Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin's Lymphoma.

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<0.001). The percentage of patients who received involved-site radiation therapy did not differ substantially between the brentuximab vedotin group and the standard-care group (53.4% and 56.8%, respectively). Toxic effects were similar in the two groups. Overall survival at 3 years was 99.3% (95% CI, 97.3 to 99.8) in the brentuximab vedotin group and 98.5% (95% CI, 96.0 to 99.4) in the standard-care group. CONCLUSIONS: The addition of brentuximab vedotin to standard chemotherapy resulted in superior efficacy, with a 59% lower risk of an event or death, and no increase in the incidence of toxic effects at 3 years. (Funded by the National Institutes of Health and others; AHOD1331 ClinicalTrials.gov number, NCT02166463.).

Targeted radiotherapy for early-stage, low-risk pediatric Hodgkin lymphoma slow early responders: a COG AHOD0431 analysis.

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.

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

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

Subsequent malignant neoplasms among children with Hodgkin lymphoma: a report from the Children's Oncology Group.

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.

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

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

Durable remission for four pediatric patients with high-risk relapsed classical Hodgkin lymphoma treated with brentuximab vedotin plus gemcitabine but without autologous stem cell transplantation: A report from the Children's Oncology Group.

Patients with therapy-refractory or high-risk relapsed classical Hodgkin lymphoma are typically treated with the high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) to consolidate the response to salvage therapy. The combination of brentuximab vedotin with gemcitabine has recently been shown to be an effective and safe salvage regimen. While the majority of patients with complete responses to this regimen ultimately underwent HDC/ASCT consolidation, four subjects, reported herein, achieved durable complete remissions lasting more than 4 years after the study treatment but without ASCT consolidation. Further investigation of treatment strategies incorporating targeted agents may allow omission of HDC/ASCT for select patients.

Prognostic value of baseline metabolic tumor volume in children and adolescents with intermediate-risk Hodgkin lymphoma treated with chemo-radiation therapy: FDG-PET parameter analysis in a subgroup from COG AHOD0031.

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 < .029). In a multivariable model controlling for important covariates including disease bulk and response to chemotherapy, MTV2BP was significantly associated with EFS (p = .012). CONCLUSION: Multiple baseline PET-derived volumetric parameters were associated with EFS. MTV2BP was highly associated with EFS when controlling for disease bulk and response to chemotherapy. Incorporation of baseline MTV into risk-based treatment algorithms may improve outcomes in intermediate-risk HL.

An evaluation of machine learning techniques to predict the outcome of children treated for Hodgkin-Lymphoma on the AHOD0031 trial: A report from the Children's Oncology Group.

In this manuscript we analyze a data set containing information on children with Hodgkin Lymphoma (HL) enrolled on a clinical trial. Treatments received and survival status were collected together with other covariates such as demographics and clinical measurements. Our main task is to explore the potential of machine learning (ML) algorithms in a survival analysis context in order to improve over the Cox Proportional Hazard (CoxPH) model. We discuss the weaknesses of the CoxPH model we would like to improve upon and then we introduce multiple algorithms, from well-established ones to state-of-the-art models, that solve these issues. We then compare every model according to the concordance index and the brier score. Finally, we produce a series of recommendations, based on our experience, for practitioners that would like to benefit from the recent advances in artificial intelligence.

Response-adapted therapy for the treatment of children with newly diagnosed high risk Hodgkin lymphoma (AHOD0831): a report from the Children's Oncology Group.

