Langerhans cell histiocytosis: NACHO update on progress, chaos, and opportunity on the path to rational cures.

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts.

Pediatric cutaneous T-cell neoplasm and mimics with gamma-delta expression: Not always aggressive.

Pediatric cutaneous T-cell lymphoma with γδ immunophenotype is extremely rare. Only a few cases of γδ T-cell neoplasm have been reported in the literature, and therefore little is known whether γδ T-cell neoplasms in children are distinct from their adult counterparts with respect to the clinicopathological presentation, behavior, and prognosis. In this study, we demonstrate three unique pediatric cutaneous T-cell neoplasm and mimics with increased γδ T cells. All cases showed an indolent clinical course.

Implementation of a tier system for IVIG indications to address IVIG shortage at a tertiary care pediatric medical center.

BACKGROUND: Drug shortages are a common issue that healthcare systems face and can result in adverse health outcomes for patients requiring inferior alternate treatment. The United States recently experienced a national drug shortage of intravenous immunoglobulin (IVIG). Several reported strategies to address the IVIG and other drug shortages have been proposed; however, there is a lack of evidence-based methods for protocol development and implementation. OBJECTIVE: To evaluate the efficacy of introducing a multidisciplinary task force and tier system of indications and to minimize adverse effects during a shortage of IVIG. METHODS: Faculty members across disciplines with expertise in IVIG use were invited to participate in a task force to address the shortage and ensure adequate supply for emergent indications. A tier system of IVIG indications was established according to the severity of diagnosis, urgency of indication, and quality of supporting evidence. Based on inventory, indications in selected tiers were auto-approved. Orders that could not be automatically approved were escalated for task force review. RESULTS: Overall, there were 342 distinct requests for IVIG during the study period (August 1, 2019 to December 31, 2019). All Tier 1 indications were approved. Of all requests, only 2.6% (9) of requests were denied, none of which resulted in adverse effects based on retrospective chart review. Seven patients who regularly receive IVIG had possible adverse effects due to dose reduction or spacing of treatment; however, each complication was multifactorial and not attributed to the shortage or tier system implementation alone. CONCLUSION: Implementation of a multidisciplinary task force and tier system to appropriately triage high-priority indications for limited pharmaceutical agents should be considered in health institutions faced with a drug shortage.

How I approach B-lymphoblastic lymphoma in children.

There are limited data pertaining to the prognostic features and optimal therapeutic approach for the 20%-25% of children with lymphoblastic lymphoma (LLy) who have the B-lymphoblastic subtype. Outcomes are favorable following treatment modeled after acute lymphoblastic leukemia (ALL) regimens, but prognosis is dismal after relapse, and there are no established features for predicting therapy response. Ongoing US and international trials will include the largest cohort of uniformly treated patients with B-LLy to date, providing an opportunity to define clinical and molecular predictors of relapse and to establish a standard of care for treatment to improve outcomes for this rare pediatric cancer.

Children's Oncology Group's 2023 blueprint for research: Non-Hodgkin lymphoma.

Pediatric non-Hodgkin lymphoma (NHL) includes over 30 histologies (many with subtypes), with approximately 800 cases per year in the United States. Improvements in survival in NHL over the past 5 decades align with the overall success of the cooperative trial model with dramatic improvements in outcomes. As an example, survival for advanced Burkitt lymphoma is now >95%. Major remaining challenges include survival for relapsed and refractory disease and long-term morbidity in NHL survivors. Langerhans cell histiocytosis (LCH) was added to the NHL Committee portfolio in recognition of LCH as a neoplastic disorder and the tremendous unmet need for improved outcomes. The goal of the Children' Oncology Group NHL Committee is to identify optimal cures for every child and young adult with NHL (and LCH). Further advances will require creative solutions, including engineering study groups to combine rare populations, biology-based eligibility, alternative endpoints, facilitating international collaborations, and coordinated correlative biology.

Children's Oncology Group's 2023 blueprint for research: Young investigators.

