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.

Effect of Poloxamer 188 vs Placebo on Painful Vaso-Occlusive Episodes in Children and Adults With Sickle Cell Disease: A Randomized Clinical Trial.

Importance: Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea. Objective: To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-ß0 thalassemia, or S-ß+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. Interventions: A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194). Main Outcomes and Measures: Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup. Results: Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%). Conclusions and Relevance: Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes. Trial Registration: ClinicalTrials.gov Identifier: NCT01737814.

Definition of cortical bone involvement in the staging of newly diagnosed pediatric Hodgkin lymphoma: A report from the International Working Group on Staging Evaluation and Response Criteria Harmonization (SEARCH).

BACKGROUND: The International Working Group on Staging Evaluation and Response Criteria Harmonization (SEARCH) seeks to provide a universally acceptable definition of cortical bone involvement in the staging of newly diagnosed pediatric Hodgkin lymphoma. PROCEDURE: A comprehensive literature search was performed using PubMed and Google Scholar with the search terms "Hodgkin lymphoma," "osseous lesions," "bony involvement," and "pediatric." Publications reviewed included case reports, retrospective analyses, and literature reviews. Each was evaluated for study design, number of participants, median age and age range at diagnosis, percentage of pediatric patients, criteria of interest definition, diagnostic tools, study objectives, and level of evidence. The final definition was based on the available data and consensus of the SEARCH working group. RESULTS: Twenty-five papers specifically addressing cortical bone involvement in Hodgkin lymphoma met the inclusion criteria. Eighteen papers were case reports with literature reviews; the remainder were observational cohort studies. Of these, 14 included pediatric patients (aged 0-21 years). The criteria for cortical bone involvement were not clearly defined in any paper, often varied within a study, and were inconsistent between publications. CONCLUSIONS: The SEARCH group for Childhood, Adolescent, and Young Adult Hodgkin Lymphoma (CAYAHL) proposes the following criteria as defining cortical bone involvement: any cortical bone biopsy-proven lesion; a positive bony window lesion on computer tomography (CT), with an FDG-PET positive correlate in a patient with biopsy-proven Hodgkin lymphoma, if there is no other typical skeletal pathology; auspicious skeletal lesions on FDG-PET or magnetic resonance imaging should be confirmed by CT or Tc-99m scan to distinguish cortical lesions from bone marrow involvement. Nodal masses that extend into bone with bony destruction are considered extranodal extension or "E" lesions and do not represent metastatic or stage IV disease.

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.

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.

A Stroke Mimic: Methotrexate-induced Neurotoxicity in the Emergency Department.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common form of childhood leukemia. The treatment of ALL involves multimodality therapy, and methotrexate (MTX) remains a mainstay of treatment. A complication of MTX therapy includes acute, subacute, and chronic neurotoxocity. Signs and symptoms may range from headaches, dizziness, and mood disorders to seizures and stroke-like symptoms. CASE REPORT: An 18-year-old woman with a history of ALL presented to the emergency department with acute onset of right-sided facial paralysis, right upper extremity flaccid paralysis, and right lower extremity weakness after receiving MTX therapy 3 days earlier. Diagnostic studies were unremarkable and the patient was treated with oral dextromethorphan for presumed MTX-induced neurotoxicity. The patient's symptoms began to improve within hours and she was discharged home within 48 hours with no neurologic deficits. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should be aware of this complication of MTX therapy given the sensitivity in regards to time with respect to cerebral vascular accidents. An awareness of this complication in the setting of the appropriate history and physical examination can lead to an accurate diagnosis and intervention and the avoidance of administering thrombolytics.

Staging Evaluation and Response Criteria Harmonization (SEARCH) for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (CAYAHL): Methodology statement.

International harmonization of staging evaluation and response criteria is needed for childhood, adolescence, and young adulthood Hodgkin lymphoma. Two Hodgkin lymphoma protocols from cooperative trials in Europe and North America were compared for areas in need of harmonization, and an evidence-based approach is currently underway to harmonize staging and response evaluations with a goal to enhance comparisons, expedite identification of effective therapies, and aid in the approval process for new agents by regulatory agencies.

Long-term outcomes for children with acute lymphoblastic leukemia (ALL) treated on The Cancer Institute of New Jersey ALL trial (CINJALL).

The Cancer Institute of New Jersey Acute Lymphoblastic Leukemia trial (CINJALL) employed a post-induction regimen centered on intensive oral antimetabolite therapy, with no intravenous methotrexate (MTX). Fifty-eight patients enrolled between 2001 and 2005. A high rate of induction death (n = 3) or induction failure (n = 1) was observed. Among those who entered remission, five-year DFS is 80 ± 8.9% for those at standard risk of relapse and 76 ± 7.8% for high-risk patients, with median follow up over six years. The estimated cumulative incidence of testicular relapse among boys was elevated (13 ± 7.2%) compared to the rate observed on contemporary protocols. We conclude that post-induction therapy using intensive oral antimetabolites for children with acute lymphoblastic leukemia (ALL) can result in overall long-term DFS comparable to that observed among children treated with regimens including intravenous MTX. However, an increased risk of late extramedullary relapse among boys was observed, supporting the prevailing opinion that high-dose MTX improves outcome for children with ALL.

