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Children’s Oncology Group (COG) trial AHOD0431 reduced systemic therapy and used response-adapted involved-field radiotherapy (IFRT) in early-stage pediatric classic Hodgkin lymphoma. We investigated the impact of positron emission tomographic response after 1 cycle (PET1) and on IFRT outcomes and pattern of relapse. Patients in AHOD0431 underwent PET1 response assessment after AVPC (doxorubicin, vincristine, prednisone, and cyclophosphamide). “Rapid early responders” (RERs) had a negative PET1 (PET1−); “slow early responders” (SERs) had a positive PET1 (PET1+). Patients with a partial response by computed tomographic and functional imaging after 3 chemotherapy cycles received 21-Gy IFRT, whereas complete responders had no IFRT. Progression-free survival (PFS) was evaluated for RERs and SERs treated with or without IFRT. Recurrence sites were initial, new, or both. Relapses involving initial sites were characterized as “within the PET1+ site” or “initially involved but outside the PET1+ site.” Median follow-up was 118 months. The 10-year PFS rate among RERs was 96.6% with IFRT and 84.1% without IFRT (P = .10), whereas SERs were 80.9% with IFRT and 64.0% without IFRT (P = .03). Among 90 RERs who did not receive IFRT, all 14 relapses included an initial site. Among 45 SERs receiving no IFRT, 14 of 16 relapses were in the initial site (9 PET1+ site only). Among 58 patients receiving IFRT, 5 of 10 relapses were in the PET1+ site. After 3 cycles of AVPC alone, RERs showed favorable results. Conversely, SERs had unfavorable outcomes with AVPC alone, although they improved with 21-Gy IFRT. RT remains an important component of treatment for SERs. This trial was registered at www.clinicaltrials.gov as #NCT00302003.

Adolescents with Hodgkin lymphoma have worse disease outcomes than children. Whether these differences persist within clinical trials is unknown. We examined survival, by age, in patients receiving response-adapted therapy for Hodgkin lymphoma on Children's Oncology Group (COG) trials.Patients (aged 1-21 years) diagnosed with classical Hodgkin lymphoma and enrolled between Sept 23, 2002, and Jan 19, 2012, on one of three phase 3 COG trials in the USA and Canada were eligible for inclusion. The three COG trials were defined by risk group according to Ann Arbor stage, B-symptoms, and bulk (AHOD0431 [low risk; NCT00302003], AHOD0031 [intermediate risk; NCT00025259], or AHOD0831 [high risk; NCT01026220]). The outcomes of this study were event-free survival (death, relapse, or subsequent neoplasm) and overall survival. Cox proportional hazards models estimated survival, adjusting for disease and treatment factors both overall and in patients with mixed cellularity or non-mixed cellularity (nodular sclerosing and not-otherwise-specified) disease.Of 2155 patients enrolled on the three trials, 1907 (88·4%; 968 [50·8%] male and 939 [49·2%] female; 1227 [64·3%] non-Hispanic White) were included in this analysis. After a median follow-up of 7·4 years (IQR 4·3-10·2), older patients (aged ≥15 years) had worse unadjusted 5-year event-free survival (80% [95% CI 78-83]) than did younger patients (aged15 years; 86% [83-88]; HR 1·38 [1·11-1·71]; p=0·0038). Older patients also had worse unadjusted 5-year overall survival than did younger patients (96% [95% CI 95-97] vs 99% [98-99]; HR 2·50 [1·41-4·45]; p=0·0012). In patients with non-mixed cellularity histology, older patients had a significantly increased risk of having an event than did younger patients with the same histology (HR 1·32 [1·03-1·68]; p=0·027). Older patients with mixed cellularity had significantly worse 5-year event-free survival than did younger patients in unadjusted (77% [95% CI 65-86] for older patients vs 94% [88-97] for younger patients; HR 2·93 [1·37-6·29]; p=0·0039) and multivariable models (HR 3·72 [1·56-8·91]; p=0·0032). Overall, older patients were more likely to die than younger patients (HR 3·08 [1·49-6·39]; p=0·0025).Adolescents (≥15 years) treated on COG Hodgkin lymphoma trials had worse event-free survival and increased risk of death compared with children (15 years). Our findings highlight the need for prospective studies to examine tumour and host biology, and to test novel therapies across the age spectrum.National Institutes of Health, St Baldrick's Foundation, and Lymphoma Research Foundation.

BACKGROUND: In adults with advanced-stage Hodgkin’s lymphoma, the CD30-directed antibody–drug conjugate brentuximab vedotin combined with multiagent chemotherapy has been shown to have greater efficacy, but also more toxic effects, than chemotherapy alone. The efficacy of this targeted therapy approach in children and adolescents with Hodgkin’s lymphoma is unclear. METHODS: We conducted an open-label, multicenter, randomized, phase 3 trial involving patients 2 to 21 years of age with previously untreated Hodgkin’s lymphoma of stage IIB with bulk tumor or stage IIIB, IVA, or IVB. Patients were assigned to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (brentuximab vedotin group) or the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (standard-care group). Slow-responding lesions, defined by a score of 4 or 5 (on a 5-point scale, with scores of 1 to 3 indicating rapid-responding lesions), were identified on centrally reviewed positron-emission tomography–computed tomography after two cycles. Involved-site radiation therapy was administered after the fifth cycle of therapy to slow-responding lesions and to large mediastinal adenopathy that was present at diagnosis. The primary end point was event-free survival, defined as the time until disease progression occurred, relapse occurred, a second malignant neoplasm developed, or the patient died. Safety and overall survival were assessed. RESULTS: Of 600 patients who were enrolled across 153 institutions, 587 were eligible. At a median follow-up of 42.1 months (range, 0.1 to 80.9), the 3-year event-free survival was 92.1% (95% confidence interval [CI], 88.4 to 94.7) in the brentuximab vedotin group, as compared with 82.5% (95% CI, 77.4 to 86.5) in the standard-care group (hazard ratio for event or death, 0.41; 95% CI, 0.25 to 0.67; P

LAG-3, through interaction with a variety of ligands, regulates T cell function via inhibition of T cell proliferation and activation. It has been demonstrated to be overexpressed on tumor infiltrating lymphocytes (TILs) of a variety of cancers with associated poor outcomes. The purpose of this study is to characterize the expression pattern and clinical significance of LAG-3 in pediatric Hodgkin lymphoma (HL). Patient tumor samples from Children's Oncology Group clinical trial AHOD0031 with matched patient outcome data were analyzed for the expression of LAG-3 and PD-L1 using immunohistochemistry. 73/115 patients (63%) demonstrated positive LAG-3 staining. No demographic or survival outcome data were significantly associated with LAG-3 expression. Interestingly, patients with the lowest density of expression were found to have the worst EFS, and those with highest density of expression demonstrated the best EFS. There was a positive statistically significant relationship between presence of LAG-3 and PD-L1 expression. This project is innovative in its characterization of LAG-3 as an immune checkpoint target in pediatric HL.