The Children's Oncology Group (COG) Young Investigators (YI) Committee is an administrative committee in which liaisons represent 30 COG committees, and was created to facilitate the integration of YIs into the organization, and prepare them for future COG leadership roles. The mentorship program has mentored over 400 YIs since 2005 and currently has 175 active participants. The COG YI Master Roster is a database YIs can join, which allows them to post their interests and accomplishments to COG leadership, and 321 YIs have already joined this list. The YI Committee has held virtual symposia designed to describe how COG operates and provide guidance on how YIs can reach their goals; over 300 YIs have attended these since 2021 and have consistently rated them as helpful. Through these and other elements of the program, the YI Committee remains committed to developing a future pipeline of new investigators.

Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: Recommendations from the North American Consortium for Histiocytosis (NACHO).

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, often associated with genetic defects of lymphocyte cytotoxicity. Though a distinctive constellation of features has been described for HLH, diagnosis remains challenging as patients have diverse presentations associated with a variety of triggers. We propose two concepts to clarify how HLH is diagnosed and treated: within the broader syndrome of HLH, "HLH disease" should be distinguished from "HLH disease mimics" and HLH subtypes should be categorized by specific etiologic associations, not the ambiguous dichotomy of "primary" and "secondary." We provide expert-based advice regarding the diagnosis and initiation of treatment for patients with HLH, rooted in improved understanding of its pathophysiology.

Mentors' perspectives on the successes and challenges of mentoring in the COG Young Investigator mentorship program: A report from the Children's Oncology Group.

BACKGROUND: Identification and development of young investigators (YI) is critical to the long-term success of research organizations. In 2004, the Children's Oncology Group (COG) created a mentorship program to foster the career development of YIs (faculty <10 years from initial appointment). This study sought to assess mentors' long-term assessment of this program. PROCEDURE: In 2018, 101 past or current mentors in the COG YI mentorship program completed an online survey. Statistical comparisons were made with the Kruskal-Walis test. RESULTS: The response rate was 74.2%. As some mentors had multiple mentees, we report on 138 total mentee-mentor pairs. Mentors were 57.4% male, and mentees were 39.1% male. Mentors rated being mentored as a YI as important with a median rating of 90 on a scale of 1-100, interquartile range (IQR) 80-100. Most mentors reported that being mentored themselves helped their own success within COG (78.2%) and with their overall career development (92.1%). Most mentors enjoyed serving in the program (72.3%) and the median success rating (on a scale of 1-100) across the mentor-mentee pairings was 75, IQR 39-90. Success ratings did not differ by mentor/mentee gender, but improved with increased frequency of mentor-mentee interactions (P < .001). Mentor-mentee pairs who set initial goals reported higher success ratings than those who did not (P < .001). Tangible successes included current mentee COG committee involvement (45.7%), ongoing mentor-mentee collaboration (53.6%), and co-authored manuscript publication (38.4%). CONCLUSION: These data indicate that mentorship is important for successful professional development. Long-term mentoring success improves when mentors and mentees set goals upfront and meet frequently.

A Rare Cause of Pancytopenia in an Exclusively Breastfed Infant.

Vitamin B12 (B12) deficiency in infancy can present with nonspecific symptoms. We report a 5-month old exclusively breastfed full-term infant with emesis, lethargy, progressive pancytopenia, hemolysis, hypofibrinogenemia, elevated lactate dehydrogenase and a hypercellular bone marrow with dyserythropoiesis. The B12 level in the serum was undetectable. The infant's lethargy resolved within 48 hours of intramuscular B12 injection, followed by rapid improvement of pancytopenia. The asymptomatic mother had a normal hemoglobin and mean corpuscular volume, but undetectable B12 level and positive antibodies to intrinsic factor, consistent with pernicious anemia masked by folate supplementation in the mother but causing symptoms in her infant.

Management of post-transplant lymphoproliferative disorders.

