RARE DISEASE
Langerhans cell histiocytosis
Langerhans cell histiocytosis
Langerhans cell histiocytosis
Synonyms: Histiocytosis X, Langerhans cell granulomatosis
Synonyms: Histiocytosis X, Langerhans cell granulomatosis
Synonyms: Histiocytosis X, Langerhans cell granulomatosis
Drug discovery
2
drugs
With orphan designations
Overview
Langerhans Cell Histiocytosis (LCH) is a rare neoplastic disorder characterized by clonal proliferation of dendritic cells with Langerhans-like features. Driven by MAPK/ERK pathway mutations (e.g., BRAF V600E), it manifests variably, ranging from localized bone/skin lesions to multisystem disease involving high-risk organs (liver, spleen, bone marrow). Diagnosis relies on biopsy (CD1a/CD207 positivity) and PET imaging. While low-risk cases often resolve with minimal intervention, high-risk disease requires systemic therapy. Targeted BRAF/MEK inhibitors show high efficacy, reducing reliance on chemotherapy [1][6][13][18].
Burden
Mortality: 5-year survival >95% in low-risk cases; high-risk organ involvement reduces survival to ~60–92% [12][17].
Morbidity: Neurodegeneration (2–5%), diabetes insipidus (25%), skeletal defects, and secondary cancers (16% in adults) [4][7][9].
Adults: Elevated non-LCH mortality (COPD, cardiovascular disease, malignancies) [7][11].
Therapies
Low-risk (single-system): Observation or local therapy (surgery/radiation) [1][17].
Multisystem: First-line vinblastine/prednisone; refractory cases use cladribine/cytarabine [3][12][16].
Targeted therapy: BRAF/MEK inhibitors (dabrafenib/trametinib) achieve 100% response in trials, reducing relapse risk [1][8][13].
Categories: rare hematological diseases, rare neoplastic diseases, rare respiratory diseases, rare systemic and rheumatological diseases, rare transplant-related disorders
Research Papers
1,279 drug discovery papers about Langerhans cell histiocytosis, with 2 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,279 drug discovery papers about Langerhans cell histiocytosis, with 2 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-01-30 | Sotatercept in Pulmonary Langerhans Cell Histiocytosis-Associated Pulmonary Hypertension: A Case Series and Systematic Review.
Pulmonary Langerhans cell histiocytosis (PLCH) frequently complicated by pulmonary hypertension (PH), which markedly worsens prognosis. We retrospectively reviewed three institutional PLCH-PH cases treated with off-label Sotatercept added to background triple therapy and performed a systematic review of published PLCH-PH reports (PubMed/Embase through May 2025). Our three patients (ages 69, 62, 49; all female) had progressive vascular disease despite optimized vasodilator therapy. Following Sotatercept, all experienced ≥ 3-fold increases in 6-min walk distance and improved functional class. Hemodynamics improved substantially: right-atrial pressure -78.6%, pulmonary vascular resistance -75.5%, pulmonary artery systolic pressure -58.5%, mean PAP - 56.0%, PA diastolic pressure -51.0%, PAWP - 47.1%; cardiac output and index rose +75.9% and +73.8%, respectively. BNP/NT-proBNP normalized. Systematic review identified 34 published cases (2010-2025): mean age 37.2 ± 13.7 years, 44.1% female, 45.7% current/former smokers. Reported management strategies included targeted vasodilators, cytotoxic PLCH therapies (e.g., cladribine), smoking cessation, and selective surgery/transplant. In this small series, Sotatercept added to background therapy produced marked clinical and hemodynamic gains in refractory PLCH-PH. These effects of Sotatercept in Group 5 PH-are encouraging but limited by sample size and retrospective design. Prospective, collaborative studies are needed to define safety, efficacy, and optimal patient selection.
2025-01-27 | O-01 A CASE OF LANGERHANS CELL HISTIOCYTOSIS WITH INVOLVEMENT OF THE HYPOTHALAMUS, BONE, AND LIVER
Abstract Introduction Langerhans cell histiocytosis (LCH) is a neoplastic disorder characterized by the abnormal infiltration of Langerhans cells, affecting multiple systems. Here, we report a rare case of LCH with involvement of the hypothalamus, liver, and bone. Clinical Case A 36-year-old female patient presented to the psychiatry department with complaints of anxiety, including sudden behavioral changes, headaches, increased forgetfulness, hypersomnia, and excessive thirst excessive eating, and memory lapses that persisted for three months. A contrast-enhanced pituitary MRI taken revealed a lobulated mass lesion, measuring 15x9x17 mm, extending into the interpeduncular cistern and anteriorly toward the optic chiasm, with cystic necrotic areas located at the base of the third ventricle (Figure 1A). Laboratory examinations indicated panhypopituitarism and central diabetes insipidus. Abdominal ultrasound revealed a hypoechoic area in liver segment 8.PET-CT showed a region of intense metabolic activity in the posterior section of the left mastoid bone (SUVmax: 12.4). In addition, a 14-mm focal area with increased fluorodeoxyglucose uptake was observed in liver segment 8 (SUVmax: 8.4) (Figure 1B).The temporal MRI showed a mass lesion extending to the petrous apex, filling the mastoid cells on the left side, with signal characteristics similar to the hypothalamic lesion (Figure 1C).Biopsy was performed on identified lesions. Both biopsy results were consistent with LCH. She was planned to administer two courses of cladribine therapy. Follow-up PET-CT after chemotherapy indicated that the liver and mastoid bone involvement had resolved. However, the patient’s neuropsychiatric symptoms did not improve following chemotherapy. Paraneoplastic autoimmune encephalitis was primarily suspected, and antibody testing was performed. Due to the progressive nature of the patient’s condition, intravenous immunoglobulin therapy was administered. On the fourth day of this treatment, the patient experienced increased agitation and delusions, and developed disorientation.50 mg of quetiapine was prescribed. Three days after starting quetiapine, the patient developed fever, tachypnea, muscle rigidity, increased confusion, and an acute increase in serum creatine kinase levels (29,000 U/L). The condition was evaluated as a neuroleptic malignant syndrome leading to the discontinuation of quetiapine. The patient was transferred to the intensive care unit (ICU).On the first day of ICU admission, the patient was intubated. Despite cardiac support, the patient died on the third day of ICU admission. Conclusion LCH is a rare but multisystemic inflammatory neoplasm. The absence of specific clinical features can lead to delays in diagnosis. Although LCH most commonly presents with bone and skin lesions, a multidisciplinary approach is crucial for an accurate diagnosis. Albeit rare, LCH should be considered in the differential diagnosis of patients presenting with hypothalamic masses.Figure 1:Magnetic resonance image of the hypothalamic mass (A), Magnetic resonance images revealing a mass lesion in the left mastoid bone (B) and a subcapsular lesion in liver segment 8 (C)
2024-12-31 | Overlap syndrome of Erdheim-Chester disease and Langerhans cell histiocytosis: A case report.
Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are exceptionally rare disorders characterized by varied clinical presentations, posing several challenges for clinicians. The concomitant occurrence of LCH and ECD is exceedingly rare and has no known etiology. In this report, we present a rare case of mixed histiocytosis (both ECD and LCH) with multisystem involvement. The patient, a 49-year-old female, initially presented with a rash 2 years ago and progressively developed exophthalmos, fatigue, and shortness of breath. She lacked the mutation in codon 600 of exon 15 of B-Raf proto-oncogene (BRAF-V600E) and subsequently underwent treatment with corticosteroids, interferon-alpha, and chemotherapy, all of which proved ineffective. This work highlights the urgent need to improve treatment outcomes for such patients. Therefore, we discuss the latest advancements in understanding treatment strategies for mixed histiocytic syndromes.
