Prognostic factors for CNS control in children with acute lymphoblastic leukemia treated without cranial irradiation.
Blood
To identify the prognostic factors that are useful to improve central nervous system (CNS) control in children with acute lymphoblastic leukemia (ALL), we analyzed the outcome of 7640 consecutive patients treated on Chinese Children's Cancer Group ALL-2015 protocol between 2015 and 2019. This protocol featured prephase dexamethasone treatment before conventional remission induction and subsequent risk-directed therapy, including 16 to 22 triple intrathecal treatments, without prophylactic cranial irradiation. The 5-year event-free survival was 80.3% (95% confidence interval [CI], 78.9-81.7), and overall survival 91.1% (95% CI, 90.1-92.1). The cumulative risk of isolated CNS relapse was 1.9% (95% CI, 1.5-2.3), and any CNS relapse 2.7% (95% CI, 2.2-3.2). The isolated CNS relapse rate was significantly lower in patients with B-cell ALL (B-ALL) than in those with T-cell ALL (T-ALL) (1.6%; 95% CI, 1.2-2.0 vs 4.6%; 95% CI, 2.9-6.3; P < .001). Independent risk factors for isolated CNS relapse included male sex (hazard ratio [HR], 1.8; 95% CI, 1.1-3.0; P = .03), the presence of BCR-ABL1 fusion (HR, 3.8; 95% CI, 2.0-7.3; P < .001) in B-ALL, and presenting leukocyte count ≥50×109/L (HR, 4.3; 95% CI, 1.5-12.2; P = .007) in T-ALL. Significantly lower isolated CNS relapse was associated with the use of total intravenous anesthesia during intrathecal therapy (HR, 0.2; 95% CI, 0.04-0.7; P = .02) and flow cytometry examination of diagnostic cerebrospinal fluid (CSF) (HR, 0.2; 95% CI, 0.06-0.6; P = .006) among patients with B-ALL. Prephase dexamethasone treatment, delayed intrathecal therapy, use of total intravenous anesthesia during intrathecal therapy, and flow cytometry examination of diagnostic CSF may improve CNS control in childhood ALL. This trial was registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-14005706).
10.1182/blood.2020010438
Prospective blinded study of BRAFV600E mutation detection in cell-free DNA of patients with systemic histiocytic disorders.
Hyman David M,Diamond Eli L,Vibat Cecile Rose T,Hassaine Latifa,Poole Jason C,Patel Minal,Holley Veronica R,Cabrilo Goran,Lu Timothy T,Arcila Maria E,Chung Young Rock,Rampal Raajit,Lacouture Mario E,Rosen Neal,Meric-Bernstam Funda,Baselga José,Kurzrock Razelle,Erlander Mark G,Janku Filip,Abdel-Wahab Omar
Cancer discovery
UNLABELLED:Patients with Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) have a high frequency of BRAF(V600E) mutations and respond to RAF inhibitors. However, detection of mutations in tissue biopsies is particularly challenging in histiocytoses due to low tumor content and stromal contamination. We applied a droplet-digital PCR assay for quantitative detection of the BRAF(V600E) mutation in plasma and urine cell-free (cf) DNA and performed a prospective, blinded study in 30 patients with ECD/LCH. There was 100% concordance between tissue and urinary cfDNA genotype in treatment-naïve samples. cfDNA analysis facilitated identification of previously undescribed KRAS(G12S)-mutant ECD and dynamically tracked disease burden in patients treated with a variety of therapies. These results indicate that cfDNA BRAF(V600E) mutational analysis in plasma and urine provides a convenient and reliable method of detecting mutational status and can serve as a noninvasive biomarker to monitor response to therapy in LCH and ECD. SIGNIFICANCE:Patients with BRAF(V600E)-mutant histiocytic disorders have remarkable responses to RAF inhibition, but mutation detection in tissue in these disorders is challenging. Here, we identify that analysis of plasma and urinary cfDNA provides a reliable method to detect the BRAF(V600E) mutation and monitor response to therapy in these disorders.
10.1158/2159-8290.CD-14-0742
Liver transplantation in an adult with sclerosing cholangitis due to Langerhans cell histiocytosis.
