Carl E. Allen

Hodgkin lymphoma (HL) is characterized by inflammatory lesions with relatively few (typically <1%) pathogenic Hodgkin Reed-Sternberg (HRS) cells. The scarcity of malignant HRS cells in HL has historically limited characterization of these disease drivers, and pathogenic mechanisms underlying HL are incompletely defined. Using multiparameter flow cytometry to purify HRS cells and immune cell populations from pediatric HL lesions and control tonsils, we sought to define transcriptional programs in pediatric HRS cells. HRS cells are thought to arise from transformed germinal center B cells. Interestingly, transcriptomic analysis of HRS cells compared to control tonsil CD30+ cells revealed disordered differentiation with multilineage gene expression patterns, and primary HRS cells had distinct transcriptomes compared to HL cell lines. Further, transcriptomic analysis revealed increased expression of senescence-related genes and downregulation of proapoptotic/mitosis-related genes. Gene expression findings were validated by immunohistochemistry and single-cell imaging. In vitro treatment of primary HRS cells with B-cell lymphoma 2 inhibitor, venetoclax, augmented the induction of apoptosis in HRS cells and other cells of the HL immune microenvironment. These findings support the further study of targeting apoptosis resistance as a potential approach to eliminate malignant HRS cells and dismantle inflammatory lesion formation in pediatric HL.

Pediatric hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome, characterized by heightened T-cell activation and overwhelming interferon gamma production. Rather than a binary “primary” vs “secondary” framework, it is best conceptualized as a threshold phenomenon that occurs when combined genetic and environmental factors exceed a critical tipping point, leading to a recognizable clinical pattern of abnormal immunopathology. In addition to classic genetic cytotoxic defects, an increasing number of genetic lesions continue to be recognized as related to HLH. Environmental triggers frequently include malignancy, infection, and rheumatologic disorders, and identifying underlying factors driving HLH is a crucial component of evaluation. The revised HLH-2004 criteria are an important tool in promptly recognizing HLH, but clinical criteria may be fulfilled by other inflammatory disorders. Genetic and functional immune testing are complementary tools for diagnosis and establishing recurrence risk. Dexamethasone and etoposide remain cornerstones of initial therapy but are best used in an individualized, response-based manner with close monitoring of inflammatory markers. Newer, more targeted agents continue to emerge and are often critical additions for achieving disease control. Most patients with inherited cytotoxic defects and other select causes require hematopoietic cell transplant for cure, which should occur as soon as feasible once adequate, not perfect, HLH control is established to minimize risk of reactivation, infection, and toxicity. This review aims to highlight key advancements in defining, diagnosing, and treating HLH based on a growing understanding of HLH pathophysiology. We also provide perspectives on practical clinical approaches that may be useful for diagnosing and treating pediatric HLH.

PURPOSE: Few data describe the modern epidemiology of pediatric HIV-associated cancers in sub-Saharan Africa, home to over 80% of the world's children living with HIV. This study evaluated the incidence of cancers among these children over 15 years after widespread antiretroviral therapy (ART) adoption in Malawi. METHODS: We conducted a retrospective population-based cohort study leveraging multiple independent data sources comprehensive of all cancer diagnoses among children living with HIV in Northern and Central Malawi between 2010 and 2024. HIV-associated cancers were defined as those cancers with well-established epidemiologic associations with HIV. Cumulative incidence and average annual percent change were estimated using joinpoint regression. Next, we conducted a subcohort analysis within the country's largest pediatric HIV clinic to evaluate cancer risk factors using log-binomial regression. RESULTS: Among 1,686 pediatric cancer diagnoses, 184 (10.9%) occurred in children with HIV. Kaposi sarcoma (KS) accounted for 96% of cases. The cumulative incidence of HIV-associated malignancies fell from 4.7 cases per million children in 2010 to 1.2 per million in 2024, representing an 84% decline from its peak in 2013 and an average annual percent decline of 13% ( P < .001). KS dropped from the third- to seventh-most common childhood cancer in the region. Notably, 58% of affected children were ART-naïve at diagnosis. Initiating ART in infancy reduced the risk of KS by 69% ( P < .001). Other HIV-associated cancers were rare, comprising 0.4% of all cases diagnosed. CONCLUSION: National ART expansion substantially reduced pediatric HIV-associated cancers in Malawi, achieving declines comparable with those seen in high-income countries. Sustained early diagnosis and ART linkage remain essential to sustain progress.

