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

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

Expert consensus statements for Waldeyer's ring involvement in pediatric Hodgkin lymphoma: The staging, evaluation, and response criteria harmonization (SEARCH) for childhood, adolescent, and young adult Hodgkin lymphoma (CAYAHL) group.

Waldeyer's ring (WR) involvement in pediatric Hodgkin lymphoma (HL) is extremely rare and criteria for determining involvement and response to treatment are unclear. The international Staging, Evaluation, and Response Criteria Harmonization for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (SEARCH for CAYAHL) Group performed a systematic review of the literature in search of involvement or response criteria, or evidence to support specific criteria. Only 166 cases of HL with WR involvement were reported in the literature, 7 of which were pediatric. To date no standardized diagnostic or response assessment criteria are available. Given the paucity of evidence, using a modified Delphi survey technique, expert consensus statements were developed by the SEARCH group to allow for a more consistent definition of disease and response evaluation related to this rare site of involvement among pediatric oncologists. The available evidence and expert consensus statements are summarized.

Preemptive immunotherapy in childhood acute myeloid leukemia for patients showing evidence of mixed chimerism after allogeneic stem cell transplantation.

Previous studies have shown that children with acute myeloid leukemia (AML) who developed mixed chimerism (MC) were at high risk for relapse after allogeneic stem-cell transplantation (allo-SCT). We investigated the feasibility of intensified preemptive immunotherapy in children receiving allo-SCT for AML. Eighty-four children were registered in our trial from May 2005 to April 2009; of these, 71 fulfilled the inclusion criteria and were treated according to the study protocol. Serial and semiquantitative analyses of posttransplantation chimerism were performed. Defined immunotherapy approaches were considered in MC patients. Continuous complete chimerism (CC) was observed in 51 of 71 patients. MC was detected in 20 patients and was followed by immunotherapy in 13. Six of 13 MC patients returned to CC without toxicity and remained in long-term remission. Overall, the probability of event-free survival (pEFS) was 66% (95% confidence interval [95% CI] = 53%-76%) for all patients and 46% (95% CI = 19%-70%) in MC patients with intervention; however, this number increased to 71% (95% CI = 26%-92%) in 7 of 13 MC patients on immunotherapy who were in remission at the time of transplantation. All MC patients without intervention relapsed. These results suggest that MC is a prognostic factor for impending relapse in childhood AML, and that preemptive immunotherapy may improve the outcome in defined high-risk patients after transplantation.

Significance of E-lesions in Hodgkin lymphoma and the creation of a new consensus definition: a report from SEARCH.

The International Staging Evaluation and Response Criteria Harmonization for Childhood, Adolescent, and Young Adult Hodgkin Lymphoma (SEARCH for CAYAHL) seeks to provide an appropriate, universal differentiation between E-lesions and stage IV extranodal disease in Hodgkin lymphoma (HL). A literature search was performed through the PubMed and Google Scholar databases using the terms "Hodgkin disease," and "extranodal," "extralymphatic," "E lesions," "E stage," or "E disease." Publications were reviewed for the number of participants; median age and age range; diagnostic modalities used for staging; and the definition, incidence, and prognostic significance of E-lesions. Thirty-six articles describing 12 640 patients met the inclusion criteria. Most articles reported staging per the Ann Arbor (72%, 26/36) or Cotswolds modification of the Ann Arbor staging criteria (25%, 9/36), and articles rarely defined E-lesions or disambiguated "extranodal disease." The overall incidence of E-lesions for patients with stage I-III HL was 11.5% (1330/11 602 unique patients). Available stage-specific incidence analysis of 3888 patients showed a similar incidence of E-lesions in stage II (21.2%) and stage III (21.9%), with E-lesions rarely seen with stage I disease (1.1%). E-lesions likely remain predictive, but we cannot unequivocally conclude that identifying E-lesions in HL imparts prognostic value in the modern era of the more selective use of targeted radiation therapy. A harmonized E-lesion definition was reached based on the available evidence and the consensus of the SEARCH working group. We recommend that this definition of E-lesion be applied in future clinical trials with explicit reporting to confirm the prognostic value of E-lesions.

Prospective Evaluation of Different Methods for Volumetric Analysis on [18F]FDG PET/CT in Pediatric Hodgkin Lymphoma.

