Histiocytosis Patients Research Articles

Subfoveal Choroidal Thickness in Patients with Histiocytosis and Multimodal Imaging Features of Choroidal Infiltrates

To evaluate choroidal findings in patients with histiocytosis, including subfoveal choroidal thickness (SFCT), and multimodal imaging in eyes with choroidal infiltrates visible by ophthalmoscopy and determine if abnormalities change with histiocytosis-directed (kinase inhibitor) therapy. Retrospective comparative study at single tertiary cancer referral center. Ninety-one patients with histiocytosis and 41 age- and sex-matched controls. Clinical examination, fundus photography, and OCT were used to assess choroidal findings. Clinically evident choroidal infiltrates by ophthalmoscopy were recorded, and choroidal vascular architecture was qualitatively examined. Subfoveal choroidal thickness and was measured using enhanced depth imaging spectral domain OCT from the outer portion of Bruch membrane to the choroidal scleral interface. Subfoveal choroidal thickness was compared with matched controls; that secondary outcome was change in SFCT on histiocytosis-directed (kinase inhibitor) therapy. Multimodal imaging of choroidal infiltrates was visible by ophthalmoscopy. One hundred and eighty-two eyes of 91 patients (46 males, 45 females) with histiocytosis (Erdheim-Chester 35, Rosai-Dorfman 21, xanthogranuloma 7, mixed histiocytosis 11, Langerhans cell histiocytosis 15, and other 2) were examined. In patients with histiocytosis, the mean SFCT was 336.2 ± 94.9 μm compared with 250.3 ± 60.7 μm in the control group (P < 0.0001). Notably, 69% of patients with histiocytosis had SFCT >275 μm compared with 27% in controls (P < 0.0001). Subtype of histiocytosis, sites of bone or central nervous disease, posterior segment/other sites of ophthalmic disease, or mutational profile did not correlate with SFCT. In a subgroup analysis of 35 patients naïve to prior treatment, with >6 months follow-up, the proportion of SFCT >275 μm significantly decreased (P= 0.0016) on histiocytosis-directed (kinase inhibitor) therapy. Notably, 19.8% of patients had clinically evident choroidal infiltration: majority were yellow creamy, geographic, located posteriorly and hyperautofluorescent; with enlarged Haller vein bordering the infiltrate, choriocapillaris compression and loss of choroidal architecture by OCT. In this cohort, 19.8% of patients with histiocytosis had clinically evident infiltration of their choroid. Furthermore, the majority of patients with histiocytosis had increased SFCT compared with age- and sex-matched controls. The thickened choroid decreases on histiocytosis-directed (kinase inhibitor) therapy and may be a marker of response to systemic treatment. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Ocular findings in patients with histiocytosis and association with clinical and molecular features

Background/aimsOcular manifestations of histiocytosis and their genetic underpinnings are poorly characterised. This study characterises ocular sites of histiocytosis, notate genetic alterations and correlates to histiocytosis clinical features including subtype and...

Exploration of treatment in childhood Langerhans cell histiocytosis based on inflammatory and malignant symptoms: a pilot study

BackgroundMultisystem childhood Langerhans cell histiocytosis (LCH) patients, especially those with risk organ (RO) involved, had not been satisfactorily treated under the international traditional schemes as high incidences of reactivation with late sequelae were largely reported. Over years, we have observed that LCH patients with varied clinical symptoms responded differently to different drugs, suggesting the current grouping strategies based only on the number of organs involved might be inadequate. LCH has been defined as an inflammatory myeloid tumor, thus this study has innovatively divided LCH pediatric patients into inflammatory or malignant symptoms group, and given different intensity treatment regimens to different groups.AimThis clinical study aimed to explore a more appropriate patient grouping system according to the LCH symptom presentations and examine the clinical outcomes of treatment strategies in different groups.MethodsAccording to the clinical manifestations, 37 cases of children were divided into Group A (only inflammatory symptoms) and Group B (malignant symptoms with or without inflammatory symptoms). Patients in Group A and B were initially treated with vindesine (VDS) and methylprednisolone (PSL), and VDS, PSL, pirarubicin (THP) and cyclophosphamide (CTX), respectively. Treatment responses were evaluated six weeks after the induction therapy in all patients, and the criteria were disease status and clinical scores of symptoms.ResultsPre- and post-treatment scores were 1.22 ± 0.547 and 0.00 ± 0.00 in Group A, and 14.79 ± 1.686 and 1.00 ± 1.563 in Group B, respectively. All patients had subsequentlly received maintenance therapy without progressive disease. The 4-year overall survival (OS) rate was 100% in both groups and the 4-year event-free survival (EFS) was 94.4% in Group A and 89.5% in Group B, respectively. There were no obvious adverse events (AE) in Group A, whereas the main AE in Group B were alopecia and non-lethal hematological toxicity.ConclusionStratification according to patients’ clinical symptoms, with low-intensity treatment for inflammatory symptoms (mild manifestations) and intensive treatment with multiple drugs for malignant symptoms (severe manifestations), is a positive exploration that simplifies stratification method, achieves good long-term remission of the disease, and obtains a higher survival rate and quality of life, which seemed to be more appropriate for LCH patients.