PURPOSE: The Children’s Oncology Group protocol AHOD0831, for pediatric patients with high-risk classical Hodgkin lymphoma (cHL), used response-adapted radiation fields, rather than larger involved-field radiation therapy (IFRT) that were historically used. This retrospective analysis of patterns of relapse among patients enrolled in the study was conducted to study the potential effect of a reduction in RT exposure. METHODS AND MATERIALS: From December 2009 to January 2012, 164 eligible patients under 22 years old with stage IIIB (43%) and stage IVB (57%) enrolled on AHOD0831. All patients received 4 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC). Those patients with a slow early response (SER) after the first 2 ABVE-PC courses were nonrandomly assigned to 2 intensification cycles with ifosfamide/vinorelbine before the final 2 ABVE-PC cycles. Response-adapted RT (21 Gy) was prescribed to initial areas of bulky disease and SER sites. Rapid early response (RER) sites without bulk were not targeted. Imaging studies at the time of progression or relapse were reviewed centrally for this retrospective analysis. Relapses were characterized with respect to site (initial, new, or both; and initial bulk or initial nonbulk), initial chemotherapy response, and radiation field (in-field, out-of-field, or both). RESULTS: Of the entire cohort, 140 patients were evaluable for the patterns of failure analyses. To investigate the pattern of failure, this analysis focuses on 23 patients who followed protocol treatment and suffered relapses at a median 1.05 years with 7.97-year median follow-up time. These 23 patients (11 RER and 12 SER) experienced a relapse in 105 total sites (median, 4; range, 1–11). Of the 105 relapsed sites, 67 sites (64%) occurred within an initial site of involvement, with 12 of these 67 sites (18%) at an initial site of bulky disease and 63 of these 67 relapses (94%) occurring in sites that were not fluorodeoxyglucose (FDG)-avid after 2 cycles of ABVE-PC (PET2-negative). Of the 105 relapsed sites, 34 sites (32%) occurred in a new site of disease (that would not have been covered by RT); and, overall, only 4 of 140 patients (2.8%) (occurring in 3 RER and 1 SER) experienced isolated out-of-field relapses that would have been covered by historical IFRT. CONCLUSIONS: For a cohort of high-risk patients with cHL patients, most failures occurred in nonbulky, initially involved sites, largely due to response-based consolidation RT delivered to patients with bulky disease. In this analysis, we discovered low rates of failures outside of these modern risk-adapted radiation treatment volumes. Also, FDG uptake on PET2 did not identify most relapse sites.

BACKGROUND Positron emission tomography (PET)-based measures of baseline total-body tumor burden may improve risk stratification in intermediate-risk Hodgkin lymphoma (HL). MATERIALS AND METHODS Evaluable patients were identified from a cohort treated homogeneously with the same combined modality regimen on the Children's Oncology Group AHOD0031 study. Eligible patients had high-quality baseline PET scans. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were each measured based on 15 thresholds for every patient. Univariate and multivariable Cox regression and Kaplan-Meier survival analyses assessed for an association of MTV and TLG with event-free survival (EFS). RESULTS From the AHOD0031 cohort (n = 1712), 86 patients were identified who (i) were treated with four cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE-PC) chemotherapy followed by involved field radiotherapy, and (ii) had a baseline PET scan that was amenable to quantitative analysis. Based on univariate Cox regression analysis, six PET-derived parameters were significantly associated with EFS. For each of these, Kaplan-Meier analyses and the log-rank test were used to compare patients with highest tumor burden (i.e., highest 15%) to the remainder of the cohort. EFS was significantly associated with all six PET parameters (all p

7504 Background: The anti-CD30 antibody drug conjugate, Brentuximab vedotin (Bv) is approved for adults with advanced stage HL but its use has not been established in children or adolescents. We compared the efficacy and safety of Bv with doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide (Bv-AVE-PC) to the standard pediatric dose intensive regimen ABVE-PC, inclusive of bleomycin. Methods: This multicenter randomized, open-label phase 3 study enrolled patients 2-21 years (yrs) with previously untreated HL, stages IIB + bulk, IIIB, IVA, IVB. Patients were randomized to 5 cycles of either ABVE-PC or Bv-AVE-PC given every 21 days with granulocyte colony-stimulating factor support. Centrally reviewed PET-CT after 2 cycles (PET2) identified slow responding lesions (SRL) defined as Deauville score > 3. Involved site radiotherapy (ISRT) was given to bulky mediastinal adenopathy and SRL. The primary objective was 3-year EFS; events include relapse/progression, second malignant neoplasm (SMN) or death. Final data cutoff was 31 December 2021. Results: 600 participants were enrolled across 151 institutions from March 2015 to August 2019; 587 were eligible. Median age was 15.6 yrs (range 3.4-21). Patient and disease characteristics were balanced across study arms. Histology was nodular sclerosing in 76.5%. Stage distribution: 20.6% IIB-bulk; 19.3% IIIB; 28.5% IVA; 31.7% IVB. At a median follow-up of 42.1 mos (0.1-80.9), 3-year EFS (95%CI) by intent-to-treat analyses was 82.5% (77.4, 86.5) with ABVE-PC and 92.1% (88.4, 94.7) with Bv-AVE-PC (HR 0.41 (0.25, 0.67), p = 0.0002). Median time to 1st event was 9.4 months for both arms but the range differs by arm (3.6-57.8 ABVE-PC; 1.3, 25.8 Bv-AVE-PC). Relapse rate was 17% following ABVE-PC and 7% with Bv-AVE-PC. One SMN is noted in each arm: thyroid cancer at 57.8 mos and acute myeloid leukemia at 20.3 mos. 3-year overall survival (95%CI) was 98.5% (96.0, 99.4) for ABVE-PC and 99.3% (97.3, 99.8) for Bv-AVE-PC (p = 0.38). PET2 SRL rates were comparable (ABVE-PC 19% vs. Bv-AVE-PC 18%, p = 0.8). As-treated ISRT receipt did not differ (ABVE-PC 55.7% vs. Bv-AVE-PC 52.7%, p = 0.69). No difference in grade 3/4 adverse events was observed; myelosuppression, reflected in a 32% incidence of > grade 3 febrile neutropenia, did not differ by arm (p = 0.67). Only 19% of patients experienced > grade 2 neuropathy by the Balis pediatric neuropathy scale, with no difference between arms (p = 0.86). Conclusions: Brentuximab vedotin with AVE-PC in a dose intensive regimen has superior efficacy to ABVE-PC for pediatric patients with high-risk HL. A 59% risk reduction in EFS was achieved with no increase in toxicity and with fewer patients receiving ISRT compared to prior pediatric trials for high-risk HL. Clinical trial information: 02166463.