Rationale: Therapy response evaluation by 18F-fluorodeoxyglucose PET/CT (FDG PET) has become a powerful tool for the discrimination of responders from non-responders in pediatric Hodgkin lymphoma (HL). Recently, volumetric analyses have been regarded as a valuable tool for disease prognostication and biological characterization in cancer. Given the multitude of methods available for volumetric analysis in HL, the AIEOP Hodgkin Lymphoma Study Group has designed a prospective analysis of the Italian cohort enrolled in the EuroNet-PHL-C2 trial. Methods: Primarily, the study aimed to compare the different segmentation techniques used for volumetric assessment in HL patients at baseline (PET1) and during therapy: early (PET2) and late assessment (PET3). Overall, 50 patients and 150 scans were investigated for the current analysis. A dedicated software was used to semi-automatically delineate contours of the lesions by using different threshold methods. More specifically, four methods were applied: (1) fixed 41% threshold of the maximum standardized uptake value (SUVmax) within the respective lymphoma site (V41%), (2) fixed absolute SUV threshold of 2.5 (V2.5); (3) SUVmax(lesion)/SUVmean liver >1.5 (Vliver); (4) adaptive method (AM). All parameters obtained from the different methods were analyzed with respect to response. Results: Among the different methods investigated, the strongest correlation was observed between AM and Vliver (rho > 0.9; p < 0.001 for SUVmean, MTV and TLG at all scan timing), along with V2.5 and AM or Vliver (rho 0.98, p < 0.001 for TLG at baseline; rho > 0.9; p < 0.001 for SUVmean, MTV and TLG at PET2 and PET3, respectively). To determine the best segmentation method, we applied logistic regression and correlated different results with Deauville scores at late evaluation. Logistic regression demonstrated that MTV (metabolic tumor volume) and TLG (total lesion glycolysis) computation according to V2.5 and Vliver significantly correlated to response to treatment (p = 0.01 and 0.04 for MTV and 0.03 and 0.04 for TLG, respectively). SUVmean also resulted in significant correlation as absolute value or variation. Conclusions: The best correlation for volumetric analysis was documented for AM and Vliver, followed by V2.5. The volumetric analyses obtained from V2.5 and Vliver significantly correlated to response to therapy, proving to be preferred thresholds in our pediatric HL cohort.

Brentuximab vedotin for paediatric relapsed or refractory Hodgkin's lymphoma and anaplastic large-cell lymphoma: a multicentre, open-label, phase 1/2 study.

BACKGROUND: Despite remarkable progress in the treatment of newly-diagnosed classical Hodgkin's lymphoma and systemic anaplastic large-cell lymphoma, treatment of relapsed or refractory disease remains challenging. The aims of this study were to assess the safety, tolerability, recommended phase 2 dose, and efficacy of brentuximab vedotin in paediatric patients with relapsed or refractory Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma. METHODS: This open-label, dose-escalation phase 1/2 study was done at 12 centres across eight countries (France, Germany, Italy, Mexico, The Netherlands, Spain, UK, and USA). We recruited paediatric patients aged 7-18 years with relapsed or refractory classical Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma, for whom standard treatment was unavailable or no longer effective. Participants were allocated to receive brentuximab vedotin at 1·4 mg/kg (phase 1) or 1·8 mg/kg (phases 1 and 2) via intravenous infusion once every 3 weeks for up to 16 cycles. Dose escalation was done via a 3+3 design. Key exclusion criteria were stem-cell transplantation less than 3 months before administration of the first dose of study drug, presence of cytomegalovirus infection after allogeneic stem-cell transplantation, previous treatment with an anti-CD30 antibody, and concurrent immunosuppressive or systemic therapy for chronic graft-versus-host disease. Primary outcomes were safety profile in the safety-evaluable population and maximum tolerated dose, recommended phase 2 dose, pharmacokinetics (phase 1), and proportion of patients who achieved best overall response (phase 2; evaluated by an independent review facility) in the response-evaluable population. This trial is registered with ClinicalTrials.gov, number NCT01492088. FINDINGS: Between April 16, 2012, and April 4, 2016, we screened 41 paediatric patients and enrolled 36 (aged 7-18 years), of whom 19 had relapsed or refractory classical Hodgkin's lymphoma and 17 had relapsed or refractory systemic anaplastic large-cell lymphoma. At the data cutoff (Oct 12, 2016), all 36 patients had discontinued study drug treatment; the most common reason was progressive disease (15 patients). The maximum tolerated dose was not reached. The recommended phase 2 dose was 1·8 mg/kg. The proportion of patients who achieved overall response was 47% (95% CI 21-73) for classical Hodgkin's lymphoma and 53% (28-77) for systemic anaplastic large-cell lymphoma. All 36 patients had a treatment-emergent adverse event and 16 patients (44%) had at least one grade 3 or worse treatment-emergent adverse event. The most common treatment-emergent adverse events were pyrexia (16 [44%] of 36) and nausea (13 [36%]). The most common grade 3 or worse treatment-emergent adverse events were neutropenia (four [11%]), increased γ-glutamyl transpeptidase (two [6%]), and pyrexia (two [6%]). 12 (33%) patients had transient, limited-severity peripheral neuropathy. Eight patients (22%) had a serious adverse event; three (8%) had a drug-related serious adverse event. One patient died of cardiac arrest (disease progression of a large huge mediastinal mass, unrelated to the study drug). Paediatric pharmacokinetic profiles were consistent with those from studies of adult patients. INTERPRETATION: Brentuximab vedotin has manageable toxicity and is associated with clinically meaningful responses in paediatric patients with relapsed or refractory Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma, and could allow subsequent stem-cell transplantation in some patients who were initially ineligible for stem-cell transplantation. FUNDING: Millennium Pharmaceuticals Inc.