Langerhans Cell Histiocytosis With Unusual Hexagonal Crystals in Addition to Usual Charcot-Leyden Crystals. Report of a Patient With Possible Process of Crystal Formation and Clinical Significance of a "Necrotic" Change.

Langerhans cell histiocytosis is a rare neoplastic disorder characterized by the proliferation of Langerhans cells and often accompanied by eosinophil infiltration. Charcot-Leyden crystals, composed of galectin 10, are occasionally observed in Langerhans cell histiocytosis; however, histological images are rarely reported. We herein present a patient with Langerhans cell histiocytosis with Charcot-Leyden crystals and hexagonal crystals by describing the histologic and immunohistochemical features of a lymph node. A unique distribution of Charcot-Leyden crystals and hexagonal crystals was observed in this patient, shedding light on their possible formation process of the latter. We discuss the biological significance of eosinophilic abscesses in Langerhans cell histiocytosis and propose that these crystals may be linked to extracellular trap-cell death (ETosis). This example challenges the conventional characterization of "necrosis" in Langerhans cell histiocytosis and underscores the importance of recognizing ETosis as a potential mechanism involved in the pathogenesis of Langerhans cell histiocytosis. Further studies are underway to validate significance of these findings in a larger cohort of Langerhans cell histiocytosis patients.

Demographics and additional haematologic cancers of patients with histiocytic/dendritic cell neoplasms.

The discovery of somatic genetic alterations established many histiocytic disorders as haematologic neoplasms. We aimed to investigate the demographic characteristics and additional haematologic cancers of patients diagnosed with histiocytic disorders in The Netherlands. We retrieved data on histiocytosis patients from the Dutch Nationwide Pathology Databank (Palga). During 1993 to 2022, more than 4000 patients with a pathologist-assigned diagnosis of a histiocytic disorder were registered in Palga. Xanthogranulomas were the most common subtype, challenging the prevailing assumption that Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder. LCH and juvenile xanthogranuloma (JXG) had a peak incidence in the first years of life; males were overrepresented among all histiocytosis subgroups. 118 patients had a histiocytic disorder and an additional haematologic malignancy, including 107 (91%) adults at the time of histiocytosis diagnosis. In 16/118 patients, both entities had been analysed for the same genetic alteration(s). In 11 of these 16 patients, identical genetic alterations had been detected in both haematologic neoplasms. This included two patients with PAX5 p.P80R mutated B cell acute lymphoblastic leukaemia and secondary histiocytic sarcoma, further supporting that PAX5 alterations may predispose (precursor) B cells to differentiate into the myeloid lineage. All 4/11 patients with myeloid neoplasms as their additional haematologic malignancyhad shared N/KRAS mutations. This population-based study highlights the frequency of xanthogranulomas. Furthermore, our data add to the growing evidence supporting clonal relationships between histiocytic/dendritic cell neoplasms and additional myeloid or lymphoid malignancies. Particularly adult histiocytosis patients should be carefully evaluated for the development of these associated haematologic cancers.

Central nervous system disorders secondary to histiocytoses: neurodegeneration with potential for improvement

Histiocytoses, including Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD), are inflammatory myeloid tumors in which monocyte lineage cells aggregate in various organs, causing tissue damage. Most of these tumors harbor oncogenic mutations in mitogen-activated protein kinase (MAPK) pathway genes, typified by BRAFV600E. Some patients with LCH develop bilateral symmetrical cerebellar lesions and brain atrophy several years after diagnosis when the initial symptoms disappear, leading to cerebellar ataxia and higher cerebral dysfunction. A similar neurological disorder has also been reported in ECD. This neurological disorder can be improved with MAPK inhibitors. When patients with this neurological disorder are identified among neurodegeneration of unknown etiology or histiocytosis patients and treated early with MAPK inhibitors, the disorder can be reversible.

