McClain, Kenneth L.

Abstract Malignant histiocytic neoplasms (MHNs) are rare tumors derived from the mononuclear phagocyte system (MPS), encompassing histiocytic sarcoma, Langerhans cell sarcoma, interdigitating dendritic cell sarcoma, and other high-grade MPS lineage tumors. Despite advances in understanding histiocytic neoplasms, MHNs remain diagnostically challenging and lack standardized treatment algorithms. Current classification systems differ in lineage framing and fail to address mixed or ambiguous phenotypes, contributing to diagnostic uncertainty and inconsistent care. To address these gaps, the Histiocyte Society convened an international working group of pathologists and oncologists, including World Health Organization and International Consensus Classification contributors, to harmonize nomenclature, define minimum diagnostic criteria, and develop pragmatic treatment recommendations. Using a modified Delphi process and case-based review, the group formulated >40 consensus statements spanning classification, pathology, molecular testing, clinical evaluation, and therapeutic strategies. Key recommendations include the adoption of a unified MHN designation, use of a minimum immunophenotypic panel, integration of broad molecular profiling, and the documentation of previous hematopoietic malignancy. Treatment algorithms emphasize surgical resection for unifocal disease and targeted therapy or immune checkpoint inhibition for multifocal disease when actionable mutations or programmed death ligand 1 expression are present. These consensus recommendations aim to reduce diagnostic ambiguity, standardize reporting, and improve outcomes for both pediatric and adult patients. Future priorities include international registries to refine risk stratification and biomarker-driven trials exploring targeted therapy, immunotherapy, and combination approaches.

Abstract Endocrinopathies are frequently the initial presentation of histiocytic neoplasms, which are rare hematologic disorders affecting multiple organ systems. Langerhans cell histiocytosis and Erdheim–Chester disease are 2 such disorders known to infiltrate the hypothalamus and/or pituitary gland, leading to arginine vasopressin deficiency (AVP-D) and anterior pituitary dysfunction (APD) in 20% to 30% of cases, often as the first manifestation. Conversely, histiocytic disorders account for a notable proportion (10-15%) of all pituitary stalk lesions. The diagnosis of histiocytoses is often delayed in such cases due to the nonspecific presentation of endocrinopathies and pituitary involvement. Consequently, endocrinologists are at the frontline and uniquely positioned to achieve early diagnosis by recognizing the varied nonendocrine features of these disorders. This article provides an overview of the endocrine manifestations of histiocytic disorders and presents a simplified algorithm to guide the diagnostic workup in cases presenting with “idiopathic” AVP-D or APD. Such cases should be evaluated for histiocytic neoplasms with additional imaging studies and biopsies of suspected disease sites. If no disease site beyond the pituitary is identified, the risks and benefits of a pituitary stalk lesion biopsy must be carefully considered. While treatments of histiocytic neoplasms are highly efficacious, endocrinopathies are considered permanent and require long-term hormone replacement. It remains unclear whether early diagnosis and novel targeted therapies can reverse these endocrine disorders. Therefore, the role of the endocrinologist role is critical in the diagnosis and management of these rare diseases.

Abstract Langerhans cell histiocytosis (LCH) can affect children and adults with a wide variety of clinical manifestations, including unifocal, single-system multifocal, single-system pulmonary (smoking-associated), or multisystem disease. The existing paradigms in the management of LCH in adults are mostly derived from the pediatric literature. Over the last decade, the discovery of clonality and MAPK-ERK pathway mutations in most cases led to the recognition of LCH as a hematopoietic neoplasm, opening the doors for treatment with targeted therapies. These advances have necessitated an update of the existing recommendations for the diagnosis and treatment of LCH in adults. This document presents consensus recommendations that resulted from the discussions at the annual Histiocyte Society meeting in 2019, encompassing clinical features, classification, diagnostic criteria, treatment algorithm, and response assessment for adults with LCH. The recommendations favor the use of 18F-Fluorodeoxyglucose positron emission tomography-based imaging for staging and response assessment in the majority of cases. Most adults with unifocal disease may be cured by local therapies, while the first-line treatment for single-system pulmonary LCH remains smoking cessation. Among patients not amenable or unresponsive to these treatments and/or have multifocal and multisystem disease, systemic treatments are recommended. Preferred systemic treatments in adults with LCH include cladribine or cytarabine, with the emerging role of targeted (BRAF and MEK inhibitor) therapies. Despite documented responses to treatments, many patients struggle with a high symptom burden from pain, fatigue, and mood disorders that should be acknowledged and managed appropriately.