Asparaginase Erwinia chrysanthemi as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia who have developed hypersensitivity to E. coli-derived asparaginase.

Asparaginase has been a mainstay of therapy in the treatment of acute lymphoblastic leukemia since the 1970s. There are two major preparations available and FDA approved in the United States today, one derived from Escherichia coli and the other from Erwinia chrysanthemi. Erwinia asparaginase is antigenically distinct from and has a considerably shorter biological half-life than E coli asparaginase. Erwinia asparaginase has been used in cases of hypersensitivity to E. coli-derived asparaginases, which has been reported in up to 30% of patients. While PEG asparaginase is increasingly used in front-line therapy for ALL, hypersensitivity still occurs with this preparation, and a change to a non-cross-reactive preparation may be necessary.

Activity and Toxicity of Intravenous Erwinia Asparaginase Following Allergy to E. coli-Derived Asparaginase in Children and Adolescents With Acute Lymphoblastic Leukemia.

BACKGROUND: Erwinia asparaginase is antigenically distinct from E.coli-derived asparaginase and may be used after E.coli-derived asparaginase hypersensitivity. In a single-arm, multicenter study, we evaluated nadir serum asparaginase activity (NSAA) and toxicity with intravenously administered asparaginase Erwinia chrysanthemi (IV-Erwinia) in children and adolescents with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma with hypersensitivity to E.coli-derived asparaginase. PATIENTS AND METHODS: Between 2012 and 2013, 30 patients (age 1-17 years) enrolled from 10 centers. Patients received IV-Erwinia, 25,000 IU/m(2)/dose on Monday/Wednesday/Friday, for 2 consecutive-weeks (6 doses = 1 cycle) for each dose of pegaspargase remaining in the original treatment plan. The primary objective was to determine the proportion of patients achieving NSAA ≥ 0.1 IU/ml 48 hr after dose 5 in Cycle 1. Secondary objectives included determining the proportion achieving NSAA ≥ 0.1 IU/ml 72 hr after Cycle 1 dose 6, and the frequency of asparaginase-related toxicities. RESULTS: Twenty-six patients completed Cycle 1; 24 were evaluable for NSAA assessment. In Cycle 1, NSAA ≥ 0.10 IU/ml was detected in 83% of patients (95% confidence interval [CI], 63-95%) 48 hr post-dose 5 (mean ± SD; 0.32 IU/ml ± 0.23), and in 43% (95% CI, 22-66%) 72 hr post-dose 6 (mean ± SD; 0.089 IU/ml ± 0.072). For all 30 patients over all cycles, hypersensitivity/infusional reactions with IV-Erwinia occurred in 37%, pancreatitis 7%, and thrombosis 3%. CONCLUSIONS: IV-Erwinia administration in children/adolescents appeared feasible and tolerable. A therapeutically-effective NSAA (≥ 0.10 IU/ml) was achieved in most patients at 48 hr, but in fewer than half 72 hr post-dosing, suggesting that monitoring NSAA levels and/or every 48 hr dosing may be indicated.

A phase 2 study of bortezomib in combination with ifosfamide/vinorelbine in paediatric patients and young adults with refractory/recurrent Hodgkin lymphoma: a Children's Oncology Group study.

A Children's Oncology Group clinical trial aimed to determine if bortezomib (B) increased the efficacy of ifosfamide and vinorelbine (IV) in paediatric Hodgkin lymphoma (HL). This study enrolled 26 relapsed HL patients (<30 years) treated with two to four cycles of IVB. The primary endpoint was anatomic complete response (CR) after two cycles. Secondary endpoints included overall response (OR: CR + partial response) at study completion compared to historical controls [72%; 95% confidence interval (CI): 59-83%]. Although few patients achieved the primary objective, OR with IVB improved to 83% (95% CI: 61-95%; p = 0.32). Although not statistically different, results suggest IVB may be a promising combination.

Stratification of treatment intensity in relapsed pediatric Hodgkin lymphoma.

Risk-adapted, response-based therapies for pediatric Hodgkin lymphoma have resulted in 5-year survival exceeding 90%. Although high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT) are considered standard for most patients with relapsed or refractory Hodgkin lymphoma, a subset of children with low risk relapse do not require AHSCT for cure. Currently there are no widely accepted criteria defining who should receive standard dose chemotherapy and/or radiotherapy, nor is there a standardized treatment regimen. We propose a risk-stratified, response-based algorithm for children with relapsed or refractory Hodgkin lymphoma that is based on a critical appraisal of published outcomes and prognostic factors.