Purpose/Objective(s) COG AHOD0831 was a multi-center, prospective study that used a response-adapted approach for patients Materials/Methods Patients from AHOD0831 were identified who had baseline PET scans that were amenable to quantitative analyses. For each patient, metabolic tumor volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake value (SUVmax), and peak SUV (SUVpeak) were obtained for mediastinal (m) and total body (t) disease. MTV was defined based on thresholds of SUV > 2.5 or > 40% SUVmax. TLG was defined as MTV * tumor SUVmean. EFS was assessed by Kaplan-Meier analyses. 2nd EFS was defined as the time to a second event, reflecting rates of successful salvage after a 1st relapse. Receiver operating characteristic analyses estimated the ability of PET parameters to predict EFS; optimized cutoff values were identified using a Youden index. Results Of 166 patients enrolled on AHOD0831, 94 (57%) had PET scans evaluable for quantitative analysis. For this subset: median age 15.5 years; 62% male; 67% white; 45% stage III, 55% stage IV; 86% bulk; 60% nodular sclerosis histology; 54% RER, 46% SER. These characteristics did not differ significantly from the complete AHOD0831 cohort. At a median follow-up of 49 months, 4-year EFS was 76% for the complete cohort (76% RERs, 75% SERs). Patients with high tMTVs and tTLGs, based on each threshold, were significantly more likely to be SERs (all P Conclusion RERs with a low baseline metabolic tumor burden experienced excellent EFS with less intensive therapy. Conversely, RERs with a high baseline tumor burden experienced poor EFS that was even worse than that of SERs. Thus, patients with a high metabolic tumor burden upfront may benefit from intensified therapy, even if they achieve a RER. PET-based measures of initial disease burden may contribute to risk-based treatment algorithms and improve outcomes in HL.

Survivors of Hodgkin lymphoma (HL) have an increased risk of subsequent malignant neoplasms (SMNs). Response-adapted treatment may decrease this risk by reducing exposure to therapy associated with SMN risk. The Children’s Oncology Group study AHOD0031 evaluated response-adapted therapy for children and adolescents with intermediate-risk HL. We report the SMNs among 1711 patients enrolled in AHOD0031. Patients were treated with 4 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide with or without involved-field radiation therapy (RT). Patients with a slow early response to initial chemotherapy were randomized to 2 additional cycles of dexamethasone, etoposide, cisplatin and cytarabine or no additional chemotherapy, and all received RT. At a median follow-up of 7.3 years, an analysis of SMNs was performed. The 10-year cumulative incidence of SMN was 1.3% (95% confidence interval [CI], 0.6-2.0). SMNs included 3 patients with acute myeloid leukemia (AML), 11 with solid tumors, and 3 with non-Hodgkin lymphoma. Sixteen of 17 patients with an SMN had received combined modality therapy. The standardized incidence ratio for SMN was 9.5 (95% CI, 4.5-15.2) with an excess absolute risk of 1.2 per 1000 person-years. The cumulative incidence of SMNs was higher among patients who received RT (P = .037). In multivariate analysis, RT, B symptoms, and race were associated with SMN risk. Given the latency from exposure, we have likely captured all cases of secondary leukemia and myelodysplastic syndrome (MDS). Longer follow-up is needed to determine the risk of solid tumors. Avoidance of RT without sacrificing disease control should remain a goal for future therapeutic approaches. This trial was registered at www.clinicaltrials.gov as #NCT00025259.

Background Pleural effusion at presentation in Hodgkin lymphoma has been associated with inferior outcome but has not been systematically evaluated. Objective To determine whether pleural effusion at presentation in children with Hodgkin lymphoma is a primary indicator of poor prognosis or secondary to associated factors. Materials and methods Children’s Oncology Group (COG) AHOD0031, a randomized, response-based, centrally reviewed protocol, enrolled 1,712 eligible patients

