Nivolumab and brentuximab vedotin with or without bendamustine for R/R Hodgkin lymphoma in children, adolescents, and young adults.

Children, adolescents, and young adults (CAYA) with relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) without complete metabolic response (CMR) before autologous hematopoietic cell transplantation (auto-HCT) have poor survival outcomes. CheckMate 744, a phase 2 study for CAYA (aged 5-30 years) with R/R cHL, evaluated a risk-stratified, response-adapted approach with nivolumab plus brentuximab vedotin (BV) followed by BV plus bendamustine for patients with suboptimal response. Risk stratification was primarily based on time to relapse, prior treatment, and presence of B symptoms. We present the primary analysis of the standard-risk cohort. Data from the low-risk cohort are reported separately. Patients received 4 induction cycles with nivolumab plus BV; those without CMR (Deauville score >3, Lugano 2014) received BV plus bendamustine intensification. Patients with CMR after induction or intensification proceeded to consolidation (high-dose chemotherapy/auto-HCT per protocol). Primary end point was CMR any time before consolidation. Forty-four patients were treated. Median age was 16 years. At a minimum follow-up of 15.6 months, 43 patients received 4 induction cycles (1 discontinued), 11 of whom received intensification; 32 proceeded to consolidation. CMR rate was 59% after induction with nivolumab plus BV and 94% any time before consolidation (nivolumab plus BV ± BV plus bendamustine). One-year progression-free survival rate was 91%. During induction, 18% of patients experienced grade 3/4 treatment-related adverse events. This risk-stratified, response-adapted salvage strategy had high CMR rates with limited toxicities in CAYA with R/R cHL. Most patients did not require additional chemotherapy (bendamustine intensification). Additional follow-up is needed to confirm durability of disease control. This trial was registered at www.clinicaltrials.gov as #NCT02927769.

Pulmonary lesions in early response assessment in pediatric Hodgkin lymphoma: prevalence and possible implications for initial staging.

BACKGROUND: Disseminated pulmonary involvement in pediatric Hodgkin lymphoma (pHL) is indicative of Ann Arbor stage IV disease. During staging, it is necessary to assess for coexistence of non-malignant lung lesions due to infection representing background noise to avoid erroneously upstaging with therapy intensification. OBJECTIVE: This study attempts to describe new lung lesions detected on interim staging computed tomography (CT) scans after two cycles of vincristine, etoposide, prednisolone, doxorubicin in a prospective clinical trial. Based on the hypothesis that these new lung lesions are not part of the underlying malignancy but are epiphenomena, the aim is to analyze their size, number, and pattern to help distinguish true lung metastases from benign lung lesions on initial staging. MATERIALS AND METHODS: A retrospective analysis of the EuroNet-PHL-C1 trial re-evaluated the staging and interim lung CT scans of 1,300 pediatric patients with HL. Newly developed lung lesions during chemotherapy were classified according to the current Fleischner glossary of terms for thoracic imaging. Patients with new lung lesions found at early response assessment (ERA) were additionally assessed and compared to response seen in hilar and mediastinal lymph nodes. RESULTS: Of 1,300 patients at ERA, 119 (9.2%) had new pulmonary lesions not originally detectable at diagnosis. The phenomenon occurred regardless of initial lung involvement or whether a patient relapsed. In the latter group, new lung lesions on ERA regressed by the time of relapse staging. New lung lesions on ERA in patients without relapse were detected in 102 (7.8%) patients. Pulmonary nodules were recorded in 72 (5.5%) patients, the majority (97%) being<10 mm. Consolidations, ground-glass opacities, and parenchymal bands were less common. CONCLUSION: New nodules on interim staging are common, mostly measure less than 10 mm in diameter and usually require no further action because they are most likely non-malignant. Since it must be assumed that benign and malignant lung lesions coexist on initial staging, this benign background noise needs to be distinguished from lung metastases to avoid upstaging to stage IV disease. Raising the cut-off size for lung nodules to ≥ 10 mm might achieve the reduction of overtreatment but needs to be further evaluated with survival data. In contrast to the staging criteria of EuroNet-PHL-C1 and C2, our data suggest that the number of lesions present at initial staging may be less important.

Response-adapted omission of radiotherapy in children and adolescents with early-stage classical Hodgkin lymphoma and an adequate response to vincristine, etoposide, prednisone, and doxorubicin (EuroNet-PHL-C1): a titration study.

