BRAF- and MEK-inhibitors in the treatment of Langerhans cell histiocytosis in children and adults: molecular basis, clinical experience and unresolved issues

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Abstract

Langerhans cell histiocytosis (LCH) is a rare clonal myeloid neoplasm driven by constitutive activation of the MAPK signaling pathway. The principal molecular alterations are activating somatic mutations in BRAF, MAP2K1, ARAF, KRAS, and NRAS. Their identification provided the rationale for BRAF and MEK inhibitors, which place in treatment depends on age, clinical subtype, and LCH molecular profile.

Aim of the work – to analyze the molecular basis, efficacy, and safety of BRAF and MEK inhibitors in children and adults with LCH and to identify unresolved issues in molecularly targeted therapy.

In a pediatric cohort, the BRAF V600E mutation was detected in 54.6 % of patients and was associated with higher rates of resistance to first-line therapy (21.9 % vs 3.3 %) and 5-year disease reactivation (42.8 % vs 28.1 %). BRAF inhibitors are used primarily for BRAF V600E, whereas MEK inhibitors target MAP2K1 mutations and other activating alterations of the MAPK cascade. Two-year overall survival in pediatric patients with LCH, treated with BRAF and MEK inhibitors is 98 %. After end of treatment 3-year event-free survival decrease up to 62 %.

In adults the BRAF V600E mutation was detected in 38.8 %, BRAF deletions in 25.4 %, and MAP2K1 mutations in 19.4 % of patients. In all cases, complete or partial responses have been observed with the use of BRAF and MEK inhibitors, but there are no results on long-term survival in adult patients with LCH.

The main limitations of molecularly targeted therapy are frequent reactivation after discontinuation, uncertain optimal treatment duration, and adverse events. BRAF inhibitors most commonly cause cutaneous toxicity, photosensitivity, arthralgia, and QT prolongation; MEK inhibitors may cause dermatologic, gastrointestinal, cardiac, and ophthalmologic complications.

BRAF and MEK inhibitors are highly effective components of personalized therapy for LCH with activating MAPK pathway alterations. The strongest evidence concerns children with relapsed or refractory multisystem disease; first-line use in children and adults are supported mainly by observational studies and small heterogeneous cohorts. So, treatment choice should account for clinical subtype, molecular profile, risk of irreversible organ damage, and expected toxicity. Treatment sequence, combinations of BRAF and MEK inhibitors, duration, discontinuation criteria, and long-term safety require prospective evaluation.

About the authors

T. T. Valiev

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University)

Author for correspondence.
Email: timurvaliev@mail.ru
ORCID iD: 0000-0002-1469-2365
Russian Federation, 23 Kashirskoe Shosse, Moscow, 115522; Build. 2, 8 Trubetskaya St., Moscow, 119048

Y. Y. Klishina

N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia

Email: timurvaliev@mail.ru
ORCID iD: 0009-0008-7086-0387
Russian Federation, 1 Ostrovityanova St., Moscow, 117513

T. S. Belysheva

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

Email: timurvaliev@mail.ru
ORCID iD: 0000-0001-5911-553X
Russian Federation, 23 Kashirskoe Shosse, Moscow, 115522

P. A. Zeynalova

I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University); Clinical Hospital "Lapino" of the "Mother and Child" Group of Companies

Email: timurvaliev@mail.ru
ORCID iD: 0000-0003-1564-424X
Russian Federation, Build. 2, 8 Trubetskaya St., Moscow, 119048; 111 1st Uspenskoe Shosse, Lapino, Moscow Region, 143081

O. A. Milovanova

Russian Medical Academy of Continuing Professional Education, Ministry of Health of Russia; Pediatric Clinical Hospital named after Z. A. Bashlyaeva, Moscow Healthcare Department

Email: timurvaliev@mail.ru
ORCID iD: 0000-0002-6260-6193
Russian Federation, Build. 1, 2 / 1 Barrikadnaya St., Moscow, 125993; 28 Geroev Panfilovtsev St., Moscow, 125373

