Erdheim‐Chester disease associated with myeloid neoplasm: Clinical features, molecular landscape, and treatment outcomes

Abstract Erdheim‐Chester disease (ECD) is frequently associated with clonal hematopoiesis and myeloid neoplasms (MN), but clinical phenotype and response to kinase inhibitors (KI) in this setting remain unclear. We analyzed 67 patients with ECD associated with MN (ECD‐MN) from a French national cohort and assessed ECD treatment response, MN progression, and leukemic transformation. Outcomes were compared with those of 348 patients with ECD without MN. ECD‐MN were characterized by low blast counts and favorable MN prognostic scores. Compared with ECD patients without MN, those with MN were older (median 65 vs. 59 years, P < 0.0001) and had more frequent cardiac (54% vs. 37%, P < 0.01), pulmonary (48% vs. 31%, P < 0.01), gastrointestinal (34% vs. 11%, P < 0.0001), and lymph node involvement (31% vs. 8%, P < 0.0001). KI therapy led to higher ECD response rates at 6 and 12 months compared with pegylated‐interferon α (Peg‐IFN) (96% vs. 58%, P = 0.02). MN progression and leukemic transformation at 6 months occurred, respectively, in 25% and 3% of KI‐treated patients versus 25% and 18% of those treated with Peg‐IFN. After a median follow‐up of 25 (12–38) months on KI, the mutational landscape remained unchanged. Median overall survival was shorter in patients with MN (76 vs. 163 months, P < 0.001). In conclusion, ECD associated with MN represents a distinct clinical entity, marked by broader organ involvement and poorer prognosis. KI therapy provides a superior response without increasing the risk of MN progression or leukemic transformation, supporting its use as a frontline treatment in this population.