Trametinib Treatment for Histiocytic Sarcoma With an Activating MAP2K1 Mutation
In a letter to the editor in The New England Journal of Medicine, Gounder et al described the successful treatment of a patient with histiocytic sarcoma and an activating MAP2K1 (MEK1) mutation with the MAPK kinase 1 and 2 inhibitor trametinib (Mekinist). As noted by the authors, patients with histiocytic sarcoma and BRAF V600E mutations have been reported to respond to the BRAF inhibitor vemurafenib (Zelboraf). Oncogenic mutations in BRAF and MAPK have been found to be mutually exclusive, and may constitute mechanisms for activation of the RAF-MEK-ERK pathway observed in histiocytic neoplasms.
The 62-year-old patient, who had a history of untreated grade 1 or grade 2 follicular lymphoma (BCL2-rearranged), presented with new-onset fatigue, persistent fever, and night sweats. Positron-emission tomography and computed tomography (PET-CT) revealed hypermetabolic visceral, nodal, and osseous lesions indicative of high-grade transformation of follicular lymphoma.
Treatment with rituximab (Rituxan) and bendamustine was ineffective. Biopsy showed pleomorphic cells positive for CD4, CD11c, CD33, and lysozyme, consistent with histiocytic sarcoma and potential transdifferentiation from follicular lymphoma. Treatment with doxorubicin and cyclophosphamide produced minimal response.
Trametinib Treatment
Next-generation sequencing identified somatic mutations in BCL10, BCL2, CDKN1B, KIT, and MAP2K1-F53L. Clinical trials of trametinib were unavailable; the patient provided consent to receive off-label trametinib at 2 mg/d.
Three days after starting treatment, the patient exhibited resolution of B symptoms, including weight loss, fatigue, and fever, and reduced leukocytosis, thrombocytosis, and anemia. Evaluation with PET-CT showed a rapid and durable complete response that was maintained for > 2 years.
The investigators concluded: “We describe a patient who had histiocytic sarcoma with an activating mutation in MAP2K1 who had a complete clinical response and a response on imaging to trametinib…. These results are consistent with preclinical findings of MAP2K1 mutations as an alternative mechanism for activating the MAPK pathway in histiocytic neoplasms. Like other types of non-Langerhans-cell histiocytosis, histiocytic sarcoma … may harbor mutations in the MAPK pathway, and tumor profiling may be helpful. Basket studies of MEK or ERK inhibitors in cancers harboring MAP2K1 mutations may be warranted.”
The work was supported by a Memorial Sloan Kettering Cancer Center core grant and the Draper Family Fund.
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