BACKGROUND: Children and adolescents with early-stage classical Hodgkin lymphoma have a 5-year event-free survival of 90% or more with vincristine, etoposide, prednisone, and doxorubicin (OEPA) plus radiotherapy, but late complications of treatment affect survival and quality of life. We investigated whether radiotherapy can be omitted in patients with adequate morphological and metabolic responses to OEPA. METHODS: The EuroNet-PHL-C1 trial was designed as a titration study and recruited patients at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed stage IA, IB, and IIA classical Hodgkin lymphoma younger than 18 years of age were assigned to treatment group 1 to be treated with two cycles of OEPA (vincristine 1·5 mg/m2 intravenously, capped at 2 mg, on days 1, 8, and 15; etoposide 125 mg/m2 intravenously, on days 1-5; prednisone 60 mg/m2 orally on days 1-15; and doxorubicin 40 mg/m2 intravenously on days 1 and 15). If no adequate response (a partial morphological remission or greater and PET negativity) had been achieved after two cycles of OEPA, involved-field radiotherapy was administered at a total dose of 19·8 Gy (usually in 11 fractions of 1·8 Gy per day). The primary endpoint was event-free survival. The primary objective was maintaining a 5-year event-free survival rate of 90% in patients with an adequate response to OEPA without radiotherapy. We performed intention-to-treat and per-protocol analyses. The trial was registered at ClinicalTrials.gov (NCT00433459) and with EUDRACT, (2006-000995-33) and is completed. FINDINGS: Between Jan 31, 2007, and Jan 30, 2013, 2131 patients were registered and 2102 patients were enrolled onto EuroNet-PHL-C1. Of these 2102 patients, 738 with early-stage disease were allocated to treatment group 1. Median follow-up was 63·3 months (IQR 60·1-69·8). We report on 714 patients assigned to and treated on treatment group 1; the intention-to-treat population comprised 713 patients with 323 (45%) male and 390 (55%) female patients. In 440 of 713 patients in the intention-to-treat group who had an adequate response and did not receive radiotherapy, 5-year event-free survival was 86·5% (95% CI 83·3-89·8), which was less than the 90% target rate. In 273 patients with an inadequate response who received radiotherapy, 5-year event-free survival was 88·6% (95% CI 84·8-92·5), for which the 95% CI included the 90% target rate. The most common grade 3-4 adverse events were neutropenia (in 597 [88%] of 680 patients) and leukopenia (437 [61%] of 712). There were no treatment-related deaths. INTERPRETATION: On the basis of all the evidence, radiotherapy could be omitted in patients with early-stage classical Hodgkin lymphoma and an adequate response to OEPA, but patients with risk factors might need more intensive treatment. FUNDING: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder, Gießen, Kinderkrebsstiftung Mainz of the Journal Oldtimer Markt, Tour der Hoffnung, Menschen für Kinder, Mitteldeutsche Kinderkrebsforschung, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.

Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma (EuroNet-PHL-C1): a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial.