Griffiths William,Davies Susan,Gibbs Paul,Thillainayagam Andrew,Alexander Graeme
Journal of hepatology
Sclerosing cholangitis due to Langerhans cell histiocytosis (LCH) is a rare cause of end-stage liver disease, seen mainly in children. Only a few adult cases have been reported worldwide. Liver transplantation may be a viable treatment option for what is otherwise an irreversible condition. We describe a 65-year-old female with LCH who developed severe sclerosing cholangitis with jaundice, intractable pruritus and peritoneal disease. She underwent orthotopic liver transplantation with complete amelioration of symptoms and remained well 14 months following her operation. Explant histology confirmed LCH involvement with an associated extensive sclerosing cholangitis. Symptomatic LCH cholangiopathy is an emerging indication for liver transplantation in adults.
10.1016/j.jhep.2005.12.024
Histiocytosis.
Lancet (London, England)
Histiocytoses constitute a heterogeneous group of rare disorders, characterised by infiltration of almost any organ by myeloid cells with diverse macrophage or dendritic cell phenotypes. Histiocytoses can start at any age. Diagnosis is based on histology in combination with appropriate clinical and radiological findings. The low incidence and broad spectrum of clinical manifestations often leads to diagnostic delay, especially for adults. In most cases, biopsy specimens infiltrated by histiocytes have somatic mutations in genes activating the MAP kinase cell-signalling pathway. These mutations might also be present in blood cells and haematopoietic progenitors of patients with multisystem disease. A comprehensive range of investigations and molecular typing are essential to accurately predict prognosis, which can vary from spontaneous resolution to life-threatening disseminated disease. Targeted therapies with BRAF or MEK inhibitors have revolutionised salvage treatment. However, the type and duration of treatment are still debated, and the prevention of neurological sequelae remains a crucial issue.
10.1016/S0140-6736(21)00311-1
Aberrant chemokine receptor expression and chemokine production by Langerhans cells underlies the pathogenesis of Langerhans cell histiocytosis.
Annels Nicola E,Da Costa Cristiana E T,Prins Frans A,Willemze Annemieke,Hogendoorn Pancras C W,Egeler R Maarten
The Journal of experimental medicine
Langerhans cell histiocytosis (LCH) is characterized by a clonal proliferation and retention of cells with a Langerhans cell (LC)-like phenotype at various sites within the body. The present study set out to elucidate whether aberrant expression of chemokine receptors or dysregulation of chemokine production in LCH lesions could explain abnormal retention of these cells. Immunohistochemical analysis on 13 LCH biopsies of bone, skin, and lymph node all expressed the immature dendritic cell (DC) marker CCR6 on the lesional LCs and absence of the mature DC marker CCR7. Furthermore, regardless of the tissue site, LCH lesions markedly overexpressed CCL20/MIP-3alpha, the ligand for CCR6. The lesional LCs appeared to be the source of this CCL20/MIP-3alpha production as well as other inflammatory chemokines such as CCL5/RANTES and CXCL11/I-TAC. These may explain the recruitment of eosinophils and CD4+CD45RO+ T cells commonly found in LCH lesions. The findings of this study emphasize that, despite abundant TNF-alpha, lesional LCs remain in an immature state and are induced to produce chemokines, which via autocrine and paracrine mechanisms cause not only the retention of the lesional LCs but also the recruitment and retention of other lesional cells. We postulate that the lesional LCs themselves control the persistence and progression of LCH.
10.1084/jem.20030137
Relapsing nodular lesions in the course of adult pulmonary Langerhans cell histiocytosis.
Tazi A,Montcelly L,Bergeron A,Valeyre D,Battesti J P,Hance A J
American journal of respiratory and critical care medicine
In most patients with pulmonary Langerhans cell histiocytosis (LCH), clinical and radiological abnormalities initially either stabilize or regress, often without treatment. Little information is available, however, concerning the subsequent evolution of disease in patients who initially follow a benign course. We describe four patients with biopsy-confirmed pulmonary LCH whose initial course was characterized by regression of parenchymal nodular lesions, but who subsequently developed one or more episodes of active disease 7 mo to 7.5 yr after their initial presentation. In each case, the subsequent episodes of active disease were characterized by the reappearance or marked increase in nodular radiographic abnormalities, whose presence was confirmed by high-resolution computed tomography (HRCT). Thus, initial regression of nodular lesions in pulmonary LCH does not preclude the reappearance of one or more episodes of active disease, and may have important consequences on the long-term prognosis of these patients.