Bronchoalveolar cytokine profile differentiates Pulmonary Langerhans cell histiocytosis patients from other smoking-related interstitial lung diseases

BackgroundPulmonary Langerhans cell histiocytosis (PLCH) is a rare interstitial lung disease (ILD) associated with smoking, whose definitive diagnosis requires the exclusion of other forms of ILD and a compatible surgical lung biopsy. Bronchoalveolar lavage (BAL) is commonly proposed for the diagnosis of ILD, including PLCH, but the diagnostic value of this technique is limited. Here, we have analyzed the levels of a panel of cytokines and chemokines in BAL from PLCH patients, in order to identify a distinct immune profile to discriminate PLCH from other smoking related-ILD (SR-ILD), and comparing the results with idiopathic pulmonary fibrosis (IPF) as another disease in which smoking is considered a risk factor.MethodsBAL samples were collected from thirty-six patients with different ILD, including seven patients with PLCH, sixteen with SR-ILD and thirteen with IPF. Inflammatory profiles were analyzed using the Human Cytokine Membrane Antibody Array. Principal component analysis (PCA) was performed to reduce dimensionality and protein–protein interaction (PPI) network analysis using STRING 11.5 database were conducted. Finally, Random forest (RF) method was used to build a prediction model.ResultsWe have found significant differences (p < 0.05) on thirty-two cytokines/chemokines when comparing BAL from PLCH patients with at least one of the other ILD. Four main groups of similarly regulated cytokines were established, identifying distinct sets of markers for each cluster. Exploratory analysis using PCA (principal component analysis) showed clustering and separation of patients, with the two first components capturing 69.69% of the total variance. Levels of TARC/CCL17, leptin, oncostatin M (OSM) and IP-10/CXCL10 were associated with lung function parameters, showing positive correlation with FVC. Finally, random forest (RF) algorithm demonstrates that PLCH patients can be differentiated from the other ILDs based solely on inflammatory profile (accuracy 96.25%).ConclusionsOur results show that patients with PLCH exhibit a distinct BAL immune profile to SR-ILD and IPF. PCA analysis and RF model identify a specific immune profile useful for discriminating PLCH.

Myeloid cells from Langerhans cell histiocytosis patients exhibit increased vesicle trafficking and an altered secretome capable of activating NK cells.

Langerhans cell histiocytosis (LCH) is a potentially life-threatening inflammatory myeloid neoplasia linked to pediatric neurodegeneration, whereby transformed LCH cells form agglomerated lesions in various organs. Although MAP-kinase pathway mutations have been identified in LCH cells, the functional consequences of these mutations and the mechanisms that cause the pathogenic behavior of LCH cells are not well understood. In our study, we used an in vitro differentiation system and RNA-sequencing to compare monocyte-derived dendritic cells from LCH patients to those derived from healthy controls or patients with Crohn's disease, a non-histiocytic inflammatory disease. We observed that interferon-γ treatment exacerbated intrinsic differences between LCH patient and control cells, including strikingly increased endo- and exocytosis gene activity in LCH patients. We validated these transcriptional patterns in lesions and functionally confirmed that LCH cells exhibited increased endo- and exocytosis. Furthermore, RNA-sequencing of extracellular vesicles revealed the enrichment of pathological transcripts involved in cell adhesion, MAP-kinase pathway, vesicle trafficking and T-cell activation in LCH patients. Thus, we tested the effect of the LCH secretome on lymphocyte activity and found significant activation of NK cells. These findings implicate extracellular vesicles in the pathology of LCH for the first time, in line with their established roles in the formation of various other tumor niches. Thus, we describe novel traits of LCH patient cells and suggest a pathogenic mechanism of potential therapeutic and diagnostic importance.

RAF-Independent MEK Mutations Drive Histiocytic Neoplasms In Vivo and Are Sensitive to Single-Agent ERK Inhibition in Patients