Biallelic deficiencies of CD27 and its ligand CD70 underlie selective susceptibility to Epstein-Barr virus (EBV) infection and its acute and chronic complications, underscoring their non-redundant roles in anti-EBV immunity. To date, 16 pathogenic CD27 variants have been reported. Here, we describe three patients from two unrelated families, homozygous for a novel loss-of-function (LOF) CD27 variant, resulting in substitution of serine 70 with proline (S70P). All three patients presented with EBV viremia and lymphoproliferative disease, with variable immune dysregulation or recurrent otosinopulmonary infections. One patient developed EBV-associated Hodgkin lymphoma. Functional studies demonstrated that the S70P variant impaired surface expression of CD27 and abolished CD70 binding, rendering complete LOF. Together, S70P represents a novel pathogenic CD27 variant causing autosomal recessive (AR) CD27 deficiency, characterized by a unified susceptibility to EBV yet variable clinical manifestations, ranging from chronic viremia to malignancy.

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder driven by mitogen-activated protein kinase (MAPK) activation in hematopoietic cells. Historically, LCH has been staged according to involvement of “risk organs” (bone marrow, liver, and spleen), based on risk of death. With improvements in supportive care and efficacy of MAPK pathway inhibitors, patients with LCH now rarely die. However, most patients with LCH with multisystem disease are not cured with current front-line chemotherapy, and treatment failure is associated with long-term morbidity, including LCH-associated neurodegeneration (LCH-ND). In this study, we evaluated the impact of extent of LCH at presentation, tumor genotype, and BRAFV600E in pretherapy peripheral blood mononuclear cells (PBMCs) and bone marrow on systemic and central nervous system outcomes in a cohort of 385 pediatric patients with LCH and 115 adults with LCH, followed up for a median of 4 years (range, 0.02-18 years). Five-year event-free survival was 50.7% for pediatric patients and 32.7% for adult patients with LCH. In the pediatric cohort, presence of BRAFV600E PBMC was strongly associated with front-line treatment failure (hazard ratio [HR], 7.7). Remarkably, BRAFV600E PBMC at diagnosis also identified patients at the highest risk of developing LCH-ND (HR, 23.1). These findings support an updated model of pediatric LCH pathogenesis in which persistence of disease reservoir and cell of origin determine extent of disease and clinical risks. We, therefore, propose a major revision of pediatric LCH diagnostic staging, shifting from focus on historical risk of death to risks of systemic treatment failure and LCH-ND based on lesion location, lesion genotype, and peripheral LCH reservoir (eg, BRAFV600E PBMC).

PURPOSE: Excellent survival for advanced (stages II with high lactate dehydrogenase, III, and IV) pediatric mature B-cell non-Hodgkin lymphoma (MB-NHL) has been achieved with intensive regimens, but adoption in sub-Saharan Africa is limited by inadequate supportive care. We provide real-world data on treating advanced MB-NHL with high-dose methotrexate (HD-MTX; ≥1,000 mg/m ² /cycle) where real-time serum MTX monitoring is unavailable. METHODS: We identified two cohorts—a retrospective (January 2017-December 2020) cohort treated with 1,000 or 3,000 mg/m ² /cycle of HD-MTX and a prospective (July 2022-July 2023) cohort—with a modified LMB96 protocol containing 3,000 mg/m ² /cycle of HD-MTX. All doses of HD-MTX were given over 3 hours. Estimates of 12-month event-free survival (EFS) and overall survival (OS) were calculated with abandonment as an event. Clinical toxicity data were available for the prospective cohort. RESULTS: The retrospective cohort had 108 patients who received HD-MTX 1,000 mg/m ² (n = 98, 91%) or 3,000 mg/m ² per cycle. The 12-month EFS and OS were 39% (95% CI, 30 to 50) and 54% (95% CI, 44 to 64), respectively. HD-MTX at 3,000 mg/m ² had superior EFS: 69% (95% CI, 49 to 96) versus 33% (95% CI, 24 to 46), P = .004. The prospective cohort had 38 patients. Two ≥grade 3 mucositis, one acute kidney injury, and three treatment-related deaths (8%) occurred. Seven (18%) abandoned treatment. With a median follow-up of 14.5 months, 12-month EFS and OS were 45% (95% CI, 32 to 65) and 59% (95% CI, 45 to 79), respectively. Most relapses were stage IV: EFS 20% versus 51% (non–stage IV; P = .057). Severe malnutrition was associated with OS of 33% versus 58% (normal) or 76% (moderate; P = .055). CONCLUSION: HD-MTX dosed at 3,000 mg/m ² /cycle is feasible in low-resource settings where routine MTX monitoring is unavailable. Stage IV disease and severe malnutrition may contribute to poorer outcomes.