2022-07-04 | Pituitary function and the response to GH therapy in patients with Langerhans cell histiocytosis: analysis of the KIMS database
To analyze the effectiveness and safety of growth hormone (GH) replacement treatment in adult patients with Langerhans cell histiocytosis (LCH) and GH deficiency (GHD) enrolled in KIMS (Pfizer International Metabolic Database).Patients with LCH and GHD were studied at baseline and some of them after 1 year of GH treatment. The effectiveness of GH is presented as change after 1 year of treatment (mean, 95% CI). The LCH population was compared to two other groups of patients enrolled in KIMS, granulomatous and lymphocytic hypophysitis.At baseline, 81 adults with LCH (27 with childhood onset, 56% females), mean age at GHD onset of 29 (15) years were studied. Diabetes insipidus was diagnosed in 86% of patients. Analysis of 1 year of GH treatment was possible in 37 patients. One-year cross-sectional values for the GH dose were 0.39 (s.d.± 0.21) mg and -0.5 (-1.2 to 0.2) for insulin-like growth factor-1 s.d. Total cholesterol decreased 0.9 (-1.5 to -0.3 (mmol/L); P < 0.05); AGHDA-QoL-score (n = 20) was improved by 2.8 points (-5.6 to 0.0; P < 0.05), while mean BMI increased 0.6 ± 3 kg/m2 (95% CI: -0.2 to 1.4). All these effects did not differ from the two other groups after adjusting for age, gender, and baseline values. In 20 of 77 patients included in the safety analysis, 36 serious adverse events were reported during 435 patient-years (82.8/1000); no new safety signals were reported.After 1 year of GH treatment in patients with LCH, metabolic variables and quality of life improved, with no new safety signals.
2019-06-20 | Pulmonary Langerhans cell histiocytosis with thyroid involvement manifesting as recurrent bilateral pneumothorax and tension bullae in a 3-year-old child
Pulmonary Langerhans cell histiocytosis (PLCH) is a well known entity in adults but is exceedingly rare in children. The main complication of PLCH is the occurrence of pneumothorax (PTX) and tension bullae with subsequent recurrence and persistence despite conservative management.A 3-year-old child was diagnosed with PLCH with thyroid involvement. Chemotherapy was immediately initiated and continued with chest tube drainage for repeated bilateral PTX. Tension bullae developed in the right lung 1 month after initiating treatment. Emergency resection of the bullae and ligation of pulmonary cysts were performed. On the tenth postoperative day, she developed a tension bulla in the left lung. Emergency thoracotomy was performed. On the tenth postoperative day, chest X-ray and CT suggested return of the right bulla and mediastinal shift, and reoperation was performed. Repeated lung biopsy showed no sign of active LCH. Although her condition improved after the operation, subsequent repeated PTXs occurred and were difficult to treat. She was discharged home after four months. Currently, she is receiving maintenance therapy as an outpatient. During the 12-month follow-up, the pulmonary lesions also showed a tendency for improvement.Although it is difficult to treat recurrent PTX and tension bullae in advanced PLCH, continuous treatment of the primary disease (LCH) and the complications of pulmonary lesions can improve prognosis.Treatment of PLCH accompanied by recurrent PTX and tension bullae is challenging. The condition can be resolved by treating the primary disease in parallel with combined modality treatment, including surgical operation for complications.
small molecules
2026-08-17 | Langerhans Cell Histiocytosis in Adults: A Canadian Multicenter Case Series.
Langerhans cell histiocytosis (LCH) is a rare clonal myeloid neoplasm. Canadian data on clinical characteristics, molecular profile, and treatment outcomes is limited. This study aims to report the initial experience of a Canadian rare diseases program, reflecting "real-world" diagnostic pathways, referral patterns, and treatment heterogeneity across multiple provinces. We conducted a retrospective review of patients managed in an adult-care cohort with histologically confirmed LCH diagnosed between 2000 and 2025 across multiple Canadian centers. Patients diagnosed as children and subsequently transferred to adult care were included. Clinical features, radiologic findings, histopathology, molecular testing, treatment approaches, and outcomes were collected and analyzed. Thirty-one patients were identified, with a median age at diagnosis of 42 years (range: 2-84) and a male predominance (65%). Bone (74%), lung (29%), and skin (16%) were the most commonly involved sites. Concomitant or subsequent malignancies were present in 19% of patients. Molecular testing found BRAFV600E mutations in 44% of tested patients. The most common first-line systemic therapy was cytarabine (n = 10), followed by other drugs such as hydroxyurea, vemurafenib, and cladribine. This series represents the initial experience of a Canadian rare disease referral program and captures the clinical heterogeneity and longitudinal adult care of patients with LCH across multiple provinces. Variability in treatment approaches highlights the need for collaborative prospective natural history studies and coordinated clinical trials.
2026-08-08 | Langerhans cell histiocytosis
Langerhans cell histiocytosis initially identified as an inflammatory disorder is now being referred as a rare dendritic/histiocytic neoplasm arising from dendritic cell differentiation with a heterogeneous clinical presentation manifesting in skin, bones, lungs, liver, lymph nodes, neurologic, and hematologic systems in any age group. Diagnostic work-up, staging investigations, prognostic markers, and therapeutic algorithms have seen a paradigm shift from pediatric-inspired chemotherapy regimens to a patient-tailored focused approach. Although chemotherapy is still the backbone in the era of novel circulating biomarkers and targeted agents in multisystem disease, chemoresistance and delayed neurological sequelae still remain challenges, resulting in dismal outcomes and poor quality of life.
2026-07-29 | Firm lesion consistency and whitish tissue exposure ingastrointestinal Langerhans cell histiocytosis
Keywords endoscopy upper GI tract - diagnosis and imaging (inc chromoendoscopy, NBI, iSCAN, FICE, CLE) - endoscopy lower GI tract - diagnosis and imaging (inc chromoendoscopy, NBI, iSCAN, FICE, CLE...) - Ulcers (peptic and other) Publication History Received: 25 May 2026 Accepted after revision: 15 July 2026 Article published online: 29 July 2026 © 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/). Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-07-27 | Current Approaches Among Medical Providers Treating Pediatric Langerhans Cell Histiocytosis.
Most pediatric Langerhans cell histiocytosis (LCH) lesions harbor activating mutations within the mitogen-activated protein kinase (MAPK) pathway. MAPK inhibitors (MAPKi) represent a rational therapeutic strategy, though there is no consensus regarding optimal use. We sought to understand how providers currently integrate MAPKi into LCH therapy and gather input regarding potential future clinical trial designs. An online survey was distributed to members of the Histiocyte Society, Children's Oncology Group, and Asian Histiocytic Disorder Collaborative Group. Domains included demographics, experience treating LCH, preferred treatment in response to clinical vignettes, and opinions regarding clinical trial design. Participants included 106 pediatric attending physicians from 26 countries. Of the 89 providers with access to MAPKi, 79% have used them to treat LCH, with most reporting use outside of a clinical trial and for recurrent/refractory LCH. Nearly all participants agreed that prospective trials are needed to study MAPKi in newly diagnosed LCH, and 90% felt their institution would open such a trial. Regarding trial design, 89% would include patients with multisystem risk organ (RO) positive disease, while 47% and 21% would include multisystem or single system RO- disease, respectively. Most participants (83%) would include a trial arm combining MAPKi with chemotherapy, with 56% of these participants favoring combination therapy throughout treatment. Additionally, 43% favored including an MAPKi monotherapy arm. MAPKi are widely available and commonly utilized in pediatric LCH. While treatment practices and trial design preferences vary, there is a strong consensus regarding the need for a prospective clinical trial incorporating MAPKi into upfront therapy.