10.1164/ajrccm.157.6.9709026
Disease course and late sequelae of Langerhans' cell histiocytosis: 25-year experience at the University of California, San Francisco.
Willis B,Ablin A,Weinberg V,Zoger S,Wara W M,Matthay K K
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:The purpose of our investigation was to correlate the extent and degree of organ involvement at presentation of Langerhans' cell histiocytosis (LCH) with subsequent disease course, survival, and late sequelae. MATERIALS AND METHODS:The medical records of 71 patients with a pathologic diagnosis of LCH, age 0 to 21 years, who presented between January 1, 1969 and June 30, 1994, were reviewed for organ involvement at diagnosis, treatment, disease course, and late sequelae. Supplementary data were obtained by mailed questionnaire. RESULTS:The median follow-up time from diagnosis for all patients was 8.1 years. Involvement at diagnosis included nine patients with skin-only disease, 22 with monostotic disease, 12 with polyostotic disease, and 28 with multisystem presentation. Treatment was surgery only in 17 and chemotherapy and/or radiotherapy in 54 patients. Recurrences were seen in 35 patients, with the highest rate in the polyostotic group. Ten patients died: seven with the multisystem presentation, two with monostotic disease, and one with skin-only disease. Causes included progressive LCH (n = 6) and late sequelae of either treatment (n = 3) or disease (n = 1). Late sequelae were seen in 64% of 51 patients with more than 3 years of follow-up data. The most common were skeletal defects in 42%, dental problems in 30%, diabetes insipidus in 25%, growth failure in 20%, sex hormone deficiency in 16%, hypothyroidism in 14%, hearing loss in 16%, and other CNS dysfunction in 14%. The overall estimated survival rates at 5, 15, and 20 years are 88%, 88%, and 77%, with an estimated event-free survival rate of only 30% at 15 years. CONCLUSION:Despite the favorable survival, more than half of LCH patients will have further dissemination of disease or late sequelae, including even some patients with single-system disease at diagnosis. Future treatment needs to be designed to prevent disease progression and late sequelae.
10.1200/JCO.1996.14.7.2073
RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions.
The Journal of experimental medicine
Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207 dendritic cells (DCs) with constitutively activated mitogen-activated protein kinase (MAPK) pathway signaling. Approximately 60% of LCH patients harbor somatic V600E mutations localizing to CD207 DCs within lesions. However, the mechanisms driving V600E LCH cell accumulation in lesions remain unknown. Here we show that sustained extracellular signal-related kinase activity induced by V600E inhibits C-C motif chemokine receptor 7 (CCR7)-mediated DC migration, trapping DCs in tissue lesions. Additionally, V600E increases expression of BCL2-like protein 1 (BCL2L1) in DCs, resulting in resistance to apoptosis. Pharmacological MAPK inhibition restores migration and apoptosis potential in a mouse LCH model, as well as in primary human LCH cells. We also demonstrate that MEK inhibitor-loaded nanoparticles have the capacity to concentrate drug delivery to phagocytic cells, significantly reducing off-target toxicity. Collectively, our results indicate that MAPK tightly suppresses DC migration and augments DC survival, rendering DCs in LCH lesions trapped and resistant to cell death.
10.1084/jem.20161881
Presence of osteoclast-like multinucleated giant cells in the bone and nonostotic lesions of Langerhans cell histiocytosis.
The Journal of experimental medicine
Langerhans cell histiocytosis (LCH) is a disease that can involve one or multiple organ systems characterized by an accumulation of CD1a(+) Langerhans-like cells as well as several other myeloid cell types. The precise origin and role of one of these populations, the multinucleated giant cell (MGC), in this disease remains unknown. This work shows that in three different lesional tissues, bone, skin, and lymph node, the MGCs expressed the characteristic osteoclast markers, tartrate-resistant acid phosphatase and vitronectin receptor, as well as the enzymes cathepsin K and matrix metalloproteinase-9. Although, in bone lesions, the osteoclast-like MGCs were only CD68(+), in the nonostotic sites, they coexpressed CD1a. The presence of osteoclast-like MGCs may be explained by the production of osteoclast-inducing cytokines such as receptor activator of nuclear factor kappaB ligand and macrophage colony-stimulating factor by both the CD1a(+) LCH cells and T cells in these lesions. As osteoclast-derived enzymes play a major role in tissue destruction, the osteoclast-like nature of MGCs in all LCH lesions makes them a potential target for the treatment of this disease.