Histiocytic neoplasms are clonal disorders of the monocyte/macrophage lineage that include Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD). Histiocytoses are defined by recurrent, mutually exclusive mutations activating MAP kinase signaling, including BRAFV600E mutations in ~50% of LCH and ECD patients, which confer robust lasting clinical responses to BRAF inhibition. Mutations in MEK1/2, ARAF, and a diverse array of other kinases are present in BRAF wild-type histiocytoses patients and are broadly responsive to the allosteric MEK1/2 inhibitor cobimetinib. Following genomic analysis of ~300 pediatric and adult patients with diverse histiocytoses, the single most common genomic alteration following BRAFV600E mutations are MEK1 E102_I103 in-frame deletions. In contrast to BRAFV600E, the biological impact of activating mutations in MEK1/2 kinases are unknown, and no cancer associated MEK1/2 mutation has ever been modeled in vivo. MEK1/2 mutations are recurrent across a wide variety of human cancers and RASopathies and are now often found at resistance to emerging KRAS-mutant selective inhibitors. These findings motivated us to generate Map2k1E102_I103del conditional knock-in mice within the endogenous locus of Map2k1 (encoding MEK1 kinase), which represent the first genetically engineered mouse model of MEK1/2 mutations. We first crossed Map2k1E102_I103del mice to inducible Mx1-cre driver mice. Interestingly, Mx1-cre Map2k1E102_I103del knock-in mice developed a 100% penetrant lethal myelomonocytic disorder by 5-6 weeks of age while their cre-negative Map2k1E102_I103del littermates did not develop disease (Figure A). Notably, recombination of the Map2k1E102_I103del alleleoccurred spontaneously without pIpC administration and resulted in strong activation of phosphorylated ERK1/2 in bone marrow and spleen mononuclear cells. Mx1-cre Map2k1E102_I103del mice developed a myelomonocytic neoplasm with suppression of B-lymphopoiesis and expansion of classical and non-classical monocyte subsets, macrophages, and Cd11b+ conventional dendritic cells. Monocyte, macrophage, and dendritic cells infiltrated hematopoietic organs (bone marrow, spleen, and peripheral blood), as well as liver and skin, each of which are common sites of LCH and ECD disease involvement. The Mx1-cre Map2k1E102_I103del disease was hematopoietic cell autonomous and could be propagated by serial hematopoietic reconstitution in irradiated recipient mice, as well as using Vav1-cre Map2k1E102_I103del knock-in mice (where Cre is expressed only in hematopoietic cells from earliest hematopoietic development). Finally, restricting MEK1 mutant expression to monocyte and dendritic cell precursors using CD11c-cre resulted in similar lethal expansions of monocyte, macrophage, and dendritic cells as seen in the Mx1-cre and Vav1-cre models. Prior in vitro work has demonstrated that MEK1 p.E102_I103del activates MEK and ERK without requiring activated GTP-bound RAS and is associated with resistance to allosteric MEK inhibitors. Consistent with this, we identified nine histiocytosis patients with this specific MEK1 mutation, three of which had de novo resistance to cobimetinib. These three patients and one treatment-naïve patient were treated with an oral ERK1/2 inhibitor ulixertinib under the FDA single-patient compassionate use program. Three of 4 patients had a clinical or radiological partial or complete response to ulixertinib (Figure B). Overall, these data identify the impact of oncogenic MEK kinase mutations in vivo as found in children and adults with histiocytoses and RASopathies. Expression of a RAF-independent MEK1 mutation in vivo gave rise to disease reminiscent of human systemic histiocytic neoplasms. Importantly, this molecular entity is resistant to MEK inhibition in some patients, a phenomenon previously undocumented, but responsive to ERK inhibition, which may be a promising therapeutic approach to histiocytic neoplasms unresponsive to allosteric MEK inhibition. The clinical observation of efficacy of ERK inhibition in MEK inhibitor resistant histiocytoses patients has resulted in a soon-to-be initiated focused phase 2 clinical trial of ulixertinib in adults with histiocytoses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pathology, Classification, Clinical Manifestations and Prognosis of Langerhan’s Cell Histiocytosis: A Single Center Experience

Objective: The aim of the study is to raise awareness about clinical features,&#x0D; histopathological and radiological analyzes and treatment details of this rare&#x0D; disease.&#x0D; Methods: A total of 55 Langerhans cell histiocytosis patients, diagnosed&#x0D; between the years 2006 and October 2020 in our department were included in the&#x0D; study. The patients were evaluated in terms of age, gender, tumor localization,&#x0D; risk groups, treatment modalities, recurrence, and disease outcome.&#x0D; Results: Twenty-three out of 55 patients were children and 32 were adults. The&#x0D; ages of the patients were between 7 months and 72 years. Thirty-seven of the&#x0D; cases were male and 18 were female. The most common clinical complaint in&#x0D; both groups was pain and swelling. The duration between the onset of the patient&#x0D; complaints and admission to the hospital varies between 7 days-12 months in&#x0D; children, and 10 days-23 years in adults. Forty-three of the cases had single-organ&#x0D; involvement and 12 had multiorgan involvement. The most frequently affected&#x0D; organ in both groups was bone. Forty of the 55 patients had follow-up data and&#x0D; the treatment modalities are as follows: Nine patients radiotherapy, 8 patients&#x0D; chemotherapy+steroid, 7 patients chemotherapy, 2 patients&#x0D; chemotherapy+radiotherapy+steroid, 1 patient steroid, and 2 patients&#x0D; chemotherapy+radiotherapy. Eleven patients were followed up without&#x0D; additional treatment after surgery. Median follow-up from the time of biopsy&#x0D; was 45.9 months in children and 41.9 months in adults.&#x0D; Conclusions: As a result, diagnosis requires a high degree of suspicion and final&#x0D; diagnosis is based on the histological examination of the lesions and biopsies

Adult Langerhans cell histiocytosis with thyroid gland involvement: clinical presentation, genomic analysis, and outcome.