2026-07-22 | Langerhans cell histiocytosis in the adult lower gastrointestinal tract.
A female in her early 80s presented with chronic anal fissures which were unresponsive to conservative therapies. Examination was concerning for possible perianal Crohn's disease, but subsequent colonoscopy and biopsies revealed Langerhans cell histiocytosis (LCH) involving the colon and anus, diagnosed per 2022 WHO Classification of Haematolymphoid Tumours criteria and confirmed by BRAF V600E mutation. Systemic staging identified two unrelated malignancies of the breast and kidney. The patient was treated with cladribine as systemic chemotherapy, resulting in complete remission of LCH symptoms and lesions.This case illustrates key diagnostic and therapeutic considerations for clinicians: LCH can mimic inflammatory bowel disease and should be included in the differential for atypical or refractory perianal disease, especially in older adults. Histological confirmation and molecular profiling are essential for accurate diagnosis and treatment planning. Additionally, cladribine is a well-tolerated and effective option for adult LCH with gastrointestinal tract involvement. Early recognition and systemic staging are critical to guide therapy and identify potential coexisting malignancies.
antibodies
2025-12-26 | Repurposing osteoporosis medications for other diseases: a narrative review by the European Calcified Tissue Society (ECTS).
This narrative review explores the therapeutic potential of repurposing medications originally developed or approved for osteoporosis to treat non-osteoporotic conditions. Given their pharmacologic profiles and safety data, these agents offer promising therapeutic alternatives in both rare and common diseases with unmet clinical needs. Evidence from preclinical models, observational data, and randomised trials supports the repositioning of several osteoporosis drugs. Cyclic etidronate has shown efficacy in halting arterial calcification progression in pseudoxanthoma elasticum. Pamidronate has demonstrated symptom improvement in adult chronic nonbacterial osteitis. Neridronate is approved only in Italy for complex regional pain syndrome type I. Denosumab has shown therapeutic effects in Langerhans cell histiocytosis and has structural benefits in erosive hand osteoarthritis and rheumatoid arthritis. Parathyroid hormone analogues (rhPTH [1-84] and teriparatide) improve calcium-phosphate homeostasis in chronic and genetic hypoparathyroidism. Calcilytics, though originally discontinued for osteoporosis, show emerging promise in autosomal dominant hypoparathyroidism. In contrast, zoledronic acid has not demonstrated consistent clinical benefit in knee osteoarthritis. Strontium ranelate, despite showing structure-modifying effects in osteoarthritis, is no longer marketed due to safety concerns. Alendronate and denosumab in fibrous dysplasia yielded mixed results, with concerns about rebound effects after denosumab withdrawal. Repurposing osteoporosis medications represents a cost-effective, timely strategy to expand treatment options across diverse clinical indications. While promising outcomes have been demonstrated-particularly in rare diseases-rigorous, indication-specific clinical trials are essential to confirm efficacy, safety, and long-term outcomes. The accumulated pharmacologic and clinical experience with these agents offers a strong foundation for their continued exploration beyond osteoporosis.
2025-09-01 | [Immune microenvironment of Langerhans cell histiocytosis: from immune suppression to targeted therapy].
Langerhans cell histiocytosis (LCH) is a rare hematologic disorder characterized by the clonal proliferation of neoplastic dendritic cells (DCs), exhibiting both immature and senescent immune phenotypes. The immunosuppressive microenvironment in LCH includes an increased proportion of regulatory T (Treg) cells with inhibitory functions, as well as exhausted CD8(+) T cells and myeloid-derived suppressor cells, which collectively exacerbate immunosuppression and facilitate the immune evasion of tumor DCs. Current therapeutic approaches for LCH are limited by the challenges of relapse and drug resistance. However, emerging strategies that target the senescent phenotype of neoplastic DCs, inhibit Treg cell activity, and reverse T cell exhaustion through immune checkpoint blockade offer promising avenues for the treatment of LCH.
2025-05-29 | A case of diagnosis and treatment of mediastinal Langerhans cytosis.
Langerhans cell histiocytosis (LCH) is a rare disease. It mainly involves abnormal proliferation and aggregation of Langerhans cells, a type of cell of the immune system.Langerhans cytosis is more common in the bone, but it has rarely been reported in the mediastinum. We present a case of mediastinal thymus tumor presented with Langerhans cell histiocytosis. A 40-year-old female patient presented with left chest and back pain in April 2024. Imaging revealed abnormal signal lesions on the patient's left rib and anterior superior mediastinum. The clinical diagnosis was bone destruction and mediastinal space occupation, and the postoperative pathological diagnosis was Langerhans cell histiocytosis. Langerhans cytosis is characterized by mediastinal and thymus occupation and is relatively rare in clinical practice. For patients who tolerate surgery for a single or local lesion, surgical removal of the primary lesion should be considered. However, for patients with multiple lesions or distant metastases, clinicians should evaluate whether surgery will benefit the patient. After surgical treatment, targeted therapy or immunotherapy should be performed.
2025-05-26 | No overshoot of bone turnover after withdrawal of denosumab treatment of adults with Langerhans cell histiocytosis: a prospective clinical trial.
Denosumab (Dmab) discontinuation in osteoporosis leads to overshoot (rebound) of bone turnover, but its cause remains largely unclear. In a prospective trial, Dmab-treated Langerhans cell histiocytosis (LCH) patients showed no overshoot of bone turnover markers despite high short-term dosing. Findings suggest that total Dmab dose does not drive the overshoot of bone turnover markers. In patients with osteoporosis, the length of treatment with denosumab (Dmab) is an important risk factor for the overshoot (rebound) of bone turnover markers following its discontinuation. Whether this is due to the higher total Dmab dose given and/or the severity of the disease is unknown. To address this question, long-term follow-up of changes in bone metabolism after stopping Dmab with doses higher than those used in osteoporosis is essential. In a prospective, single-arm, open label, phase 2b clinical trial, ten adult patients with Langerhans cell histiocytosis (LCH), eight with bone lesions (four single, four multiple) and two without, were treated with Dmab sc injections 120 mg/2 months for 6 months (total 480 mg) and were followed for 24 months after the last injection. Treatment reduced bone turnover markers to about 10% of pretreatment values, which increased after treatment arrest to a peak that did not exceed pretreatment levels; mean (± SD) peak serum CTX 0.522 ± 0.366 ng/mL and P1NP 72.2 ± 35.9 ng/mL were not significantly different from baseline (p = 0.11 and 0.65, respectively). Moreover, pretreatment and peak serum CTX values were significantly correlated (rs = 0.818, p = 0.007). No vertebral fractures, bone loss, or hypercalcemia were observed. Dmab withdrawal in patients with LCH was not followed by an overshoot of bone turnover markers or bone loss despite the administration in 6 months of a total dose equal to that given in osteoporosis for 4 years. Total Dmab dose is, thus, not an important determinant of the bone turnover overshoot after treatment withdrawal.