Abstract Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK (RAS-RAF-MEK-ERK) pathway mutations. Typical findings of ECD include central diabetes insipidus, restrictive pericarditis, perinephric fibrosis, and sclerotic bone lesions. The histopathologic diagnosis of ECD is often challenging due to nonspecific inflammatory and fibrotic findings on histopathologic review of tissue specimens. Additionally, the association of ECD with unusual tissue tropism and an insidious onset often results in diagnostic errors and delays. Most patients with ECD require treatment, except for a minority of patients with minimally symptomatic single-organ disease. The first ECD consensus guidelines were published in 2014 on behalf of the physicians and researchers within the Erdheim-Chester Disease Global Alliance. With the recent molecular discoveries and the approval of the first targeted therapy (vemurafenib) for BRAF-V600–mutant ECD, there is a need for updated clinical practice guidelines to optimize the diagnosis and treatment of this disease. This document presents consensus recommendations that resulted from the International Medical Symposia on ECD in 2017 and 2019. Herein, we include the guidelines for the clinical, laboratory, histologic, and radiographic evaluation of ECD patients along with treatment recommendations based on our clinical experience and review of literature in the molecular era.

Abstract Background Langerhans cell histiocytosis (LCH) is a heterogeneous disease whose myriad manifestations result from accumulation of Langerhans cells in a variety of organs most commonly including skin, bone, central nervous system, liver, lymph nodes, and bone marrow. The disease can affect people of any age. Treatment is primarily driven by disease extent and organ involvement and can range from focused radiation or surgery to multi-agent chemotherapy. There is a relatively high recurrence rate following complete remissions with conventional chemotherapy. In the first-time-in-human (FTIH) study of the oral pan-AKT inhibitor afuresertib (GSK2110183), in patients with hematologic malignancies, a patient with refractory multi-system LCH experienced a prolonged period (> 3 years) of clinical benefit on 125mg oral once daily afuresertib. This observation led to the evaluation of the use of afuresertib in patients with LCH. Methods This single-arm, open-label trial was designed to evaluate the efficacy and safety of afuresertib, administered at 125 mg once daily, in adults and adolescents with relapsed/refractory LCH and adults with treatment-naïve LCH. Secondary objectives included pharmacokinetics. Diagnosis of LCH was confirmed by pathology review of archival tissue. The Histiocyte Society criteria were used for response evaluation at three and six months with safety and pharmacokinetic assessments performed at pre-specified intervals. BRAF status from archival tissue was evaluated by Sanger sequencing. Results 17 patients (16 adults, 10 females) were enrolled; median age was 38 years (15-75). 3/17 patients had isolated pulmonary disease, 1/17 had single-system multifocal-bone disease, 1/17 had single-system skin disease, and 12/17 had multi-system disease. Seven patients were treatment-naïve; 10 had relapsed/refractory disease, including the one adolescent. The most frequent (>20% of patients) adverse events (AEs), regardless of causality, were nausea (59%), fatigue (59%), upper respiratory infection (47%), diarrhea (47%), dyspepsia (35%), bone pain (39%), asthenia (24%), memory impairment (24%), decreased appetite (24%) and vomiting (24%). Most AEs were Grade 1 or 2 in severity; no Grade 4 AEs were reported and no Grade 3 AEs occurring in more than 1 subject were reported. 6/17 (35%) had afuresertib dose modifications (interruption or reduction). Afuresertib plasma concentrations in the adult patients were similar to values seen in adult patients with other hematologic malignancies in the FTIH study. Following a single dose, the concentration-time profile in the adolescent patient was similar to adults in the FTIH study (Tmax = 3h: Cmax 229 ng/ml: AUC24 = 3893 ng*h/mL). 15 patients had archival tissues collected for BRAF testing; 13 had DNA suitable for analysis. 2/13 was BRAF V600E mutant and 11/13 were BRAF wild type. Upon evaluation of the all-treated patient population, 5/17 (29%) patients were reported as better at the three and/or six month disease assessment. Among the 5 responders, three were treatment-naïve and two had relapsed/refractory disease. The median duration on study for all patients was 214 (44-426) days. For the 5 patients who responded, the median duration on study was 372 (255-426) days. Conclusion The pharmacokinetic and safety profile of afuresertib in patients with LCH was consistent with that observed in patients with other hematologic malignancies evaluated in the FTIH study. Afuresertib was active in patients with both treatment-naïve and relapsed/refractory disease. Additional evaluation, including molecular profiling, may be warranted alone or in combination with BRAF inhibitors or established therapies for LCH to determine the optimal population of patients with LCH who might benefit from afuresertib Disclosures: Vassallo: GlaxoSmithKline: Research Funding. Oliff:GlaxoSmithKline: Employment. Morris:GlaxoSMithKline: Employment. Reedy:GlaxoSmithKline: Employment. Portnoy:GlaxoSmithKline: Stock, prior employee Other. Smith:GlaxoSmithKline: Employment, Equity Ownership. Noble:GlaxoSmithKline: Employment, stock Other. Murnane:GlaxoSmithKline: Employment, stock Other. Szabo:GlaxoSmithKline: Employment. Heaney:Novartis: Research Funding; Sanofi-Aventis: Consultancy, Research Funding; Onconova: Research Funding; Incyte: Consultancy, Research Funding.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune activation and dysregulation resulting in extreme and often life‐threatening inflammation. HLH has been well recognized in pediatric populations, and most current diagnostic and therapeutic guidelines are based on pediatric HLH. Recently there has been recognition of HLH in adults, especially secondary to immune deregulation by an underlying rheumatologic, infectious, or malignant condition. This review is focused on malignancy‐associated HLH (M‐HLH), in which possible mechanisms of pathogenesis include severe inflammation, persistent antigen stimulation by the tumor cells, and loss of immune homeostasis because of chemotherapy, hematopoietic stem cell transplantation, or infection. Previously considered rare, M‐HLH may occur in up to 1% of patients with hematologic malignancies. M‐HLH is often missed or diagnosed late in most published studies, and it has been associated with a poor median survival of less than 2 months. Identification of the clinical and laboratory features specific to M‐HLH in adults may allow early detection, consultation with HLH experts, and intervention. Improved management of adult M‐HLH with optimal combinations of T‐lympholytic and immunosuppressive agents and the incorporation of novel agents based on the pediatric experience hopefully will improve outcomes in adults with M‐HLH. Cancer 2017;123:3229‐40. © 2017 American Cancer Society.

