by T2w transverse sequences without fs (86%, 49%, 16%, and 59%, respectively) and longitudinal relaxation time-weighted contrast-enhanced transverse sequences with fs (74%, 35%, 57%, and 55%, respectively). Conclusion: T2w transverse sequences with fs yielded the highest detection rates and are well suited for accurate whole-body PET/MRI in lymphoma patients. There is no evidence to recommend the use of contrast agents.

Vital organ sparing with proton therapy for pediatric Hodgkin lymphoma: Toxicity and outcomes in 50 patients

Background and purposeWith high survival rates for pediatric Hodgkin lymphoma (HL), attention has turned to minimizing treatment-related morbidity and mortality. Chemotherapy and dose of radiation to organs at risk (OARs) contribute to elevated risks of secondary malignancy and cardiopulmonary disease. We sought to characterize the radiation dose to OARs, toxicities, and outcomes for pediatric HL patients treated with proton therapy (PT). Materials and methodsFifty patients aged 11–21 with HL consecutively treated with PT were evaluated 1–2 months following completion of PT and every 6 months thereafter. Acute and late toxicities were captured retrospectively using CTCAE v5. Patterns of relapse were characterized, and survival was assessed using Kaplan-Meier method. ResultsMost (47, 94%) patients received PT to the mediastinum. Median mean heart dose was 4.3 Gy (RBE) and median bilateral lung V20Gy was 5.8%. Median integral dose was 1.7 Gy. For the 27 female patients, a median mean dose of 0.4 and 0.3 Gy (RBE) was delivered to ipsilateral and contralateral breast tissue, respectively. No on-treatment grade 3–5 toxicities were seen. At a median follow-up of 5.3 years, no PT-related grade 3–5 toxicities or secondary malignancies developed. Five patients relapsed at a median time of 9.2 months after PT (range 2.5–24.9 months; 5-year recurrence free survival 90%). Recurrences were both in- and out-of-field in all 5 cases with no marginal failures. All relapsed patients were successfully salvaged (5-year overall survival 100%). ConclusionFor pediatric HL patients, proton treatment resulted in marked dose sparing of OARs with low rates of toxicity, no marginal failures, and excellent 5-year survival.

Late effects in pediatric Hodgkin lymphoma survivors after uniform treatment with ABVD with or without radiotherapy.

ABVD (doxorubicin, bleomycin,vinblastine, and dacarbazine) is not a standard regimen in children due to concerns regarding late effects. However, no studies have evaluated long-term toxicities of ABVD in children. Total 154 pediatric Hodgkin lymphoma (HL) survivors uniformly treated with ABVD were clinically followed up as per institutional protocol. All participants were evaluated for cardiac, pulmonary, and thyroid function abnormalities by multigated acquisition scan (MUGA) scan, spirometry with diffusion capacity of lung for the uptake of carbon monoxide (DLCO), and thyroid profile test, respectively, at a single time point. Predictors of toxicity were also analyzed. The median duration of follow-up of the cohort was 10.3years (6.04-16.8). No secondary malignant neoplasm (SMN) or symptomatic cardiac/pulmonary toxicities were detected. Nine patients (5.9%) had left ventricular ejection fraction (LVEF) <55%. Subclinical and overt hypothyroidism were observed in 78 (50.6%) and 16 (10.4%) survivors, respectively. Abnormal spirometry and reduced DLCO was observed in 43.2% and 42.0% survivors, respectively. Receiving neck radiation was significantly associated with thyroid dysfunction (odds ratio [OR] 16.04, p<.001); age ≥10years predicted reduced DLCO (OR 4.12, p=.001). Sixty-three and 33 patients had one and two late adverse effects, respectively; receiving neck radiation predicted development of multiple late effects (proportional OR 4.72, p<0.001). Cumulative dose of chemotherapy did not predict toxicity. Overall, ABVD appears safe in children at a relatively short follow-up. Long-term safety data are required before it can be adopted for treating pediatric HL patients. Children receiving neck radiation require close follow-up.