2024-11-17 | Abstract C017: Exploring the composition of and interaction of the tumor microenvironment in Langerhans cell histiocytosis
Abstract Langerhans cell histiocytosis (LCH) is a rare inflammatory hematological neoplasm, characterized by the accumulation of LCH cells in various tissues and organs. These LCH cells originate from myeloid progenitors that carry a MAPK-pathway mutation. Once these mutated cells enter the tissue from the periphery, they differentiate into so-called LCH cells. In addition to LCH cells, the tumor microenvironment (TME) consists of a wide variety of immune cells. However, the interactions between these cells within the TME and their contribution to disease progression remain poorly understood. In this study, we focus on understanding the role of lymphocytes in LCH lesions. We used single-cell RNA sequencing to comprehensively profile the immune populations in LCH lesions on the transcriptomic level, which will be supplemented with spatial profiling. Our analysis identified a wide variety of infiltrating immune cells within LCH lesions with high cellular heterogeneity among patients. LCH- and T cells are the most prevalent cell types, suggesting a key role in lesion development and maintenance. Furthermore, the immune landscape includes several dendritic cell subsets – such as plasmacytoid DCs (pDCs), cDC1, and mature regulatory dendritic cells (mregDCs) – alongside tumor-associated macrophages (TAMs), monocytes, NK cells, B cells, and plasmablasts. Among T cells, regulatory T cells (Tregs) are particularly abundant and appear to be heavily influenced by LCH cells and other myeloid cells via the TNF-TNFR2 and CD86-CTLA4 pathways. Additionally, LCH cells express high levels of TGFβ – a known regulator of T cell activity – and MMP9 – which might hamper cytotoxic T cell infiltration. This suggests that LCH cells actively contribute to creating an immunosuppressive environment. Surprisingly, pDCs seem to be a major immune regulator within lesions and are likely to interact with T cells via TNFSF9 and Granzyme B. These insights into the immunosuppressive environment within LCH lesions highlight the critical role of Tregs as central regulators within the tumor microenvironment. The implications of these findings will be further explored and validated through in-vitro experiments and high-plex spatial protein profiling. Ultimately, our work may pave the way for developing targeted therapies aimed at modulating the TME, potentially enhancing anti-tumor immunity, and offering new strategies for treating LCH. Citation Format: Wouter van Midden, Raphaela Schwentner, Sebastian Eder, Philipp Ben Soussia-Weiss, Giulio Abagnale, Caroline Hutter. Exploring the composition of and interaction of the tumor microenvironment in Langerhans cell histiocytosis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C017.
cell therapies
2026-06-12 | Craniotomy with local autologous bone dust in pediatric single Langerhans cell histiocytosis
The treatment paradigm for surgery in patients with Langerhans cell histiocytosis (LCH) varies depending on the size and location of the tumor. Here, we illustrate an effective treatment modality through craniotomy with local autologous bone dust. An 8-year-old child presented with a 4-month history of a bumpy scalp on the right parietal region every time he combed his hair. Contrast-enhanced computed tomography (CT) of the brain revealed a single right parietal lytic bony defect measuring 2 × 2 × 1 cm, giving a punched-out appearance. The ultrasound of the abdomen, axial skeleton, and vertebral column was normal. A craniotomy and en bloc resection, including a 2 cm surrounding bone margin, were performed. The healthy skull bone edges (outer table) were drilled, and bone dust was used for reconstruction. The bone dust was spread over the dura to completely fill the defect site, followed by tack-up stitches. The healthy periosteum was laid over the defect and sutured. A follow-up brain CT before discharge and at 1 year showed evidence of cranial bone regeneration. Histopathology specimens showed LCH features. Complete excision, including the margin, followed by covering the defect using autologous bone dust, promotes osteoblast activity in pediatric calvarial. The peripheral tack-up stitches of the dura and periosteum contribute to osteogenesis by contact. This strategy is simple, inexpensive, and has good cosmetic results.
2026-05-31 | Progressive cochlear ossification secondary to Langerhans cell histiocytosis requiring sequential bilateral cochlear implantation: a case report.
Langerhans cell histiocytosis (LCH) is a rare disorder that may involve the temporal bone and, in rare cases, result in sensorineural hearing loss. This report highlights the importance of close radiological surveillance and timely cochlear implantation in the setting of progressive otic capsule ossification. A 21-year-old male presented with a five-year history of progressive bilateral hearing loss, tinnitus, vertigo and imbalance. Following multidisciplinary team (MDT) discussion, cochlear implantation was deferred until completion of chemotherapy. Repeat CT imaging demonstrated progressive cochlear ossification involving the otic capsules. A repeat discussion followed, which led to an expedited cochlear implantation. The left side was implanted first due to lesser ossification, achieving full electrode insertion. Sequential implantation of the contralateral ear was performed four months later. However, insertion was limited due to advanced ossification. The second implantation was technically more challenging, with only partial electrode insertion possible due to advanced ossification. We advocate for close surveillance in the case of LCH to monitor for signs of otic capsule ossification. This case demonstrates that cochlear ossification in LCH may progress rapidly, narrowing the window for optimal implantation. Early cochlear implantation should be strongly considered in such cases.
2026-03-31 | Pathogenic myeloid phenotypes drive disease pathology in a novel human neurohistiocytosis model.
Innate immunity is increasingly recognized as a driver of neurodegeneration, though pathogenic mechanisms are incompletely understood. Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplastic disorder caused by activating somatic mutations in mitogen-activated protein kinase (MAPK) pathway genes, most commonly BRAFV600E, in myeloid precursors. A subset of LCH patients develop progressive neurodegeneration (LCH-ND). We generated a human induced pluripotent stem cell (iPSC) model from patients with somatic hematologic mosaicism for BRAFV600E. Brain macrophages/microglia from LCH iPSCs exhibit unique disease specific pathogenic features. Stepwise differentiation identified hematopoietic progenitors as hyperproliferative, whereas brain macrophages were apoptosis resistant. Through application of cerebral organoids and a humanized murine xenotransplantation model we identify marked heterogeneity of differentiation potential within clonal BRAFV600E lines in vivo. This model phenocopied human specific phenotypes including dense basal ganglia foci of abnormal macrophages, marked neurodegeneration with astrogliosis, and progressive ataxia. This approach will allow for preclinical testing of therapeutics for LCH-ND.
2026-03-20 | Case Report: Complete remission of refractory Langerhans cell sarcoma following CLAG-M chemotherapy and allogeneic hematopoietic stem cell transplant.
Langerhans Cell Sarcoma (LCS) is an extremely rare and aggressive neoplasm with limited consensus on optimal treatment. We report the case of a 56-year-old woman with refractory Langerhans Cell Histiocytosis (LCH) that transformed into Langerhans Cell Sarcoma (LCS) who achieved complete remission following chemotherapy with cladribine, high-dose cytarabine, G-CSF, and mitoxantrone (CLAG-M), and subsequent allogeneic hematopoietic stem cell transplantation (HSCT). This case highlights the potential role of allogeneic HSCT as an effective therapeutic option for refractory LCS and underscores the importance of reporting additional cases to guide future management strategies in this rare malignancy.
