Julien Haroche

Erdheim–Chester disease (ECD) is a rare histiocytic neoplasm characterized by heterogeneous clinical manifestations and limited evidence to guide targeted therapy. While MEK inhibitors (MEKi) are increasingly used, data on their real‐world efficacy, durability, and safety remain incomplete. We analyzed outcomes of patients with ECD treated with MEKi monotherapy across eight countries and assessed the dynamics and predictors of response, treatment retention, and the safety profile of MEKi. We included 170 patients and were able to evaluate response in 159 (94%) of them. Objective responses were observed in 112 patients (70%), disease stabilization in 35 (22%), and disease progression in 12 (8%). Response rates were independent of treatment lines and underlying molecular alterations. The median time to best response was 14 months, with an estimated 2‐year probability of response of 61% (95% CI 51%–67%). In multivariable analysis, dyslipidemia (odds ratio [OR] 0.359, 95% CI 0.171–0.745) and neurodegeneration (OR 0.354, 95% CI 0.144–0.864) were associated with a lower probability of response to MEKi, while cutaneous and gastrointestinal involvement with a higher probability. After a median follow‐up of 27 months (interquartile range [IQR] 12–57), the treatment retention rate was 76%, with most discontinuations attributable to toxicity. Adverse events were reported in 106 patients (62%) and were severe in 39 patients (23%). The estimated 2‐year event‐free survival was 65% (95% CI 57%–72%), and the estimated 2‐year overall survival was 80% (95% CI 72%–86%). MEKi monotherapy provides robust and durable clinical efficacy in patients with ECD, with high response rates and favorable long‐term outcomes, despite a substantial burden of toxicity.

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Neurodegeneration (ND) is a severe complication of Langerhans cell histiocytosis (LCH), yet its underlying biology and reliable biomarkers remain poorly defined. The aim of this study was to (1) gain insight into neuroimmunological mechanisms governing ND and (2) assess the clinical value of established and novel biomarkers for ND‐LCH. We applied targeted proteomics and neurofilament light chain (NFL) assays to cerebrospinal fluid (CSF) and plasma from LCH patients with and without ND, with control cohorts. ND‐LCH exhibited a distinct CSF proteomic profile characterized by increased decoy receptors, including interleukin‐1 receptor type 2 (IL‐1RT2), macrophage activation markers, and cytotoxic and immunoregulatory proteins. CSF IL‐1RT2 showed higher specificity for ND‐LCH than CSF NFL (0.99 [0.99–1.0] vs. 0.88 [0.80–0.96]) and tracked longitudinal disease changes. Plasma analyses revealed a complementary immune signature in which NFL correlated with CSF markers, including IL‐1RT2, and distinguished ND‐LCH from controls. In independent plasma NFL cohorts from France and Japan, elevated levels were confirmed in adults with histiocytosis‐associated ND. These findings define a neuroinflammatory signature of ND‐LCH and identify IL‐1RT2 as a novel candidate biomarker for diagnosis and monitoring.

Glomeruloid haemangiomas and extensive angiomas occurred in a small subset of Erdheim-Chester disease patients, all showing markedly elevated vascular endothelial growth factor-A (VEGF-A) levels despite the absence of POEMS (polyneuropathy, organomegaly, M-spike, and skin disease) syndrome. Molecular analyses demonstrated mitogen-activated protein kinase (MAPK)-activated histiocytes without endothelial mutations, supporting a paracrine VEGF-A-driven angiogenesis mechanism underlying these atypical cutaneous lesions.

Background: Erdheim‐Chester Disease ( ECD ) and Rosai‐Dorfman Disease ( RDD ) Are Rare Non‐Langerhans Cell Histiocytoses That Share Several Clinical and Histological Features, Including the Accumulation of CD1a ‐ Histiocytes in Organs. Cladribine, a Purine Analog, Leads to an Overall Response Rate ( ORR ) of 91% in Langerhans‐Cell Histiocytoses. Whether the Same Results Could Be Obtained in Non‐Langerhans Cell Histiocytoses Remains To Be Determined. Patients and Methods: We retrospectively assessed the efficacy of cladribine according to clinical and radiological responses in consecutive patients with a diagnosis of ECD, RDD, or non‐classified non‐Langerhans cell histiocytosis. Results: Twenty‐One Patients Were Included in This Study (17 Males, Median Age at Cladribine Treatment 53 Years). The Clinical ORR Was 62% (44% in ECD , 70% in RDD ), whereas the Radiological ORR Was 43% (44% in ECD , 30% in RDD ). Four of Five Patients With Cranial Nerve Palsy Responded Clinically (80%), whereas Pseudo‐Degenerative CNS Involvement Did Not Improve ( n = 3). Six Patients With Multisystemic Involvement Did Not Require Additional Treatment After Achieving a Radiological Response ( n = 4) or After Achieving Radiological Stable Disease ( n = 2), with a Median Follow‐Up of 2.3 Years (Range 0.5–9.5). After They Achieved a Radiological Response, 4/9 (44%) Patients Relapsed in a Median Time of 18 Months (Range 6–95). The Safety Profile Showed That 19/19 Patients Experienced Lymphopenia, Whereas Only 2/19 Had Clinical Infectious Events (9%). Conclusions: These Results Provide New Evidence of the Efficacy of Cladribine in Non‐Langerhans Cell Histiocytosis and Brings New Data on the Safety Profile of This Drug in Histiocytoses.

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.