The AHOD0831 study for paediatric patients with high risk Hodgkin lymphoma tested a response-based approach designed to limit cumulative alkylator exposure and reduce radiation volumes. Patients (Stage IIIB/IVB) received two cycles of ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide). Rapid early responders [RER, no positron emission tomography (PET) activity above mediastinal blood pool] were consolidated with 2 cycles of ABVE-PC. Slow early responders (SER) received 2 cycles of ifosfamide/vinorelbine and 2 cycles of ABVE-PC. Radiotherapy was administered to sites of initial bulk and/or SER. By intent-to-treat analysis, 4-year second event-free survival (EFS; freedom from second relapse or malignancy) was 91·9% [95% confidence interval (CI): 86·1-95·3%], below the projected baseline of 95% (P = 0·038). Five-year first EFS and overall survival (OS) rates are 79·1% (95% CI: 71·5-84·8%) and 95% (95% CI: 88·8-97·8%). Eight of 11 SER patients with persistent PET positive lesions at the end of chemotherapy had clinical evidence of active disease (3 biopsy-proven, 5 with progressive disease or later relapses). Although this response-directed approach did not reach the ambitiously high pre-specified target for second EFS, EFS and OS rates are comparable with results of recent trials despite the reduction in radiotherapy volumes from historical involved fields. Persistent PET at end of chemotherapy identifies a cohort at an especially high risk for relapse/early progression.

Brentuximab vedotin with gemcitabine for paediatric and young adult patients with relapsed or refractory Hodgkin's lymphoma (AHOD1221): a Children's Oncology Group, multicentre single-arm, phase 1-2 trial.

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.

Results of the AHOD0431 trial of response adapted therapy and a salvage strategy for limited stage, classical Hodgkin lymphoma: A report from the Children's Oncology Group.

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.

Outcomes in intermediate-risk pediatric lymphocyte-predominant Hodgkin lymphoma: A report from the Children's Oncology Group.

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.

Variant histology, IgD and CD30 expression in low-risk pediatric nodular lymphocyte predominant Hodgkin lymphoma: A report from the Children's Oncology Group.

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.

Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study.

BACKGROUND: Most patients with juvenile myelomonocytic leukemia (JMML) are curable only with allogeneic hematopoietic cell transplantation (HCT). However, the current standard conditioning regimen, busulfan-cyclophosphamide-melphalan (Bu-Cy-Mel), may be associated with higher risks of morbidity and mortality. ASCT1221 was designed to test whether the potentially less-toxic myeloablative conditioning regimen containing busulfan-fludarabine (Bu-Flu) would be associated with equivalent outcomes. PROCEDURE: Twenty-seven patients were enrolled on ASCT1221 from 2013 to 2015. Pre- and post-HCT (starting Day +30) mutant allele burden was measured in all and pre-HCT therapy was administered according to physician discretion. RESULTS: Fifteen patients were randomized (six to Bu-Cy-Mel and nine to Bu-Flu) after meeting diagnostic criteria for JMML. Pre-HCT low-dose chemotherapy did not appear to reduce pre-HCT disease burden. Two patients, however, received aggressive chemotherapy pre-HCT and achieved low disease-burden state; both are long-term survivors. All four patients with detectable mutant allele burden at Day +30 post-HCT eventually progressed compared to two of nine patients with unmeasurable allele burden (P = 0.04). The 18-month event-free survival of the entire cohort was 47% (95% CI, 21-69%), and was 83% (95% CI, 27-97%) and 22% (95% CI, 03-51%) for Bu-Cy-Mel and Bu-Flu, respectively (P = 0.04). ASCT1221 was terminated early due to concerns that the Bu-Flu arm had inferior outcomes. CONCLUSIONS: The regimen of Bu-Flu is inadequate to provide disease control in patients with JMML who present to HCT with large burdens of disease. Advances in molecular testing may allow better characterization of biologic risk, pre-HCT responses to chemotherapy, and post-HCT management.

Significance of pleural effusion at diagnosis in pediatric Hodgkin lymphoma: a report from Children's Oncology Group protocol AHOD0031.