The present study aims to evaluate the characteristics and treatment outcomes of adult Langerhans cell histiocytosis (LCH) patients with thyroid involvement. We retrospectively described the clinical, biological, and genomic characteristics of a series of 36 LCH patients with thyroid involvement in our center between January 2001 and December 2021. At the time of diagnosis, only one patient was classified as having single-system LCH, and 35 patients were classified as having multisystem (MS) LCH. Three patients had coexisting papillary thyroid carcinoma. Patients with thyroid gland involvement had higher frequencies of pituitary (88.6% vs. 53.4%, P < 0.001), liver (45.7% vs. 20.7%, P = 0.003), and lymph node (54.3% vs. 31.6%, P = 0.012) involvement and a lower frequency of bone (45.7% vs. 72.0%, P = 0.003) involvement than patients without thyroid gland involvement. Sixteen patients had abnormal thyroid function, including nine patients with primary hypothyroidism, one patient with central hypothyroidism, and six patients with subclinical hypothyroidism. BRAFV600E, BRAF N486_P490, and MAP2K1 mutations were detected in 14.3%, 57.1%, and 7.1% of patients, respectively. After a 43-month median follow-up, none of the patients died, and 15 patients experienced reactivation. The median event-free survival was 37.5months. Two of 6 patients with subclinical hypothyroidism had normal thyroid function, and 12 patients still had hypothyroidism after treatment. As the largest adult LCH cohort with thyroid gland involvement to date, we found that patients with thyroid gland involvement had different clinical characteristics, genetic profiles, and outcomes than patients without thyroid gland involvement.

Overcoming barriers to tumor genomic profiling through direct patient social media outreach.

6532 Background: Tumor genomic profiling is increasingly used to identify actionable genomic alterations as a guide to therapy selection. To overcome barriers to genomic testing for patients with rare cancers, we initiated a program to offer free clinical tumor genomic testing worldwide to patients with select rare cancer subtypes. Methods: Patients were recruited through social media outreach, engagement with disease advocacy groups, or via physician referral, with a focus on recruiting patients with histiocytosis, germ cell tumors and rare pediatric cancers. Tumor and patient-matched germline DNA were analyzed using the MSK-IMPACT targeted sequencing next generation sequencing panel with return of results to patients and their local physicians. Whole exome recapture of MSK-IMPACT DNA sequencing libraries was performed for patients with female germ cell tumors to define the genomic landscape of this rare cancer subtype. Results: 359 cancer patients expressed interest in the Make-an-IMPACT program, of whom 333 were enrolled. Tumor tissue was received for 288 (86.4%), with 250 (86.8%) having tumor DNA of sufficient quantity and quality for MSK-IMPACT testing. 14 histiocytosis patients have received genomically guided therapy to date, of whom 13 (93%) have had clinical benefit based on local MD response assessment with a mean treatment duration of 16.7 months (range 3-32+). Whole exome sequencing of ovarian GCTs identified a subset with fully haploid genotypes, a phenotype rarely observed in other cancer types. Actionable genomic alterations were rare in ovarian GCT (28%), however, 2 ovarian GCTs and squamous transformation had high tumor mutational burden, one of whom had a complete response to pembrolizumab. Conclusions: Social media outreach can facilitate the assembly of cohorts of rare cancers of sufficient size to define their genomic landscape. By profiling tumors in a clinical laboratory, results could be reported to patients and their local physicians where they could be used to guide treatment selection. This can also open the door to diversifying and being able to study the genomic landscape in a diverse cohort.