AbstractBackgroundLangerhans cell histiocytosis (LCH) is a clonal neoplasm characterized by widely varied clinical presentations, including multisystem involvement and systemic inflammatory symptoms. The AKT pathway is relevant to survival and proliferation of dendritic cells, and is also often upregulated in hematopoietic malignancies. A clinical response in an adult patient with LCH participating in the first‐in‐human trial of afuresertib prompted this prospective trial.ProcedureThe population in the current study included treatment‐naïve (n = 7) and recurrent/refractory patients with LCH (n = 10), who received oral afuresertib (125 mg). The majority of patients were treated for > 24 weeks, with four patients receiving treatment for > 48 weeks.ResultsPharmacokinetic analysis showed similar exposures in previously reported patients with other hematologic malignancies. Primary drug‐related toxicities included Grade 1/2 nausea, diarrhea, dyspepsia, and vomiting. Grade 3 toxicities included fatigue, diarrhea, and pain (one of each). Another severe adverse event involved soft tissue necrosis. The overall response rate in evaluable subjects was 33% in treatment‐naïve patients and 28% in patients with recurrent/refractory disease, which did not meet the predefined Bayesian criteria for efficacy.ConclusionAfuresertib has clinical activity in some patients with newly diagnosed and advanced LCH.

Abstract Erdheim-Chester disease (ECD) is a rare, non-Langerhans histiocytosis. Recent findings suggest that ECD is a clonal disorder, marked by recurrent BRAFV600E mutations in >50% of patients, in which chronic uncontrolled inflammation is an important mediator of disease pathogenesis. Although ∼500 to 550 cases have been described in the literature to date, increased physician awareness has driven a dramatic increase in ECD diagnoses over the last decade. ECD frequently involves multiple organ systems and has historically lacked effective therapies. Given the protean clinical manifestations and the lack of a consensus-derived approach for the management of ECD, we provide here the first multidisciplinary consensus guidelines for the clinical management of ECD. These recommendations were outlined at the First International Medical Symposium for ECD, comprised of a comprehensive group of international academicians with expertise in the pathophysiology and therapy of ECD. Detailed recommendations on the initial clinical, laboratory, and radiographic assessment of ECD patients are presented in addition to treatment recommendations based on critical appraisal of the literature and clinical experience. These formalized consensus descriptions will hopefully facilitate ongoing and future research efforts in this disorder.