843P - Challenges and insights in treating Langerhans cell histiocytosis: Persistent mutations and novel therapeutic approaches

Background

Langerhans cell histiocytosis (LCH) is a challenging clonal disorder characterized by the proliferation of CD207+ dendritic cells. Despite advancements with MEK inhibitors, achieving durable remission remains problematic due to frequent relapses and the onset of neurodegenerative syndromes after treatment cessation. This study aims to identify persistent disease mechanisms and improve therapeutic strategies by analyzing residual mutated cells in patients continuously treated with MEK inhibitors.

Methods

In our methods, we applied advanced single-cell multi-omic techniques, such as single RNA Seq long read and TAPESTRI, to examine the transcriptional profiles of these resilient cells within the bone marrow. Furthermore, a genetically engineered mouse model was employed, consisting of mice with the BRAFV600ECa/-; Scl-creER genotype crossed with Rosa26 LSL-YFP/LSL-YFP mice. These mice underwent tamoxifen-induced activation of the BRAFV600E mutation. Subsequently, they were divided into three groups: one received trametinib, another received a combination of venetoclax and trametinib, and a control group was treated with a solution of 0.5% NaCl and 5% DMSO.

Results

The results showed significant organ size reduction in mice treated with trametinib alone, suggesting its effectiveness in reducing pathological manifestations. However, the survival rates in this group decreased, indicating potential issues with long-term efficacy or tolerability. The group receiving combination therapy exhibited initial survival advantages but faced possible increased toxicity over time, highlighting the complexity of treatment responses.

Conclusions

The study emphasizes the persistence of mutated cells despite ongoing treatment and the potential for combination therapies to improve outcomes. The findings advocate for further optimization of dosing and scheduling to enhance the efficacy and safety of treatments. Future research integrating molecular insights with clinical strategies is crucial for developing more sophisticated and durable therapeutic approaches for LCH. This comprehensive approach could move us closer to achieving durable remission for all patients affected by this disease.

Clinical trial identification

#38265-2022082408356578.

Editorial acknowledgement

Legal entity responsible for the study

C. Bigenwald.

Funding

Institut Gustave Roussy.

Disclosure

All authors have declared no conflicts of interest.