Outcomes within Five Years from Diagnosis in Pediatric Hodgkin Lymphoma Patients Following Contemporary Therapy

Background: Survival rates for pediatric Hodgkin lymphoma (HL) exceed 95% with contemporary therapy. To reduce long-term morbidity while maintaining excellent survival, risk-adapted therapy including tailored use of radiation has been developed. Studies of 5-year survivors and cohorts treated in the 1970s-1990s have shown pediatric HL survivors are at increased risk for treatment-related chronic health conditions, including subsequent malignancies, cardiopulmonary disease, thyroid dysfunction, and infertility. However, little is known about chronic conditions associated with contemporary therapy presenting during the first 5 years from diagnosis (early outcomes). The purpose of this study was to analyze survival and early outcomes of pediatric HL patients treated with contemporary therapy.Methods: We conducted a retrospective review of HL patients diagnosed <21 years of age and treated at our institution from 2011-2014. Three patients treated with surgery only were excluded. Three-year overall (OS) and event-free (EFS) survival were calculated with Kaplan Meier statistics using SAS 9.4. Results of screening (per Children's Oncology Group and Institutional Fertility Preservation Screening Guidelines) for targeted toxicities that developed between 2 and 5 years from diagnosis were identified and graded per CTCAE criteria. Censoring occurred at date of death, 5 years after diagnosis, or December 31, 2016. Data from the last collection point were used for prevalence calculations in cases with multiple evaluations. Descriptive statistics were calculated for the cohort.Results: We identified 62 patients (52% male; 39% non-Hispanic white; mean age at diagnosis 13.6 ± 3.6 years) with a median time since diagnosis of 3.3 years (range 0.06-5.0). Initial treatment included: 49 (79%) chemotherapy only and 13 (21%) multimodality treatment. Chemotherapy comprised ABVE-PC (56%), BEACOPP (19%), COPP/ABV (16%), or other (8%). Four patients with relapsed/refractory disease received salvage treatment including chemotherapy (n=1), multimodality therapy (n=1), or multimodality treatment including stem cell transplant (SCT; n=2). One patient remained on treatment at the time of censoring.The 3-year OS across all stages was 98.4% with an EFS of 91.9% (89.7% chemotherapy only, 100% multimodality treatment). The one mortality was due to toxic death during chemotherapy.At our institution, patients are referred to survivor clinic at 2 years from completion of therapy. Of the 44 patients eligible for survivor clinic, 35 (80%) attended during the study period, 5 (11%) were seen after the study period, 3 (7%) were lost to follow-up, and 1 (2%) was followed by the primary oncologist only. Early outcomes for patients who received exposure-based screening are listed in Table 1. No patients developed pulmonary dysfunction greater than CTCAE Grade 1, hyperthyroidism, thyroid nodules, cardiac dysfunction, or a subsequent neoplasm during the study period.Anti-mullerian hormone (AMH) below the normal range was found in all 8 evaluated females who received procarbazine-based regimens (BEACOPP or COPP/ABV; 6 received chemotherapy alone, 2 received chemotherapy with supradiaphragmatic radiation). All 8 females who received ABVE-PC with or without radiation (1 abdominal) had normal AMH levels. No males had abnormal gonadotropins.Conclusions: With the incorporation of novel agents in HL therapy, defining the baseline early outcomes of contemporary regimens is germane to future comparative medicine initiatives. This study is the first to evaluate early outcomes in pediatric HL survivors. While the cohort is young, the results indicate contemporary chemotherapy and a lower rate of radiation therapy utilization leads to excellent 3 year survival rates with minimal early toxicities. Females treated with procarbazine-based regimens are at increased risk for diminished ovarian reserve compared to those receiving ABVE-PC and should be prioritized for fertility preservation approaches prior to initiation of therapy. We plan to further expand our experience to include patients diagnosed since 2005 and evaluate the relationship between cumulative alkylating agent exposure and female gonadal dysfunction.[Chemotherapy abbreviations: (A) Adriamycin, (B) Bleomycin, (C) Cyclophosphamide, (E) Etoposide, (O) Vincristine, (P) Prednisone, (P) Procarbazine, (V) Vinblastine] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Increased Rate of Pulmonary Toxicity in Pediatric Patients with Relapsed Hodgkin Lymphoma Receiving Brentuximab Vedotin