Introduction While 5-year event-free (EFS) and overall survival (OS) in Hodgkin lymphoma (HL) generally exceed 85% and 95%, respectively, outcomes may not be as favorable in adolescents and young adults (15 - 39 years [y]) compared to children. Small clinical trials have reported better outcomes for pediatric but not adult patients with mixed cellularity (MC) vs. nodular sclerosing (NS) histology, suggesting the possibility of biologic differences across the age-spectrum in HL. We examined survival by age and histology in patients receiving risk-based, response-adapted therapy for de novo HL on contemporary Children's Oncology Group (COG) trials. Methods This was a pooled analysis of individual-level data from 1,907 patients enrolled on three Phase 3 COG clinical trials for treatment of low-risk (AHOD0431), intermediate risk (AHOD0031) and high-risk (AHOD0831) HL between 2002 and 2012. Histologic subgroups included MC, NS and classical HL, not-otherwise-specified (cHL, NOS). Five-year cumulative incidence of relapse, EFS and OS were compared by age group ( Results Between 2002 and 2012, N= 2155 patients 1 - 21 y enrolled on three COG trials, 1,907 (88%) of whom were included in this analysis. Mean age of the cohort was 14.6 y (± 3.5) with N= 871 (46%) Survival: Median follow up was 6.9 years. In unadjusted analyses, 5-year EFS and OS were 83% and 97%, respectively. The 5-year EFS was lower for patients ≥15 y vs. The effect of age on EFS varied by histologic subgroup. Among those with non-MC histology, cumulative incidence of relapse did not significantly differ by age in unadjusted models (Figure A), however 5-year EFS was significantly worse in the older group (Figure B). In multivariable analyses, age ≥15 y (vs. younger) was associated with a 1.3-fold increased risk of EFS (HR: 1.3; 1.03 - 1.7, p= 0.03) (Table). Among patients with MC histology, age ≥15 y (vs. younger) was associated with significantly higher relapse rate (22% vs. 5%, p< 0.01) (Figure C) and significantly worse 5-year EFS (75% vs. 94%, p< 0.01) (Figure D). This remained significant in multivariable models: patients with MC histology who were ≥15 y (vs. younger) had a 3.7-fold increased risk of EFS (HR: 3.7, 95% CI: 1.6, 8.9, p< 0.01) (Table). Conclusion In patients receiving response-adapted therapy for de novo HL on contemporary COG trials, adolescents ≥15 y had worse EFS and OS compared to younger groups. The magnitude of the effect of age was higher in patients with MC disease. Although recent pediatric trials in HL have indicated better survival for some children with MC histology, alternative approaches or novel therapies should be considered for older adolescents with MC disease, whose outcomes appear more like adults. Disclosures No relevant conflicts of interest to declare.

Introduction: The role of the immune system and the microenvironment in Hodgkin Lymphoma (HL) has been well established. However, little is known about the effects of treatment on the immune cells in the peripheral blood or the frequency of tumor specific T cell responses to non-EBV HL specific antigens in pediatric and adolescent patients with HL. The goal of this project was to evaluate whether patients had increased tumor specific cytotoxic T cell responses and a pro-inflammatory cytokine milieu after treatment compared to at diagnosis. Methods: Peripheral blood samples were collected at diagnosis(pre) and following completion of treatment (post) from newly diagnosed high risk classical HL patients ages ≥2 to 22 years enrolled on a Children's Oncology Group sponsored Phase 3 clinical trial AHOD1331 randomizing to therapy containing the anti-CD30 immunoconjugate Brentuximab(Bv-AVEPC) vs. standard chemotherapy (ABVE-PC) (NCT02166463). Peripheral blood mononuclear cells (PBMC) and plasma were isolated using Ficoll Density gradient and analyzed in 206 patients to date. Pre and post plasma samples from 175 patients were tested for Th1/Th2 cytokines by Luminex assay. Tumor specific T cell responses at pre and post treatment have been tested in 64 of the 175 patients. Briefly, non-adherent T cells were stimulated ex vivo with autologous dendritic cells pulsed with HL specific pepmixes for the non-EBV tumor associated antigens (TAA) MAGEA4, PRAME and Survivin and expanded for a week in the presence of cytokines. TAA specificity was then tested using Interferon-γ ELISPOT assay. Immunophenotyping of the T cell subsets and the exhaustion marker profile was performed by flow cytometry in 49 patients with available PBMCs at both time points. Changes in cytokine levels pre versus post treatment were compared in univariate and multivariate analyses including the following variables: age at diagnosis, gender, stage, B symptoms, bulky disease and EBER status. Results: There was no difference in patient characteristics between the entire study cohort (n=587) and patients analyzed (n=206). There was a significant decrease in peripheral blood helper T cells (CD3+CD4+) and an increase in cytotoxic T cells (CD3+/CD8+) after treatment compared to at diagnosis (n=49 patients; p Conclusions: T cell responses to tumor associated antigens can be detected in patients with HL at diagnosis and after treatment. Increased T cell responses to MAGE4 and PRAME post therapy suggests that recovery post anti-HL treatment can promote tumor antigen specific T cell immunity in vivo. Further, reduced IL-13 and increased Interferon-γ following treatment suggest a favorable milieu for T cell expansion. Correlations between immune responses and clinical outcomes will be performed once outcome data are available. The impact of Bv will be evaluated by comparing the differences of the immune responses by treatment arm. Our results will help identify immune markers of response that can guide future immunotherapies for HL. Disclosures Bollard: Mana Therapeutics: Other: IP.

PURPOSE Population-based studies of children and adolescents with Hodgkin lymphoma (HL) report a survival disadvantage in nonwhite—non-Hispanic black (NHB) and Hispanic—patients. Whether disparities persist after adjustment for clinical and treatment-related variables is unknown. We examined survival by race/ethnicity in children receiving risk-based, response-adapted, combined-modality therapy for HL in contemporary Children’s Oncology Group trials. PATIENTS AND METHODS This pooled analysis used individual-level data from 1,605 patients (younger than age 1 to 21 years) enrolled in phase III trials for low-risk (AHOD0431), intermediate-risk (AHOD0031), and high-risk (AHOD0831) HL from 2002 to 2012. Event-free survival (EFS) and overall survival (OS) were compared between non-Hispanic white (NHW) and nonwhite patients. Cox proportional hazards for survival were estimated for both de novo and relapsed HL, adjusting for demographics, disease characteristics, and therapy. RESULTS At median follow up of 6.9 years, cumulative incidence of relapse was 17%. Unadjusted 5-year EFS and OS were 83% (SE, 1.2%) and 97% (SE, < 1%), respectively. Neither differed by race/ethnicity. In multivariable analyses for OS, nonwhite patients had a 1.88× higher hazard of death (95% CI, 1.1 to 3.3). Five-year postrelapse survival probabilities by race were as follows: NHW, 90%; NHB, 66%; and Hispanic, 80% ( P < .01). Compared with NHW, Hispanic and NHB children had 2.7-fold (95% CI, 1.2 to 6.2) and 3.5-fold (95% CI, 1.5 to 8.2) higher hazard of postrelapse mortality, respectively. CONCLUSION In patients who were treated for de novo HL in contemporary Children’s Oncology Group trials, EFS did not differ by race/ethnicity; however, adjusted OS was significantly worse in nonwhite patients, a finding driven by increased postrelapse mortality in this population. Additional studies examining treatment and survival disparities after relapse are warranted.

