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.).

Treatment of Monomorphic Posttransplant Lymphoproliferative Disorder in Pediatric Solid Organ Transplant: A Multicenter Review.

Posttransplant lymphoproliferative disorder (PTLD) is the most common posttransplant malignancy in children. We reviewed data from 3 Canadian pediatric centers to determine patient characteristics, treatment approaches, and outcomes for children with monomorphic PTLD. There were 55 eligible children diagnosed between January 2001 to December 2021. Forty-eight patients (87.2%) had B-cell PTLD: Burkitt lymphoma (n = 25; 45.4%) and diffuse large B-cell lymphoma (n = 23; 41.2%), the remainder had natural killer (NK)/T-cell lymphoma (n = 5; 9.1%), Hodgkin lymphoma (n = 1;1.8%), or other (n = 1;1.8%). Thirty-nine (82.1%) patients with B-cell PTLD were treated with rituximab and chemotherapy with or without a reduction in immunosuppression (reduced immune suppression). The chemotherapy used was primarily one of 2 regimens: Mature Lymphoma B-96 protocol in 22 patients (56.4%) and low-dose cyclophosphamide with prednisone in 14 patients (35%). Most patients with T/NK-cell lymphoma were treated with reduced immune suppression + chemotherapy (n = 4; 80%). For all patients with monomorphic PTLD, the projected 3-year event-free survival/3-year overall survival was 62% and 77%, respectively. Of the patients, 100% with T/NK-cell PTLD 100% progressed or relapsed and, subsequently, died of disease. For patients with B-cell PTLD, there was no significant difference in outcome between the two main chemotherapy regimens employed.

School Attendance Among Pediatric Oncology Patients During the COVID-19 Pandemic in Ontario, Canada.

Supporting schooling for current and past pediatric oncology patients is vital to their quality of life and psychosocial recovery. However, no study has examined the perspectives toward in-person schooling among pediatric oncology families during the COVID-19 pandemic. In this online survey study, we determined the rate of and attitudes toward in-person school attendance among current and past pediatric oncology patients living in Ontario, Canada during the 2020-2021 school year. Of our 31-family cohort, 23 children (74%) did attend and 8 (26%) did not attend any in-person school during this time. Fewer children within 2 years of treatment completion attended in-person school (5/8; 62%) than those more than 2 years from treatment completion (13/15; 87%). Notably, 22 of 29 parents (76%) felt that speaking to their care team had the greatest impact compared to other potential information sources when deciding about school participation, yet 13 (45%) were unaware of their physician's specific recommendation regarding whether their child should attend. This study highlights the range in parental comfort regarding permitting in-person schooling during the COVID-19 pandemic. Pediatric oncologists should continue to address parental concerns around in-person school during times of high transmission of COVID-19 and potentially other communicable diseases in the future.

Treatment patterns and outcomes in adolescents and young adults with nodular lymphocyte-predominant Hodgkin lymphoma: an IMPACT cohort study.

We leveraged population-based clinical and healthcare data to identify treatment patterns and long-term outcomes among adolescents and young adults (AYA) with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). All Ontario, Canada, AYA aged 15-21 years at diagnosis with NLPHL between 1992 and 2012 were identified, and their detailed clinical data were collected. Linkage to healthcare databases identified additional events (subsequent malignant neoplasms [SMN], relapses and deaths). Event-free survival (EFS) and overall survival (OS) were compared by locus of care (adult vs. paediatric) and predictors of outcomes determined. Of 1014 AYA with Hodgkin lymphoma, 54 (5.3%) had NLPHL; 15 (27.8%) were treated at a paediatric centre. No paediatric centre patient received radiation only versus 16 (41.0%) of adult centre patients. Excision only was more common in paediatric centres (p < 0.001). The 20-year EFS and OS rates were 82.9% ± 5.2% and 100% respectively. Advanced stage (hazard ratio: 4.9, 95% CI: 1.3-18.4; p = 0.02) was associated with inferior EFS. Although the 25-year cumulative incidence of SMN was 19.3% ± 9.6% for the entire cohort, there were no SMN among the patients treated with excision only. AYA with NLPHL have outstanding long-term survival. Resection alone was rare outside of paediatric institutions but associated with excellent outcomes. Given substantial SMN risks, chemotherapy-sparing and radiation-sparing strategies for appropriate subsets of patients are warranted.