PURPOSE OF REVIEW: Post-transplant lymphoproliferative disease (PTLD) is a major complication of hematopoietic stem cell and solid organ transplantation. The incidence of transplantation in childhood has been steadily rising, making PTLD the most common form of lymphoproliferation in childhood. The purpose of this review is to summarize the role of the Epstein-Barr virus (EBV) in the pathophysiology and discuss the management of PTLD. RECENT FINDINGS: More than 90% of pediatric PTLD is EBV-positive. In immunocompetent hosts, the virus is controlled by cytotoxic T-cells, the cells targeted by immunosuppression to avoid graft-versus-host disease and/or organ rejection in transplant patients. The majority of pediatric transplant candidates are EBV-negative prior to transplant increasing the risk of EBV-induced lymphoproliferation upon seroconversion after transplant. Treatment options include reduction of immunosuppression, anti-CD20 monoclonal antibodies, and/or chemotherapy. Advanced understanding of the importance of cellular immunity in controlling lymphoproliferation has led to the development of cellular therapies targeting virus-specific antigens. SUMMARY: PTLD is the most common form of lymphoproliferation in childhood due to the rising incidence of transplantation. EBV plays a pivotal role in the pathophysiology. Cellular therapies targeting viral antigens may replace chemotherapy in the treatment of PTLD in the near future.

Genomic characterization of pediatric B-lymphoblastic lymphoma and B-lymphoblastic leukemia using formalin-fixed tissues.

BACKGROUND: Recurrent genomic changes in B-lymphoblastic leukemia (B-ALL) identified by genome-wide single-nucleotide polymorphism (SNP) microarray analysis provide important prognostic information, but gene copy number analysis of its rare lymphoma counterpart, B-lymphoblastic lymphoma (B-LBL), is limited by the low incidence and lack of fresh tissue for genomic testing. PROCEDURE: We used molecular inversion probe (MIP) technology to analyze and compare copy number alterations (CNAs) in archival formalin-fixed paraffin-embedded pediatric B-LBL (n = 23) and B-ALL (n = 55). RESULTS: Similar to B-ALL, CDKN2A/B deletions were the most common alteration identified in 6/23 (26%) B-LBL cases. Eleven of 23 (48%) B-LBL patients were hyperdiploid, but none showed triple trisomies (chromosomes 4, 10, and 17) characteristic of B-ALL. IKZF1 and PAX5 deletions were observed in 13 and 17% of B-LBL, respectively, which was similar to the reported frequency in B-ALL. Immunoglobulin light chain lambda (IGL) locus deletions consistent with normal light chain rearrangement were observed in 5/23 (22%) B-LBL cases, compared with only 1% in B-ALL samples. None of the B-LBL cases showed abnormal, isolated VPREB1 deletion adjacent to IGL locus, which we identified in 25% of B-ALL. CONCLUSIONS: Our study demonstrates that the copy number profile of B-LBL is distinct from B-ALL, suggesting possible differences in pathogenesis between these closely related diseases.

Fulminant Liver Failure in a Child With ß-Thalassemia on Deferasirox: A Case Report.

Deferesirox (DFX), an oral chelating agent, is used to treat chronic iron overload in several hematological diseases such as ß-thalassemia, sickle cell disease, and myelodysplastic anemia. DFX is generally well tolerated with the exception of gastrointestinal disturbances and rash, although cases of renal toxicity, as well as acute and chronic liver failure, have been reported in adults and children. Here we describe a 3-year-old girl with ß-thalassemia undergoing treatment with DFX who presented with acute liver failure and Fanconi's syndrome. It is important for pediatric gastroenterologists, hepatologists, and hematologists to be aware that the commonly used drug DFX can lead to acute liver failure in children, and liver function should be monitored closely in all patients taking DFX.

Epstein-Barr virus-associated smooth muscle tumors in children following solid organ transplantation: a review.

EBV-SMT are a rare entity following organ transplantation. Given the rarity of the tumor, there is no standard approach to diagnosis and treatment. A literature search identified 28 reported cases of EBV-SMT in addition to our own experience with one case. The aim of this review is to summarize the existing data regarding pathogenesis, diagnosis, and treatment.

Identifying predictive factors for posttransplant lymphoproliferative disease in pediatric solid organ transplant recipients with Epstein-Barr virus viremia.