Background/Objectives: Kaposi sarcoma (KS) is a common lymphatic endothelial cancer among children with and without HIV in central and eastern Africa. Despite its clinical heterogeneity, its various clinical phenotypes are often grouped together in staging and treatment algorithms. Patients with KS tumor-associated edema, referring to hard, non-pitting lesions which often lead to chronic disability, represent a unique, understudied subgroup of children with KS. To continue our work defining the distinct phenotypes of pediatric KS, this study aimed to assess the clinical progression and outcomes of KS edema in children. Methods: A retrospective cohort study was conducted at Kamuzu Central Hospital in Lilongwe, Malawi, focusing on children diagnosed with KS edema between 2010 and 2023. Results: We identified 52 children with KS edema, representing 27% of all patients with KS. Initial chemotherapy resulted in a clinical response in 92% of patients, but 46% experienced relapse or disease progression with a median time to first relapse of 12 months. Multiple progressions were common, with 31% of patients experiencing two or more events. Event-free survival at two years was 32%, dropping to 24% at five years, while overall survival was 73% at two years and 57% at five years. Relapse was more common among patients with KS edema versus those without it (relative risk = 2.1; 95%CI, 1.4–3.2; p < 0.001). Eight patients (15%) relapsed with visceral disease, five of whom originally presented with KS edema alone. Conclusions: Patients with KS edema have a unique, relapsing-remitting pattern of disease with a high risk of relapse relative to other forms of KS with subsequent long-term mortality, even after initial positive treatment responses. Late relapse and mortality with visceral disease are possible even among children presenting initially with KS edema alone. Children with KS edema require long-term follow-up, and novel treatment approaches tailored towards preventing frequent relapse are needed.

Defining prognostic variables in T-lymphoblastic lymphoma (T-LL) remains a challenge. AALL1231 was a Children’s Oncology Group phase 3 clinical trial for newly diagnosed patients with T acute lymphoblastic leukemia or T-LL, randomizing children and young adults to a modified augmented Berlin-Frankfurt-Münster backbone to receive standard therapy (arm A) or with addition of bortezomib (arm B). Optional bone marrow samples to assess minimal residual disease (MRD) at the end of induction (EOI) were collected in T-LL analyzed to assess the correlation of MRD at the EOI to event-free survival (EFS). Eighty-six (41%) of the 209 patients with T-LL accrued to this trial submitted samples for MRD assessment. Patients with MRD <0.1% (n = 75) at EOI had a superior 4-year EFS vs those with MRD ≥0.1% (n = 11) (89.0% ± 4.4% vs 63.6% ± 17.2%; P = .025). Overall survival did not significantly differ between the 2 groups. Cox regression for EFS using arm A as a reference demonstrated that MRD EOI ≥0.1% was associated with a greater risk of inferior outcome (hazard ratio, 3.73; 95% confidence interval, 1.12-12.40; P = .032), which was independent of treatment arm assignment. Consideration to incorporate MRD at EOI into future trials will help establish its value in defining risk groups. CT# NCT02112916.