BACKGROUND: Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment with vincristine, etoposide, prednisone, and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) and radiotherapy, but long-term treatment effects affect survival and quality of life. We aimed to investigate whether radiotherapy can be omitted in patients with morphological and metabolic adequate response to OEPA and whether modified consolidation chemotherapy reduces gonadotoxicity. METHODS: Our study was designed as a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial, and was carried out at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed intermediate-stage (treatment group 2) and advanced-stage (treatment group 3) classical Hodgkin lymphoma who were younger than 18 years and stratified according to risk using Ann Arbor disease stages IIAE, IIB, IIBE, IIIA, IIIAE, IIIB, IIIBE, and all stages IV (A, B, AE, and BE) were included in the study. Patients with early disease (treatment group 1) were excluded from this analysis. All patients were treated with two cycles of OEPA (1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1, 8, and 15; 125 mg/m2 etoposide taken intravenously on days 1-5; 60 mg/m2 prednisone taken orally on days 1-15; and 40 mg/m2 doxorubicin taken intravenously on days 1 and 15). Patients were randomly assigned to two (treatment group 2) or four (treatment group 3) cycles of COPP (500 mg/m2 cyclophosphamide taken intravenously on days 1 and 8; 1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1 and 8; 40 mg/m2 prednisone taken orally on days 1 to 15; and 100 mg/m2 procarbazine taken orally on days 1 to 15) or COPDAC, which was identical to COPP except that 250 mg/m2 dacarbazine administered intravenously on days 1 to 3 replaced procarbazine. The method of randomisation (1:1) was minimisation with stochastic component and was centrally stratified by treatment group, country, trial sites, and sex. The primary endpoint was event-free survival, defined as time from treatment start until the first of the following events: death from any cause, progression or relapse of classical Hodgkin lymphoma, or occurrence of secondary malignancy. The primary objectives were maintaining 90% event-free survival at 5 years in patients with adequate response to OEPA treated without radiotherapy and to exclude a decrease of 8% in event-free survival at 5 years in the embedded COPDAC versus COPP randomisation to show non-inferiority of COPDAC. Efficacy analyses are reported per protocol and safety in the intention-to-treat population. The trial is registered with ClinicalTrials.gov (trial number NCT00433459) and EUDRACT (trial number 2006-000995-33), and is closed to recruitment. FINDINGS: Between Jan 31, 2007, and Jan 30, 2013, 2102 patients were recruited. 737 (35%) of the 2102 recruited patients were in treatment group 1 (early-stage disease) and were not included in our analysis. 1365 (65%) of the 2102 patients were in treatment group 2 (intermediate-stage disease; n=455) and treatment group 3 (advanced-stage disease; n=910). Of these 1365, 1287 (94%) patients (435 [34%] of 1287 in treatment group 2 and 852 [66%] of 1287 in treatment group 3) were included in the titration trial per-protocol analysis. 937 (69%) of 1365 patients were randomly assigned to COPP (n=471) or COPDAC (n=466) in the embedded trial. Median follow-up was 66·5 months (IQR 62·7-71·7). Of 1287 patients in the per-protocol group, 514 (40%) had an adequate response to treatment and were not treated with radiotherapy (215 [49%] of 435 in treatment group 2 and 299 [35%] of 852 in treatment group 3). 773 (60%) of 1287 patients with inadequate response were scheduled for radiotherapy (220 [51%] of 435 in the treatment group 2 and 553 [65%] of 852 in treatment group 3. In patients who responded adequately, event-free survival rates at 5 years were 90·1% (95% CI 87·5-92·7). event-free survival rates at 5 years in 892 patients who were randomly assigned to treatment and analysed per protocol were 89·9% (95% CI 87·1-92·8) for COPP (n=444) versus 86·1% (82·9-89·4) for COPDAC (n=448). The COPDAC minus COPP difference in event-free survival at 5 years was -3·7% (-8·0 to 0·6). The most common grade 3-4 adverse events (intention-to-treat population) were decreased haemoglobin (205 [15%] of 1365 patients during OEPA vs 37 [7%] of 528 treated with COPP vs 20 [2%] of 819 treated with COPDAC), decreased white blood cells (815 [60%] vs 231 [44%] vs 84 [10%]), and decreased neutrophils (1160 [85%] vs 223 [42%] vs 174 [21%]). One patient in treatment group 2 died of sepsis after the first cycle of OEPA; no other treatment-related deaths occurred. INTERPRETATION: Our results show that radiotherapy can be omitted in patients who adequately respond to treatment, when consolidated with COPP or COPDAC. COPDAC might be less effective, but is substantially less gonadotoxic than COPP. A high proportion of patients could therefore be spared radiotherapy, eventually reducing the late effects of treatment. With more refined criteria for response assessment, the number of patients who receive radiotherapy will be further decreased. FUNDING: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder Gießen, Kinderkrebsstiftung Mainz, Tour der Hoffnung, Menschen für Kinder, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.

Assessment of Waldeyer's ring in pediatric and adolescent Hodgkin lymphoma patients-Importance of multimodality imaging: Results from the EuroNet-PHL-C1 trial.