Epstein-Barr virus (EBV) viremia (EV) in pediatric solid organ transplant (SOT) recipients is a significant risk factor for posttransplant lymphoproliferative disease (PTLD) but not all patients with EV develop PTLD. We identify predictive factors for PTLD in patients with EV. We conducted a retrospective chart review of all pediatric SOT recipients (0 to 21 y) at a single institution between 2001 and 2009. A total of 350 pediatric patients received a SOT and 90 (25.7%) developed EV. Of EV patients, 28 (31%) developed PTLD. The median age at transplant was 11.5 months in the PTLD group and 21.5 months in the EV-only group (P=0.003). Twenty-three (37%) EV-only patients had immunosuppression increased before EV, compared with 28 (100%) of PTLD patients (P<0.001). The median peak EBV level was 3212 EBV copies/10 lymphocytes for EV-only and 8392.5 EBV copies/10 lymphocytes for PTLD (P=0.005). All patients who developed PTLD had ≥1 clinical symptoms. Younger age at transplant, increased immunosuppression before EV, higher peak EBV level, and presence of clinical symptoms have predictive value in the development of PTLD in SOT patients with EV.

Successful Management of Febrile Infection-Related Epilepsy Syndrome Using Cytokine-Directed Therapy.

Here we describe a pediatric patient with febrile infection-related epilepsy syndrome with a good functional and neurologic outcome after treatment with early and aggressive cytokine-directed immunomodulatory therapy and a seizure management strategy that intentionally avoided a barbiturate coma. A 5-year-old previously healthy male presented with staring, behavioral arrest, and encephalopathy evolving to super-refractory status epilepticus. He had had onset of fever 5 days prior. He was treated with early and aggressive immunomodulatory therapy targeted to his evolving cytokine profile. He was also treated with the ketogenic diet, antiseizure medications, and continuous anesthetic infusions. Pentobarbital was purposely avoided. Now, 2½ years later, he attends mainstream school, has attention-deficit hyperactivity disorder (ADHD), mild neurocognitive impairment, and well-controlled epilepsy. By using cytokine-directed immunotherapy and avoiding a barbiturate coma, we were able to successfully treat a pediatric patient with febrile infection-related epilepsy syndrome and achieve a good outcome.

Durable immunity to EBV after rituximab and third-party LMP-specific T cells: a Children's Oncology Group study.

ABSTRACT: Posttransplant lymphoproliferative disease (PTLD) in pediatric solid organ transplant (SOT) recipients is characterized by uncontrolled proliferation of Epstein-Barr virus-infected (EBV+) B cells due to decreased immune function. This study evaluated the feasibility, safety, clinical and immunobiological outcomes in pediatric SOT recipients with PTLD treated with rituximab and third-party latent membrane protein-specific T cells (LMP-TCs). Newly diagnosed (ND) patients without complete response to rituximab and all patients with relapsed/refractory (R/R) disease received LMP-TCs. Suitable LMP-TC products were available for all eligible subjects. Thirteen of 15 patients who received LMP-TCs were treated within the prescribed 14-day time frame. LMP-TC therapy was generally well tolerated. Notable adverse events included 3 episodes of rejection in cardiac transplant recipients during LMP-TC therapy attributed to subtherapeutic immunosuppression and 1 episode of grade 3 cytokine release syndrome. Clinical outcomes were associated with disease severity. Overall response rate (ORR) after LMP-TC cycle 1 was 70% (7/10) for the ND cohort and 20% (1/5) for the R/R cohort. For all cohorts combined, the best ORR for LMP-TC cycles 1 and 2 was 53% and the 2-year overall survival was 70.7%. vßT-cell receptor sequencing showed persistence of adoptively transferred third-party LMP-TCs for up to 8 months in the ND cohort. This study establishes the feasibility of administering novel T-cell therapies in a cooperative group clinical trial and demonstrates the potential for positive outcomes without chemotherapy for ND patients with PTLD. This trial was registered at www.clinicaltrials.gov as #NCT02900976 and at the Children's Oncology Group as ANHL1522.

Post-transplant lymphoproliferative disease in pediatric solid organ transplant recipients.

Post-transplant lymphoproliferative disease (PTLD) in solid organ transplant (SOT) recipients has become one of the most common forms of lymphoproliferation in childhood and is a serious complication of SOT. More than 90% of cases are of B-cell origin, Epstein Barr virus (EBV) positive and are mostly occurring in the early post-transplant period. Pathologically and clinically it is a heterogenous disease ranging from being responsive to reduced immunosuppression without further intervention to rapidly progressive fulminant PTLD requiring prompt initiation of therapy. Prognosis overall is favorable. Current treatment strategies as well new promising targeted immune-based therapies such as rituximab and EBV-specific cytotoxic T-lymphocytes are being discussed.