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Anales de Pediatria Aug 2018Haemophagocytic syndrome, or haemophagocytic lymphohistiocytosis (HLH), is a disorder with high mortality, typically recognised at paediatric age. Without proper... (Review)
Review
Haemophagocytic syndrome, or haemophagocytic lymphohistiocytosis (HLH), is a disorder with high mortality, typically recognised at paediatric age. Without proper treatment, HLH can be fatal. The risk of a rapid progression to multi-organ failure and central nervous system involvement leading to long-term sequelae, are the most feared consequences of a diagnostic delay. Therefore, HLH is a medical emergency that paediatricians should be able to identify in a patient with fever and progressive worsening of general condition. The application of the HLH diagnostic criteria, which include clinical and analytical data (as well as a bone marrow aspirate), and the search for a trigger (infectious, oncological, rheumatological, or metabolic). These are decisive for the establishment of a targeted treatment, which aims at neutralising the trigger and reducing the hyper-inflammation. The most relevant data for general paediatricians are presented in this review, including the physiopathology, diagnosis, and treatment of this serious disease.
Topics: Child; Early Diagnosis; Humans; Lymphohistiocytosis, Hemophagocytic
PubMed: 29871839
DOI: 10.1016/j.anpedi.2018.05.003 -
Cancer Discovery Feb 2016Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans...
UNLABELLED
Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAF(V600E) mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAF(V600E)-wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAF(V600E)-wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders.
SIGNIFICANCE
We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders.
Topics: Anaplastic Lymphoma Kinase; Gene Expression Profiling; Histiocytosis, Langerhans-Cell; Histiocytosis, Non-Langerhans-Cell; Humans; MAP Kinase Kinase 1; MAP Kinase Signaling System; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Receptor Protein-Tyrosine Kinases; Receptor, trkA; Sequence Analysis, DNA
PubMed: 26566875
DOI: 10.1158/2159-8290.CD-15-0913 -
Clinical Lymphoma, Myeloma & Leukemia Jan 2021Histiocytic disorders are an exceptionally rare group of diseases with diverse manifestations and a paucity of approved treatments, thereby leading to various challenges... (Review)
Review
Highlights of the Management of Adult Histiocytic Disorders: Langerhans Cell Histiocytosis, Erdheim-Chester Disease, Rosai-Dorfman Disease, and Hemophagocytic Lymphohistiocytosis.
Histiocytic disorders are an exceptionally rare group of diseases with diverse manifestations and a paucity of approved treatments, thereby leading to various challenges in their diagnosis and management. With the discovery of novel molecular targets and the incorporation of targeted agents in the management of various adult histiocytic disorders, their management has become increasingly complex. In an attempt to improve the understanding of the clinical features and management of common adult histiocytic disorders (Langerhans cell histiocytosis, Erdheim-Chester disease, Rosai-Dorfman disease, and hemophagocytic lymphohistiocytosis), we created this document based on existing literature and expert opinion.
Topics: Adult; Drug Therapy, Combination; Erdheim-Chester Disease; Histiocytosis, Langerhans-Cell; Histiocytosis, Sinus; Humans; Lymphohistiocytosis, Hemophagocytic; Treatment Outcome
PubMed: 32943371
DOI: 10.1016/j.clml.2020.08.007 -
Actas Dermo-sifiliograficas Nov 2020Juvenile xanthogranulomas (JXGs) are rare, benign lesions that belong to the large group of non-Langerhans cell histiocytoses. JXG presents with 1 or more erythematous... (Review)
Review
Juvenile xanthogranulomas (JXGs) are rare, benign lesions that belong to the large group of non-Langerhans cell histiocytoses. JXG presents with 1 or more erythematous or yellowish nodules that are usually located on the head or neck. Most JXG lesions are congenital or appear during the first year of life. Extracutaneous involvement is rare, but the literature traditionally suggests investigating the possibility of ocular compromise. JXG is mainly a clinical diagnosis, but a skin biopsy may sometimes be needed for confirmation. JXGs on the skin are self-limiting and usually do not require treatment. This review describes the clinical and therapeutic aspects of JXG, emphasizing available evidence and the diagnosis of extracutaneous involvement.
Topics: Biopsy; Histiocytosis, Non-Langerhans-Cell; Humans; Skin; Xanthogranuloma, Juvenile
PubMed: 32721389
DOI: 10.1016/j.ad.2020.07.004 -
Nature Medicine Dec 2019Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental...
Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.