BACKGROUND: In the EuroNet Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials, decision on Waldeyer's ring (WR) involvement is usually based on clinical assessment, that is, physical examination and/or nasopharyngoscopy. However, clinical assessment only evaluates mucosal surface and is prone to interobserver variability. Modern cross-sectional imaging technology may provide valuable information beyond mucosal surface, which may lead to a more accurate WR staging. PATIENTS, MATERIALS, AND METHODS: The EuroNet-PHL-C1 trial recruited 2102 patients, of which 1752 underwent central review including reference reading of their cross-sectional imaging data. In 14 of 1752 patients, WR was considered involved according to clinical assessment. In these 14 patients, the WR was re-assessed by applying an imaging-based algorithm considering information from 18 F-fluorodeoxyglucose positron emission tomography, contrast-enhanced computed tomography, and/or magnetic resonance imaging. For verification purposes, the imaging-based algorithm was applied to 100 consecutive patients whose WR was inconspicuous on clinical assessment. RESULTS: The imaging-based algorithm confirmed WR involvement only in four of the 14 patients. Of the remaining 10 patients, four had retropharyngeal lymph node involvement and six an inconspicuous WR. Applying the imaging-based algorithm to 100 consecutive patients with physiological appearance of their WR on clinical assessment, absence of WR involvement could be confirmed in 99. However, suspicion of WR involvement was raised in one patient. CONCLUSIONS: The imaging-based algorithm was feasible and easily applicable at initial staging of young patients with Hodgkin lymphoma. It increased the accuracy of WR staging, which may contribute to a more individualized treatment in the future.

Treatment of classical Hodgkin lymphoma in young adults aged 18-30 years with a modified paediatric Hodgkin lymphoma protocol. Results of a multicentre phase II clinical trial (CRUK/08/012).

This phase II trial was designed to determine the safety and efficacy of a modified paediatric risk-stratified protocol in young adults (18-30 years) with classical Hodgkin Lymphoma. The primary end-point was neurotoxicity rate. The incidence of grade 3 neurotoxicity was 11% (80% CI, 5-19%); a true rate of neuropathy of >15% cannot be excluded. Neuropathy and associated deterioration in quality of life was largely reversible. The overall response rate was 100% with 40% complete remission (CR) rate. Twelve months disease-free survival (DFS) was 91%. We demonstrate that a risk-stratified paediatric combined modality treatment approach can be delivered to young adults without significant irreversible neuropathy.

Whole-body MRI for staging and interim response monitoring in paediatric and adolescent Hodgkin's lymphoma: a comparison with multi-modality reference standard including 18F-FDG-PET-CT.

OBJECTIVES: To prospectively investigate concordance between whole-body MRI (WB-MRI) and a composite reference standard for initial staging and interim response evaluation in paediatric and adolescent Hodgkin's lymphoma. METHODS: Fifty patients (32 male, age range 6-19 years) underwent WB-MRI and standard investigations, including 18F-FDG-PET-CT at diagnosis and following 2-3 chemotherapy cycles. Two radiologists in consensus interpreted WB-MRI using prespecified definitions of disease positivity. A third radiologist reviewed a subset of staging WB-MRIs (n = 38) separately to test for interobserver agreement. A multidisciplinary team derived a primary reference standard using all available imaging/clinical investigations. Subsequently, a second multidisciplinary panel rereviewed all imaging with long-term follow-up data to derive an enhanced reference standard. Interobserver agreement for WB-MRI reads was tested using kappa statistics. Concordance for correct classification of all disease sites, true positive rate (TPR), false positive rate (FPR) and kappa for staging/response agreement were calculated for WB-MRI. RESULTS: There was discordance for full stage in 74% (95% CI 61.9-83.9%) and 44% (32.0-56.6%) of patients against the primary and enhanced reference standards, respectively. Against the enhanced reference standard, the WB-MRI TPR, FPR and kappa were 91%, 1% and 0.93 (0.90-0.96) for nodal disease and 79%, < 1% and 0.86 (0.77-0.95) for extra-nodal disease. WB-MRI response classification was correct in 25/38 evaluable patients (66%), underestimating response in 26% (kappa 0.30, 95% CI 0.04-0.57). There was a good agreement for nodal (kappa 0.78, 95% CI 0.73-0.84) and extra-nodal staging (kappa 0.60, 95% CI 0.41-0.78) between WB-MRI reads CONCLUSIONS: WB-MRI has reasonable accuracy for nodal and extra-nodal staging but is discordant with standard imaging in a substantial minority of patients, and tends to underestimate disease response. KEY POINTS: • This prospective single-centre study showed discordance for full patient staging of 44% between WB-MRI and a multi-modality reference standard in paediatric and adolescent Hodgkin's lymphoma. • WB-MRI underestimates interim disease response in paediatric and adolescent Hodgkin's lymphoma. • WB-MRI shows promise in paediatric and adolescent Hodgkin's lymphoma but currently cannot replace conventional staging pathways including 18F-FDG-PET-CT.