10.1084/jem.20041785
Langerhans cell histiocytosis: fascinating dynamics of the dendritic cell-macrophage lineage.
Egeler R Maarten,van Halteren Astrid G S,Hogendoorn Pancras C W,Laman Jon D,Leenen Pieter J M
Immunological reviews
In its rare occurrence, Langerhans cell histiocytosis (LCH) is a dangerous but intriguing deviation of mononuclear phagocytes, especially dendritic cells (DCs). Clinically, the disease ranges from self-resolving or well manageable to severe and even fatal. LCH lesions in skin, bone, and other sites contain high numbers of cells with phenotypic features resembling LCs admixed with macrophages, T cells, eosinophils, and multinucleated giant cells. Here we review current progress in the LCH field based on two central questions: (i) are LCH cells intrinsically aberrant, and (ii) how does the lesion drive pathogenesis? We argue that LCH cells may originate from different sources, including epidermal LCs, tissue Langerin(+) DCs, or mononuclear phagocyte precursors. Current and prospective in vitro and in vivo models are discussed. Finally, we discuss recent insights into plasticity of T-helper cell subsets in light of the lesion microenvironment. LCH continues to provide urgent clinical questions thereby inspiring innovative DC lineage research.
10.1111/j.0105-2896.2009.00883.x
Langerhans-cell histiocytosis 'insight into DC biology'.
Laman Jon D,Leenen Pieter J M,Annels Nicola E,Hogendoorn Pancras C W,Egeler R Maarten
Trends in immunology
Langerhans-cell histiocytosis (LCH) is caused by an uncontrolled pathogenic clonal proliferation of dendritic cells (DCs) with Langerhans-cell (LC) characteristics. LCH cells are arrested in an immature, partially activated stage and show a deviant regulation of cell division. Their aberrant interactions with T cells and the lesional microenvironment are typified by high level production of diverse cytokines. Chemokine and chemokine receptor patterns probably explain LCH predilection sites and lesion composition, reminiscent of chronic granulomatous inflammation. Recent advances in LCH immunology suggest that clonal changes in DCs might underlie the aberrant immune interaction with T cells, leading to a unique pathological picture, which combines features of carcinogenesis and chronic inflammation.
10.1016/s1471-4906(03)00063-2
Notch-dependent cooperativity between myeloid lineages promotes Langerhans cell histiocytosis pathology.
Science immunology
Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated protein kinase (MAPK) pathway activation. LCH cells may trigger destructive pathology yet remain in a precarious state finely balanced between apoptosis and survival, supported by a unique inflammatory milieu. The interactions that maintain this state are not well known and may offer targets for intervention. Here, we used single-cell RNA-seq and protein analysis to dissect LCH lesions, assessing LCH cell heterogeneity and comparing LCH cells with normal mononuclear phagocytes within lesions. We found LCH discriminatory signatures pointing to senescence and escape from tumor immune surveillance. We also uncovered two major lineages of LCH with DC2- and DC3/monocyte-like phenotypes and validated them in multiple pathological tissue sites by high-content imaging. Receptor-ligand analyses and lineage tracing in vitro revealed Notch-dependent cooperativity between DC2 and DC3/monocyte lineages during expression of the pathognomonic LCH program. Our results present a convergent dual origin model of LCH with MAPK pathway activation occurring before fate commitment to DC2 and DC3/monocyte lineages and Notch-dependent cooperativity between lineages driving the development of LCH cells.
10.1126/sciimmunol.add3330
Langerhans cell histiocytosis reveals a new IL-17A-dependent pathway of dendritic cell fusion.