Intermediate-dose cytarabine is an effective therapy for adults with non-Langerhans cell histiocytosis

BackgroundNon-Langerhans cell histiocytosis, including Erdheim–Chester disease (ECD), Rosai–Dorfman disease (RDD), indeterminate cell histiocytosis (ICH), and unclassified histiocytosis, is a rare disorder lacking a standard treatment strategy. We report our experience using intermediate-dose cytarabine as the first or subsequent therapy in non-Langerhans cell histiocytosis.ResultsNine ECD patients, 5 RDD patients, 1 ICH patient and 1 unclassified histiocytosis patient were enrolled. Intermediate-dose cytarabine therapy was administered as 0.5–1.0 g/m2 of intravenous cytarabine every 12 h for 3 days every 5 weeks. The median age at cytarabine initiation was 47.5 years (range 18–70 years). The median number of cycles of cytarabine administered was 5.5 (range 2–6). The overall response rate (ORR) was 87.5% in the overall cohort, including 12.5% with complete response and 75.0% with partial response. One patient experienced disease recurrence 19 months after cytarabine therapy. The median follow-up duration for the entire cohort was 15.5 months (range 6–68 months). The estimated 2-year progression-free survival and overall survival rates were 85.6% and 92.3%, respectively. The most common toxicity was haematological adverse events, including grade 4 neutropenia and grade 3–4 thrombocytopenia. No treatment-related deaths occurred.ConclusionsIntermediate-dose cytarabine is an efficient treatment option for non-Langerhans cell histiocytosis patients, especially for those with CNS involvement.

CLINICAL FEATURES AND OUTCOME IN CHILDREN WITH LANGERHANS CELL HISTIOCYTOSIS. A SINGLE INSTITUTION EXPERIENCE FROM PAKISTAN

Objective: To find out the clinical manifestations, treatment given and outcome of children with diagnosis of Langerhans cell histiocytosis.&#x0D; Study Design: Retrospective observational study.&#x0D; Place and Duration of Study: Shaukat Khanum Cancer Hospital, Lahore Pakistan, from Jan 2005 to Dec 2015.&#x0D; Methodology: Medical charts were reviewed in detail along with the available imaging for the patients. The data included age at the time of diagnosis, extent of the disease, involvement of risk organs, treatment given, response at 6th week of chemotherapy and at the end of the treatment, and outcome in terms of disease progression during the treatment, relapse of disease on follow up and cause of death either due to treatment related mortality or disease complications.&#x0D; Results: There were 29 patients, 12 patients (41%) had single system and 17 (58%) had multisystem involvement. 7 patients (41%) had risk organ involvement in the multisystem group. All the patients of multisystem and 6 patients of single system were treated according to the Langerhans cell histiocytosis III protocol. Commonest sites of involvement were bone in 22 (75%), followed by lymph nodes in 18 (62%) patients. Disease relapse was seen in 6 patients and all of them had multisystem disease. Mortality was observed only in multisystem Langerhans cell histiocytosis patients and more than 50% were risk organ positive.&#x0D; Conclusion: Langerhans cell histiocytosis is a highly heterogeneous disease. Some forms are curable without chemotherapy, while the multisystem disease requires aggressive treatment. However, despite intensive treatment, the multisystem disease and risk organs involved have poor...........

849P Demographics of Langerhans cell histiocytosis patients who died during the 2010-2017

Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm that originates from the dendritic cell and manifests as locally advanced disease or multisystem involvement. The overall 5-year survival rate of a person diagnosed with LCH is >90% (100% for patients with single-system disease and 91.7% for patients with multi-system disease). Management of single system or multisystem disease involves a combination of steroids and/or chemotherapy. Utilizing the NCDB, we aim to study the clinical and demographic characteristics of LCH patients who died during the period of 2010-2017.

Phase 2 Trial of Single-Agent Cobimetinib for Adults with BRAF V600-Mutant and Wild-Type Histiocytic Disorders

