Langerhans cell histiocytosis: promises and caveats of targeted therapies in high-risk and CNS disease

Abstract

Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm driven by activating mutations in the MAPK pathway, most commonly BRAF-V600E and MAP2K1. It affects children and adults, with a wide spectrum of clinical presentations ranging from self-limited to multisystem (MS) life-threatening forms. LCH is defined by the accumulation of CD1a+/CD207+ cells in different organs, and patients with liver, spleen, or hematopoietic system involvement have a higher risk of mortality. Patients with neurodegeneration (ND) have devastating outcomes and are resistant to systemic therapies. MS-LCH is treated with risk-adapted therapy, but many patients require multiple salvage regimens that are myelosuppressive and expensive. MAPK inhibitors are increasingly being used, but most patients relapse upon discontinuation of therapy. Here, we review the management of central nervous system disease and how novel cerebrospinal fluid biomarkers might predict patients at high risk of ND who could benefit from early MAPK inhibition. Further, we discuss treatment strategies for refractory/relapsed (R/R) LCH, with a focus on MAPK inhibitors' efficacy and challenges (ie, the unknown): long-term toxicity in children, optimal duration, if they are curative, whether it is safe to combine them with chemotherapy, and their high price tag. Lastly, emerging strategies, such as the new panRAF inhibitor (Day 101) in patients with R/R LCH, ERK1/2 or CSF1R inhibition in patients with MEK1/2 inhibitor resistance, and targeting the microenvironment (checkpoint plus MEK inhibition) or senescent cells (mTOR or BCL-XL inhibitors) in R/R patients, are also examined.

Graphical abstract

Figure 1.

Clinical, pathological, and radiographic features of LCH with cutaneous toxicities of MAPK inhibitors. (A) Scaly scalp rash in a 2-year-old boy. (B) LCH with a rich inflammatory background including osteoclast-like giant cells, eosinophils, and neutrophils (hematoxylin and eosin). (C) Immunostain showing surface CD1a expression. (D) Mutant-specific BRAF-VE1 immunostain with dark granular cytoplasmic staining in the lesional histiocytes (immunostain 400 × ). (E) Granulomatous CNS-LCH: brain MRI sagittal T1W image lacking posterior pituitary bright spot. (F) Brain MRI in a patient with granulomatous CNS-LCH: axial contrast-enhanced T1W image showing extensive bilateral lesions in the choroid plexus. (G) ND-LCH: axial T2-weighted image showing extensive dentate nucleus and white matter cerebellar neurodegeneration. (H) Skin hyperkeratosis pilaris of the left arm in a patient treated with a BRAF inhibitor. (I) Lobular panniculitis of the right leg in a patient on a MEK inhibitor. (J) Cutaneous squamous cell carcinoma in a adult treated with a BRAF inhibitor.

Figure 2.

(A) Summary of diverse kinase alterations discovered by next-generation sequencing techniques in LCH in the past 13 years: pie chart illustrating a composite of the diverse kinase alterations driving LCH, many of which are targetable. (B) Diagram of the MAPK and PI3K-AKT signaling pathways: description of the activation of the RAS proteins with annotation of the signaling proteins affected by genetic alterations in the histiocytic neoplasms.

Figure 3.

Algorithm for the management of CNS-LCH.

Figure 4.

Algorithm for the management of relapsed/refractory LCH.