*Kelly E Faulk and Jenna Sopfe contributed equally to this work and are considered co-first authors.Background: In pediatric patients with relapsed or refractory Hodgkin lymphoma, intensification of conventional chemotherapy and radiation has shown limited success with high rates of treatment-associated morbidity and highlighted the need for alternative, targeted approaches in this high-risk population. Brentuximab vedotin (Bv) is an anti-CD30 monoclonal antibody-drug conjugated to monomethyl auristatin E that has improved outcomes and reduced toxicity compared to standard salvage regimens. It is now approved for use in relapsed or refractory Hodgkin lymphoma and several ongoing pediatric clinical trials are underway to test the effectiveness of Bv as frontline therapy. In the existing literature, acute pulmonary toxicity has been described in adults with Bv but typically in the setting of concurrent administration with bleomycin, whereas the incidence of lung toxicity attributed to Bv alone has been reported at only 5% (Moskowitz 2015). There is little published data on lung toxicity of Bv in pediatric patients. This study aims to evaluate the prevalence of acute pulmonary toxicity among pediatric and young adult relapsed Hodgkin lymphoma patients and define risk factors for this complication, specifically examining the association of Bv with pulmonary toxicity when adjusting for other exposures.Methods: We performed a retrospective cohort study of relapsed or refractory Hodgkin lymphoma patients who were originally diagnosed from 2006-2016 and treated at Children's Hospital Colorado. We examined demographic, clinical and treatment characteristics among patients who developed acute pulmonary toxicity (defined as hypoxemia, dyspnea or radiographic pneumonitis of ≥ grade 3 and/or newly abnormal pulmonary function testing occurring at any time from initiation of relapse therapy until 6 months off therapy) to determine potential risk factors. A Fisher's exact test was used to determine the statistical significance in the difference of the primary outcome (pulmonary toxicity) for those exposed and not exposed to Bv. Univariate and multivariate logistic regression modeling was performed to evaluate the association of Bv with pulmonary toxicity, adjusting for cumulative bleomycin and pulmonary radiation dose received as well other risk factors identified in univariate analysis.Results : We identified 22 patients, age 6-24 years (median 15) at time of initial diagnosis, who underwent treatment at our institution. Twelve (52.2%) were male. Nine patients (40.9%) received Bv as a component of their relapse therapy regimen. On preliminary analysis, acute pulmonary toxicity was seen in 6 patients (27.3%). There was a statistically significant difference in pulmonary toxicity among patients who received Bv compared to patients who did not receive Bv (p=0.023); of patients who received Bv, 5/9 (55.6%) experienced acute pulmonary toxicity, compared to 1/13 (7.7%) patient who did not receive Bv. Further analyses of additional risk factors and calculation of odds ratios, adjusted for bleomycin and radiation exposure, are forthcoming.Conclusions: At our institution, the administration of Bv in pediatric and young adult patients with relapsed or refractory Hodgkin lymphoma is associated with a higher rate of acute pulmonary toxicity than has previously been reported. Ongoing analysis will examine the magnitude of risk associated with Bv and the interaction of other known risk factors. As investigation into the use of Bv continues, this emerging safety and toxicity profile data will be important in understanding the risk of pulmonary toxicity and ensuring appropriate monitoring. DisclosuresNo relevant conflicts of interest to declare.

Automated quantification of baseline imaging PET metrics on FDG PET/CT images of pediatric Hodgkin lymphoma patients

PurposeFor pediatric lymphoma, quantitative FDG PET/CT imaging features such as metabolic tumor volume (MTV) are important for prognosis and risk stratification strategies. However, feature extraction is difficult and time-consuming in cases of high disease burden. The purpose of this study was to fully automate the measurement of PET imaging features in PET/CT images of pediatric lymphoma.Methods18F-FDG PET/CT baseline images of 100 pediatric Hodgkin lymphoma patients were retrospectively analyzed. Two nuclear medicine physicians identified and segmented FDG avid disease using PET thresholding methods. Both PET and CT images were used as inputs to a three-dimensional patch-based, multi-resolution pathway convolutional neural network architecture, DeepMedic. The model was trained to replicate physician segmentations using an ensemble of three networks trained with 5-fold cross-validation. The maximum SUV (SUVmax), MTV, total lesion glycolysis (TLG), surface-area-to-volume ratio (SA/MTV), and a measure of disease spread (Dmaxpatient) were extracted from the model output. Pearson’s correlation coefficient and relative percent differences were calculated between automated and physician-extracted features.ResultsMedian Dice similarity coefficient of patient contours between automated and physician contours was 0.86 (IQR 0.78–0.91). Automated SUVmax values matched exactly the physician determined values in 81/100 cases, with Pearson’s correlation coefficient (R) of 0.95. Automated MTV was strongly correlated with physician MTV (R = 0.88), though it was slightly underestimated with a median (IQR) relative difference of − 4.3% (− 10.0–5.7%). Agreement of TLG was excellent (R = 0.94), with median (IQR) relative difference of − 0.4% (− 5.2–7.0%). Median relative percent differences were 6.8% (R = 0.91; IQR 1.6–4.3%) for SA/MTV, and 4.5% (R = 0.51; IQR − 7.5–40.9%) for Dmaxpatient, which was the most difficult feature to quantify automatically.ConclusionsAn automated method using an ensemble of multi-resolution pathway 3D CNNs was able to quantify PET imaging features of lymphoma on baseline FDG PET/CT images with excellent agreement to reference physician PET segmentation. Automated methods with faster throughput for PET quantitation, such as MTV and TLG, show promise in more accessible clinical and research applications.

