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Langerhans cell histiocytosis (LCH) commonly co-occurs with additional myeloid malignancies. The introduction of targeted therapies, blocking “driver” mutations (e.g.,  BRAF V600E ), enabled long-term remission in patients with LCH. The effect of  BRAF  inhibition on the course and the prognosis of co-existing clonal hematopoiesis is poorly understood. We report on a 61-year-old patient with systemic  BRAF V600E  positive LCH and concomitant  BRAF  wild-type (wt) clonal cytopenia of unknown significance (CCUS) with unfavorable somatic mutations including loss of function (LOF) of  NF1 . While manifestations of LCH improved after blocking  BRAF  by dabrafenib treatment, the  BRAF  wt CCUS progressed to acute myeloid leukemia (AML). The patient eventually underwent successful allogeneic hematopoietic stem cell transplantation (HSCT). We performed an in-depth analyzes of the clonal relationship of CCUS and the tissue affected by LCH by using next-generation sequencing (NGS). The findings suggest activation of the mitogen-activated protein (MAP) kinase pathway in the CCUS clone due to the presence of the  RAS  deregulating  NF1  mutations and wt  BRAF , which is reportedly associated with paradoxical activation of  CRAF  and hence  MEK . Patients with LCH should be carefully screened for potential additional clonal hematological diseases. NGS can help predict outcome of the latter in case of  BRAF  inhibition. Blocking the MAP kinase pathway further downstream (e.g., by using MEK inhibitors) or allogeneic HSCT may be options for patients at risk.

Case Report: Opposite Effects of BRAF Inhibition on Closely Related Clonal Myeloid Disorders