This study examines whether 6-thioguanine resistant T cells (mutant) from metastatic melanoma patients are enriched for melanoma-associated T cells compared to T cells obtained analogously without thioguanine selection (wild-type). Melanoma-associated antigen pentamer staining was performed on 5 tumour and 9 peripheral blood samples from metastatic melanoma patients. T cell receptor beta chain repertoire was examined via Sanger sequencing of mutant and wild-type in blood and tumour from metastatic melanoma patients at times of tumour progression (n = 8) and via Illumina sequencing in tumour derived T cells and in uncultured T cells (uncultured), wild-type and mutant from blood before and after immune checkpoint blockade (n = 1). Mutant from tumour (3 of 5; P < 0.001), but not blood (0 of 9), were enriched compared to wild-type for binding melanoma-associated antigen pentamers. T cell receptor beta analysis in patients with tumour progression (n = 8) detected increased melanoma associated T cells in mutant compared to wild-type from blood (Monte Carlo P = 10). Comparison of blood samples before and after immune checkpoint blockade with prior tumor from one metastatic melanoma patient detected increased T cell receptor beta sharing between tumour and mutant compared to tumour and wild-type or tumour and uncultured: 11.0% (72/656), 1.5% (206/13 639) and 1.3% (381/29 807), respectively (Monte Carlo P = 10 for mutant versus wild-type and mutant versus uncultured). These data demonstrate that mutant in metastatic melanoma patients are enriched for melanoma-associated T cells and are candidate probes to study in vivo melanoma-reactive T cells.

BACKGROUND Effective poststroke rehabilitation care can speed patient recovery and minimize patient functional disabilities. Veterans affairs (VA) community living centers (CLCs) and VA-contracted community nursing homes (CNHs) are the 2 major sources of institutional long-term care for Veterans with stroke receiving care under VA auspices. OBJECTIVES This study compares rehabilitation therapy and restorative nursing care among Veterans residing in VA CLCs versus those Veterans in VA-contracted CNHs. RESEARCH DESIGN Retrospective observational. SUBJECTS All Veterans diagnosed with stroke, newly admitted to the CLCs or CNHs during the study period who completed at least 2 Minimum Data Set assessments postadmission. MEASURES The outcomes were numbers of days for rehabilitation therapy and restorative nursing care received by the Veterans during their stays in CLCs or CNHs as documented in the Minimum Data Set databases. RESULTS For rehabilitation therapy, the CLC Veterans had lower user rates (75.2% vs. 76.4%, P=0.078) and fewer observed therapy days (4.9 vs. 6.4, P

Background: While survival in Hodgkin lymphoma (HL) is excellent, disparities by race/ethnicity have been described. Population-based and single-center studies of children and adolescents with Hodgkin lymphoma (HL) report a survival disadvantage in non-Hispanic black (NHB) and Hispanic (vs. non-Hispanic white [NHW]) patients (Grubb, Pediatr Blood Cancer 2016; Metzger, JCO 2008). These studies, though suggestive of a significant public health disparity, are often limited by lack of information about disease characteristics and therapeutic exposures. Thus, whether racial/ethnic disparities persist after adjustment for clinical and treatment-related variables remains a subject of debate. We examined event-free survival (EFS) and overall survival (OS) in NHW, NHB and Hispanic patients receiving risk-stratified, response-adapted therapy for de novo HL on contemporary Children’s Oncology Group (COG) trials. Methods: This was a pooled analysis of individual, patient-level data from 1,605 children and adolescents ( Results: Between 2002 and 2012, 2,155 patients enrolled on COG trials for the treatment of newly diagnosed HL; 1,605 (76%) were included in this study. Patients treated outside of the United States (N= 299), with lymphocyte predominant histology (N= 86), and who withdrew consent after one cycle (N= 37), were excluded. For the purpose of this study, analyses were restricted to patients who were NHW, NHB, and Hispanic. In total, N= 49 patients who were Asian/Pacific Islander and N= 79 patients who were other/mixed race were excluded. Sixty-seven percent of the study cohort (N= 1,083) was NHW. Among non-white patients (N= 522), 13% were NHB and 20% were Hispanic. Median age was 14.6 years (± 3.5 years). Approximately 16% of NHW patients vs. 41% and 44% of NHB and Hispanic patients had public or government insurance (P< 0.01). Non-white patients were also more to come from low-income households (P < 0.01). Compared with non-white patients, a higher proportion of NHW children had nodular sclerosing histology (P< 0.01). A higher proportion of non-white patients presented with stage III/IV (vs. I/II, P< 0.01) and bulky disease (P= 0.04); however, there was no difference in receipt of RT by race/ethnicity. At median follow-up of 6.9 years, cumulative incidence of relapse was 17% and did not significantly differ by race/ethnicity. Unadjusted 5-year EFS and OS were 83% (standard error [SE]: 1.2%) and 97% (SE: Conclusion: In the controlled setting of COG clinical trials, treatment with dose-dense, response-adapted therapy for newly diagnosed HL eliminates racial/ethnic differences in EFS. This observation suggests that current approaches to risk stratification with response-adapted regimens are highly effective for both NHW and non-white children with HL. Though there was no difference in EFS across NHW and non-white patients in our cohort, the striking difference in the risk of all-cause mortality lends weight to the possibility that differences in cancer therapy or supportive care outside of the cooperative group setting may be driving the disparities observed at the population level. Critical areas of future study to reduce racial disparities in HL should focus on improving health equity, expanding clinical trial participation, and dentifying drivers of racial/ethnic disparities in children with relapsed disease. Research support: This work was supported by the Children’s Oncology Group Chair Grant No. U10CA98543, the Children’s Oncology Group Statistics and Data Center Grant No. U10CA098413, the National Clinical Trials Network Operations Center Grant No. U10CA180886, and the National Clinical Trials Network Statistics and Data Center Grant No. U10CA180899. This work was also supported by the St. Baldrick’s Foundation, the Lymphoma Research Foundation, and by a KL2 Mentored Career Development Award Grant No. KL2-TR001874 from the Irving Institute for Clinical and Translational Research at Columbia University Irving Medical Center. Citation Format: Justine Kahn, Kara M. Kelly, Qinglin Pei, Rizvan Bush, Debra L. Friedman, Frank G. Keller, Smita Bhatia, Tara O. Henderson, Cindy L. Schwartz, Sharon M. Castellino. Survival by race and ethnicity in pediatric and adolescent patients with Hodgkin lymphoma: A report from the Children’s Oncology Group [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr IA37.