Background: Use of BRAF inhibitors in BRAFV600 mutant Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) leads to near universal and prolonged response and has transformed the management of these disorders. However, nearly 50% of histiocytosis patients lack a BRAFV600-mutation and therefore cannot receive BRAF inhibitors creating an ongoing need for new therapies in histiocytosis. Comprehensive profiling of these BRAFV600 wildtype (BRAF-wt) ECD/LCH patients has demonstrated that nearly all harbor mutations activating the Mitogen Activated Protein Kinase (MAPK) pathway. This finding raised the possibility of treatment of BRAF-wt histiocytosis with MEK1/2 inhibition. Here we present data on 11 patients with histiocytosis treated with single-agent of the MEK1/2 inhibitor Cobimetinib (Clinicaltrials.gov, NCT02649972).Methods: This is an open-label phase 2 trial of Cobimetinib 60mg daily for patients with (1) BRAF-wt histiocytosis or (2) BRAFV600-mutant histiocytosis intolerant or without access to BRAF inhibitor therapy. The primary outcome is metabolic response by 18F-FDG PET scan. Maximal FDG standardized uptake value (SUV) was observed in up to 5 target lesions, normalized for body weight; this was compared between baseline and subsequent scans. Secondary endpoints included progression-free survival (PFS) as determined by 18F-FDG PET scan, overall survival (OS), and patient-centered outcomes measuring disease-related symptoms (with a disease-specific symptom scale), symptoms of systemic inflammation (Sickness Behavior Inventory; SBI), and psychological states (Hospital Anxiety and Depression Scale). Based on prior data identifying systemic immune perturbation in the sera of histiocytosis patients, we quantitatively analyzed 40 cytokines, chemokines, and growth factors in serial sera of the patients in this trial. Data cut-off was June 22, 2017.Results: 11 patients (8 ECD, 1 Rosai-Dorfman disease [RDD], 1 mixed ECD/RDD, 1 LCH) have enrolled with a median age of 53. Eight patients have BRAF-wt disease, the remainder are BRAFV600-mutant positive. Ten patients have had response assessments at the time of data cut-off. The response rate was 90% (9/10), with 40% (4 patients) having a complete metabolic response (resolution of FDG avidity to organ background), 50% (5 patients) a partial metabolic response (50% or greater reduction in FDG avidity), and 10% (one patient) stable metabolic disease (Figure A-B). No patient has developed progressive disease. Mean symptom severity (scored 0-50) decreased by 31% (mean score 38 to 27) after 4 cycles of treatment for 9 patients with longitudinal assessment. 8 of these 9 patients with either anxiety or depression at baseline, and 4 had neither after 4 cycles of treatment. Mean SBI (scored 0-36) decreased 39% (mean score 22 to 13) in 5 patients with longitudinal assessment (Figure C). Cytokine analysis identified dramatic effects of Cobimetinib upon reducing IL-8, TNF-alpha, and MIP1b levels (amongst other cytokines) as well as coordinate increase in eotaxin and Flt3-L levels (Figure D). One patient died on study from Grade 5 respiratory failure, unrelated to drug, and one patient was removed from study due to drug toxicity (Grade 3 retinal vein occlusion). Grade 3/4 toxicities have been decreased lymphocyte count (23%), hyponatremia (23%), increased lipase (15%), diarrhea (8%), and hypocalcemia (8%).Conclusions: This trial demonstrates robust efficacy of single-agent MEK1/2 inhibition with Cobimetinib in histiocytic disorders, across both BRAF-wt and BRAFV600-mutant patients, measured by radiologic as well as patient-centered outcomes. Toxicities have been manageable and largely similar to those observed in previous trials of Cobimetinib. These data extend the spectrum of patients eligible to be treated with therapies targeting the activating somatic MAPK alterations driving histiocytoses. [Display omitted] DisclosuresDogan:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche Pharmaceuticals: Consultancy; Peer Review Institute: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy.

Frequency detection of BRAF V600E mutation in a cohort of pediatric langerhans cell histiocytosis patients by next-generation sequencing

BackgroundLangerhans cell histiocytosis (LCH) is a rare neoplastic disease that occurs in both children and adults, and BRAF V600E is detected in up to 64% of the patients. Several studies have discussed the associations between BRAF V600E mutation and clinicopathological manifestations, but no clear conclusions have been drawn regarding the clinical significance of the mutation in pediatric patients.ResultsWe retrieved the clinical information for 148 pediatric LCH patients and investigated the BRAF V600E mutation using next-generation sequencing alone or with droplet digital PCR. The overall positive rate of BRAF V600E was 60/148 (41%). The type of sample (peripheral blood and formalin-fixed paraffin-embedded tissue) used for testing was significantly associated with the BRAF V600E mutation status (p-value = 0.000 and 0.000). The risk of recurrence declined in patients who received targeted therapy (p-value = 0.006; hazard ratio 0.164, 95%CI: 0.046 to 0.583). However, no correlation was found between the BRAF V600E status and gender, age, stage, specific organ affected, TP53 mutation status, masses close to the lesion or recurrence.ConclusionsThis is the largest pediatric LCH study conducted with a Chinese population to date. BRAF V600E in LCH may occur less in East Asian populations than in other ethnic groups, regardless of age. Biopsy tissue is a more sensitive sample for BRAF mutation screening because not all of circulating DNA is tumoral. Approaches with low limit of detection or high sensitivity are recommended for mutation screening to avoid type I and II errors.

