Advances in our understanding of genetic markers and targeted therapies for pediatric LCH

ABSTRACT

Introduction

Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm, encompassing a diverse clinical spectrum ranging from localized bone or skin lesions to a multisystemic life-threatening condition. Over the past decade, there has been an expansion in understanding the molecular biology of LCH, which translated into innovative targeted therapeutic approaches.

Areas covered

In this article, we will review the molecular alterations observed in pediatric LCH and the relationship between these molecular changes and the clinical phenotype, as well as targeted therapies in LCH.

Expert opinion

Mitogen-activated protein kinase (MAPK) pathway mutation is a hallmark of LCH and is identified in 80% of the cases. Notably, BRAFV600E mutation is seen in ~50–60% of the cases, ~30% has other MAPK pathway mutations, while 15–20% have no detected mutations. While the first line therapeutic approach is vinblastine and prednisone, targeted therapies – specifically BRAF/MEK inhibitors – emerged as a promising second-line salvage strategy, particularly when a mutation is identified. Most patients respond to BRAF/MEK inhibitors but at least 75% reactivate after stopping, however, most patients respond again when restarting inhibitors.

KEYWORDS:

• LCH
• pediatric
• MAPK pathway
• BRAF inhibitors
• MEK inhibitors

Article highlights

• Langerhans Cell Histiocytosis (LCH) is characterized by MAPK pathway genetic alteration leading to pathway activation.

• BRAFV600E mutation is the most commonly seen alteration, occurring in approximately 50% of cases, followed by MAP2KA alteration.

• MAPK pathway mutations, particularly BRAFV600E, correlate with disease extent, treatment response, and risk of reactivation, informing prognosis and treatment decisions.

• BRAF/MEK inhibitors have emerged as promising targeted therapies for relapsed LCH, showing rapid symptom response.

• Although targeted therapy with BRAF/MEK inhibitors is very promising, ongoing research is needed to address safety concerns, therapy duration, and resistance mechanisms, with potential future therapies including newer generation of inhibitors and combination approaches.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

A Bahabri worked on literature review and drafting the manuscript. O Abla is the senior author that outlined the manuscript focus, and reviewed the paper and final edits.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17474086.2024.2353772.

Additional information

Funding

This paper was not funded.