Introduction
Erdheim Chester Disease (ECD) is a rare, non-Langerhans cell histiocytic disease, characterized as a clonal hematopoietic malignancy in 2016. MAP Kinase and PI3-AKT pathway somatic mutations and/or fusion genes play a significant role in disease pathogenesis, and now shape the landscape of targetable treatment options for this patient population. Additionally, previous research has shown that patients with ECD have a higher frequency of concomitant myeloid neoplasms, with clonal hematopoietic mutations detected in peripheral monocytes in such patients.
Methods
A retrospective analysis of 19 patients diagnosed with ECD at a single institution over a twenty-year period (2002-2022) was conducted. Inclusion criteria included patients age ≥18, histopathologic diagnosis of ECD, and clinical correlation of disease. The following clinical information was collected for each patient: demographics, molecular diagnostics (if utilized), imaging, treatments rendered and best treatment outcomes. Clinical treatments were divided into ‘conventional’ treatments including chemotherapy, immunotherapy, systemic corticosteroids, surgery or radiation, or targeted therapy including all small molecular inhibitors. Information was translated into binary data for comparison of outcomes by treatment type, time to diagnosis and use of targeted agents. Statistical analysis was performed by unpaired-T tests. Variation in treatment response assessment depended on several factors including the anatomic site(s) of disease, extent of disease burden at diagnosis and imaging modality used to assess disease. Determination of stable, progressive, or complete response was made using RECIST assessments (if CT or MR imaging used) or PERCIST assessments (if PET utilized), in addition to overall clinical response.
Results
In this analysis, 47% of the patients were females; average age at diagnosis was 51.2 years. 36% of patients were diagnosed within 12 months of symptoms onset. Molecular diagnostics were utilized in 100% of patients, (immunohistochemistry 94%, and sequencing 26%). The most common mutations identified were BRAFV600E (7 of 19) and CD68 (7), followed by CD163 (6), S100+ (5) and specific MAP Kinase pathway mutations (3). Most common primary disease site was extranodal (94% of patients), followed by osseous (63%), dermal (52%) and the central nervous system (36%). 57% of patients were treated with targeted therapy, followed by myelosuppressive therapy and steroids (42%), immunotherapy and radiation (10% each). Partial response or better was observed in 83% of patients. Stable disease was seen more often in patients treated with conventional therapy (33%) as compared to patients treated with targeted molecular therapy (11%) and partial response more often in patients treated with targeted therapy (55%). Complete response was more common with conventional therapy than molecular (66 % versus 33%). Lastly, an evaluation of peripheral blood absolute monocytes in all patients who had progressed on therapy identified a decrease in pre-progression absolute monocytes compared to post-progression monocytes after re-initiation of therapy by a mean value of 0.2 K/µL, although results were imprecise (p = 0.3125, 95% CI -0.2373 to 0.6373) (Figure 1A). A decrease in pre-therapy absolute monocytes compared to post-therapy monocytes was observed as well (averages of.0.49 and 0.33 respectively; p = 0.0988, 95% CI -0.0302 to 0.3408) (Figure 1B).
Conclusions
Peripheral monocytes have been discovered to play a role in histiocytic disease, but to our knowledge, we are the first to look at progression and activity in ECD, as ECD is not commonly known to have overt blood or marrow disease. We theorize that an increase in circulating monocytes may exist as a direct response to disease progression as monocytes may differentiate into dendritic cells and upregulate major histocompatibility class II expression, although this mechanism remains poorly understood. This observation may further explain the high frequency of concomitant myeloid malignancies seen in patients with ECD who have also been found tp harbor clonal hematopoietic mutations in peripheral blood monocytes. Based on our findings, we advocate for the use of absolute monocyte count as an early marker for disease activity or progression. Further studies to explore this trend are in progress.
Disclosures
No relevant conflicts of interest to declare.