References

  1. Emile J.F., Abla O., Fraitag S. et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood 2016;127(22):2672–81. doi: 10.1182/blood-2016-01-690636
  2. Goyal G., Tazi A., Go R.S. et al. International expert consensus recommendations for the diagnosis and treatment of Langerhans cell histiocytosis in adults. Blood 2022;139(17):2601–21. doi: 10.1182/blood.2021014343
  3. Lorillon G., Tazi A. How I manage pulmonary Langerhans cell histiocytosis. Eur Respir Rev 2017;26(145):170070. doi: 10.1183/16000617.0070-2017
  4. Salotti J.A., Nanduri V., Pearce M.S. et al. Incidence and clinical features of Langerhans cell histiocytosis in the UK and Ireland. Arch Dis Child 2009;94(5):376–80. doi: 10.1136/adc.2008.144527
  5. Liu H., Stiller C.A., Crooks C.J. et al. Incidence, prevalence and survival in patients with Langerhans cell histiocytosis: a national registry study from England, 2013–2019. Br J Haematol 2022;199(5):728–38. doi: 10.1111/bjh.18459
  6. Guyot-Goubin A., Donadieu J., Barkaoui M. et al. Descriptive epidemiology of childhood Langerhans cell histiocytosis in France, 2000–2004. Pediatr Blood Cancer 2008;51(1):71–5. doi: 10.1002/pbc.21498
  7. Tang X., Gao J., Ma Z.G. et al. Clinical and prognostic characteristics of 95 cases of Langerhans cell histiocytosis in children: a single-institute experience from 2013 to 2020. Ann Med 2021;53(1):1537–46. doi: 10.1080/07853890.2021.1966085
  8. Haupt R., Minkov M., Astigarraga I. et al. Langerhans cell histiocytosis (LCH): guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years. Pediatr Blood Cancer 2013;60(2):175–84. doi: 10.1002/pbc.24367
  9. Gadner H., Minkov M., Grois N. et al. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood 2013;121(25):5006–14. doi: 10.1182/blood-2012-09-455774
  10. Neuberg D., Arceci R.J. When “rare” is no excuse for progress. Blood 2013;121(25):4970–2. doi: 10.1182/blood-2013-05-498675
  11. Donadieu J., Bernard F., van Noesel M. et al.; Salvage Group of the Histiocyte Society. Cladribine and cytarabine in refractory multisystem Langerhans cell histiocytosis: results of an international phase 2 study. Blood 2015;126(12):1415–23. doi: 10.1182/blood-2015-03-635151
  12. Parekh D., Lin H., Batajoo A. et al. Clofarabine monotherapy in aggressive, relapsed and refractory Langerhans cell histiocytosis. Br J Haematol 2024;204(5):1888–93. doi: 10.1111/bjh.19376
  13. Pegoraro F., Kondyli M., Prudowsky Z.D., van Halteren A.G.S. Histiocyte Society blueprint for Langerhans cell histiocytosis research: from cell-of-origin to a more comprehensive cure. Haematologica 2025;110(11):2588–602. doi: 10.3324/haematol.2024.286478
  14. Histiocyte Society. LCH-IV: international collaborative treatment protocol for children and adolescents with langerhans cell histiocytosis. ClinicalTrials.gov identifier NCT02205762. Available at: https://clinicaltrials.gov/study/NCT02205762 (accessed July 2026)
  15. Lehrnbecher T. Clinical Study Report LCH-IV-G 2016: German treatment optimization study for children with de novo and relapsed Langerhans cell histiocytosis (LCH) as part of the international study LCH-IV. Frankfurt am Main: Goethe University; 2025. EudraCT No. 2016-003568-38. Available at: https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-003568-38/results (accessed July 2026.)
  16. Badalian-Very G., Vergilio J.A., Degar B.A. et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 2010;116(11):1919–23. doi: 10.1182/blood-2010-04-279083
  17. Chakraborty R., Hampton O.A., Shen X. et al. Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood 2014;124(19):3007–15. doi: 10.1182/blood-2014-05-577825
  18. Héritier S., Emile J.F., Barkaoui M.A. et al. BRAF mutation correlates with high-risk Langerhans cell histiocytosis and increased resistance to first-line therapy. J Clin Oncol 2016;34(25):3023–30. doi: 10.1200/JCO.2015.65.9508
  19. Lavoie H., Therrien M. Regulation of RAF protein kinases in ERK signalling. Nat Rev Mol Cell Biol 2015;16(5):281–98. doi: 10.1038/nrm3979
  20. Cope N., Novak B., Candelora C. et al. Biochemical characterization of full-length oncogenic BRAF V600E together with molecular dynamics simulations provide insight into the activation and inhibition mechanisms of RAF kinases. ChemBioChem 2019;20(22):2850–61. doi: 10.1002/cbic.201900266
  21. Dankner M., Rose A.A.N., Rajkumar S. et al. Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations. Oncogene 2018;37(24):3183–99. doi: 10.1038/s41388-018-0171-x
