Progress towards molecular-based management of childhood Langerhans cell histiocytosis

Abstract

Langerhans cell histiocytosis (LCH) is characterized by inflammatory lesions containing abundant CD1a+ CD207+ histiocytes that lead to the destruction of affected tissues. This disease has a remarkable pleiotropic clinical presentation and most commonly affects young children. Although the current mortality rate is very low for childhood LCH patients (<2%), reactivation frequently occurs after a long period of disease control and the rates of permanent complications and sequelae remain high. Advances in genomic sequencing technologies in this past decade have highlighting somatic molecular alterations responsible for the disease in around 80% of childhood LCH cases. More than half these cases harbored the BRAF V600E mutation, and most other mutations also concerned proteins involved in the MAPKinase pathway. In addition to improving what is known about the LCH pathology, this molecular knowledge provides opportunities to optimize patient management. The BRAF V600E mutation is associated with more severe presentations of the disease, a high reactivation rate, and a high permanent complications rate; thus, this mutation paves the way for future stratified management approaches. These therapies would be based on the patient's molecular status as well as other clinical characteristics of the disease that are independently associated with undesired events. Moreover, as observed in patients with solid tumors, the BRAF V600E allele can be detected in the circulating cell-free DNA of patients with severe BRAF V600Emutated LCH. Quantification of the plasmatic BRAF V600E load for this group of patient can precisely monitor response to therapy. Finally, targeted therapies, such as BRAF inhibitors, are new therapeutic options especially for refractory multi-systemic LCH involving risk organs. However, the long-term efficacy, long-term tolerance, optimal protocol scheme, and appropriate modalities of administration for these innovative therapies for children still need to be defined and this is a huge challenge.

Childhood Langerhans cell histiocytosis with severe lung involvement: a nationwide cohort study

“…Two of our patients were treated with targeted therapy and showed continued clinical and radiological improvement, from the beginning of therapy, and both remain alive currently. Molecular knowledge of histiocytosis has provided new avenues of potential progress in histiocytosis, particularly in terms of treatment [28]. In patients with LCH associated with BRAF V600E mutations (55% of children with LCH [4]), a BRAF inhibitor showed efficient effects.…”

“…Molecular knowledge of histiocytosis has provided new avenues of potential progress in histiocytosis, particularly in terms of treatment [ 28 ]. In patients with LCH associated with BRAF V600E mutations (55% of children with LCH [ 4 ]), a BRAF inhibitor showed efficient effects.…”

“…In patients with LCH associated with BRAF V600E mutations (55% of children with LCH [ 4 ]), a BRAF inhibitor showed efficient effects. The other mutations associated with LCH ( MAP2K1 , BRAF indel) were responsive to MEK inhibitors [ 28 ]. Thus, considering the severity of this LCH presentation, we believe that the use of targeted therapy would be justified, because it showed rapid efficacy in LCH [ 29 , 38 , 39 ].…”

“…Due to recent progress broadening LCH pathogenesis molecular understanding [28], LCH has been associated with a very low mortality rate. Indeed, patients with BRAF V600E mutations and MS RO+ LCH historically had the worst prognosis.…”

Recent advances in the understanding of the molecular pathogenesis and targeted therapy options in Langerhans cell histiocytosis

“…Langerhans cell histiocytosis (LCH) is a myeloproliferative disorder characterized by inflammatory lesions with the accumulation of CD1a+/CD207+ histiocytes, leading to the destruction of affected tissues [1,2]. While LCH invades bones and skin commonly, it can involve any organ, including the liver, spleen, lungs, lymph nodes, central nervous system, and hematopoietic system.…”