High prevalence of myeloid neoplasms in adults with non-Langerhans cell histiocytosis

Abstract

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis that most commonly affects adults and is driven by a high frequency of mutations in BRAF, MAP2K1, and kinases promoting MAPK signaling. Because of the relative rarity of ECD, key clinical features of the disease may not be well defined. Across a multi-institutional cohort of 189 patients with ECD and ECD overlapping with Langerhans cell histiocytosis (so-called mixed histiocytosis [MH]), we identified an unexpected and heretofore undescribed frequent occurrence of myeloid neoplasms among patients with ECD and MH. Some 10.1% (19/189) of patients with ECD have an overlapping myeloid neoplasm, most commonly occurring as a myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), or mixed MDS/MPN overlap syndrome (including chronic myelomonocytic leukemia). Consistent with this, molecular analysis frequently detected hallmark driver mutations of myeloid neoplasms (such as JAK2V617F and CALR mutations) coexisting with those characteristic of histiocytosis (such as BRAFV600E and MAP2K1 mutations). Histiocytosis patients diagnosed with a concomitant myeloid malignancy were significantly older at diagnosis and more commonly presented with MH than those without a myeloid malignancy. In some cases, the presence of distinct kinase mutations in the histiocytosis and myeloid neoplasm resulted in discordant and adverse responses to kinase-directed targeted therapies. These data highlight the clinical importance of evaluating adults with histiocytosis for a concomitant myeloid neoplasm.

Figure 1.

Distribution of myeloid neoplasms in patients with concomitant non-LCH and genetic analysis of both disorders. (A) Pie chart demonstrating proportion of non-LCH patients with concomitant myeloid neoplasm and types of myeloid neoplasms diagnosed. ET, essential thrombocytosis; MDS, myelodysplastic syndrome; MF, primary myelofibrosis; PV, polycythemia vera; sAML, secondary acute myeloid leukemia transformed from antecedent hematological malignancy. (B) Genetic analysis of non-LCH and concomitant myeloid neoplasm. Each patient is noted by a column. Patients had clinical diagnosis of ECD or an overlap of ECD plus LCH or ECD/LCH plus Rosai Dorfman disease (RDD) based on tissue biopsy and clinical evaluation in addition to a form of WHO-classified myeloid. Mutations identified in histiocytosis tissue lesion biopsy alone in each patient are noted in the middle boxes, and those mutations detected in PB or BM mononuclear cells are noted in bottom boxes.

Figure 2.

Effect of targeted therapies on non-LCH and concomitant myeloid neoplasm. (A-E) Effect of vemurafenib on a 75-year-old patient with BRAFV600E-mutant ECD and concomitant JAK2V617F/IDH2R140Q-mutant MDS/MPN. (A) Absolute monocytes (orange line; left y-axis) and urinary BRAFV600E cell-free DNA quantitation (red line; right y-axis) pre- and postvemurafenib therapy (shaded area represents period of vemurafenib treatment). (B) ¹⁸F-FDG PET scan pre- (left) and postvemurafenib (right) with corresponding fused computed tomography/¹⁸F-FDG PET below. (C) Hematoxylin and eosin–stained biopsies of femoral bone revealing characteristic xanthogranulomatous lesion of ECD within a fibrotic background (histiocytes were CD68⁺ by immunohistochemistry [not shown]). Original magnification ×400. (D) Evidence of myeloid neoplasm because of the presence of dysplastic myeloid cells (hypogranulation and pseudo–Pelger-Huet cell) in BM aspirate (left; original magnification ×400), increased number of CD34⁺ cells (middle; original magnification ×100), and hematoxylin and eosin stain revealing hypercellular marrow with dysplastic megakaryocytes (right; original magnification ×200). (E-G) Effect of MEK inhibitor therapy on monocytosis and PB counts on the 66-year-old patient with NRASQ61R-mutant ECD and CMML described in Figure 1. ¹⁸F-FDG PET (F) and fused computed tomography/¹⁸F-FDG PET (G) pre- and 2 months posttrametinib treatment in this same patient.