PD-L1 and PD-1 expression in pediatric post-transplant Burkitt lymphoma and other monomorphic post-transplant lymphoproliferative disorders.

BACKGROUND: Post-transplant lymphoproliferative disorders (PTLD) develop as a consequence of immune suppression. Programmed death protein 1 (PD-1), a regulator of host immune activation, binds to programmed death-ligand 1 (PD-L1) to suppress the T-cell immune response. PD-1/PD-L1 pathway may play a role in PTLD. The objective was to describe intratumoral expression of PD-L1 and PD-1 in pediatric monomorphic PTLD, and assess if density of these cells is associated with progression-free survival (PFS) and overall survival (OS). PROCEDURE: Clinical variables and outcome data were collected on B-cell monomorphic PTLD treated in Toronto, Canada between 2000 and 2017. Diagnostic area from tumor tissue was identified to count CD3-positive or PD-1-positive cells and CD3-negative lymphoma B cells or PD-L1-positive cells. CD3+ , PD-1+ , and PD-L1+ cell densities were compared between cases of PTLD. OS and PFS were analyzed. RESULTS: We identified 25 cases of B-cell monomorphic PTLD; majority Burkitt lymphoma (32%) and diffuse large B-cell lymphoma (56%). All cases had CD3+ cells infiltrating the tumor, and median percentage of CD3+ cells was 14% (interquartile range: 6.2%-25%). Twelve cases (48%) had PD-1+ cell infiltrating (range: 1%-83%) and 13 cases (52%) had no PD-1+ cells infiltrating. Sixteen cases (64%) had PD-L1+ cells present; however, there was no PD-L1 expression on any Burkitt lymphoma tissue. When comparing PD-1 and PD-L1 expression, there was no difference in OS or PFS. CONCLUSION: Intratumoral presence of PD-1+ and PD-L1+ cells varied in pediatric patients with monomorphic PTLD; however, no relationship to OS and PFS was identified.

How essential are in-person clinic visits during maintenance treatment of children with acute lymphoblastic leukemia?

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Treatment consists of an initial intensive phase of chemotherapy, followed by a prolonged period of maintenance chemotherapy intended to reduce the risk of relapse. During the COVID-19 pandemic, the need arose to identify and reduce non-essential hospital visits. OBJECTIVE: We aimed to determine which proportion of in-person clinic visits during ALL maintenance therapy was associated with a change of management based on the results of the physical examination. PATIENTS AND METHODS: Medical records of children receiving maintenance chemotherapy for B-precursor ALL between September 2019 and February 2020 were reviewed. Visits with a new finding on physical examination were divided into those where an in-person assessment was deemed essential versus not essential. Finally, we determined the proportion of essential in-person visits that resulted in a change of management. RESULTS: A total of 240 maintenance visits by 75 children were analyzed. An abnormal finding on physical examination was noted during 20 visits (8.3%). Of those, 14 (5.8%) uncovered a new finding, six (2.5%) were classified as "in-person visit essential," and among those six visits, three (1.2%) resulted in a change of patient management (one for acute otitis media, one for wheezing, and one for limp). CONCLUSION: Our findings support the evaluation of care delivery models other than in-person visits during ALL maintenance therapy. A prospective study is required to delineate criteria, benefits/risks, and families' perspectives associated with virtual care delivery and the optimal frequency of in-person visits.

How I approach: The workup and management of patients with progressive transformation of the germinal center.

Progressive transformation of the germinal center (PTGC) is a common and underrecognized cause of pediatric lymphadenopathy. PTGC may be associated with numerous systemic medical conditions that require further workup and management, including malignancy, autoimmune conditions, lymphoproliferative conditions, immunodeficiency, and infection. Given the breadth and rarity of the associated conditions, workup should be tailored to the individual patient and occur in a tiered approach. Patients with PTGC require ongoing follow-up, given their long-term risk of malignancy and recurrent PTGC.

Non-Hodgkin Lymphoma Imaging Spectrum in Children, Adolescents, and Young Adults.