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 <22 years of age with initial presentation of intermediate risk, biopsy-proven Hodgkin lymphoma; 1,423 had available imaging for retrospective review. We coded effusions as fluid-only or with associated pleural nodule or adjacent lung or bone involvement and correlated this with disease stage, tumor response, large mediastinal adenopathy, and mass effect on the superior vena cava (SVC) and left innominate vein. We recorded change in size and character of effusions post-chemotherapy. RESULTS: Pleural effusions were present in 217, with 204 having fluid-only and 13 having associated solid components. Patients with effusions were more likely to have large mediastinal adenopathy (P<0.0001), be slow early responders (P<0.0001) and have higher relapse rate (P<0.0001). Vascular compression was not significantly correlated with pleural effusion. Of 121 patients with adequate [F-18]2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET)/CT imaging, no FDG PET avidity was seen in any pleural effusion but was present in solid components. The side of the pleural effusion in those with moderate or large effusions was highly associated with the side of large mediastinal adenopathy (P<0.0001). Statistical analysis indicates that pleural effusion is an independent risk factor for poorer response and relapse. CONCLUSION: Pleural effusion in Hodgkin lymphoma is an important independent poor prognostic indicator for response and relapse.

Poststroke Rehabilitation and Restorative Care Utilization: A Comparison Between VA Community Living Centers and VA-contracted Community Nursing Homes.

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<0.001) than CNH Veterans. However, the CLC Veterans had higher adjusted odds for therapy (odds ratio=1.16, P=0.033), although they had fewer average therapy days (coefficient=-1.53±0.11, P<0.001). For restorative nursing care, CLC Veterans had higher user rates (33.5% vs. 30.6%, P<0.001), more observed average care days (9.4 vs. 5.9, P<0.001), higher adjusted odds (odds ratio=2.28, P<0.001), and more adjusted days for restorative nursing care (coefficient=5.48±0.37, P<0.001). CONCLUSION: Compared with their counterparts at VA-contracted CNHs, Veterans at VA CLCs had fewer average rehabilitation therapy days (both unadjusted and adjusted), but they were significantly more likely to receive restorative nursing care both before and after risk adjustment.

Concordance and discordance between measured and perceived balance and the effect on gait speed and falls following stroke.

OBJECTIVE: To ascertain the existence of discordance between perceived and measured balance in persons with stroke and to examine the impact on walking speed and falls. DESIGN: A secondary analysis of a phase three, multicentered randomized controlled trial examining walking recovery following stroke. SUBJECTS: A total of 352 participants from the Locomotor Experience Applied Post-Stroke (LEAPS) trial. METHODS: Participants were categorized into four groups: two concordant and two discordant groups in relation to measured and perceived balance. Number and percentage of individuals with concordance and discordance were evaluated at two and 12 months. Walking speed and fall incidence between groups were examined. MAIN MEASURES: Perceived balance was measured by the Activities-Specific Balance Confidence scale, measured balance was determined by the Berg Balance Scale and gait speed was measured by the 10-meter walk test. RESULTS: Discordance was present for 35.8% of participants at two months post stroke with no statistically significant change in proportion at 12 months. Discordant participants with high perceived balance and low measured balance walked 0.09 m/s faster at two months than participants with concordant low perceived and measured balance (p < 0.05). Discordant participants with low perceived balance and high measured balance walked 0.15 m/s slower than those that were concordant with high perceived and measured balance (p ⩽ 0.0001) at 12 months. Concordant participants with high perceived and measured balance walked fastest and had fewer falls. CONCLUSIONS: Discordance existed between perceived and measured balance in one-third of individuals at two and 12 months post-stroke. Perceived balance impacted gait speed but not fall incidence.

A conditional predictive p-value to compare a multinomial with an overdispersed multinomial in the analysis of T-cell populations.

Immunological experiments that record primary molecular sequences of T-cell receptors produce moderate to high-dimensional categorical data, some of which may be subject to extra-multinomial variation caused by technical constraints of cell-based assays. Motivated by such experiments in melanoma research, we develop a statistical procedure for testing the equality of two discrete populations, where one population delivers multinomial data and the other is subject to a specific form of overdispersion. The procedure computes a conditional-predictive p-value by splitting the data set into two, obtaining a predictive distribution for one piece given the other, and using the observed predictive ordinate to generate a p-value. The procedure has a simple interpretation, requires fewer modeling assumptions than would be required of a fully Bayesian analysis, and has reasonable operating characteristics as evidenced empirically and by asymptotic analysis.

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

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