TO THE EDITOR: Pericardial effusion in patients with Hodgkin lymphoma (HL) occurs in 5% to 24% of patients at diagnosis.[1][1][⇓][2]-[3][3] However, little is known about the incidence, clinical characteristics, and outcomes for these patients. Most cases are clinically silent, and the effusion

Purpose Optimal management of patients with intermediate-risk lymphocyte-predominant Hodgkin lymphoma (LPHL) is unclear due to their small numbers in most clinical trials. Children's Oncology Group AHOD0031, a randomized phase III trial of pediatric patients with intermediate-risk Hodgkin lymphoma (HL), included patients with LPHL. We report the outcomes of these patients and present directions for future therapeutic strategies. Procedure Patients received two cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) followed by response evaluation. Slow early responders were randomized to two additional ABVE-PC cycles ± two dexamethasone, etoposide, cisplatin, and cytarabine cycles and all received involved field radiotherapy (IFRT). Rapid early responders (RERs) received two additional ABVE-PC cycles. RERs with complete response (CR) were randomized to IFRT or no further therapy. RERs without CR received IFRT. Results Ninety-six (5.6%) of 1711 patients on AHOD0031 had LPHL. Patients with LPHL were more likely to achieve RER (93.6% vs. 81.0%; P = 0.002) and CR (74.2% vs. 49.3%; P = 0.000005) following chemotherapy compared with patients with classical HL. Five-year event-free survival (EFS) was superior in patients with LPHL (92.2%) versus classical HL (83.5%) (P = 0.04), without difference in overall survival (OS). Among RERs with CR following chemotherapy (n = 33), there was no difference in EFS or OS between those randomized to receive or not receive IFRT. Conclusion Children and adolescents with intermediate-risk LPHL represent ideal candidates for response-adapted therapy based on their favorable outcomes. The majority of patients treated with the ABVE-PC backbone achieve RER with CR status and can be treated successfully without IFRT.

Background The Children's Oncology Group AHOD0431 study evaluated a response-directed treatment paradigm in which minimal initial chemotherapy and low-dose radiation was received only by patients who did not achieve a complete remission, and a chemotherapy/low-dose radiation salvage regimen was received by those who had a protocol-defined, low-risk recurrence. Methods Patients younger than 21 years who had stage IA or IIA nonbulky disease were eligible. The treatment strategy was evaluated by determining the proportion that received minimal chemotherapy alone, the proportion that had a first or second remission without the receipt of high-dose chemotherapy/stem cell rescue or higher dose involved-field radiation therapy (>21 grays), and overall survival. Results In total, 278 patients were eligible. At 4 years, 49.0% had received minimal chemotherapy and no radiation, 88.8% were in remission without receiving high-dose chemotherapy with stem cell rescue or >21 grays of involved-field radiation therapy, and the overall survival rate was 99.6%. Patients who had mixed cellularity histology had a 4-year event-free survival (EFS) rate of 95.2%, which was significantly better than the 75.8% EFS for those who had nodular sclerosis histology (P = .008). A red blood cell sedimentation rate ≤20 mm/hour and a negative fluorodeoxyglucose-positron emission tomography scan after 1 cycle of chemotherapy (PET1) were associated with a favorable EFS outcome. The study was closed early when the receipt of radiation therapy exceeded the predefined monitoring boundary. Conclusions This limited chemotherapy response-based approach was successful in patients who had a negative PET1 result, had MC histology, or had a low red blood cell sedimentation rate. In this treatment paradigm, evaluation of increased chemotherapy intensity or the integration of active new agents is indicated for patients who have nodular sclerosis histology with a high ESR or who have a positive PET1 result. Cancer 2018. © 2018 American Cancer Society.

Summary Background Patients with primary refractory Hodgkin's lymphoma or early relapse have a poor prognosis. Although many salvage regimens have been developed, there is no standard of care. Brentuximab vedotin and gemcitabine have been shown to be active in patients with relapsed or refractory Hodgkin's lymphoma when used as monotherapy, and each has been successfully used in combination with other agents. Preclinical data suggest that brentuximab vedotin can sensitise lymphoma cells to gemcitabine, supporting the use of the combination. We aimed to define the safety and efficacy of brentuximab vedotin with gemcitabine in children and young adults with primary refractory Hodgkin's lymphoma or early relapse. Methods In this Children's Oncology Group, multicentre, single-arm, phase 1–2 trial, we recruited patients with Hodgkin's lymphoma from hospitals across the USA and Canada. Eligible patients were aged younger than 30 years, had no previous brentuximab vedotin exposure, and had primary refractory disease or relapse of less than 1 year from completion of initial treatment. Each 21-day cycle consisted of 1000 mg/m2 intravenous gemcitabine on days 1 and 8 and intravenous brentuximab vedotin on day 1 at 1·4 mg/kg or 1·8 mg/kg. The primary objectives were to establish the recommended phase 2 dose of brentuximab vedotin in this combination, the safety of the combination, and the proportion of patients who achieved a complete response among those treated at the recommended phase 2 level, within four cycles of treatment. This trial is registered with ClinicalTrials.gov, number NCT01780662. Findings Between Feb 5, 2013, and Aug 19, 2016, 46 patients were enrolled, including one who was found to be ineligible, in the two phases of the study. The recommended phase 2 dose of brentuximab vedotin was 1·8 mg/kg in combination with gemcitabine 1000 mg/m2. 24 (57%) of 42 evaluable patients (95% CI 41–72) given this dose level had a complete response within the first four cycles of treatment. Four (31%) of 13 patients with a partial response or stable disease had all target lesions with Deauville scores of 3 or less after cycle 4. By modern response criteria, these were also complete responses (total number with complete response 28 [67%] of 42 [95% CI 51–80]). The most common grade 3–4 adverse events in all 42 participants treated at the recommended phase 2 dose were neutropenia (15 [36%]), rash (15 [36%]), transaminitis (9 [21%]), and pruritus (4 [10%]). There were no treatment-related deaths. Interpretation Brentuximab vedotin with gemcitabine is a safe combination treatment with a tolerable toxicity profile for patients with primary refractory Hodgkin's lymphoma or high-risk relapse. The preliminary activity of this combination shown in this trial warrants further investigation in randomised controlled trials. Funding National Institutes of Health and the St. Baldrick's Foundation.