Whole-body magnetic resonance imaging in paediatric Hodgkin lymphoma - evaluation of quantitative magnetic resonance metrics for nodal staging.

BACKGROUND: Whole-body MRI is used for staging paediatric Hodgkin lymphoma, commonly using size thresholds, which fail to detect disease in normal-size lymph nodes. OBJECTIVE: To investigate quantitative whole-body MRI metrics for nodal characterisation. MATERIALS AND METHODS: Thirty-seven children with Hodgkin lymphoma underwent 1.5-tesla (T) whole-body MRI using short tau inversion recovery (STIR) half-Fourier-acquisition single-shot turbo-spin-echo and diffusion-weighted imaging (DWI). 18Flourine-2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET)/CT was acquired as the reference standard. Two independent readers assessed 11 nodal sites. The readers measured short-axis-diameter, apparent diffusion coefficient, (ADC) and normalised T2-signal intensity of the largest lymph node at each site. We used receiver operating characteristics (ROC)/area-under-the-curve (AUC) analysis for each MRI metric and derived sensitivity and specificity for nodes with short-axis diameter ≥10 mm. Sub-analysis of sensitivity and specificity was performed with application of ADC cut-off values (<0.77, <1.15 and <1.79×10-3 mm2 s-1) to 5- to 9-mm nodes. RESULTS: ROC/AUC values for reader 1/reader 2 were 0.80/0.80 and 0.81/0.81 for short-axis-diameter measured using DWI and STIR half-Fourier-acquisition single-shot turbo spin echo, respectively; 0.67/0.72 for normalised T2 signal intensity and 0.74/0.67 for ADC. Sensitivity and specificity for a short-axis diameter ≥10 mm were 84.2% and 66.7% for Reader 1 and 82.9% and 68.9% for Reader 2. Applying a short-axis-diameter ≥10-mm threshold followed by ADC cut-offs to normal-size 5- to 9-mm nodes resulted in sensitivity and specificity for Reader 1 of 88.8% and 60%, 92.1% and 56.7%, and 100% and 16.7%; and for Reader 2, 86.1% and 67.2%, 95.3% and 65.6%, and 100% and 19.7%; and ADC thresholds of <0.77, <1.15, and <1.79×10-3 mm2 s-1, respectively. CONCLUSION: Nodal size measurement provides the best single classifier for nodal disease status in paediatric Hodgkin lymphoma. Combined short-axis diameter and ADC thresholds marginally improve sensitivity and drop specificity compared with size classification alone.

Treatment outcome in children and adolescents with relapsed Hodgkin lymphoma--results of the UK HD3 relapse treatment strategy.

The purpose of this national retrospective study was to evaluate the outcome in children with relapsed or primary refractory Hodgkin lymphoma [HL] after a primary chemotherapy alone treatment strategy. Between 2000 and 2005, 80 children with relapsed [n = 69] or primary refractory [n = 11] HL were treated on a standardized treatment protocol of 4-6 cycles of EPIC [etoposide, prednisolone, ifosfamide and cisplatin] chemotherapy. Radiotherapy was recommended to all relapsed sites. High dose therapy with stem cell rescue [SCT] was recommended for patients with poor response. The 5-year overall survival [OS] and progression-free survival from relapse was 75·8% [64·8-83·9] and 59·9% [48·3-69·7] respectively. Duration of first remission was strongly associated with OS; risk of death was decreased by 53% [Hazard ratio (HR): 0·47, 95% confidence interval (CI): 0·19-1·18] for those with a time from end of treatment to relapse of 3-12 months (compared to <3 months) and reduced by 80% (HR 0·20, 95% CI: 0·04-0·90) for those >12 months after end of treatment. Other poor prognostic factors included advanced stage disease at relapse and B symptoms at first diagnosis. The most important factor associated with salvage failure was time to relapse. Survival outcome in children with primary refractory HL is poor.

Hodgkin lymphoma: hypodense lesions in mediastinal masses.