Survival and long-term toxicities of pediatric Hodgkin lymphoma after combined modality treatment: a single institute experience

PurposeTo analyze the clinical outcomes and long-term toxicity of pediatric patients with Hodgkin lymphoma after combined-modality treatment (CMT) with involved-field or involved-nodal radiotherapy (RT).Materials and MethodsWe retrospectively reviewed the records of 27 pediatric Hodgkin lymphoma patients who received CMT at a single institution between January 1990 and July 2017. Patients with stage I–III received a heterogeneous chemotherapy regimen depending on their risk group followed by 19.8–36 Gy RT, with the dose based on their response to the chemotherapy before RT. An optional 9–20 Gy boost was delivered to residual sites. The risk group was determined based on the initial stage, the presence of bulky disease, and any B symptoms. We evaluated overall survival, event-free survival, and long-term toxicities.ResultsA total of 27 patients completed the CMT. At a median follow-up of 125 months (range, 9 to 337 months), the estimated 5-year event-free survival and overall survival were 88.9% and 96.3%, respectively. Late symptomatic cardiopulmonary toxicity was not observed, and only one patient was positive on a subclinical obstructive pulmonary function test. The incidence of hypothyroidism was 58.3% among 12 patients with an available thyroid function test. There was one papillary thyroid cancer diagnosed 7.2 years after treatment.ConclusionCMT for pediatric Hodgkin lymphoma with involved-field and involved-nodal RT achieved an excellent survival with only modest long-term toxicity. Smaller-field RT seemed to decrease long-term toxicities and had good local control.

Liver involvement in pediatric Hodgkin lymphoma: A systematic review by an international collaboration on Staging Evaluation and Response Criteria Harmonization (SEARCH) for Children, Adolescent, and Young Adult Hodgkin Lymphoma (CAYAHL).

Hepatic involvement in Hodgkin lymphoma (HL) is uncommon (∼5% of patients) but always implies stage IV disease. Accurate staging is mandatory for making the appropriate risk assignment and treatment decisions. The Staging Evaluation and Response Criteria Harmonization for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (SEARCH for CAYAHL) international working group conducted a systematic literature review of liver involvement in HL patients with the aim to propose a universally acceptable definition for liver involvement in pediatric HL. Thirty-three articles describing 6985 pediatric and adult HL patients were reviewed, of which 539 (7.7%) mentioned liver involvement. The literature did not provide a uniform definition of hepatic involvement and we propose consensus criteria derived from the EuroNet and Children's Oncology Group protocols, where liver involvement is defined as any hepatic lesion on computed tomography scan that correlates with 18 F-FDG uptake greater than background liver. A clear definition of liver lesions is necessary to consistently identify liver involvement and compare its impact on outcomes among protocols worldwide.

Differences in Epstein-Barr Virus Characteristics and Viral-Related Microenvironment Could Be Responsible for Lymphomagenesis in Children.

In Argentina, Epstein-Barr virus (EBV) presence is associated with Hodgkin lymphoma (HL) in patients younger than 10 years, suggesting a relationship between low age of EBV infection and HL. Given that HL is derived from germinal centers (GC), our aim was to compare EBV protein expression and microenvironment markers between pediatric HL patients and EBV+GC in children. Methods: EBV presence and immune cell markers were assessed by in situ hybridization and immunohistochemistry (IHC). Results: Viral latency II pattern was proved in all HL patients and in 81.8% of EBV+ tonsillar GCs. LMP1 and LMP2 co-expression were proved in 45.7% HL cases, but only in 7.7% EBV+ GC in pediatric tonsils. An increase in CD4+, IL10, and CD68+ cells was observed in EBV+ GC. In pediatric HL patients, only the mean of IL10+ cells was statistically higher in EBV+ HL. Conclusions: Our findings point us out to suggest that LMP1 expression may be sufficient to drive neoplastic transformation, that an immune regulatory milieu counteracts cytotoxic environment in EBV-associated Hodgkin lymphoma, and that CD4+ and CD68+ cells may be recruited to act in a local collaborative way to restrict, at least in part, viral-mediated lymphomagenesis in tonsillar GC.