Coury Fabienne,Annels Nicola,Rivollier Aymeric,Olsson Selma,Santoro Alessandra,Speziani Carole,Azocar Olga,Flacher Monique,Djebali Sophia,Tebib Jacques,Brytting Maria,Egeler R Maarten,Rabourdin-Combe Chantal,Henter Jan-Inge,Arico Maurizio,Delprat Christine
Nature medicine
IL-17A is a T cell-specific cytokine that is involved in chronic inflammations, such as Mycobacterium infection, Crohn's disease, rheumatoid arthritis and multiple sclerosis. Mouse models have explained the molecular basis of IL-17A production and have shown that IL-17A has a positive effect not only on granuloma formation and neurodegeneration through unknown mechanisms, but also on bone resorption through Receptor activator of NF-kappaB ligand (RANKL) induction in osteoblasts. Langerhans cell histiocytosis (LCH) is a rare disease of unknown etiology, lacking an animal model, that cumulates symptoms that are found separately in various IL-17A-related diseases, such as aggressive chronic granuloma formation, bone resorption and soft tissue lesions with occasional neurodegeneration. We examined IL-17A in the context of LCH and found that there were high serum levels of IL-17A during active LCH and unexpected IL-17A synthesis by dendritic cells (DCs), the major cell type in LCH lesions. We also found an IL-17A-dependent pathway for DC fusion, which was highly potentiated by IFN-gamma and led to giant cells expressing three major tissue-destructive enzymes: tartrate resistant acidic phosphatase and matrix metalloproteinases 9 and 12. IFN-gamma expression has been previously documented in LCH and observed in IL-17A-related diseases. Notably, serum IL-17A-dependent fusion activity correlates with LCH activity. Thus, IL-17A and IL-17A-stimulated DCs represent targets that may have clinical value in the treatment of LCH and other IL-17A-related inflammatory disorders.
10.1038/nm1694
BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups.
Berres Marie-Luise,Lim Karen Phaik Har,Peters Tricia,Price Jeremy,Takizawa Hitoshi,Salmon Hélène,Idoyaga Juliana,Ruzo Albert,Lupo Philip J,Hicks M John,Shih Albert,Simko Stephen J,Abhyankar Harshal,Chakraborty Rikhia,Leboeuf Marylene,Beltrão Monique,Lira Sérgio A,Heym Kenneth M,Bigley Venetia,Collin Matthew,Manz Markus G,McClain Kenneth,Merad Miriam,Allen Carl E
The Journal of experimental medicine
Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207(+) dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207(+) DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c(+) and CD14(+) fractions and in bone marrow (BM) CD34(+) hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207(+) DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.
10.1084/jem.20130977
Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:Off-label use of vemurafenib (VMF) to treat mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. PATIENTS AND METHODS:Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score. RESULTS:LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 ( < .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; < .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the clone. CONCLUSION:VMF seemed safe and effective in children with refractory -positive LCH. Additional studies are needed to find effective maintenance therapy approaches.
10.1200/JCO.19.00456
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.
JAMA oncology
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.
10.1001/jamaoncol.2017.5029
Reproducible and sustained efficacy of targeted therapy with vemurafenib in patients with BRAF(V600E)-mutated Erdheim-Chester disease.
Haroche Julien,Cohen-Aubart Fleur,Emile Jean-François,Maksud Philippe,Drier Aurélie,Tolédano Dan,Barete Stéphane,Charlotte Frédéric,Cluzel Philippe,Donadieu Jean,Benameur Neïla,Grenier Philippe A,Besnard Sophie,Ory Jean-Paul,Lifermann François,Idbaih Ahmed,Granel Brigitte,Graffin Bruno,Hervier Baptiste,Arnaud Laurent,Amoura Zahir
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:Histiocytoses are rare disorders with heterogeneous prognosis. BRAF(V600E) mutations have been observed in half of patients with Langerhans cell histiocytosis (LCH) and in 50% to 100% of patients with Erdheim-Chester disease (ECD) patients. We recently reported short-term efficacy of a BRAF inhibitor (vemurafenib) in three patients with multisystemic ECD. PATIENTS AND METHODS:Vemurafenib was given to eight patients with multisystemic ECD with CNS and/or cardiac involvement. All patients were refractory to first-line treatment and harbored a BRAF(V600E) mutation. Four patients also had LCH lesions. Positron emission tomography (PET) scan response at month 6 was used as the main evaluation criterion. Secondary evaluation criteria were comparison at baseline and at last visit of PET and of cardiovascular and cerebral infiltrations (computed tomography scan and magnetic resonance imaging [MRI]). RESULTS:All patients were partial metabolic responders at 6 months of vemurafenib, and the median reduction in maximum standardized uptake value was 63.5% (range, 41.3% to 86.9%). Evaluation of cardiac and aortic infiltrations showed that seven patients had a partial response and one patient had stable disease according to surface measurements derived from RECIST criteria. The four patients with infratentorial CNS infiltration had an objective decrease of the lesions on MRI. All patients had an improvement of general symptoms and a persistent response to vemurafenib, with a median follow-up time of 10.5 months (range, 6 to 16 months). Skin adverse effects were frequent and severe. CONCLUSION:Vemurafenib has an objective and sustained efficacy in BRAF(V600E)-mutated ECD as second-line therapy. In contrast to melanoma, no resistance has emerged to date after 6 to 16 months.