2026-01-27 | Hematopoietic cell transplantation for Langerhans histiocytosis
Langerhans cell histiocytosis is a rare myeloid neoplasm that primarily affects children. Initial treatment depends on risk stratification, but overall survival is excellent. Patient with high-risk disease with risk organ involvement can experience disease reactivation or refractoriness to front-line therapy. A standard approach is not established in the literature, with different reported strategies, including conventional chemotherapy, MAPK-inhibitors and allogeneic hematopoietic (HCT). Allogeneic HCT is supported by retrospective studies with overall survival ranging from 56 to 77% in the largest series. Disease status at the time of HCT and the conditioning regimen (reduced-intensity conditioning versus myeloablative conditioning) correlates with survival and toxicity. Most recently, reduced-intensity conditioning modality has emerged as the preferred option for patients diagnosed with Langerhans cell histiocytosis who require allogeneic HCT.
proteins
2026-01-30 | Sotatercept in Pulmonary Langerhans Cell Histiocytosis-Associated Pulmonary Hypertension: A Case Series and Systematic Review.
Pulmonary Langerhans cell histiocytosis (PLCH) frequently complicated by pulmonary hypertension (PH), which markedly worsens prognosis. We retrospectively reviewed three institutional PLCH-PH cases treated with off-label Sotatercept added to background triple therapy and performed a systematic review of published PLCH-PH reports (PubMed/Embase through May 2025). Our three patients (ages 69, 62, 49; all female) had progressive vascular disease despite optimized vasodilator therapy. Following Sotatercept, all experienced ≥ 3-fold increases in 6-min walk distance and improved functional class. Hemodynamics improved substantially: right-atrial pressure -78.6%, pulmonary vascular resistance -75.5%, pulmonary artery systolic pressure -58.5%, mean PAP - 56.0%, PA diastolic pressure -51.0%, PAWP - 47.1%; cardiac output and index rose +75.9% and +73.8%, respectively. BNP/NT-proBNP normalized. Systematic review identified 34 published cases (2010-2025): mean age 37.2 ± 13.7 years, 44.1% female, 45.7% current/former smokers. Reported management strategies included targeted vasodilators, cytotoxic PLCH therapies (e.g., cladribine), smoking cessation, and selective surgery/transplant. In this small series, Sotatercept added to background therapy produced marked clinical and hemodynamic gains in refractory PLCH-PH. These effects of Sotatercept in Group 5 PH-are encouraging but limited by sample size and retrospective design. Prospective, collaborative studies are needed to define safety, efficacy, and optimal patient selection.
2025-01-27 | O-01 A CASE OF LANGERHANS CELL HISTIOCYTOSIS WITH INVOLVEMENT OF THE HYPOTHALAMUS, BONE, AND LIVER
Abstract Introduction Langerhans cell histiocytosis (LCH) is a neoplastic disorder characterized by the abnormal infiltration of Langerhans cells, affecting multiple systems. Here, we report a rare case of LCH with involvement of the hypothalamus, liver, and bone. Clinical Case A 36-year-old female patient presented to the psychiatry department with complaints of anxiety, including sudden behavioral changes, headaches, increased forgetfulness, hypersomnia, and excessive thirst excessive eating, and memory lapses that persisted for three months. A contrast-enhanced pituitary MRI taken revealed a lobulated mass lesion, measuring 15x9x17 mm, extending into the interpeduncular cistern and anteriorly toward the optic chiasm, with cystic necrotic areas located at the base of the third ventricle (Figure 1A). Laboratory examinations indicated panhypopituitarism and central diabetes insipidus. Abdominal ultrasound revealed a hypoechoic area in liver segment 8.PET-CT showed a region of intense metabolic activity in the posterior section of the left mastoid bone (SUVmax: 12.4). In addition, a 14-mm focal area with increased fluorodeoxyglucose uptake was observed in liver segment 8 (SUVmax: 8.4) (Figure 1B).The temporal MRI showed a mass lesion extending to the petrous apex, filling the mastoid cells on the left side, with signal characteristics similar to the hypothalamic lesion (Figure 1C).Biopsy was performed on identified lesions. Both biopsy results were consistent with LCH. She was planned to administer two courses of cladribine therapy. Follow-up PET-CT after chemotherapy indicated that the liver and mastoid bone involvement had resolved. However, the patient’s neuropsychiatric symptoms did not improve following chemotherapy. Paraneoplastic autoimmune encephalitis was primarily suspected, and antibody testing was performed. Due to the progressive nature of the patient’s condition, intravenous immunoglobulin therapy was administered. On the fourth day of this treatment, the patient experienced increased agitation and delusions, and developed disorientation.50 mg of quetiapine was prescribed. Three days after starting quetiapine, the patient developed fever, tachypnea, muscle rigidity, increased confusion, and an acute increase in serum creatine kinase levels (29,000 U/L). The condition was evaluated as a neuroleptic malignant syndrome leading to the discontinuation of quetiapine. The patient was transferred to the intensive care unit (ICU).On the first day of ICU admission, the patient was intubated. Despite cardiac support, the patient died on the third day of ICU admission. Conclusion LCH is a rare but multisystemic inflammatory neoplasm. The absence of specific clinical features can lead to delays in diagnosis. Although LCH most commonly presents with bone and skin lesions, a multidisciplinary approach is crucial for an accurate diagnosis. Albeit rare, LCH should be considered in the differential diagnosis of patients presenting with hypothalamic masses.Figure 1:Magnetic resonance image of the hypothalamic mass (A), Magnetic resonance images revealing a mass lesion in the left mastoid bone (B) and a subcapsular lesion in liver segment 8 (C)
2024-12-31 | Overlap syndrome of Erdheim-Chester disease and Langerhans cell histiocytosis: A case report.
Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are exceptionally rare disorders characterized by varied clinical presentations, posing several challenges for clinicians. The concomitant occurrence of LCH and ECD is exceedingly rare and has no known etiology. In this report, we present a rare case of mixed histiocytosis (both ECD and LCH) with multisystem involvement. The patient, a 49-year-old female, initially presented with a rash 2 years ago and progressively developed exophthalmos, fatigue, and shortness of breath. She lacked the mutation in codon 600 of exon 15 of B-Raf proto-oncogene (BRAF-V600E) and subsequently underwent treatment with corticosteroids, interferon-alpha, and chemotherapy, all of which proved ineffective. This work highlights the urgent need to improve treatment outcomes for such patients. Therefore, we discuss the latest advancements in understanding treatment strategies for mixed histiocytic syndromes.
2022-07-04 | Pituitary function and the response to GH therapy in patients with Langerhans cell histiocytosis: analysis of the KIMS database
To analyze the effectiveness and safety of growth hormone (GH) replacement treatment in adult patients with Langerhans cell histiocytosis (LCH) and GH deficiency (GHD) enrolled in KIMS (Pfizer International Metabolic Database).Patients with LCH and GHD were studied at baseline and some of them after 1 year of GH treatment. The effectiveness of GH is presented as change after 1 year of treatment (mean, 95% CI). The LCH population was compared to two other groups of patients enrolled in KIMS, granulomatous and lymphocytic hypophysitis.At baseline, 81 adults with LCH (27 with childhood onset, 56% females), mean age at GHD onset of 29 (15) years were studied. Diabetes insipidus was diagnosed in 86% of patients. Analysis of 1 year of GH treatment was possible in 37 patients. One-year cross-sectional values for the GH dose were 0.39 (s.d.± 0.21) mg and -0.5 (-1.2 to 0.2) for insulin-like growth factor-1 s.d. Total cholesterol decreased 0.9 (-1.5 to -0.3 (mmol/L); P < 0.05); AGHDA-QoL-score (n = 20) was improved by 2.8 points (-5.6 to 0.0; P < 0.05), while mean BMI increased 0.6 ± 3 kg/m2 (95% CI: -0.2 to 1.4). All these effects did not differ from the two other groups after adjusting for age, gender, and baseline values. In 20 of 77 patients included in the safety analysis, 36 serious adverse events were reported during 435 patient-years (82.8/1000); no new safety signals were reported.After 1 year of GH treatment in patients with LCH, metabolic variables and quality of life improved, with no new safety signals.