Hypodense volumes (HDV) in mediastinal masses can be visualized in a computed tomography scan in Hodgkin lymphoma. We analyzed staging CT scans of 1178 patients with mediastinal involvement from the EuroNet-PHL-C1 trial and explored correlations of HDV with patient characteristics, mediastinal tumor volume and progression-free survival. HDV occurred in 350 of 1178 patients (29.7%), typically in larger mediastinal volumes. There were different patterns in appearance with single lesions found in 243 patients (69.4%), multiple lesions in 107 patients (30.6%). Well delineated lesions were found in 248 cases (70.1%), diffuse lesions were seen in 102 cases (29.1%). Clinically, B symptoms occurred more often in patients with HDV (47.7% compared to 35.0% without HDV (p = 0.039)) and patients with HDV tended to be in higher risk groups. Inadequate overall early-18F-FDG-PET-response was strongly correlated with the occurrence of hypodense lesions (p < 0.001). Patients with total HDV > 40 ml (n = 80) had a 5 year PFS of 79.6% compared to 89.7% (p = 0.01) in patients with HDV < 40 ml or no HDV. This difference in PFS is not caused by treatment group alone. HDV is a common phenomenon in HL with mediastinal involvement.

Diffusion-weighted MRI of lymphoma: prognostic utility and implications for PET/MRI?

PURPOSE: With the recent introduction of PET/MRI, we investigated whether diffusion-weighted imaging (DWI) can complement PET for predicting local treatment response in Hodgkin lymphoma. METHODS: This retrospective study included 39 patients selected from a hospital database with a histological diagnosis of Hodgkin lymphoma undergoing whole-body MRI (supplemented by DWI) and PET/CT before and after two cycles of vincristine, etoposide, prednisolone and doxorubicin (OEPA). The pretreatment volume, MRI apparent diffusion coefficient (ADC) and PET maximum standardized uptake value (SUV(max)) of the largest nodal mass were determined quantitatively for evaluation of the local response following two cycles of OEPA. Quantitative pretreatment imaging biomarkers (disease volume, ADC, SUV(max)) were compared between sites with an adequate and those with an inadequate response using Fisher's exact test and Mann Whitney statistics. Multivariate models predictive of an inadequate response based on demographic/clinical features, pretreatment disease volume and SUV(max) without (model 1) and with (model 2) the addition of ADC were derived and crossvalidated. The ROC area under curve (AUC) was calculated for both models using the full dataset (training) and the crossvalidation (test) data. RESULTS: Sites with an adequate response had a significantly lower median pretreatment ADC (1.0 × 10(-3)mm(2)s(-1)) than those with an inadequate response (1.26 × 10(-3)mm(2)s(-1); p < 0.01). There were no significant differences in patient demographic/clinical parameters, pretreatment SUV(max) or pretreatment nodal volume between sites with inadequate and adequate response. The ROC-AUCs for prediction of an inadequate response for the training and test data for model 1 were 0.90 and 0.53, and for model 2 were 0.84 and 0.71, respectively. CONCLUSION: DWI complements PET for prediction of site-specific interim response to chemotherapy.

Dynamic contrast-enhanced MRI improves accuracy for detecting focal splenic involvement in children and adolescents with Hodgkin disease.

BACKGROUND: Accurate assessment of splenic disease is important for staging Hodgkin lymphoma. OBJECTIVE: The purpose of this study was to assess T2-weighted imaging with and without dynamic contrast-enhanced (DCE) MRI for evaluation of splenic Hodgkin disease. MATERIALS AND METHODS: Thirty-one children with Hodgkin lymphoma underwent whole-body T2-weighted MRI with supplementary DCE splenic imaging, and whole-body PET-CT before and following chemotherapy. Two experienced nuclear medicine physicians derived a PET-CT reference standard for splenic disease, augmented by follow-up imaging. Unaware of the PET-CT, two experienced radiologists independently evaluated MRI exercising a locked sequential read paradigm (T2-weighted then DCE review) and recorded the presence/absence of splenic disease at each stage. Performance of each radiologist was determined prior to and following review of DCE-MRI. Incorrect MRI findings were ascribed to reader (lesion present on MRI but missed by reader) or technical (lesion not present on MRI) error. RESULTS: Seven children had splenic disease. Sensitivity/specificity of both radiologists for the detection of splenic involvement using T2-weighted images alone was 57%/100% and increased to 100%/100% with DCE-MRI. There were three instances of technical error on T2-weighted imaging; all lesions were visible on DCE-MRI. CONCLUSIONS: T2-weighted imaging when complemented by DCE-MRI imaging may improve evaluation of Hodgkin disease splenic involvement.

Nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents--a comprehensive review of biology, clinical course and treatment options.

Nodular lymphocyte predominant Hodgkin lymphoma (nLPHL) is a unique variant of Hodgkin lymphoma with an overall good prognosis. It is conspicuously different from classical Hodgkin lymphoma (cHL) and is now recognized as distinctive form of B cell lymphoma. Although it has an indolent clinical course, it has a propensity for multiple and often late relapses. Although the majority of children present with early stage disease and without B symptoms, treatment strategy has, until recently, been identical to that used for cHL. This approach is excessively toxic as it predisposes these children and adolescents to serious late effects including end organ damage to heart, gonads, lungs, thyroid and second malignant neoplasms. The aim of this article is to review the published literature on the treatment outcomes of nLPHL in affected children and adolescents, and discuss the options for treatment including surgery, chemotherapy, radiotherapy and targeted anti-CD 20 antibody therapy.

Management of relapsed and refractory classical Hodgkin lymphoma in children and adolescents.

There are a number of options for salvage treatment in children and adolescents with relapsed and refractory classical Hodgkin Lymphoma. These include salvage with standard dose chemotherapy, high dose chemotherapy with autologous stem cell transplant, allogeneic stem cell transplant or other novel approach. Radiotherapy has an important role in the salvage of some patients as part of a combined modality approach. This review outlines these salvage approaches and discusses whether the evidence from paediatric studies justifies a risk-adapted approach to salvage for individual patients or whether all patients should receive consolidation with high dose chemotherapy and autologous stem cell transplantation, which is often described as standard salvage management in adults. The important prognostic factors and how these may be used to allocate patients to standard versus high dose chemotherapy regimens are discussed. The role of allogeneic transplantation, novel agents and late effects will also be discussed.

18F-FDG PET/MRI for Staging and Interim Response Assessment in Pediatric and Adolescent Hodgkin Lymphoma: A Prospective Study with 18F-FDG PET/CT as the Reference Standard.

Treatment regimens for pediatric Hodgkin lymphoma (HL) depend on accurate staging and treatment response assessment, based on accurate disease distribution and metabolic activity depiction. With the aim of radiation dose reduction, we compared the diagnostic performance of 18F-FDG PET/MRI with a 18F-FDG PET/CT reference standard for staging and response assessment. Methods: Twenty-four patients (mean age, 15.4 y; range, 8-19.5 y) with histologically proven HL were prospectively and consecutively recruited in 2015 and 2016, undergoing both 18F-FDG PET/CT and 18F-FDG PET/MRI at initial staging (n = 24) and at response assessment (n = 21). The diagnostic accuracy of 18F-FDG PET/MRI for both nodal and extranodal disease was compared with that of 18F-FDG PET/CT, which was considered the reference standard. Discrepancies were retrospectively classified as perceptual or technical errors, and 18F-FDG PET/MRI and 18F-FDG PET/CT were corrected by removing perceptual error. Agreement with Ann Arbor staging and Deauville grading was also assessed. Results: For nodal and extranodal sites combined, corrected staging 18F-FDG PET/MRI sensitivity was 100% (95% CI, 96.7%-100%) and specificity was 99.5% (95% CI, 98.3%-99.9%). Corrected response-assessment 18F-FDG PET/MRI sensitivity was 83.3% (95% CI, 36.5%-99.1%) and specificity was 100% (95% CI, 99.2%-100%). Modified Ann Arbor staging agreement between 18F-FDG PET/CT and 18F-FDG PET/MRI was perfect (κ = 1.0, P = 0.000). Deauville grading agreement between 18F-FDG PET/MRI and 18F-FDG PET/CT was excellent (κ = 0.835, P = 0.000). Conclusion:18F-FDG PET/MRI is a promising alternative to 18F-FDG PET/CT for staging and response assessment in children with HL.

Pediatric and adolescent lymphoma: comparison of whole-body STIR half-Fourier RARE MR imaging with an enhanced PET/CT reference for initial staging.