10.1200/JCO.2014.57.1950
A maelstrom of migrating monocytes drives neurodegeneration.
Immunity
Neurodegeneration is a devastating complication of Langerhans cell histiocytosis (LCH), but it is not clear how it develops. In this issue of Immunity, Wilk et al. demonstrate that circulating BRAFV600E myeloid cells damage the blood-brain barrier and infiltrate the brain. Dual inhibition of the MAPK and senescence pathways can block parenchymal injury, providing a potential therapeutic avenue for histiocytic neurodegeneration.
10.1016/j.immuni.2023.11.014
Three-dimensional characterization of pathologic lesions in pulmonary langerhans cell histiocytosis.
Kambouchner Marianne,Basset Francoise,Marchal Joelle,Uhl Jean Francois,Hance Allan J,Soler Paul
American journal of respiratory and critical care medicine
The characteristic lesions of pulmonary Langerhans cell histiocytosis (LCH) associate destructive granulomas containing large numbers of Langerhans cells and cysts. The lesions are usually considered to develop around small airways, and cysts are thought to result from destruction of the bronchiolar wall by the granulomatous reaction. However, the extent to which the granulomatous reaction is truly bronchocentric remains unknown, and the mode of formation of the cysts has not been defined. By using serial sections, this study aimed to explore further the relationships between pulmonary LCH lesions and distal airways, and the development of cysts. The results demonstrated that the granulomatous process of pulmonary LCH affected exclusively small airways, in an acinar distribution. The lesions extended without interruption along the bronchiolar axis, forming a continuous sheath around distal airways. The granulomatous reaction seemed to progress along the bronchiolar axis over time, extending the abnormalities in both the proximal and distal directions. Cystic lesions resulted from the destruction of the bronchiolar wall and progressive dilatation of the lumen, subsequently circumscribed by fibrous tissue. Because pulmonary LCH lesions affect and progressively destroy distal airways, it may be proper to consider the disease a bronchiolitis rather than an interstitial lung disorder.
10.1164/rccm.2201050
BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy.
Héritier Sébastien,Emile Jean-François,Barkaoui Mohamed-Aziz,Thomas Caroline,Fraitag Sylvie,Boudjemaa Sabah,Renaud Florence,Moreau Anne,Peuchmaur Michel,Chassagne-Clément Catherine,Dijoud Frédérique,Rigau Valérie,Moshous Despina,Lambilliotte Anne,Mazingue Françoise,Kebaili Kamila,Miron Jean,Jeziorski Eric,Plat Geneviève,Aladjidi Nathalie,Ferster Alina,Pacquement Hélène,Galambrun Claire,Brugières Laurence,Leverger Guy,Mansuy Ludovic,Paillard Catherine,Deville Anne,Armari-Alla Corinne,Lutun Anne,Gillibert-Yvert Marion,Stephan Jean-Louis,Cohen-Aubart Fleur,Haroche Julien,Pellier Isabelle,Millot Frédéric,Lescoeur Brigitte,Gandemer Virginie,Bodemer Christine,Lacave Roger,Hélias-Rodzewicz Zofia,Taly Valérie,Geissmann Frédéric,Donadieu Jean
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAF(V600E) mutation occurs frequently, but clinical significance remains to be determined. PATIENTS AND METHODS:BRAF(V600E) mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae. RESULTS:Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAF(V600E) mutation. Patients with BRAF(V600E) manifested more severe disease than did those with wild-type BRAF. Patients with BRAF(V600E) comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P < .001). BRAF(V600E) mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAF(V600E) more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001). CONCLUSION:In children with LCH, BRAF(V600E) mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy.
10.1200/JCO.2015.65.9508
Is high-resolution computed tomography a reliable tool to predict the histopathological activity of pulmonary Langerhans cell histiocytosis?