2019-06-20 | Pulmonary Langerhans cell histiocytosis with thyroid involvement manifesting as recurrent bilateral pneumothorax and tension bullae in a 3-year-old child
Pulmonary Langerhans cell histiocytosis (PLCH) is a well known entity in adults but is exceedingly rare in children. The main complication of PLCH is the occurrence of pneumothorax (PTX) and tension bullae with subsequent recurrence and persistence despite conservative management.A 3-year-old child was diagnosed with PLCH with thyroid involvement. Chemotherapy was immediately initiated and continued with chest tube drainage for repeated bilateral PTX. Tension bullae developed in the right lung 1 month after initiating treatment. Emergency resection of the bullae and ligation of pulmonary cysts were performed. On the tenth postoperative day, she developed a tension bulla in the left lung. Emergency thoracotomy was performed. On the tenth postoperative day, chest X-ray and CT suggested return of the right bulla and mediastinal shift, and reoperation was performed. Repeated lung biopsy showed no sign of active LCH. Although her condition improved after the operation, subsequent repeated PTXs occurred and were difficult to treat. She was discharged home after four months. Currently, she is receiving maintenance therapy as an outpatient. During the 12-month follow-up, the pulmonary lesions also showed a tendency for improvement.Although it is difficult to treat recurrent PTX and tension bullae in advanced PLCH, continuous treatment of the primary disease (LCH) and the complications of pulmonary lesions can improve prognosis.Treatment of PLCH accompanied by recurrent PTX and tension bullae is challenging. The condition can be resolved by treating the primary disease in parallel with combined modality treatment, including surgical operation for complications.
small molecules
2026-08-17 | Langerhans Cell Histiocytosis in Adults: A Canadian Multicenter Case Series.
Langerhans cell histiocytosis (LCH) is a rare clonal myeloid neoplasm. Canadian data on clinical characteristics, molecular profile, and treatment outcomes is limited. This study aims to report the initial experience of a Canadian rare diseases program, reflecting "real-world" diagnostic pathways, referral patterns, and treatment heterogeneity across multiple provinces. We conducted a retrospective review of patients managed in an adult-care cohort with histologically confirmed LCH diagnosed between 2000 and 2025 across multiple Canadian centers. Patients diagnosed as children and subsequently transferred to adult care were included. Clinical features, radiologic findings, histopathology, molecular testing, treatment approaches, and outcomes were collected and analyzed. Thirty-one patients were identified, with a median age at diagnosis of 42 years (range: 2-84) and a male predominance (65%). Bone (74%), lung (29%), and skin (16%) were the most commonly involved sites. Concomitant or subsequent malignancies were present in 19% of patients. Molecular testing found BRAFV600E mutations in 44% of tested patients. The most common first-line systemic therapy was cytarabine (n = 10), followed by other drugs such as hydroxyurea, vemurafenib, and cladribine. This series represents the initial experience of a Canadian rare disease referral program and captures the clinical heterogeneity and longitudinal adult care of patients with LCH across multiple provinces. Variability in treatment approaches highlights the need for collaborative prospective natural history studies and coordinated clinical trials.
2026-08-08 | Langerhans cell histiocytosis
Langerhans cell histiocytosis initially identified as an inflammatory disorder is now being referred as a rare dendritic/histiocytic neoplasm arising from dendritic cell differentiation with a heterogeneous clinical presentation manifesting in skin, bones, lungs, liver, lymph nodes, neurologic, and hematologic systems in any age group. Diagnostic work-up, staging investigations, prognostic markers, and therapeutic algorithms have seen a paradigm shift from pediatric-inspired chemotherapy regimens to a patient-tailored focused approach. Although chemotherapy is still the backbone in the era of novel circulating biomarkers and targeted agents in multisystem disease, chemoresistance and delayed neurological sequelae still remain challenges, resulting in dismal outcomes and poor quality of life.
2026-07-29 | Firm lesion consistency and whitish tissue exposure ingastrointestinal Langerhans cell histiocytosis
Keywords endoscopy upper GI tract - diagnosis and imaging (inc chromoendoscopy, NBI, iSCAN, FICE, CLE) - endoscopy lower GI tract - diagnosis and imaging (inc chromoendoscopy, NBI, iSCAN, FICE, CLE...) - Ulcers (peptic and other) Publication History Received: 25 May 2026 Accepted after revision: 15 July 2026 Article published online: 29 July 2026 © 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/). Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-07-27 | Current Approaches Among Medical Providers Treating Pediatric Langerhans Cell Histiocytosis.
Most pediatric Langerhans cell histiocytosis (LCH) lesions harbor activating mutations within the mitogen-activated protein kinase (MAPK) pathway. MAPK inhibitors (MAPKi) represent a rational therapeutic strategy, though there is no consensus regarding optimal use. We sought to understand how providers currently integrate MAPKi into LCH therapy and gather input regarding potential future clinical trial designs. An online survey was distributed to members of the Histiocyte Society, Children's Oncology Group, and Asian Histiocytic Disorder Collaborative Group. Domains included demographics, experience treating LCH, preferred treatment in response to clinical vignettes, and opinions regarding clinical trial design. Participants included 106 pediatric attending physicians from 26 countries. Of the 89 providers with access to MAPKi, 79% have used them to treat LCH, with most reporting use outside of a clinical trial and for recurrent/refractory LCH. Nearly all participants agreed that prospective trials are needed to study MAPKi in newly diagnosed LCH, and 90% felt their institution would open such a trial. Regarding trial design, 89% would include patients with multisystem risk organ (RO) positive disease, while 47% and 21% would include multisystem or single system RO- disease, respectively. Most participants (83%) would include a trial arm combining MAPKi with chemotherapy, with 56% of these participants favoring combination therapy throughout treatment. Additionally, 43% favored including an MAPKi monotherapy arm. MAPKi are widely available and commonly utilized in pediatric LCH. While treatment practices and trial design preferences vary, there is a strong consensus regarding the need for a prospective clinical trial incorporating MAPKi into upfront therapy.
2026-07-22 | Langerhans cell histiocytosis in the adult lower gastrointestinal tract.