Background. Paresis in stroke is largely a result of damage to descending corticospinal and corticobulbar pathways. Recovery of paresis predominantly reflects the impact on the neural consequences of this white matter lesion by reactive neuroplasticity (mechanisms involved in spontaneous recovery) and experience-dependent neuroplasticity, driven by therapy and daily experience. However, both theoretical considerations and empirical data suggest that type of stroke (large vessel distribution/lacunar infarction, hemorrhage), locus and extent of infarction (basal ganglia, right-hemisphere cerebral cortex), and the presence of leukoaraiosis or prior stroke might influence long-term recovery of walking ability. In this secondary analysis based on the 408 participants in the Locomotor Experience Applied Post-Stroke (LEAPS) study database, we seek to address these possibilities. Methods. Lesion type, locus, and extent were characterized by the 2 neurologists in the LEAPS trial on the basis of clinical computed tomography and magnetic resonance imaging scans. A series of regression models was used to test our hypotheses regarding the effects of lesion type, locus, extent, and laterality on 2- to 12-month change in gait speed, controlling for baseline gait speed, age, and Berg Balance Scale score. Results. Gait speed change at 1 year was significantly reduced in participants with basal ganglia involvement and prior stroke. There was a trend toward reduction of gait speed change in participants with lacunar infarctions. The presence of right-hemisphere cortical involvement had no significant impact on outcome. Conclusions. Type, locus, and extent of lesion, and the loss of substrate for neuroplastic effect as a result of prior stroke may affect long-term outcome of rehabilitation of hemiparetic gait.

Literature review and cross-sectional study.Direct access to physical therapy necessitates greater responsibility to determine appropriateness of care by recognizing the potential for concomitant disease or systemic involvement. Recent research has identified excessive variability in the reporting of red flag symptoms. An initial step to improve the identification of red flag symptoms is the development of a standardized screening tool.To describe the development of a review-of-systems screening tool appropriate for use by orthopaedic physical therapists.First, a red flag symptom item bank was compiled from a systematic literature review to allow for further psychometric testing and development of a screening tool. Second, physical therapists in 11 outpatient clinics recruited patients presenting with primary complaints of neck, shoulder, low back, or knee pain. Patients completed the red flag symptom item bank and standard questionnaires for comorbidities, negative mood, quality of life, pain, and function. The development of the screening tool involved identifying and combining different 3-item sets that characterized the highest number of patients reporting at least 1 positive symptom response (operationally defined as "red flag symptom responder").The literature search yielded 103 studies that met the inclusion criteria, and the final item bank consisted of 97 items representing 8 body systems. Four hundred thirty-one patients with primary complaints of neck (n = 93), shoulder (n = 108), low back (n = 119), or knee (n = 111) disorders contributed to the cross-sectional study. The number of red flag symptom responders was 393 of 431 (91.2%). These patients were older, more likely to be female, had lower income, and were more likely to report neck or back pain (all, P.05). A 10-item review-of-systems screening tool correctly identified 372 of 393 (94.7%) responders, and a 23-item version identified all 393 (100%) responders. The review-of-systems screening tools and the complete 97-item bank had similar correlations with concurrent clinical measures, except for depressive symptoms.Concise red flag symptom identification appears to be feasible in outpatient orthopaedic physical therapy settings. Future research will determine how this review-of-systems screening tool needs refinement for different patient populations and whether it predicts clinical outcomes or the need for referral to other providers.

Background Evidence-based guidelines are needed to inform rehabilitation practice, including the effect of number of exercise training sessions on recovery of walking ability after stroke. Objective The objective of this study was to determine the response to increasing number of training sessions of 2 interventions—locomotor training and strength and balance exercises—on poststroke walking recovery. Design This is a secondary analysis of the Locomotor Experience Applied Post-Stroke (LEAPS) randomized controlled trial. Setting Six rehabilitation sites in California and Florida and participants’ homes were used. Participants Participants were adults who dwelled in the community (N=347), had had a stroke, were able to walk at least 3 m (10 ft) with assistance, and had completed the required number of intervention sessions. Intervention Participants received 36 sessions (3 times per week for 12 weeks), 90 minutes in duration, of locomotor training (gait training on a treadmill with body-weight support and overground training) or strength and balance training. Measurements Talking speed, as measured by the 10-Meter Walk Test, and 6-minute walking distance were assessed before training and following 12, 24, and 36 intervention sessions. Results Participants at 2 and 6 months after stroke gained in gait speed and walking endurance after up to 36 sessions of treatment, but the rate of gain diminished steadily and, on average, was very low during the 25- to 36-session epoch, regardless of treatment type or severity of impairment. Limitations Results may not generalize to people who are unable to initiate a step at 2 months after stroke or people with severe cardiac disease. Conclusions In general, people who dwelled in the community showed improvements in gait speed and walking distance with up to 36 sessions of locomotor training or strength and balance exercises at both 2 and 6 months after stroke. However, gains beyond 24 sessions tended to be very modest. The tracking of individual response trajectories is imperative in planning treatment.