The Clinical and Laboratory Characteristics of Adult Langerhans Cell Histiocytosis Patients and the Influencing Factors of Prognosis

To observe the clinical and laboratory characteristics of adult Langerhans cell histiocytosis(LCH) patients and to analyze the influencing factors of its prognosis. The clinical and laboratory charac-teristics of 38 adult LCH patients treated in our hospital from January 2010 to August 2019 were retrospective analyzed, and the clinical prognosis of the patients was analyzed. The median age of 38 patients was 41 (21-65) years old, and the ratio of male and female was about 2∶1. Among 38 patients, 44.7% (17/38) were involved in multiple systems, and 31.6% (12/38) were involved in high-risk organs (including liver, lung, hematopoietic system or spleen). The bone involvement was the most common (21/38, 55.3%), and the most common clinical symptom was pain (19/38, 50.0%). The result of laboratory showed that anemia (4/38，10.5%), thrombocytopenia (1/38，2.6%), neutropenia (2/38，5.3%), lymphopenia (6/38，15.8%), monocytosis (11/38，28.9%), C-reactive protein increasing (6/21，28.6%), erythrocyte sedimentation rate increasing (10/18, 55.3%), and ferritin protein increasing (9/17, 55.3%). The median follow-up time was 53 months, and a total of 5 patients were died. The 10-year overall survival rate of patients with single-system involvement was 100%, which was significantly higher than that of patients with multiple-system involvement (70.1%) (P=0.0078). The prognosis of patients without risk-organ involvement was better than that of patients with risk-organ involvement (10-year overall survival rate: 100% vs 60.6%) (P=0.0007). Further analysis showed that in addition to multiple-system involvement and risk-organ involvement, the increase of peripheral blood monocyte cells and the increase of ferritin protein were also associated with poorer prognosis of the patients. The multiple system involve-ment and risk-organ involvement, the increasing of monocyte cells and the increasing of ferritin protein were the independent risk factors of adult LCH patients.

Long-term complications in uniformly treated paediatric Langerhans histiocytosis patients disclosed by 12 years of follow-up of the JLSG-96/02 studies.

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasia derived from immature myeloid dendritic cells with the mitogen-activated protein kinase (MAPK) pathway gene mutation. LCH is rarely fatal, but patients develop various permanent consequences (PCs). We report the frequencies of LCH-related PCs in paediatric patients (n=317) treated by the JLSG-96/02 AraC-containing regimens. One-third of LCH patients had at least one PC at a median follow-up of 12years. Central nervous system (CNS)-related PCs (neurological and endocrinological) accounted for 21·5%, non-CNS-related 16·7%. We require novel therapeutic measures to further reduce the frequency of LCH-related PCs.

The Contribution of MicroRNAs to the Inflammatory and Neoplastic Characteristics of Erdheim-Chester Disease.

Simple SummaryIn the last two decades, new molecules, named microRNAs, have been identified. Impairment of microRNA function can lead to the development of diseases such as cancer; therefore, analyzing microRNAs expression, may help to explain the development of diseases. Moreover, these molecules can be obtained easily from blood, with little discomfort to the patient, and this may help to develop them as substances that could help to diagnose diseases and determine response to treatment. Here, we studied how microRNAs are involved in a rare clonal hematological malignancy named Erdheim–Chester disease (ECD). We found a differential expression microRNA signature between ECD patients and healthy controls. Our analysis suggests that reduced expression of microRNAs in ECD results in upregulation of target genes that participate in cell survival signaling and inflammation. This study expands our knowledge of the molecular basis of ECD and may enable improved treatment for affected patients. The pathogenesis of histiocytic neoplasms is driven by mutations activating the MAPK/ERK pathway, but little is known about the transcriptional and post-transcriptional alterations involved in these neoplasms. We analyzed microRNA (miRNA) expression in plasma samples and tissue biopsies of Erdheim–Chester disease (ECD) and Langerhans cell histiocytosis (LCH) patients. In silico analysis revealed a potential role of miRNAs in regulating gene expression in these neoplasms as compared with healthy controls (HC). NanoString analysis revealed 101 differentially expressed plasma miRNAs in 16 ECD patients as compared with 11 HC, 95% of which were downregulated. MiRNAs-15a-5p, -15b-5p, -21-5p, -107, -221-3p, -320e, -630, and let-7 family miRNAs were further evaluated by qRT-PCR in an extended cohort of 32 ECD patients, seven LCH and 15 HC. Six miRNAs (let-7a, let-7c, miR-15a-5p, miR-15b-5p, miR-107 and miR-630) were highly expressed in LCH plasma and tissue samples as compared with ECD. Pathway enrichment analysis indicated the miRNA contribution to inflammatory and pro-survival signaling pathways. Moreover, the let-7 family members were downregulated in untreated ECD patients as compared with HC, while treatment with MAPK/ERK signaling inhibitors for 16 weeks resulted in their upregulation, which was in parallel with the radiologic response seen by PET-CT. The study highlights the potential contribution of miRNA to the inflammatory and neoplastic characteristics of ECD and LCH.