A female in her early 80s presented with chronic anal fissures which were unresponsive to conservative therapies. Examination was concerning for possible perianal Crohn's disease, but subsequent colonoscopy and biopsies revealed Langerhans cell histiocytosis (LCH) involving the colon and anus, diagnosed per 2022 WHO Classification of Haematolymphoid Tumours criteria and confirmed by BRAF V600E mutation. Systemic staging identified two unrelated malignancies of the breast and kidney. The patient was treated with cladribine as systemic chemotherapy, resulting in complete remission of LCH symptoms and lesions.This case illustrates key diagnostic and therapeutic considerations for clinicians: LCH can mimic inflammatory bowel disease and should be included in the differential for atypical or refractory perianal disease, especially in older adults. Histological confirmation and molecular profiling are essential for accurate diagnosis and treatment planning. Additionally, cladribine is a well-tolerated and effective option for adult LCH with gastrointestinal tract involvement. Early recognition and systemic staging are critical to guide therapy and identify potential coexisting malignancies.
antibodies
2025-12-26 | Repurposing osteoporosis medications for other diseases: a narrative review by the European Calcified Tissue Society (ECTS).
This narrative review explores the therapeutic potential of repurposing medications originally developed or approved for osteoporosis to treat non-osteoporotic conditions. Given their pharmacologic profiles and safety data, these agents offer promising therapeutic alternatives in both rare and common diseases with unmet clinical needs. Evidence from preclinical models, observational data, and randomised trials supports the repositioning of several osteoporosis drugs. Cyclic etidronate has shown efficacy in halting arterial calcification progression in pseudoxanthoma elasticum. Pamidronate has demonstrated symptom improvement in adult chronic nonbacterial osteitis. Neridronate is approved only in Italy for complex regional pain syndrome type I. Denosumab has shown therapeutic effects in Langerhans cell histiocytosis and has structural benefits in erosive hand osteoarthritis and rheumatoid arthritis. Parathyroid hormone analogues (rhPTH [1-84] and teriparatide) improve calcium-phosphate homeostasis in chronic and genetic hypoparathyroidism. Calcilytics, though originally discontinued for osteoporosis, show emerging promise in autosomal dominant hypoparathyroidism. In contrast, zoledronic acid has not demonstrated consistent clinical benefit in knee osteoarthritis. Strontium ranelate, despite showing structure-modifying effects in osteoarthritis, is no longer marketed due to safety concerns. Alendronate and denosumab in fibrous dysplasia yielded mixed results, with concerns about rebound effects after denosumab withdrawal. Repurposing osteoporosis medications represents a cost-effective, timely strategy to expand treatment options across diverse clinical indications. While promising outcomes have been demonstrated-particularly in rare diseases-rigorous, indication-specific clinical trials are essential to confirm efficacy, safety, and long-term outcomes. The accumulated pharmacologic and clinical experience with these agents offers a strong foundation for their continued exploration beyond osteoporosis.
2025-09-01 | [Immune microenvironment of Langerhans cell histiocytosis: from immune suppression to targeted therapy].
Langerhans cell histiocytosis (LCH) is a rare hematologic disorder characterized by the clonal proliferation of neoplastic dendritic cells (DCs), exhibiting both immature and senescent immune phenotypes. The immunosuppressive microenvironment in LCH includes an increased proportion of regulatory T (Treg) cells with inhibitory functions, as well as exhausted CD8(+) T cells and myeloid-derived suppressor cells, which collectively exacerbate immunosuppression and facilitate the immune evasion of tumor DCs. Current therapeutic approaches for LCH are limited by the challenges of relapse and drug resistance. However, emerging strategies that target the senescent phenotype of neoplastic DCs, inhibit Treg cell activity, and reverse T cell exhaustion through immune checkpoint blockade offer promising avenues for the treatment of LCH.
2025-05-29 | A case of diagnosis and treatment of mediastinal Langerhans cytosis.
Langerhans cell histiocytosis (LCH) is a rare disease. It mainly involves abnormal proliferation and aggregation of Langerhans cells, a type of cell of the immune system.Langerhans cytosis is more common in the bone, but it has rarely been reported in the mediastinum. We present a case of mediastinal thymus tumor presented with Langerhans cell histiocytosis. A 40-year-old female patient presented with left chest and back pain in April 2024. Imaging revealed abnormal signal lesions on the patient's left rib and anterior superior mediastinum. The clinical diagnosis was bone destruction and mediastinal space occupation, and the postoperative pathological diagnosis was Langerhans cell histiocytosis. Langerhans cytosis is characterized by mediastinal and thymus occupation and is relatively rare in clinical practice. For patients who tolerate surgery for a single or local lesion, surgical removal of the primary lesion should be considered. However, for patients with multiple lesions or distant metastases, clinicians should evaluate whether surgery will benefit the patient. After surgical treatment, targeted therapy or immunotherapy should be performed.
2025-05-26 | No overshoot of bone turnover after withdrawal of denosumab treatment of adults with Langerhans cell histiocytosis: a prospective clinical trial.
Denosumab (Dmab) discontinuation in osteoporosis leads to overshoot (rebound) of bone turnover, but its cause remains largely unclear. In a prospective trial, Dmab-treated Langerhans cell histiocytosis (LCH) patients showed no overshoot of bone turnover markers despite high short-term dosing. Findings suggest that total Dmab dose does not drive the overshoot of bone turnover markers. In patients with osteoporosis, the length of treatment with denosumab (Dmab) is an important risk factor for the overshoot (rebound) of bone turnover markers following its discontinuation. Whether this is due to the higher total Dmab dose given and/or the severity of the disease is unknown. To address this question, long-term follow-up of changes in bone metabolism after stopping Dmab with doses higher than those used in osteoporosis is essential. In a prospective, single-arm, open label, phase 2b clinical trial, ten adult patients with Langerhans cell histiocytosis (LCH), eight with bone lesions (four single, four multiple) and two without, were treated with Dmab sc injections 120 mg/2 months for 6 months (total 480 mg) and were followed for 24 months after the last injection. Treatment reduced bone turnover markers to about 10% of pretreatment values, which increased after treatment arrest to a peak that did not exceed pretreatment levels; mean (± SD) peak serum CTX 0.522 ± 0.366 ng/mL and P1NP 72.2 ± 35.9 ng/mL were not significantly different from baseline (p = 0.11 and 0.65, respectively). Moreover, pretreatment and peak serum CTX values were significantly correlated (rs = 0.818, p = 0.007). No vertebral fractures, bone loss, or hypercalcemia were observed. Dmab withdrawal in patients with LCH was not followed by an overshoot of bone turnover markers or bone loss despite the administration in 6 months of a total dose equal to that given in osteoporosis for 4 years. Total Dmab dose is, thus, not an important determinant of the bone turnover overshoot after treatment withdrawal.
