Characteristics and Therapeutic Response of Erdheim-Chester Disease Associated with Myeloid Neoplasm, an Observational Multicenter Study

Introduction : Erdheim-Chester disease (ECD) is L-group histiocytosis with adult-onset and life-threatening multisystemic involvement. ECD is frequently reported in association with clonal hematopoiesis and myeloid neoplasm (MN). Due to its rarity, clinical, hematological, and mutational characteristic of ECD associated with MN, as well as their evolution under targeted therapy, are actually not known. Methods : We performed a retrospective study of 67 patients with ECD or mixed histiocytosis associated with MN. All data were collected from medical records before and under treatment. Therapeutic response was assessed by CRP and FDG-PET-CT at 6 and 12 months. Characteristics were compared to a control cohort of 348 ECD without MN. The mutational profile was obtained at MN diagnosis and under kinase inhibitor (KI i.e. BRAF and/or MEK inhibitors) through deep targeted sequencing analysis. Results : A total of 67 patients with ECD and MN were reported, including 33 chronic myelomonocytic leukemia (CMML), 18 with myelodysplastic syndromes (MDS), 15 with myeloproliferative neoplasms (MPN) and one acute myeloid leukemia (AML). MDS cases and CMML cases had low blasts and favorable prognosis score respectively. ECD patients with MN were significantly older at histiocytosis diagnosis (65 years vs. 59 years, p <0.0001) and exhibited more frequent cardiac (54% vs. 37%, p < 0.01), pulmonary (48% vs. 31%, p < 0.01), perirenal (84% vs. 64%, p = 0.004), and digestive (34% vs. 11%, p < 0.0001) involvement than those without MN. The most frequent myeloid mutations in the cohort were TET2, KRAS, SRSF2, ASXL1, NRAS and CBL. There was an increase in the number of myeloid mutations from 78 to 99 mutations after a mean reassessment time of 25 months under KI. MN progression or transformation occurred in 25% of patients, similarly in those treated with kinase inhibitor or IFN. Median survival-rate of ECD patients with MN was 76 months compared to 163 months in ECD without MN (p < 0.001). Conclusion : ECD associated with MN affects older patients, with more frequent cardiac, pulmonary, and digestive involvement, as well as increased mortality compared to ECD without MN. Our study shows no evidence of increased risk of progression of underlying myeloid neoplasm under kinase inhibitor.