In children, adolescents, and young adults (CAYA), non-Hodgkin lymphoma (NHL) is characterized by various age-related dissimilarities in tumor aggressiveness, prevailing pathologic subtypes, and imaging features, as well as potentially different treatment outcomes. Understanding the imaging spectrum of NHL in CAYA with particular attention to children and adolescents is critical for radiologists to support the clinical decision making by the treating physicians and other health care practitioners. The authors discuss the currently performed imaging modalities including radiography, US, CT, MRI, and PET in the diagnosis, staging, and assessment of the treatment response. Familiarity with diagnostic imaging challenges during image acquisition, processing, and interpretation is required when managing patients with NHL. The authors describe potentially problematic and life-threatening scenarios that require prompt management. Moreover, the authors address the unprecedented urge to understand the imaging patterns of possible treatment-related complications of the therapeutic agents used in NHL clinical trials and in practice. Online supplemental material is available for this article. ©RSNA, 2022.

Implementing compassion in pediatric healthcare: A qualitative study of Canadian patients', parents', and healthcare providers' perspectives.

BACKGROUND: Compassion has received significant scholarly attention over the past decade. Research has been largely theoretical, with interventions focused on self-care practices of healthcare providers (HCPs), rather than implementation at a systems level. This study aimed to identify how compassion can be operationalized within pediatric healthcare. DESIGN AND METHODS: Data was analyzed from a secondary dataset of a larger Straussian grounded theory study of perspectives and experiences of compassion in pediatric healthcare. Patients (n = 33); parents (n = 16); and HCPs (n = 17) were asked specifically how compassion could be implemented within the clinical culture and healthcare system. RESULTS: 66 participants generated an operational model of compassion indicating how compassion could be implemented across the organization and larger healthcare system. The data revealed four themes and associated subthemes: teach and train; recognize and reward; measure and report; and embed compassion across the healthcare system. CONCLUSIONS: Improving compassion in pediatric healthcare needs to extend beyond the efforts of individual HCPs. Compassion is the responsibility of the entire healthcare system and needs to traverse the patient and family experience. In addition to embedding compassion in policy, procedures, practice, and education, compassion should be considered a performance indicator that is measured and reported. PRACTICE IMPLICATIONS: This study provides a preliminary framework for organizational leaders to operationalize compassion across the services, structures, polices, procedures and practices of pediatric healthcare. This includes ongoing compassion training across the organization; assessing compassion, recognizing compassion as a performance indicator, and ensuring that the infrastructure and ancillary services of the organization reflect compassion.

Compassion in pediatric oncology: A patient, parent and healthcare provider empirical model.

OBJECTIVE: Compassion has long been considered a cornerstone of quality pediatric healthcare by patients, parents, healthcare providers and systems leaders. However, little dedicated research on the nature, components and delivery of compassion in pediatric settings has been conducted. This study aimed to define and develop a patient, parent, and healthcare provider informed empirical model of compassion in pediatric oncology in order to begin to delineate the key qualities, skills and behaviors of compassion within pediatric healthcare. METHODS: Data was collected via semi-structured interviews with pediatric oncology patients (n = 33), parents (n = 16) and healthcare providers (n = 17) from 4 Canadian academic medical centers and was analyzed in accordance with Straussian Grounded Theory. RESULTS: Four domains and 13 related themes were identified, generating the Pediatric Compassion Model, that depicts the dimensions of compassion and their relationship to one another. A collective definition of compassion was generated-a beneficent response that seeks to address the suffering and needs of a person and their family through relational understanding, shared humanity, and action. CONCLUSIONS: A patient, parent, and healthcare provider informed empirical pediatric model of compassion was generated from this study providing insight into compassion from both those who experience it and those who express it. Future research on compassion in pediatric oncology and healthcare should focus on barriers and facilitators of compassion, measure development, and intervention research aimed at equipping healthcare providers and system leaders with tools and training aimed at improving it.

Safety of administration of BNT162b2 mRNA (Pfizer-BioNTech) COVID-19 vaccine in youths and young adults with a history of acute lymphoblastic leukemia and allergy to PEG-asparaginase.