Soler P,Bergeron A,Kambouchner M,Groussard O,Brauner M,Grenier P,Crestani B,Mal H,Tazi A,Battesti J P,Loiseau P,Valeyre D
American journal of respiratory and critical care medicine
High-resolution computed tomography (HRCT) has proved to be very useful in the diagnosis and follow-up of pulmonary Langerhans cell histiocytosis (PLCH), but the precise relationships between nodules and thin-wall cysts observed by HRCT, and granulomatous or cystic lesions present in lung tissue, remain to be established. The aim of this study was to compare quantitative data obtained by HRCT and those obtained by histopathological examination of corresponding lung tissue specimens in patients with biopsy-proven PLCH. The results demonstrated that the extent of nodular abnormalities was strongly correlated with the density of florid granulomatous lesions in lung tissue. A strong correlation was also found between the extent of cystic abnormalities and the density of cavitary lesions, but the latter included both still inflammatory cavitary granulomas and cicatricial fibrous cysts. Interestingly, small isolated florid granulomas were found in lung tissue from most patients with a predominant cystic CT scan pattern. Taken together, these results demonstrate that HRCT has to be considered with caution to evaluate the histopathological activity of PLCH. Patients presenting with predominant HRCT cystic abnormalities should benefit from a long-term follow-up. Because these patients are susceptible to developing severe respiratory insufficiency, they should also be considered for treatment as soon as an effective therapy for LCH is available.
10.1164/ajrccm.162.1.9906010
Epigenomics and Single-Cell Sequencing Define a Developmental Hierarchy in Langerhans Cell Histiocytosis.
Halbritter Florian,Farlik Matthias,Schwentner Raphaela,Jug Gunhild,Fortelny Nikolaus,Schnöller Thomas,Pisa Hanja,Schuster Linda C,Reinprecht Andrea,Czech Thomas,Gojo Johannes,Holter Wolfgang,Minkov Milen,Bauer Wolfgang M,Simonitsch-Klupp Ingrid,Bock Christoph,Hutter Caroline
Cancer discovery
Langerhans cell histiocytosis (LCH) is a rare neoplasm predominantly affecting children. It occupies a hybrid position between cancers and inflammatory diseases, which makes it an attractive model for studying cancer development. To explore the molecular mechanisms underlying the pathophysiology of LCH and its characteristic clinical heterogeneity, we investigated the transcriptomic and epigenomic diversity in primary LCH lesions. Using single-cell RNA sequencing, we identified multiple recurrent types of LCH cells within these biopsies, including putative LCH progenitor cells and several subsets of differentiated LCH cells. We confirmed the presence of proliferative LCH cells in all analyzed biopsies using IHC, and we defined an epigenomic and gene-regulatory basis of the different LCH-cell subsets by chromatin-accessibility profiling. In summary, our single-cell analysis of LCH uncovered an unexpected degree of cellular, transcriptomic, and epigenomic heterogeneity among LCH cells, indicative of complex developmental hierarchies in LCH lesions. SIGNIFICANCE: This study sketches a molecular portrait of LCH lesions by combining single-cell transcriptomics with epigenome profiling. We uncovered extensive cellular heterogeneity, explained in part by an intrinsic developmental hierarchy of LCH cells. Our findings provide new insights and hypotheses for advancing LCH research and a starting point for personalizing therapy...
10.1158/2159-8290.CD-19-0138
Pathogenesis of Langerhans cell histiocytosis.
Badalian-Very Gayane,Vergilio Jo-Anne,Fleming Mark,Rollins Barrett J
Annual review of pathology
Langerhans cell histiocytosis (LCH) combines in one nosological category a group of diseases that have widely disparate clinical manifestations but are all characterized by accumulation of proliferating cells with surface markers and ultrastructural features similar to cutaneous Langerhans cells (LCs). Despite this unified nosology, important questions about LCH remain unanswered. First, despite having phenotypic features of LCs, LCH cell gene-expression patterns differ from those in LCs. Although this observation suggests that LCH may arise from an earlier precursor, it is not necessarily inconsistent with the hypothesis that LCs are the cell of origin for LCH. Second, LCH's prominent inflammatory component and occasional benign clinical course suggest that LCH may not be a neoplasm. However, the demonstration that LCH cells are clonal, along with the recent discovery of activating BRAF mutations in LCH cells, strongly suggests that LCH is a neoplastic disease. These new observations point the way to rationally targeted therapies.
10.1146/annurev-pathol-020712-163959