PURPOSE: The presented protocol for pediatric intermediate-risk Hodgkin lymphoma evaluated the use of a dose-intensive chemotherapy regimen (ABVE-PC [doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, prednisone]) with response-based therapy augmentation (addition of DECA [dexamethasone, etoposide, cisplatin, cytarabine]) or therapy reduction (elimination of radiation). METHODS AND MATERIALS: A central review of the radiation therapy data for quality assurance was performed, and the association between radiation protocol deviation (RPD) and relapse was assessed in the pediatric group (age

Background Patients with Parkinson disease (PD) are at high risk of hospital encounters with increasing morbidity and mortality. This study aimed to determine the rate of hospital encounters in a cohort followed over 5 years and to identify associated factors. Methods We queried the data from the International Multicenter National Parkinson Foundation Quality Improvement study. Multivariate logistic regression with backward selection was performed to identify factors associated with hospital encounter prior to baseline visit. Kaplan-Meier estimates were obtained and Cox regression performed on time to hospital encounter after the baseline visit. Results Of the 7,507 PD patients (mean age 66.5±9.9 years and disease duration 8.9±6.4 years at baseline visit), 1919 (25.6%) had a history of a hospital encounter prior to their baseline visit. Significant factors associated with a history of a hospital encounter prior to baseline included race (white race: OR 0.49), utilization of physical therapy (OR 1.47), history of deep brain stimulation (OR 1.87), number of comorbidities (OR 1.30), caregiver strain (OR 1.17 per standard deviation), and the standardized Timed Up and Go Test (OR 1.21). Patients with a history of hospitalization prior to the baseline were more likely to have a re-hospitalization (HR1.67, P

Huanguang Jia,1 Qinglin Pei,1 Charles T Sullivan,1 Diane C Cowper Ripley,1 Samuel S Wu,1 W Bruce Vogel,1 Xinping Wang,1 Douglas E Bidelspach,2 Jennifer L Hale-Gallardo,1 Barbara E Bates3 1Center of Innovation on Disability and Rehabilitation Research, North Florida/South Georgia Veterans Health System, Gainesville, FL, 2Physical Medicine and Rehabilitation Service, Department of Veterans Affairs, Washington, DC, 3Aleda E. Lutz VA Medical Center, Saginaw, MI, USA Introduction: Effective post-acute multidisciplinary rehabilitation therapy improves stroke survivors’ functional recovery and daily living activities. The US Department of Veterans Affairs (VA) places veterans needing post-acute institutional care in private community nursing homes (CNHs). These placements are made under the same rules and regulations across the VA health care system and through individual per diem contracts between local VA facilities and CNHs. However, there is limited information about utilization of these veterans’ health services as well as the geographic variation of the service utilization. Aim: The aims of this study were to determine rehabilitation therapy and restorative nursing care utilization by veterans with stroke in VA-contracted CNHs and to assess risk-adjusted regional variations in the utilization of rehabilitation therapy and restorative nursing care. Methods: This retrospective study included all veterans diagnosed with stroke residing in VA-contracted CNHs between 2006 and 2009. Minimum Dataset (a health status assessment tool for CNH residents) for the study CNHs was linked with veterans’ inpatient and outpatient data within the VA health care system. CNHs were grouped into five VA-defined geographic regions: the North Atlantic, Southeast, Midwest, Continental, and Pacific regions. A two-part model was applied estimating risk-adjusted utilization probability and average weekly utilization days. Two dependent variables were rehabilitation therapy and restorative nursing care utilization by veterans during their CNH stays. Results: The study comprised 6,206 veterans at 2,511 CNHs. Rates for utilization of rehabilitation therapy and restorative nursing care were 75.7% and 30.1%, respectively. Veterans in North Atlantic and Southeast CNHs were significantly (p

Background Histologic prognostic factors have been described for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). This study examines histologic and immunophenotypic variants in a clinical trial for pediatric NLPHL. Procedure One hundred sixty-eight cases of localized NLPHL were examined for histologic variants, CD30 and immunoglobulin D (IgD) expression, and outcome. Histologic types were scored categorically as 0 = 0, 1 ≤ 25%, and 2 > 25% of the sample. Results Fifty-eight (35.1%) cases showed only typical nodular with or without serpiginous histology (types A and B). The remainder showed mixtures of histologies. The numbers of patients with score 2 are 85 (50.6%) type A, 21 (12.5%) type B, 46 (27.4%) with extranodular large B cells (type C), 3 with T-cell-rich nodular pattern (type D), 55 (32.7%) with diffuse T-cell-rich (type E) pattern, and 2 (1.2%) with diffuse B-cell pattern (type F). Higher level of types C (P = 0.048) and D (P = 0.033) resulted in lower event-free survival (EFS). Cytoplasmic IgD was found in 65 of 130 tested (50%), did not significantly associate with EFS but positively correlated with types C and E histology (P < 0.0001) and negatively correlated with types A (P = 0.0003) and B (P = 0.006). Seventeen (10%) expressed CD30, with no adverse effect. Conclusions Variant histology is common in pediatric NLPHL, especially types C and E, which are associated with IgD expression. Type C variant histology and possibly type D are associated with decreased EFS, but neither IgD nor CD30 are adverse features. Variant histology may warrant increased surveillance, but did not affect overall survival.

10064 Background: CIPN is a common, but under-recognized complication of tubulin toxins, which are key to curative therapy for HL. In the absence of validated, self- or proxy-report measures for children, CIPN reporting has depended on clinical grading scales. The goal of this study was to assess the psychometric properties of the FACT-GOG-Ntx measure in a pediatric population. Methods: Youth (11+ yrs) and parents of all children (5-18 yrs) with newly diagnosed high risk HL, enrolled on AHOD1331 (NCT02166463), serially completed the FACT-GOG-Ntx, a validated measure of CIPN in adults. Cronbach’s alpha coefficient (reliability) and intra-class coefficients (ICC) were calculated. FACT-GOG-Ntx total scale and 4-item sensory subscale scores (Ntx4) at Cycle 5 (dose peak) and 6-8 weeks after last cycle (End Rx) were compared to mandatory clinical grading, using the Balis Scale with any neuropathy defined as > grade 1 on Balis. Results: 279 youth and 291 parents completed study measures. Cronbach’s alpha exceeded 0.80 for both raters. Inter-rater agreement was strong (ICC=0.89). Sixty (20%) patients had any neuropathy on Balis. Those with CIPN had significantly lower total and Ntx4 scores than those without at cycle 5 and End Rx and for both raters (p