Topics: Adolescent; Adult; Aminopyridines; Anaplastic Lymphoma Kinase; Benzothiazoles; Child; Child, Preschool; Female; Genome, Human; Hematologic Neoplasms; Histiocytosis; Humans; Infant; Male; Mutation; Picolinic Acids; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Pyrazoles; Pyridines; Pyrroles; Receptor Protein-Tyrosine Kinases; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Twins, Monozygotic; Exome Sequencing; Young Adult
PubMed: 31768065
DOI: 10.1038/s41591-019-0653-6 -
Nature Mar 2019Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK)... (Clinical Trial)
Clinical Trial
Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway. For the 50% of patients with histiocytosis who have BRAF mutations, RAF inhibition is highly efficacious and has markedly altered the natural history of the disease. However, no standard therapy exists for the remaining 50% of patients who lack BRAF mutations. Although ERK dependence has been hypothesized to be a consistent feature across histiocytic neoplasms, this remains clinically unproven and many of the kinase mutations that are found in patients who lack BRAF mutations have not previously been biologically characterized. Here we show ERK dependency in histiocytoses through a proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, in patients with histiocytoses. Patients were enrolled regardless of their tumour genotype. In parallel, MAPK alterations that were identified in treated patients were characterized for their ability to activate ERK. In the 18 patients that we treated, the overall response rate was 89% (90% confidence interval of 73-100). Responses were durable, with no acquired resistance to date. At one year, 100% of responses were ongoing and 94% of patients remained progression-free. Cobimetinib treatment was efficacious regardless of genotype, and responses were observed in patients with ARAF, BRAF, RAF1, NRAS, KRAS, MEK1 (also known as MAP2K1) and MEK2 (also known as MAP2K2) mutations. Consistent with the observed responses, the characterization of the mutations that we identified in these patients confirmed that the MAPK-pathway mutations were activating. Collectively, these data demonstrate that histiocytic neoplasms are characterized by a notable dependence on MAPK signalling-and that they are consequently responsive to MEK inhibition. These results extend the benefits of molecularly targeted therapy to the entire spectrum of patients with histiocytosis.
Topics: Azetidines; Histiocytic Disorders, Malignant; Histiocytosis; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Mutation; Piperidines; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-raf
PubMed: 30867592
DOI: 10.1038/s41586-019-1012-y -
British Journal of Haematology Dec 2019
Topics: Histiocytosis, Langerhans-Cell; Humans; Molecular Targeted Therapy; Mutation; Neoplasms; Neurodegenerative Diseases
PubMed: 31309539
DOI: 10.1111/bjh.16099 -
Pediatric Blood & Cancer Feb 2013These guidelines for the management of patients up to 18 years with Langerhans cell histiocytosis (LCH) have been set up by a group of experts involved in the Euro...
These guidelines for the management of patients up to 18 years with Langerhans cell histiocytosis (LCH) have been set up by a group of experts involved in the Euro Histio Net project who participated in national or international studies and in peer reviewed publications. Existing guidelines were reviewed and changed where new evidence was available in the literature up to 2012. Data and publications have been ranked according to evidence based medicine and when there was a lack of published data, consensus between experts was sought. Guidelines for diagnosis, initial clinical work-up, and treatment and long-term follow-up of LCH patients are presented.
Topics: Adolescent; Child; Child, Preschool; Histiocytosis, Langerhans-Cell; Humans
PubMed: 23109216
DOI: 10.1002/pbc.24367 -
JAMA Oncology Mar 2018The histiocytic neoplasms Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) are highly enriched for BRAF V600 mutations and have been previously...
Vemurafenib for BRAF V600-Mutant Erdheim-Chester Disease and Langerhans Cell Histiocytosis: Analysis of Data From the Histology-Independent, Phase 2, Open-label VE-BASKET Study.
IMPORTANCE
The histiocytic neoplasms Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) are highly enriched for BRAF V600 mutations and have been previously shown to be responsive to treatment with vemurafenib, an inhibitor of the BRAF V600 kinase. However, the long-term efficacy and safety of prolonged vemurafenib use in these patients are not defined. Here we analyze the final efficacy and safety data for vemurafenib in patients with ECD and LCH enrolled in the VE-BASKET study.
OBJECTIVE
To determine the efficacy and safety of vemurafenib in adults with ECD or LCH enrolled in the VE-BASKET study.
DESIGN, SETTING, AND PARTICIPANTS
The VE-BASKET study was an open-label, nonrandomized, multicohort study for patients with nonmelanoma cancers harboring the BRAF V600 mutation. Patients with BRAF V600-mutant ECD or LCH were enrolled in an "other solid tumor" cohort of the VE-BASKET study, and they were enrolled in the present study.
