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.

Clinical, radiological and molecular responses to combination chemotherapy with MAPK pathway inhibition in relapsed and refractory Langerhans cell histiocytosis.

Optimal therapeutic approaches for advanced Langerhans cell histiocytosis (LCH) are not known. We assessed the safety and efficacy of combined chemotherapy with MAPK pathway inhibition in 10 patients with refractory systemic disease and/or LCH-associated neurodegeneration. Overall response rate was 9/10 (90%) for the entire cohort: 5/5 (100%) for patients with systemic disease and 6/7 (86%) for patients with central nervous system disease. BRAFV600E+ peripheral blood fraction decreased in 5/6 (83%). Toxicities included fever, skin rash, myalgias, neuropathy, cytopenias and hypocalcaemia. Prospective trials are required to optimize combination strategies, determine potential to achieve cure and compare outcomes to chemotherapy or MAPK inhibitor monotherapy.

Clofarabine monotherapy in aggressive, relapsed and refractory Langerhans cell histiocytosis.

Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.

Overcoming T-cell exhaustion in LCH: PD-1 blockade and targeted MAPK inhibition are synergistic in a mouse model of LCH.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with persistent MAPK pathway activation. Standard-of-care chemotherapies are inadequate for most patients with multisystem disease, and optimal strategies for relapsed and refractory disease are not defined. The mechanisms underlying development of inflammation in LCH lesions, the role of inflammation in pathogenesis, and the potential for immunotherapy are unknown. Analysis of the immune infiltrate in LCH lesions identified the most prominent immune cells as T lymphocytes. Both CD8+ and CD4+ T cells exhibited "exhausted" phenotypes with high expression of the immune checkpoint receptors. LCH DCs showed robust expression of ligands to checkpoint receptors. Intralesional CD8+ T cells showed blunted expression of Tc1/Tc2 cytokines and impaired effector function. In contrast, intralesional regulatory T cells demonstrated intact suppressive activity. Treatment of BRAFV600ECD11c LCH mice with anti-PD-1 or MAPK inhibitor reduced lesion size, but with distinct responses. Whereas MAPK inhibitor treatment resulted in reduction of the myeloid compartment, anti-PD-1 treatment was associated with reduction in the lymphoid compartment. Notably, combined treatment with MAPK inhibitor and anti-PD-1 significantly decreased both CD8+ T cells and myeloid LCH cells in a synergistic fashion. These results are consistent with a model that MAPK hyperactivation in myeloid LCH cells drives recruitment of functionally exhausted T cells within the LCH microenvironment, and they highlight combined MAPK and checkpoint inhibition as a potential therapeutic strategy.

Treatment of Langerhans cell histiocytosis with subcutaneous cytarabine.

Patients with Langerhans cell histiocytosis (LCH) have been effectively treated with intravenous cytarabine. Intravenous or subcutaneous cytarabine infusions have been effective for leukemia patients, and pharmacokinetic studies have shown very similar blood levels of the drug with either route. We present three LCH patients treated with subcutaneous cytarabine either because intravenous access could not be maintained or due to patient refusal. One patient with pulmonary and skin LCH had a complete response. Another patient had a partial response of pulmonary and cutaneous lesions, but progressive bone disease. The third patient was treated for LCH-related cerebellar changes eight years after the diagnosis of isolated diabetes insipidus, with stable brain MRI for 5 years post-treatment. Subcutaneous cytarabine administration provides an alternative for patients with LCH in whom vascular access is not possible or practical, such as in some resource-limited circumstances.

Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders.

BACKGROUND: Pediatric nonmalignant lymphoproliferative disorders (PLPDs) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD. OBJECTIVE: The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes. METHODS: PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant Epstein-Barr virus (EBV) infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing. RESULTS: Whole exome sequencing identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, P = .03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs 90%; P = .002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients. CONCLUSIONS: PLPD defines children at high risk for mortality, and whole exome sequencing informs clinical risks and therapeutic opportunities for this diagnosis.

Histiocytic Disorders of Childhood.

Histiocytic disorders of childhood represent a wide spectrum of conditions that share the common histologic feature of activated or transformed "histiocytes." Langerhans cell histiocytosis (LCH) is the most common, with an incidence of approximately 5 per million children. LCH may be difficult to distinguish from more ubiquitous causes of skin rashes, bone pain, or fever. Current chemotherapy fails to cure more than 50% of children with multifocal disease, and treatment failure is associated with increased risks of long-term sequelae. Somatic activating mitogen-activated protein kinase (MAPK) pathway-activating mutations (most often BRAFV600E) have been identified in hematopoietic precursors in patients with LCH. Opportunities to improve outcomes with targeted therapies are under investigation. Juvenile xanthogranuloma (JXG) and Rosai-Dorfman disease (RDD) are less common than LCH and are distinguished by specific histologic and clinical features. Recurrent MAPK pathway gene mutations are also identified in JXG and RDD. In many cases, these conditions spontaneously resolve, but disseminated disease can be fatal. Although there has been historic debate regarding the nature of these conditions as inflammatory versus neoplastic, LCH, JXG, and RDD are now considered myeloid neoplastic disorders. In contrast, hemophagocytic lymphohistiocytosis (HLH) is clearly a disorder of immune dysregulation. HLH is characterized by extreme immune activation driven by hyperactivated T cells. HLH arises in approximately 1 child per million and is nearly universally fatal without prompt recognition and immune suppression. Outcomes of treated children are poor, with approximately 60% survival. Emapalumab, which targets interferon-γ signaling, was recently approved for patients with recurrent or refractory HLH, and additional cytokine-directed therapies are under investigation.

Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis.

The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole-exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over the course of 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation at younger than 1 year of age (P < .0001). Digenic fHLH variants were observed but lacked statistical support for disease association. In 28 (58%) of 48 subjects, research whole-exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45%, and increased mortality correlated with HLH triggered by infection or malignancy (P < .05). Differences in survival did not correlate with genetic profile or extent of therapy. HLH should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most patients with HLH, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole-exome sequencing, however, may identify specific therapeutic opportunities and affect hematopoietic stem cell transplantation options for these patients.

Severe therapy-related toxicities after treatment for Hodgkin lymphoma due to a pathogenic TERT variant and shortened telomeres.

Telomere biology disorders predispose affected individuals to specific malignancies and organ fibrosis in tissues sensitive to telomere length (TL) shortening, especially after exposure to chemotherapy and radiation. We report a case of a 17-year-old female with Hodgkin lymphoma who developed severe chemotherapy-related toxicities. She was subsequently found to have peripheral blood lymphocyte TL < 1st percentile and a pathogenic variant in TERT inherited from her father. This case demonstrates that early genetic evaluation of patients who experience greater than expected therapy-related toxicities may be warranted to help guide further decisions regarding therapy, imaging modalities, and lifelong cancer prevention surveillance.

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.

CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions.

BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+ CD33+ CD163+ P2RY12- ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20. © 2018 American Cancer Society.

Anti TNF-α therapy in patients with relapsed and refractory Langerhans cell histiocytosis: a phase II study.

Tumor necrosis factor alpha (TNF-α) is produced in Langerhans cell histiocytosis (LCH) lesions and is elevated in plasma of patients with active LCH. It has been postulated that TNF-α may play a role in the pathophysiology of LCH. Etanercept, an anti-TNF-α antibody, has been used in TNF-modulated diseases such as rheumatoid arthritis (RA). We conducted a phase II study to determine the efficacy of etanercept for patients with refractory or relapsed LCH. Five LCH patients who had failed at least 2 prior treatments (range 2-9) received etanercept at a dose of 0.4 mg/kg twice weekly for up to a total of 24 doses. Disease response was assessed at 4 and 8 weeks. None of the five patients had improvement in their disease with etanercept treatment. Three progressed at week 4 and 1 progressed at week 8. One subject died after 3 weeks of treatment from disease progression. During the study, only one drug-related toxicity was noted which spontaneously resolved. The study was concluded early due to lack of response to etanercept and insufficient accrual rate. This data suggests that etanercept as given in this study may not be effective for relapsed or refractory LCH. However, the number of patients treated was not adequate enough to power this study and it is possible that a different dose and regimen of etanercept may be required to successfully treat this disease.

Rituximab therapy for patients with Langerhans cell histiocytosis-associated neurologic dysfunction.

OBJECTIVE: Since patients with langerhans cell histiocytosis and neurologic dysfunction (LCH-ND) often have incomplete treatment responses we sought a new treatment regimen. Because of clinical benefit from rituximab in multiple sclerosis patients with neurodegeneration, we evaluated its use in patients with LCH-ND. PARTICIPANTS: Eight LCH-ND patients who had failed prior therapies. METHODS: Charts of the 8 patients treated with rituximab were reviewed. Signs/symptoms and MRI responses were assessed. RESULTS: Seven of eight patients experienced some clinical improvement: gait abnormalities and tremors in four children, proprioceptive deficits in 2, and dysarthria/dysphagia in 2. Five of eight patients demonstrated improvement in intellectual/behavioral/psychological symptoms. CONCLUSION: These findings suggest that prospective studies are warranted to define safety and efficacy of rituximab for patients with LCH-ND.

Evaluation of maternal and perinatal characteristics on childhood lymphoma risk: A population-based case-control study.

BACKGROUND: Lymphoma is one of the most common pediatric malignancies; however, there are few well-established risk factors. Therefore, we investigated if maternal and perinatal characteristics influenced the risk of childhood lymphoma. PROCEDURE: Information on cases (n = 374) diagnosed with lymphoma and born in Texas for the period 1995-2011 was obtained from the Texas Cancer Registry. Birth certificate controls were randomly selected at a ratio of 10 controls per 1 case for the same period of 1995-2011. Unconditional logistic regression was used to generate unadjusted (OR) and adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the following histologic subtypes: Hodgkin (HL), Burkitt (BL), and non-BL non-HLs (non-BL NHLs). RESULTS: Overall, our findings indicate specific maternal and perinatal characteristics influence childhood lymphoma risk. Mexico-born mothers were more likely to have offspring who developed BL compared to mothers born in the United States (U.S.; aOR: 2.15; 95% CI: 1.06-4.36). Further, mothers who resided at time of delivery in a county on the U.S.-Mexico border were more likely to give birth to offspring who developed non-BL NHL (aOR: 1.72; 95% CI: 1.11-2.67) compared to mothers not living on the U.S.-Mexico border at time of infant birth. Last, infants born large-for-gestational-age experienced a twofold increase in BL risk (aOR: 2.00; 95% CI: 1.10-3.65). CONCLUSIONS: In this population-based assessment, we confirmed previously reported risk predictors of childhood lymphoma, including sex of infant, while highlighting novel risk factors that warrant assessment in future studies.