PURPOSE: To compare the diagnostic performance of rapid whole-body anatomic magnetic resonance (MR) staging of pediatric and adolescent lymphoma to an enhanced positron emission tomographic (PET)/computed tomographic (CT) reference standard. MATERIALS AND METHODS: Ethical permission was given by the University College London Hospital ethics committee, and informed written consent was obtained from all participants and/or parents or guardians. Thirty-one subjects (age range, 7.3-18.0 years; 18 male, 11 female) with histologically proved lymphoma were prospectively recruited. Pretreatment staging was performed with whole-body short inversion time inversion-recovery (STIR) half-Fourier rapid acquisition with relaxation enhancement (RARE) MR imaging, fluorine 18 fluorodeoxyglucose PET/CT, and contrast agent-enhanced chest CT. Twenty-six subjects had posttreatment PET/CT and compromised our final cohort. Eleven nodal and 11 extranodal sites per patient were assessed on MR imaging by two radiologists in consensus, with a nodal short-axis threshold of >1 cm and predefined extranodal positivity criteria. The same sites were independantly evaluated by two nuclear medicine physicians on PET/CT images. Disease positivity was defined as a maximum standardized uptake value >2.5 or nodal size >1 cm. An unblinded expert panel reevaluated the imaging findings, removing perceptual errors, and derived an enhanced PET/CT reference standard (taking into account chest CT and 3-month follow-up imaging) against which the reported and intrinsic performance of MR imaging was assessed by using the kappa statistic. RESULTS: There was very good agreement between MR imaging and the enhanced PET/CT reference standard for nodal and extranodal staging (kappa = 0.96 and 0.86, respectively) which improved following elimination of perceptual errors (kappa = 0.97 and 0.91, respectively). The sensitivity and specificity of MR imaging (following removal of perceptual error) were 98% and 99%, respectively, for nodal disease and 91% and 99%, respectively, for extranodal disease. CONCLUSION: Whole-body STIR half-Fourier RARE MR imaging of pediatric and adolescent lymphoma can accurately depict nodal and extranodal disease and may provide an alternative nonionizing imaging method for anatomic disease assessment at initial staging.

Risk and Response Adapted Treatment Guidelines for Managing First Relapsed and Refractory Classical Hodgkin Lymphoma in Children and Young People. Recommendations from the EuroNet Pediatric Hodgkin Lymphoma Group.

The objective of this guideline is to aid clinicians in making individual salvage treatment plans for pediatric and adolescent patients with first relapse or refractory (R/R) classical Hodgkin lymphoma (cHL). While salvage with standard dose chemotherapy followed by high dose chemotherapy and autologous stem cell transplant is often considered the standard of care in adult practice, pediatric practice adopts a more individualized risk stratified and response adapted approach to salvage treatment with greater use of non-transplant salvage. Here, we present on behalf of the EuroNet Pediatric Hodgkin Lymphoma group, evidence and consensus-based guidelines for standardized diagnostic, prognostic and response procedures to allocate children and adolescents with R/R cHL to stratified salvage treatments.

Novel markers in pediatric-type follicular lymphoma.

The aim of this study was to review the histopathological, phenotypic, and molecular characteristics of pediatric-type follicular lymphoma (PTFL) and to assess the diagnostic value of novel immunohistochemical markers in distinguishing PTFL from follicular hyperplasia (FH). A total of 13 nodal PTFLs were investigated using immunohistochemistry, fluorescence in situ hybridization (FISH), and PCR and were compared with a further 20 reactive lymph nodes showing FH. Morphologically, PTFL cases exhibited a follicular growth pattern with irregular lymphoid follicles in which the germinal centers were composed of numerous blastoid cells showing a starry-sky appearance. Immunohistochemistry highlighted preserved CD10 (13/13) and BCL6 (13/13) staining, CD20 (13/13) positivity, a K light chain predominance (7/13), and partial BCL2 expression in 6/13 cases (using antibodies 124, E17, and SP66). The germinal center (GC)-associated markers stathmin and LLT-1 were positive in most of the cases (12/13 and 12/13, respectively). Interestingly, FOXP-1 was uniformly positive in PTFL (12/13 cases) in contrast to reactive GCs in FH, where only a few isolated positive cells were observed. FISH revealed no evidence of BCL2, BCL6, or MYC rearrangements in the examined cases. By PCR, clonal immunoglobulin gene rearrangements were detected in 100% of the tested PTFL cases. Our study confirmed the unique morphological and immunophenotypic features of PTFL and suggests that FOXP-1 can represent a novel useful diagnostic marker in the differential diagnosis between PTFL and FH.