Urine Proteomic Analysis Reveals Disease-Specific Patterns in Pediatric Patients with Classical Hodgkin's Disease(HD). an Addon Study to the Euronet-PHL-C2 Trial

Background HD is a B-lineage lymphoma characterized, depending on subtype, by a prominent inflammatory infiltrate and fibrosis. Clinically, inflammatory symptoms like fever, weight loss and night sweats (B-symptoms) and increased blood biomarkers of inflammation, including ESR and CRP, are characteristic of more advanced disease. The clinical trial EURONET-PHL-C2 (Second International Inter-Group Study for Classical Hodgkin's Lymphoma in Children and Adolescents) is a randomized, prospective trial that compares chemo- and radiotherapy treatment concepts of different intensities in patients with intermediate and advanced HD. Patients are stratified by risk into 3 therapy groups (TL-1 to TL-3). An ESR&gt; 30mm/h had been a risk factor for relapse in previous studies and leads to upstaging from the lowest (TL-1, Ann Arbor stage I and IIa without additional risk factors) to the intermediate risk group TL-2 in the current study. This addon pilot study tested urine proteomic patterns from pediatric patients with HD at diagnosis and compared them to the patterns of normal children. The questions were: Is there a HD-specific pattern, a pattern that identifies high risk or a pattern that correlates with inflammatory markers? Patients and methods Capillary electrophoresis coupled to mass spectrometry (CE-MS) was used to compare the peptide profiles in the mass range of 0.8 to 20 kDa of urine samples (N=34) from 16 children with pediatric Hodgkin lymphoma (PHL) as case and 32 age-matched children with no evidence of a disease (N=28) or with urinary tract infection (N=4) as control groups. Marker selection was based on a two-step strategy. First, a group-wise comparison of rank sum differences was performed on a set of 2418 annotated peptides with distribution frequencies above 30% in at least one of the groups with subsequent adjustment for multiple testing by the method of Bonferroni. In the second step marker candidates were further restricted to those demonstrating a significant positive or negative Spearman rho correlation coefficient (≥0.34 or ≤-0.34) to the Ann-Arbor classification criteria. From the resulting peptides a multivariate peptide marker classifier was established by support vector machine modeling and applied to an independent confirmation set of PHL (N=16, 31 urine samples) and control (N=18, 18 urine samples) patients to determine classification accuracy in receiver operating characteristics (ROC) analysis. Peptides included in the PHL classifier were resolved in their amino acid sequence by tandem mass spectrometry to identify the proteins from which the peptide markers are derived. Results The established multivariate peptide marker model consisting of 40 naturally occurring urinary peptides enabled absolute differentiation between PHL patients and children without signs of disease or urinary tract infection in independent validation as revealed by an area under the ROC curve value of 1.0 (95% confidence interval: 0.93 to 1.00, p&lt;0.0001). Amino acid sequencing revealed that the majority of peptides are interstitial collagen fragments from specific hot-spot regions within the proteins linear sequence and in part with overlapping amino acid sequences indicative for the activity of specific extracellular matrix degrading proteases. Other PHL peptide markers are derived from the tumor associated proteins S100-A9, Prostaglandin-H2 D-isomerase and Cytokeratin-8. Conclusions and perspective We were able to identify a proteomic pattern characteristic for HD, markers for relapse risk group or HD-associated inflammation were not yet identified. Disclosures Metzger: Mosaiques Diagnostics: Employment.

