Impact of additional genetic variants in the course of erdheim-chester disease and their evolution on treatment: A multicentric longitudinal Study of 445 french patients

Abstract Introduction. Erdheim-Chester disease (ECD) is a histiocytic disorder with activating MAPK (mitogen-activated protein kinases) signalization pathway mutations. ECD patients frequently harbor bone marrow additional genetic variants, also defined as clonal hematopoiesis of indeterminate potential (CHIP) but their consequences are unknown. The aim of our work was to describe theses mutations, to compare their impact on the characteristics and prognosis of patients and to study the evolution of main additional variants under treatment. Methods. We conducted a multicentric longitudinal study including 445 French patients with ECD from the worldwide cohort. We collected data about medical history, and especially focused on the existence of solid neoplasm or hematological malignancies, the presence of CHIP and the different ECD therapies. Additional variants were identified through Next Generation Sequencing targeting genes involved in myeloid neoplasms (panel of 64 genes), with a variant allele frequency (VAF) minimal threshold of 1% to detect mutation. Results. Patients were mainly middle-aged (58.8±13.9 years old) men (n=321; 72.1%) with long bone involvement, hairy kidneys or large vessel infiltration in more than 50% of all cases. A driving mutation BRAFV600E was found in 243 patients (54.6%). Bone marrow aspiration identified mutations for 168 patients (37.8%) with a mean number of variants of 2.3±1.7. Fifty-five (12.4%) patients had a malignant myeloid hemopathy. CHIP existed for 106 (30.3%) patients without any hemopathy, involving TET2 (26.9%), DNMT3A (16.8%), ASXL1 (10.8%), and CBL (6.0%). Patients without malignant hemopathy but with CHIP were older (p<0.0001), smoked more (p=0.029) and had more coronary artery disease (p=0.041), and more orbit involvement (p=0.027) than those without CHIP. Overall mortality reached 33.7% (n=150) for a mean follow-up period of 73.5 ± 63.5 months. Survival analysis showed a higher mortality in patients with MPN (p<0.0001) than those without MPN. This difference disappeared when comparing patients without MPN with or without CHIP (p=0.056). There was no significant difference in VAF before and after initiation of interferon alpha or targeted therapies whatever the additional variants.Conclusion. CHIP is common in patients with ECD, even without hematological condition. MPN was associated with an increased mortality, but CHIP was not significantly associated with a poorer prognosis. VAF of additional mutations remain stable under treatment.