INTERVENTIONS
Patients received vemurafenib, 960 mg, twice daily continuously until disease progression, study withdrawal, or occurrence of intolerable adverse effects.
MAIN OUTCOMES AND MEASURES
The primary end point was confirmed objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Secondary end points included progression-free survival (PFS), overall survival (OS), metabolic response by modified positron-emission tomography (PET) Response Criteria in Solid Tumors (PERCIST) using 18F-fluorodeoxyglucose (FDG)-PET/computed tomography (CT), and safety.
RESULTS
A total of 26 patients from the VE-BASKET trial (22 with ECD, 4 with LCH) were included in the present study (14 women and 12 men; median age, 61 years; age range, 51-74 years). The confirmed ORR was 61.5% (95% CI, 40.6%-79.8%) in the overall cohort and 54.5% (95% CI, 32.2%-75.6%) in patients with ECD. All evaluable patients achieved stable disease or better. The median PFS and OS had not been reached in the overall cohort at study closure despite a median follow-up of 28.8 months; 2-year PFS was 86% (95% CI, 72%-100%), and 2-year OS was 96% (95% CI, 87%-100%). All 15 patients evaluated by FDG-PET/CT achieved a metabolic response, including 12 patients (80%) with a complete metabolic response. The most common adverse events (AEs) in the overall cohort included arthralgia, maculopapular rash, fatigue, alopecia, prolonged QT interval, skin papilloma, and hyperkeratosis. Hypertension and dermatologic AEs occurred at higher rates than those reported in metastatic melanoma.
CONCLUSIONS AND RELEVANCE
In this study, vemurafenib had prolonged efficacy in patients with BRAF V600-mutant ECD and LCH and warrants consideration as a new standard of care for these patients.
Topics: Aged; Amino Acid Substitution; Erdheim-Chester Disease; Female; Fluorodeoxyglucose F18; Histiocytosis, Langerhans-Cell; Humans; Male; Middle Aged; Mutation, Missense; Positron Emission Tomography Computed Tomography; Prognosis; Proto-Oncogene Proteins B-raf; Survival Analysis; Treatment Outcome; Valine; Vemurafenib
PubMed: 29188284
DOI: 10.1001/jamaoncol.2017.5029 -
Blood Nov 1994The term histiocyte refers to cells of either the macrophage or Langerhans cell lineages. The histiocytic disorders are characterized by the proliferation of cells of... (Review)
Review
The term histiocyte refers to cells of either the macrophage or Langerhans cell lineages. The histiocytic disorders are characterized by the proliferation of cells of these lineages. With recent advances in knowledge of the developmental biology of histiocytic cells, it is now possible to formulate a reasonable catalogue of histiocytic diseases based on ultra-structural and phenotypic markers of cellular origins and molecular or chromosomal markers of malignancy. The catalogue includes the following groups of diseases. Nonmalignant reactive macrophage disorders include (1) macrophage storage diseases, (2) several benign proliferative macrophage disorders that predominantly involve skin and bone, and (3) several hemophagocytic syndromes that vary from indolent and benign to fulminant and fatal. In some of the latter disorders, viruses have been identified as the inciting stimulus. The malignant macrophage disorders include (1) acute monocytic leukemia and (2) chronic myelomonocytic leukemia. A rare disorder that gave rise to a permanent cell line with an anomaly of chromosomal segment 5q35 may also be an example of a histiocytic malignancy. The existence of a separate category of true histiocytic lymphoma of macrophage type is uncertain. Reactive Langerhans cell disorders include (1) congenital self-healing histiocytosis, (2) the many variants of eosinophilic granuloma, and (3) a related disorder designated as relapsing Langerhans cell histiocytosis that is characterized by a relapsing course and infiltration of bone and soft tissues by Langerhans cells. Presumptively neoplastic diseases of Langerhans and dendritic cells include (1) progressive Langerhans cell histiocytosis, a disease with prominent involvement of blood and BM as well as skin and viscera; (2) Langerhans cell lymphoma, and (3) dendritic cell lymphoma. However, clonality as a marker of malignancy has not been proven in these disorders.
Topics: Antigens, CD; Antigens, CD34; Biomarkers; Cell Differentiation; Dendritic Cells; Hematopoietic Stem Cells; Histiocytes; Histiocytosis; Humans; Langerhans Cells
PubMed: 7524755
DOI: No ID Found