Using Childhood International Prognostic Scoring in Pediatric Hodgkin Lymphoma Patients Treated with ABVD Can Mitigate Use of Interim PET in LMIC

Background &amp; aim:Although 'interim' positron emission tomography (PET) may inform therapeutic decisions, Risk stratification at diagnosis allows earlier and potentially better modification during treatment of HL. the prognosis of HL in our center.In this study, we aimed to identify the prognostic role of both the IPET and validate Childhood Hodgkin International Prognostic Score (CHIPS) in predicting the prognosis of HL at our hospital. Patients and methods:This is a retrospective, single-center study where a total of 1140 patients with newly diagnosed Hodgkin lymphoma were enrolled. Only 737 patients were eligible for analysis of both IPET and CHIPS scoring. PET scan was performed at baseline and after two cycles of chemotherapy (ABVD). Treatment was not changed according to the results of the interim scan. Stage 4 disease, large mediastinal mass, albumin (&amp;lt;3.5), and fever were each assigned one point in the CHIPS. Log-rank testing was used to compare EFS for each CHIPS (0-3) secondary analysis to detect EFS in relation to IPET was done. Results : Only 737 patients were eligible for analysis of both IPET and CHIPS scoring. The 5-year EFS was 95% for patients with CHIPS=0, 94% for patients with CHIPS=1, 84.3% for patients with CHIPS=2, 82.4% for patients with CHIPS=3 and 70% for CHIPS=4 (P-value 0.001).The 5-year OS was 97.4% for patients with CHIPS=0, 97.9% for patients with CHIPS=1, 93.1% for patients with CHIPS=2, 94.7% for patients with CHIPS=3 and 85.6% for CHIPS=4 (P-value 0.039). Slow early responders as detected by PET have 5-years EFS 73.8%, in comparison, those with evidence of response by PET had 5-year EFS of 91.3 %. Among this better risk patients, CHIPS can further classify patients; EFS 96.4% of patients with CHIPS 0 or 1 versus 85.8% for those with CHIPS 2, 3 or 4 who had an adverse outcome, even in the setting of response by PET (P&amp;lt;0.001). Conclusion: CHIPS is a good tool for predicting risk in patients with HL that may help to tailor therapy to risk factors known early at diagnosis. The benefit of using CHIPS versus early response PET scan suggests the feasibility of eliminating the costly PET scans, especially in LMIC. Figure Disclosures No relevant conflicts of interest to declare.

Pediatric hodgkin lymphoma: disparities in survival by race

The purpose of this study was to examine factors associated with disparities in overall survival (OS) by race in pediatric Hodgkin Lymphoma (HL) patients. We evaluated clinical features and survival among patients ≤21 years of age diagnosed with stage I–IV HL from 2004 to 2015 from the National Cancer DataBase (NCDB) using a multivariable Cox proportional hazards model. Among 11,546 patients with pediatric HL, 9285 patients met eligibility criteria. Black patients experienced a 5-year OS of 91.5% vs 95.9% in White patients (p < .0001). After adjusting for confounders, Black race was associated with a significantly decreased OS (HR = 1.50; 95% CI: 1.12–1.99; p < .01). In stratified analysis by ages ≤15 years, 16–18 years, and >18 years, Black race was associated with poorer OS among compared to Whites with rates of 95.4% vs 97.7%, 87.1% vs 96.1%, and 91.6% vs 94.6% respectively. Overall, Black pediatric HL patients had lower overall survival in this study.

Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma.

We used hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA) of pediatric Hodgkin lymphoma (PHL) patients to determine pathogenic mechanisms and assess the clinical utility of this method. Hodgkin-Reed/Sternberg (HRS) cell-derived single nucleotide variants, insertions/deletions, translocations and VH-DH-JH rearrangements were detected in pretherapy ccfDNA of 72 of 96 patients. Number of variants per patient ranged from 1 to 21 with allele frequencies from 0.6 to 42%. Nine translocation breakpoints were detected. Genes involved in JAK/STAT, NFkB and PI3K signaling and antigen presentation were most frequently affected. SOCS1 variants, mainly deletions, were found in most circulating tumor (ct) DNAs, and seven of the nine translocation breakpoints involved SOCS1. Analysis of VH-DH-JH rearrangements revealed an origin of PHL HRS cells from partially selected germinal center B cells. Amounts of pretherapy ctDNA were correlated with metabolic tumor volumes. Furthermore, in all ccfDNA samples of 43 patients with early response assessment quantitative qPET < 3, indicative of a favorable clinical course, ctDNA was not detectable. In contrast, in five of six patients with qPET > 3, indicative of an unfavorable clinical course, ctDNA remained detectable. ccfDNA analysis of PHL is thus a suitable approach to determine pathogenic mechanisms and monitor therapy response.