Vaccinationis a critical tool in the prevention of COVID-19 infection for individuals and for communities. The mRNA vaccines contain polyethylene glycol (PEG) as a stabilizer. Currently, in North America, only the BNT162b2 (Pfizer-BioNTech) mRNA vaccine is approved for individuals aged 12-17. Most patients treated with contemporary regimens for acute lymphoblastic leukemia receive PEG-asparaginase (PEG-ASNase) and 10%-30% will develop allergic reactions. Optimizing access and safety for vaccine administration for these patients is critical. This report describes a process developed to support COVID vaccination in a cohort of adolescents and young adults with a history of PEG-ASNase allergy.

Hodgkin Lymphoma in an Adolescent With Isolated Bone Marrow and Bone Involvement: A Case Report and a Review of the Literature.

BACKGROUND: Primary presentation of Hodgkin lymphoma (HL) with bone and/or bone marrow involvement is a rare entity. Diagnostic criteria, treatment approaches, and follow-up strategies for these patients have not been standardized. OBSERVATION: We report a unique case of bone and bone marrow HL in an adolescent male without lymph node involvement. CONCLUSIONS: It is important to keep HL in the differential diagnosis of isolated and multifocal bone lesions. Evidence is needed to define the best management of these patients.

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.

Posttransplant Lymphoproliferative Disorder in Children: A 360-degree Perspective.

An earlier incorrect version of this article appeared online. This article was corrected on December 17, 2019.

Impact of Videotaped Information on the Experience of Parents of Children with Acute Lymphoblastic Leukemia.

Videotaped information has been shown to be effective in reducing parental anxiety and facilitating knowledge transfer in various clinical settings. There is lack of literature on the use of videotaped information during the pediatric oncology initial family disclosure meeting. The purpose of this study was to deliver an informative DVD, highlighting information on childhood acute lymphoblastic leukemia (ALL), to parents of children with newly diagnosed ALL and to assess if the DVD provided increased levels of satisfaction and decreased levels of anxiety in parents around the time of diagnosis. We surveyed 24 parents of children on active treatment for ALL, diagnosed between the ages of 1 and 18 years from 2008 to 2016 at The Hospital for Sick Children, Toronto, Canada. Parents were provided a survey questionnaire assessing levels of satisfaction with information communicated by the healthcare team and anxiety following verbal disclosure and were asked to report satisfaction and anxiety levels immediately following viewing the DVD intervention. Twenty-three/24 (95.8%) parents surveyed reported seeking information from additional resources after disclosure. Of the 24 parents who watched the DVD, 12 (50.0%) watched it once, while 12 (50.0%) watched it twice or more. All parents were satisfied with DVD information, and there was a significant decrease in anxiety after viewing (P = 0.03). All 24 parents felt that the DVD was a useful educational tool. Videotaped information after verbal disclosure is an effective educational resource and is associated with reduced anxiety among parents of children with ALL.

Posttransplant lymphoproliferative disorder in pediatric patients: Survival rates according to primary sites of occurrence and a proposed clinical categorization.

Posttransplant lymphoproliferative disorder (PTLD) is a devastating complication of organ transplant. In a hospital-based registry, we identified biopsy-proven cases of PTLD among children during a 15-year period and reviewed trends in PTLD rates, the sites of involvement, and the associated survival rates. Cases that were included had at least 1 year of follow-up after the diagnosis of PTLD. We studied 82 patients with first-episode PTLD. Median age at diagnosis was 6.4 years (IQR 3.2-12.3 years). The most frequent PTLD sites were tonsillar/adenoidal (T/A [34%]) and gastrointestinal (32%), followed by miscellaneous (defined as less common sites including central nervous system, kidney, lung, and soft tissue [12%]), lymph node (11%), and multisite (11%). Kaplan-Meier survival curves showed that T/A PTLD was associated with decreased all-cause mortality compared with PTLD at other sites (log-rank 0.004), even after adjustment for histological subtype (P = .047). PTLD-related mortality was also decreased among T/A PTLD (log-rank 0.012) but showed a trend toward significance only after adjustment for histological subtype (P = .09). Among first episodes of PTLD, T/A PTLD was associated with a survival advantage compared with PTLD at other sites, even after adjustment for potential confounders. Based on our observations, we propose a clinical categorization of PTLD according to anatomical site of occurrence.