  22. Bollag G., Hirth P., Tsai J. et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 2010;467(7315):596–9. doi: 10.1038/nature09454
  23. Heidorn S.J., Milagre C., Whittaker S. et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 2010;140(2):209–21. doi: 10.1016/j.cell.2009.12.040
  24. Chapman P.B., Hauschild A., Robert C. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364(26):2507–16. doi: 10.1056/NEJMoa1103782
  25. Lacouture M.E., Duvic M., Hauschild A. et al. Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist 2013;18(3):314–22. doi: 10.1634/theoncologist.2012-0333
  26. U.S. Food and Drug Administration. ZELBORAF (vemurafenib) prescribing information. Initial U.S. approval: 2011. Silver Spring (MD): FDA, 2011. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202429s000lbl.pdf
  27. U.S. Food and Drug Administration. Approval package for ZELBORAF (vemurafenib), NDA 202429/S-016: Erdheim–Chester disease with BRAF V600 mutation. Approval date: November 6, 2017. Silver Spring (MD): FDA, 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/202429Orig1s016.pdf
  28. Donadieu J., Larabi I.A., Tardieu M. et al. Vemurafenib for refractory multisystem Langerhans cell histiocytosis in children: an international observational study. J Clin Oncol 2019;37(31):2857–65. doi: 10.1200/JCO.19.00456
  29. U.S. Food and Drug Administration. FDA approves dabrafenib with trametinib for pediatric patients with low-grade glioma with a BRAF V600E mutation. Silver Spring (MD): FDA, 2023. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-dabrafenib-trametinib-pediatric-patients-low-grade-glioma-braf-v600e-mutation
  30. Yang Y., Wang D., Cui L. et al. Effectiveness and safety of dabrafenib in the treatment of 20 Chinese children with BRAF V600E-mutated Langerhans cell histiocytosis. Cancer Res Treat 2021;53(1):261–9. doi: 10.4143/crt.2020.769
  31. Whitlock J.A., Geoerger B., Dunkel I.J. et al. Dabrafenib, alone or in combination with trametinib, in BRAF V600-mutated pediatric Langerhans cell histiocytosis. Blood Adv 2023;7(15):3806–15. doi: 10.1182/bloodadvances.2022008414
  32. Ouyang H., Yao H., He C. et al. Dabrafenib or trametinib in pediatric Langerhans cell histiocytosis with bone lesions: a retrospective efficacy and safety study. BMC Cancer 2026;26(1):604. doi: 10.1186/s12885-026-15940-4
  33. Cournoyer E., Ferrell J., Sharp S. et al. Dabrafenib and trametinib in Langerhans cell histiocytosis and other histiocytic disorders. Haematologica 2024;109(4):1137–48. doi: 10.3324/haematol.2023.283295
  34. Lei J., Wang W., Lin D. et al. Vemurafenib combined with chemotherapy achieved sustained remission in pediatric LCH: a multi-center observational study. J Cancer Res Clin Oncol 2024;150(1):31. doi: 10.1007/s00432-023-05551-y
  35. Evseev D., Osipova D., Kalinina I. et al. Vemurafenib combined with cladribine and cytarabine results in durable remission of pediatric BRAF V600E-positive LCH. Blood Adv 2023;7(18):5246–57. doi: 10.1182/bloodadvances.2022009067
  36. Donadieu J., Evseev D., Pegoraro F. et al. Long-term MAPK inhibition of childhood refractory-Langerhans cell histiocytosis: an observational study of 288 patients. Blood Adv 2026;10(10):3733–43. doi: 10.1182/bloodadvances.2025018651
  37. Cao X.X., Duan M.H., Zhao A.L. et al. Treatment outcomes and prognostic factors of patients with adult Langerhans cell histiocytosis. Am J Hematol 2022;97(2):203–8. doi: 10.1002/ajh.26412
  38. U.S. Food and Drug Administration. COTELLIC (cobimetinib) prescribing information. Silver Spring (MD): FDA, 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/206192s005lbl.pdf
  39. Diamond E.L., Subbiah V., Lockhart A.C. et al. Vemurafenib for BRAF V600-mutant Erdheim–Chester disease and Langerhans cell histiocytosis: analysis of data from the histology-independent, phase 2, open-label VE-BASKET study. JAMA Oncol 2018;4(3):384–8. doi: 10.1001/jamaoncol.2017.5029
  40. Diamond E.L., Durham B.H., Ulaner G.A. et al. Efficacy of MEK inhibition in patients with histiocytic neoplasms. Nature 2019;567(7749):521–4. doi: 10.1038/s41586-019-1012-y
  41. Reiner A.S., Durham B.H., Yabe M. et al. Outcomes after interruption of targeted therapy in patients with histiocytic neoplasms. Br J Haematol 2023;203(3):389–94. doi: 10.1111/bjh.18964
  42. Awada G., Seremet T., Fostier K. et al. Long-term disease control of Langerhans cell histiocytosis using combined BRAF and MEK inhibition. Blood Adv 2018;2(16):2156–8. doi: 10.1182/bloodadvances.2018021782

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