Early [¹8F]fluorodeoxyglucose positron emission tomography-based response evaluation after treatment with gemcitabine and vinorelbine for refractory Hodgkin disease: a children's oncology group report.

The International Harmonization Project defined complete response (CR) after treatment for Hodgkin disease (HD) by absence of fluorodeoxyglucose avidity, regardless of the size of residual masses. Residual avidity after initial treatment is known to predict inferior survival. In the setting of retrieval therapy, early positron emission tomography (PET) scans may improve assessment of treatment efficacy. Retrospective analysis after 2 cycles of gemcitabine and vinorelbine for refractory HD revealed 6 CR among 13 patients by PET and 1 CR in 13 by computed tomography (CT). No relationship between PET response and event-free or overall survival could be discerned, presumably because of the heterogeneity of subsequent therapies.

Phase II study of weekly gemcitabine and vinorelbine for children with recurrent or refractory Hodgkin's disease: a children's oncology group report.

PURPOSE: The Children's Oncology Group conducted this phase II study to assess the efficacy and toxicity of gemcitabine and vinorelbine (GV) in pediatric patients with heavily pretreated relapsed/refractory Hodgkin's disease. Both agents have significant single-agent response rates in this setting. METHODS: GV was given on days 1 and 8 of each 21-day treatment cycle: vinorelbine 25 mg/m(2)/dose administered via intravenous (IV) push before gemcitabine 1,000 mg/m(2)/dose IV over 100 minutes. Any patients who demonstrated a measurable response (complete response [CR], very good partial response [VGPR], or partial response [PR]) were considered to have experienced a response to GV. Response was evaluated after every two cycles. A two-stage minimax rule was used to test the null hypothesis that the response rate is

Cord Compression due to Extramedullary Hematopoiesis in an Adolescent with Known Beta Thalassemia Major.

We describe a 16 year-old male with ß thalassemia major and gait disturbances that had not been given blood transfusions due to a severe childhood transfusion reaction. Thoracic spine MRI demonstrated hematopoietic marrow throughout the spine and epidural masses causing cord compression consistent with extramedullary hematopoiesis (EMH). After treatment with steroids, radiotherapy and monitored blood transfusions, the patient demonstrated significant improvement of his paraspinal lesions and near complete resolution of his neurological symptoms. While EMH causing cord compression in adolescents is rare in the current era of bone marrow transplantation or chronic transfusions, it should be considered when thalassemia major patients present with neurological deficits. The well defined imaging features of EMH can play a central role in its diagnosis and management, especially because surgical and / or radiotherapeutic intervention are often considered in cases of failed medical treatment.

Deep venous thrombosis in adolescents due to anatomic causes.

Aberrant or anomalous anatomy is an under appreciated risk for venous thromboembolic events (VTE). Five adolescents with VTE and predisposing anatomic abnormalities are presented. In three cases, knowledge of the underlying anatomic abnormalities resulted in changes in treatment and management. In two other cases, failure to consider or correct the underlying defect resulted in recurrent thrombosis or post-thrombotic complications. Few case reports are found in the pediatric literature, but a MEDLINE search across all age groups suggests these anomalies are frequently found when appropriate radiological imaging is obtained.

Phase 2B trial of aminopterin in multiagent therapy for children with newly diagnosed acute lymphoblastic leukemia.

PURPOSE: Aminopterin offers advantages over the related antifolate, methotrexate, including greater potency, complete bioavailability, and more consistent accumulation and metabolism by patients' blasts. This current trial was done to document the toxicity of the aminopterin within a multiagent therapeutic regimen for children with newly diagnosed ALL. EXPERIMENTAL DESIGN: Patients at high risk of relapse were non-randomly assigned to therapy including oral aminopterin 4 mg/m(2), in two doses 12 h apart, in place of methotrexate 100 mg/m(2) in four divided doses. RESULTS: Thirty-two patients, 22 with pre-B ALL and ten with T-lineage ALL, have been treated with aminopterin, with median follow up of 40 months. Hematologic, mucosal and hepatic toxicity has been tolerable and reversible. There have been no toxic deaths among patients in remission. During weekly AMT therapy, higher mean neutrophil counts were observed among patients who were wild type for polymorphisms in methylene tetrahydrofolate reductase and methionine synthase reductase. CONCLUSIONS: Aminopterin can be safely incorporated in multiagent therapy for patients with ALL, in place of systemic methotrexate, without causing excessive toxicity. These results support a larger trial comparing the efficacy and toxicity of aminopterin and methotrexate in therapy for patients with ALL.