Targeted inhibition of the MAPK pathway: emerging salvage option for progressive life-threatening multisystem LCH

Kolenová, Alexandra; Schwentner, Raphaela; Jug, Gunhild; Simonitsch‐Klupp, Ingrid; Kornauth, Christoph; Plank, L; Horáková, Júlia; Bodova, Ivana; Sýkora, T.; Geczova, Lucia; Holter, Wolfgang; Minkov, Milen; Hutter, Caroline

doi:10.1182/bloodadvances.2016003533

Cited by 41 publications

(66 citation statements)

References 25 publications

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“…Mutations within MAP kinase pathways concerning precursors to macrophages of distinct origin (bone marrow or yolk bag) result in the occurrence of the overlapping syndrome of LCH and Erdheim-Chester disease or chronic myeloid leukaemia [1,2,4,5,16]. In patients with LCH, activating mutations of the BRAF, ARAF, MAP2K1, N/K/HRAS and PIK3CA genes have been found [4][5][6][16][17][18]. The scheme illustrating signalling pathways involved in the control of histiocytic cell proliferation is shown in Figure 1.…”

Section: Pathogenesismentioning

confidence: 99%

“…In advanced forms of the condition, nodules retrogress and cysts are formed and pulmonary distension increases. The biggest accumulation of lesions is found in the upper and middle lung fields, and the costophrenic angles in 90% of cases remain unaffected [3,16]. useful at early nodular stages of the condition, in the cases with the presence of thick-walled lacunae and in patients with MS-LCH [3].…”

Section: Histological Examinationmentioning

confidence: 99%

“…The patients qualified for targeted therapy need to be tested for mutations within the BRAF, ARAS, NRAS, KRAS and MAP2K genes [16][17][18][19]. Moreover, a novel diagnostic technique used in monitoring of treatment with BRAF inhibitors, is the analysis of the BRAF V600E gene mutation in circulating serum DNA [17].…”

Section: Pulmonary Function Testingmentioning

confidence: 99%

“…The researches conducted among French LCH children have shown that detection of BRAF mutation was associated with a weaker response not only to the first-line treatment (vinblastine and steroids) but also a weaker response to a second-line treatment and a higher proportion of recurrence [16,19,49].…”

Section: Vemurafenib and Other Braf Inhibitorsmentioning

confidence: 99%

“…Furthermore, it is vital to remember that presented mutations in Langerhans' cells are not excluding mutations, thus, in particular cases, there are recommendations to apply double targeted therapy [10,16].…”

Section: Map Kinase Inhibitorsmentioning

confidence: 99%

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Pulmonary Langerhans' Cell Histiocytosis in Adults

Radzikowska¹

2017

Advances in Respiratory Medicine

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Pulmonary Langerhans' cell histiocytosis (PLCH) is a rare disorder of unknown cause characterised by the infiltration of the lungs and other organs by the bone marrow derived Langerhans' cells, which carry mutations of BRAF gene and/or NRAS, KRAS and MAP2K1 genes. It occurs predominantly in young smokers, without gender predominance. The disease is characterised by formation of eosinophilic granulomas with the presence of Langerhans' cells infiltrating and destroying distal airways. High-resolution computed tomography of the chest (HRCT) plays an outstanding role in PLCH diagnosis. The typical radiological picture of PLCH is the presence of small intralobular nodules, often forming 'tree in bud' lesions, cavitated nodules, thin-and thick-walled cystic lesions frequently confluent. Definite diagnosis requires the finding of characteristic lesions in histological examination and demonstration of antigen CD1a or CD207 presenting cells in immunohistochemistry. Smoking cessation is the most important recommendation for PLCH patients. There are no evidence based data regarding systemic steroid therapy. The treatment of progressive PLCH is based on cladribine or cytarabine as salvage therapy. The prognosis is good, and over 85% of patients survive 10 years.

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Section: Pathogenesismentioning

confidence: 99%

Section: Histological Examinationmentioning

confidence: 99%

Section: Pulmonary Function Testingmentioning

confidence: 99%

Section: Vemurafenib and Other Braf Inhibitorsmentioning

confidence: 99%

Section: Map Kinase Inhibitorsmentioning

confidence: 99%

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Pulmonary Langerhans' Cell Histiocytosis in Adults

Radzikowska¹

2017

Advances in Respiratory Medicine

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Langerhans Cell Histiocytosis

Fraïtag¹,

Donadieu²

2019

Harper's Textbook of Pediatric Dermatology

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Clinical outcomes and prognostic risk factors of Langerhans cell histiocytosis in children: Results from the BCH‐LCH 2014 protocol study

et al. 2023

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Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm mainly affecting young children. This study aimed to evaluate the outcomes of 449 pediatric patients enrolled in the BCH‐LCH 2014 study. 52.6% of patients were classified with single‐system (SS) LCH, 28.1% with multisystem (MS) risk organ negative (RO−) LCH, and 19.4% with MS RO+ LCH. Three hundred ninety‐six patients (88.2%) were initially treated with first‐line therapy based on the vindesine‐prednisone combination. One hundred thirty‐nine patients who lacked a response to initial treatment were shifted to second‐line therapy, 72 to intensive treatment Arm S1 (a combination of cytarabine, cladribine, vindesine, and dexamethasone), and 67 to Arm S2 (without cladribine). The 5‐year overall survival (OS), progression‐free survival (PFS), and relapse rates were 98.2% (median: 97.6 months), 54.6% (median: 58.3 months), and 29.9%, respectively. MS RO+ patients had the worst prognosis among the three clinical subtypes. For the patients initially treated with first‐line therapy, the 5‐year OS, PFS, and relapse rates were 99.2%, 54.5%, and 29.3%, respectively. Patients in Arm S1 had a significantly better prognosis than patients in Arm S2 (5‐year PFS: 69.2% vs. 46.5%, p = .042; relapse rate: 23.4% vs. 44.2%, p = .031). Multivariate analysis revealed that early treatment response, the involvement of RO, skin, and oral mucosa, as well as laboratory parameters, including CRP and γ‐GT, were independent risk factors for the PFS of LCH. Thus, the prognosis of LCH in children has been improved significantly with stratified chemotherapy, and progression and relapse remained the challenges, especially for RO+ patients.

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Targeted inhibition of the MAPK pathway: emerging salvage option for progressive life-threatening multisystem LCH

Abstract: Single-agent vemurafenib leads to a rapid and sustained clinical response in severe multisystem LCH but does not eradicate the disease.Longitudinal assessment of V600E during treatment shows that clinical remission can occur despite significant amounts of mutated BRAF.

Cited by 41 publications

References 25 publications

Pulmonary Langerhans' Cell Histiocytosis in Adults

Pulmonary Langerhans' Cell Histiocytosis in Adults

Langerhans Cell Histiocytosis

Clinical outcomes and prognostic risk factors of Langerhans cell histiocytosis in children: Results from the BCH‐LCH 2014 protocol study

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