Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2023 Aug 8;7(15):3984-3992.
doi: 10.1182/bloodadvances.2022009013.

Successful treatment of non-Langerhans cell histiocytosis with the MEK inhibitor trametinib: a multicenter analysis

Ashley Aaroe  1 , Razelle Kurzrock  2   3 , Gaurav Goyal  4 , Aaron M Goodman  5 , Harsh Patel  6 , Gordon Ruan  7 , Gary Ulaner  8 , Jason Young  7 , Ziyi Li  1 , Derek Dustin  1 , Ronald S Go  7 , Eli L Diamond  9 , Filip Janku  10
Affiliations
Multicenter Study

Successful treatment of non-Langerhans cell histiocytosis with the MEK inhibitor trametinib: a multicenter analysis

Ashley Aaroe et al. Blood Adv. .

Abstract

Erdheim-Chester disease (ECD) and Rosai-Dorfman disease (RDD) are rare non-Langerhans cell histiocytoses (non-LCHs), for which therapeutic options are limited. MAPK pathway activation through BRAFV600E mutation or other genomic alterations is a histiocytosis hallmark and correlates with a favorable response to BRAF inhibitors and the MEK inhibitor cobimetinib. However, there has been no systematic evaluation of alternative MEK inhibitors. To assess the efficacy and safety of the MEK inhibitor trametinib, we retrospectively analyzed the outcomes of 26 adult patients (17 with ECD, 5 with ECD/RDD, 3 with RDD, and 1 with ECD/LCH) treated with orally administered trametinib at 4 major US care centers. The most common treatment-related toxicity was rash (27% of patients). In most patients, the disease was effectively managed at low doses (0.5-1.0 mg trametinib daily). The response rate of the 17 evaluable patients was 71% (73% [8/11] without a detectable BRAFV600E achieving response). At a median follow-up of 23 months, treatment effects were durable, with a median time-to-treatment failure of 37 months, whereas the median progression-free and overall survival were not reached (at 3 years, 90.1% of patients were alive). Most patients harbored mutations in BRAF (either classic BRAFV600E or other BRAF alterations) or alterations in other genes involved in the MAPK pathway, eg, MAP2K, NF1, GNAS, or RAS. Most patients required lower than standard doses of trametinib but were responsive to lower doses. Our data suggest that the MEK inhibitor trametinib is an effective treatment for ECD and RDD, including those without the BRAFV600E mutation.

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest disclosure: E.L.D. receives unpaid editorial support from Pfizer Inc. and paid advisory board membership with Day One Biopharmaceuticals, Springworks Therapeutics, and Opna Bio, all outside the submitted work. R.K. has received research funding from Biological Dynamics, Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant Health, Incyte Corporation, Konica Minolta, Medimmune, Merck Serono, OmniSeq, Pfizer, Sequenom, Takeda, and TopAlliance; consultantcy, speaker fees, and/or advisory board for Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, Biological Dynamics, Caris, Datar Cancer Genetics, Eisai, EOM Pharmaceuticals, Iylon, Merck, NeoGenomics, Neomed, Pfizer, Prosperdtx, Roche, TD2/Volastra, Turning Point Therapeutics, and XBiotech; has an equity interest in CureMatch, CureMetrix, and IDbyDNA; serves on the board of CureMatch and CureMetrix; and is a cofounder of CureMatch. F.J. reports research support from Astex, Novartis, BioMed Valley Discoveries, Fore Biotherapeutics, Deciphera, Bristol Myers Squibb, Asana, IDEAYA Biosciences, Sanofi, Merck, F-star, JS InnoPharm, BioXcel, Lilly, Bicara Therapeutics, PureTech Health, FUJIFILM Pharmaceuticals, SOTIO, Synlogic, NextCure, and Hutchinson MediPharma; is on the scientific advisory boards of IDEAYA Biosciences, Synlogic, SOTIO, PureTech Health, Deciphera, Crown Bioscience, Asana, Fore Biotherapeutics, Novartis, Bicara Therapeutics, and PegaOne; is a paid consultant for Mersana Therapeutics, Flame Biosciences, Cardiff Oncology, MedinCell, and ImmunoMet Therapeutics; and has an ownership interest in Cardiff Oncology. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Kaplan-Meier curves showing the TTF, PFS, and OS. TTF (left), PFS (middle), and OS (right).
Figure 2.
Figure 2.
Swimmer plot showing time on therapy segregated by best response and genotype. Arrows indicate patients still on treatment.
See this image and copyright information in PMC

References

    1. Emile JF, Abla O, Fraitag S, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016;127(22):2672–2681. - PMC - PubMed
    1. Munoz J, Janku F, Cohen PR, Kurzrock R. Erdheim-Chester disease: characteristics and management. Mayo Clin Proc. 2014;89(7):985–996. - PubMed
    1. Haroche J, Amoura Z, Wechsler B, Veyssier-Belot C, Charlotte F, Piette JC. [Erdheim-Chester disease] La Presse Medicale. 2007;36(11):1663–1668. - PubMed
    1. Andre M, Delevaux I, de Fraissinette B, et al. Two enlarged kidneys: a manifestation of Erdheim-Chester disease. Am J Nephrol. 2001;21(4):315–317. - PubMed
    1. Ozkaya N, Rosenblum MK, Durham BH, et al. The histopathology of Erdheim-Chester disease: a comprehensive review of a molecularly characterized cohort. Mod Pathol. 2018;31(4):581–597. - PMC - PubMed

Publication types

MeSH terms

Substances