Lymphocyte subset at time of Epstein-Barr viremia post-allogeneic hematopoietic stem cell transplantation in children may predict development of post-transplant lymphoproliferative disease: CD8:CD20 ratio as a sensitive predictor.

EBV-associated PTLD following allogeneic HSCT is a serious complication associated with significant mortality. In this retrospective study, we evaluated whether lymphocyte subset numbers and CD8:CD20 ratio at time of EBV viremia in children undergoing allogeneic HSCT could predict development of PTLD. Absolute lymphocyte count, lymphocyte subsets, and CD8:CD20 ratio at the time of EBV viremia were analyzed. Patients who were treated preemptively with rituximab for high blood EBV viral load were excluded. Out of 266 patients transplanted during the study period, 26 patients were included in the analysis. Patients were divided into two cohorts; cohort 1 included patients with EBV-associated PTLD (n = 5; four with proven, one with probable PTLD). Cohort 2 included patients with EBV viremia without PTLD (n = 21). Lymphocyte recovery was slower in the PTLD group. CD8:CD20 ratio was significantly lower in the PTLD group (median 0.15) compared to the non-PTLD group (median 2.4, P = .012). Using the ROC curve and 1 as the cutoff value, CD8:CD20 ratios were analyzed. In the PTLD group, 4/5 patients (80%) had a ratio <1 whereas in the non-PTLD group, all 21 patients had a ratio >1. Sensitivity and specificity were 80% and 100%, respectively. Negative and PPVs were 95% and 100%, respectively. Profoundly low T-cell count and CD8:CD20 ratio may be used to predict development of PTLD in the context of EBV viremia in children post-allogeneic HSCT. Further studies are needed to validate this finding.

Hemophagocytic lymphohistiocytosis is a sign of poor outcome in pediatric Epstein-Barr virus-associated post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation.

EBV-related PTLD developing after HSCT is a potentially life-threatening disease. HLH is uncommon after allogeneic HSCT. Data on outcome of patients with PTLD and concomitant HLH after allogeneic HSCT are limited. In this retrospective study, we collected demographic, clinical, laboratory, and outcome data for 408 patients who underwent allogeneic HSCT from 2006 to 2015. Graft source included CB (n = 135; 33.1%), PBSCs (n = 34; 8.3%), and BM (n = 239; 58.6%). Eight out of 408 patients (2%) developed EBV-PTLD with a median age at HSCT of 5.9 years (range: 2.3-17.3). All eight patients received ATG as part of the conditioning regimen. Graft source was PBSC in three patients (37.5%), BM in four patients (50%), and CB in one patient (12.5%). Donors were matched unrelated in five patients (62.5%) and matched sibling in three patients (37.5%). Seven out of eight patients developed EBV-PTLD within the first 100-day post-HSCT. Lymph node biopsy revealed early lesions in three patients, polymorphic in three patients, and monomorphic PTLD in two patients. Three patients (37.5%) died within 1 month of EBV-PTLD diagnosis. All deceased patients developed HLH manifestations with two of them meeting HLH diagnostic criteria and one having an incomplete workup. PTLD after allogeneic HSCT with manifestations of HLH is associated with high mortality. Early identification and treatment of EBV-PTLD seems imperative to control the disease, especially if signs of HLH are evolving.

Asymptomatic Pulmonary Artery Embolization by a Port-a-Cath Fragment in a Child With Acute Lymphoblastic Leukemia.

Broken catheter embolism is a rare but often fatal complication of implantable venous access devices. Prompt removal is key to avoiding an adverse outcome.

Value of flow cytometric analysis of peripheral blood samples in children diagnosed with acute lymphoblastic leukemia.

Diagnostic procedures in children with acute lymphoblastic leukemia (ALL) are typically performed under general anesthesia. Anticipation of the diagnosis based on findings in peripheral blood allows scheduling of the first dose of intrathecal chemotherapy and diagnostic bone marrow (BM) aspirate during a single anesthetic. We retrospectively compared paired results of peripheral blood (PB) flow cytometric analysis and BM evaluation in 383 children with ALL diagnosed consecutively at a single center and found very high concordance of results between both tests. We conclude that PB flow cytometry may help streamline planning of procedure-related anesthetics during diagnosis and early treatment of childhood ALL.