2024-11-17 | Abstract C017: Exploring the composition of and interaction of the tumor microenvironment in Langerhans cell histiocytosis
Abstract Langerhans cell histiocytosis (LCH) is a rare inflammatory hematological neoplasm, characterized by the accumulation of LCH cells in various tissues and organs. These LCH cells originate from myeloid progenitors that carry a MAPK-pathway mutation. Once these mutated cells enter the tissue from the periphery, they differentiate into so-called LCH cells. In addition to LCH cells, the tumor microenvironment (TME) consists of a wide variety of immune cells. However, the interactions between these cells within the TME and their contribution to disease progression remain poorly understood. In this study, we focus on understanding the role of lymphocytes in LCH lesions. We used single-cell RNA sequencing to comprehensively profile the immune populations in LCH lesions on the transcriptomic level, which will be supplemented with spatial profiling. Our analysis identified a wide variety of infiltrating immune cells within LCH lesions with high cellular heterogeneity among patients. LCH- and T cells are the most prevalent cell types, suggesting a key role in lesion development and maintenance. Furthermore, the immune landscape includes several dendritic cell subsets – such as plasmacytoid DCs (pDCs), cDC1, and mature regulatory dendritic cells (mregDCs) – alongside tumor-associated macrophages (TAMs), monocytes, NK cells, B cells, and plasmablasts. Among T cells, regulatory T cells (Tregs) are particularly abundant and appear to be heavily influenced by LCH cells and other myeloid cells via the TNF-TNFR2 and CD86-CTLA4 pathways. Additionally, LCH cells express high levels of TGFβ – a known regulator of T cell activity – and MMP9 – which might hamper cytotoxic T cell infiltration. This suggests that LCH cells actively contribute to creating an immunosuppressive environment. Surprisingly, pDCs seem to be a major immune regulator within lesions and are likely to interact with T cells via TNFSF9 and Granzyme B. These insights into the immunosuppressive environment within LCH lesions highlight the critical role of Tregs as central regulators within the tumor microenvironment. The implications of these findings will be further explored and validated through in-vitro experiments and high-plex spatial protein profiling. Ultimately, our work may pave the way for developing targeted therapies aimed at modulating the TME, potentially enhancing anti-tumor immunity, and offering new strategies for treating LCH. Citation Format: Wouter van Midden, Raphaela Schwentner, Sebastian Eder, Philipp Ben Soussia-Weiss, Giulio Abagnale, Caroline Hutter. Exploring the composition of and interaction of the tumor microenvironment in Langerhans cell histiocytosis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C017.
cell therapies
2026-06-12 | Craniotomy with local autologous bone dust in pediatric single Langerhans cell histiocytosis
The treatment paradigm for surgery in patients with Langerhans cell histiocytosis (LCH) varies depending on the size and location of the tumor. Here, we illustrate an effective treatment modality through craniotomy with local autologous bone dust. An 8-year-old child presented with a 4-month history of a bumpy scalp on the right parietal region every time he combed his hair. Contrast-enhanced computed tomography (CT) of the brain revealed a single right parietal lytic bony defect measuring 2 × 2 × 1 cm, giving a punched-out appearance. The ultrasound of the abdomen, axial skeleton, and vertebral column was normal. A craniotomy and en bloc resection, including a 2 cm surrounding bone margin, were performed. The healthy skull bone edges (outer table) were drilled, and bone dust was used for reconstruction. The bone dust was spread over the dura to completely fill the defect site, followed by tack-up stitches. The healthy periosteum was laid over the defect and sutured. A follow-up brain CT before discharge and at 1 year showed evidence of cranial bone regeneration. Histopathology specimens showed LCH features. Complete excision, including the margin, followed by covering the defect using autologous bone dust, promotes osteoblast activity in pediatric calvarial. The peripheral tack-up stitches of the dura and periosteum contribute to osteogenesis by contact. This strategy is simple, inexpensive, and has good cosmetic results.
2026-05-31 | Progressive cochlear ossification secondary to Langerhans cell histiocytosis requiring sequential bilateral cochlear implantation: a case report.
Langerhans cell histiocytosis (LCH) is a rare disorder that may involve the temporal bone and, in rare cases, result in sensorineural hearing loss. This report highlights the importance of close radiological surveillance and timely cochlear implantation in the setting of progressive otic capsule ossification. A 21-year-old male presented with a five-year history of progressive bilateral hearing loss, tinnitus, vertigo and imbalance. Following multidisciplinary team (MDT) discussion, cochlear implantation was deferred until completion of chemotherapy. Repeat CT imaging demonstrated progressive cochlear ossification involving the otic capsules. A repeat discussion followed, which led to an expedited cochlear implantation. The left side was implanted first due to lesser ossification, achieving full electrode insertion. Sequential implantation of the contralateral ear was performed four months later. However, insertion was limited due to advanced ossification. The second implantation was technically more challenging, with only partial electrode insertion possible due to advanced ossification. We advocate for close surveillance in the case of LCH to monitor for signs of otic capsule ossification. This case demonstrates that cochlear ossification in LCH may progress rapidly, narrowing the window for optimal implantation. Early cochlear implantation should be strongly considered in such cases.
2026-03-31 | Pathogenic myeloid phenotypes drive disease pathology in a novel human neurohistiocytosis model.
Innate immunity is increasingly recognized as a driver of neurodegeneration, though pathogenic mechanisms are incompletely understood. Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplastic disorder caused by activating somatic mutations in mitogen-activated protein kinase (MAPK) pathway genes, most commonly BRAFV600E, in myeloid precursors. A subset of LCH patients develop progressive neurodegeneration (LCH-ND). We generated a human induced pluripotent stem cell (iPSC) model from patients with somatic hematologic mosaicism for BRAFV600E. Brain macrophages/microglia from LCH iPSCs exhibit unique disease specific pathogenic features. Stepwise differentiation identified hematopoietic progenitors as hyperproliferative, whereas brain macrophages were apoptosis resistant. Through application of cerebral organoids and a humanized murine xenotransplantation model we identify marked heterogeneity of differentiation potential within clonal BRAFV600E lines in vivo. This model phenocopied human specific phenotypes including dense basal ganglia foci of abnormal macrophages, marked neurodegeneration with astrogliosis, and progressive ataxia. This approach will allow for preclinical testing of therapeutics for LCH-ND.
2026-03-20 | Case Report: Complete remission of refractory Langerhans cell sarcoma following CLAG-M chemotherapy and allogeneic hematopoietic stem cell transplant.
Langerhans Cell Sarcoma (LCS) is an extremely rare and aggressive neoplasm with limited consensus on optimal treatment. We report the case of a 56-year-old woman with refractory Langerhans Cell Histiocytosis (LCH) that transformed into Langerhans Cell Sarcoma (LCS) who achieved complete remission following chemotherapy with cladribine, high-dose cytarabine, G-CSF, and mitoxantrone (CLAG-M), and subsequent allogeneic hematopoietic stem cell transplantation (HSCT). This case highlights the potential role of allogeneic HSCT as an effective therapeutic option for refractory LCS and underscores the importance of reporting additional cases to guide future management strategies in this rare malignancy.
2026-01-27 | Hematopoietic cell transplantation for Langerhans histiocytosis
Langerhans cell histiocytosis is a rare myeloid neoplasm that primarily affects children. Initial treatment depends on risk stratification, but overall survival is excellent. Patient with high-risk disease with risk organ involvement can experience disease reactivation or refractoriness to front-line therapy. A standard approach is not established in the literature, with different reported strategies, including conventional chemotherapy, MAPK-inhibitors and allogeneic hematopoietic (HCT). Allogeneic HCT is supported by retrospective studies with overall survival ranging from 56 to 77% in the largest series. Disease status at the time of HCT and the conditioning regimen (reduced-intensity conditioning versus myeloablative conditioning) correlates with survival and toxicity. Most recently, reduced-intensity conditioning modality has emerged as the preferred option for patients diagnosed with Langerhans cell histiocytosis who require allogeneic HCT.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Langerhans cell histiocytosis, including 1 approved therapy.
2 orphan drug designations for Langerhans cell histiocytosis, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
cobimetinib [Cotellic] | small molecules | FDA | 2021-04-26 | 2022-10-28 | Genentech, Inc. |
Vemurafenib | small molecules | EMA | 2016-05-30 | — | Groupe d'étude des histiocytoses |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.