-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

3181 Subclassification of Erdheim-Chester Disease: Distinct Clinical and Molecular Findings between Classical and Non-Classical Forms

Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Diseases, Myeloid Malignancies
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Dongni Yi, MD1*, Ronald S Go, M.D.2, Gordon J Ruan, M.D.2, N. Nora Bennani, MD2, Mithun V Shah, M.D., Ph.D.2, Karen L Rech, M.D.3*, Aishwarya Ravindran, M.B.B.S.4*, Jay H Ryu, M.D.5*, Robert Vassallo, M.D.5*, Matthew J Koster, M.D.6*, Caroline J Davidge-Pitts, M.B., B.Ch.7*, Lucinda M Gruber, M.D.7*, William Oliver Tobin, M.B., B.Ch., B.A.O., Ph.D.8*, Julio C Sartori Valinotti, M.D.9*, Talal Hilal, MD10, Liuyan Jiang, M.D.11, Muhamad Alhaj Moustafa, M.D., M.S.12, Asra Z. Ahmed, M.D.13, Gaurav Goyal, MD14 and Jithma P Abeykoon, MD2

1Department of Internal Medicine, Mayo Clinic, Rochester, MN
2Division of Hematology, Mayo Clinic, Rochester, MN
3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
4Department of Laboratory Medicine, University of Alabama at Birmingham, Birmingham, AL
5Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN
6Division of Rheumatology, Mayo Clinic, Rochester, MN
7Division of Endocrinology, Mayo Clinic, Rochester, MN
8Department of Neurology, Mayo Clinic, Rochester, MN
9Department of Dermatology, Mayo Clinic, Rochester, MN
10Division of Hematology, Mayo Clinic, Phoenix, AZ
11Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL
12Division of Hematology, Mayo Clinic, Jacksonville, FL
13Division of Hematology and Medical Oncology, University of Michigan, Ann Arbor, MI
14Division of Hematology and Medical Oncology, University of Alabama at Birmingham, Birmingham, AL

Background:

Erdheim-Chester disease (ECD) manifests as multi-organ infiltration of clonal histiocytes with mutations primarily in the mitogen-activated protein kinase (MAPK) pathway. The revised classification of histiocytosis (2016) categorizes ECD with typical bilateral, symmetric osteosclerosis of the lower extremity long bones as classical (C) and as non-classical (NC) if otherwise. The clinical and biological significance of this classification is unclear. This study compared the clinical and genotypic findings of the 2 subtypes within a large cohort of ECD patients.

Methods:

We included patients seen at our institution since 1990 meeting the following criteria: A) had an ECD diagnosis based on the revised criteria by Haroche J, et al. (Blood 2020;135:1311-1318); B) completed whole-body imaging studies including long bones of the legs. Classification as C-ECD required symmetric osteosclerosis of the distal femur and/or proximal tibia/fibula.

Results:

A total of 145 patients were enrolled, comprising a male-to-female ratio of 2:1 (66.2% male). C-ECD was diagnosed in 77.2% of cases, and NC-ECD in 22.8%. The median age at diagnosis was similar with 58.5 years (range, 18-82) in C-ECD and 55 years (range, 20-81) in NC-ECD, (p=0.65).

The most frequently affected systems included skeletal (81.4%), renal (60.0%), vascular (45.5%), cardiac (40.0%), central nervous (38.6%), sinus (37.2%), pulmonary (36.6%), and adrenal (32.4%). The numbers of organs involved were significantly higher in C-ECD compared to NC-ECD (median 5 vs 3, p<0.01). Higher rates of skeletal (100% vs. 18.2%, p<0.01), adrenal gland (37.5% vs. 15.2%, p=0.02), and sinus (44.6% vs. 12.1%, p<0.01) involvement were observed in C-ECD. Arginine vasopressin deficiency (AVP-D) was exclusively observed in C-ECD (20.7% vs. 0%, p<0.01). NC-ECD had a higher rate of cardiac involvement (69.7% vs. 31.3%, p<0.01). No significant differences were found in other systems.

The overall median time between onset of the first symptoms/signs to diagnosis was 15 months with no significant difference between C-ECD and NC-ECD (17.5 vs. 12 months, p=0.18). The median time to diagnosis of ECD in patients with AVP-D was 38.5 months, compared to 12 months without AVP-D (p=0.09).

Genetic testing was conducted in 86.2% of patients and B-Raf proto-oncogene (BRAF) alterations were identified in 59.2% of the tested cases. BRAFV600E was more prevalent in C-ECD (61.3% vs. 21.9%, p<0.01), whereas non-V600 mutations were more commonly found in NC-ECD (12.5% vs. 1.1%, p<0.01). There was no significant difference in the frequency of BRAF fusions. NC-ECD patients exhibited a higher rate of MAP2K1 mutations (25.0% vs. 5.4%, p<0.01). Other frequently mutated genes included KRAS (4.0%), NRAS (2.4%), and CSF1R (2.4%), although no significant difference was observed in their frequency between C-ECD and NC-ECD.

Testicular involvement appeared to be more common in patients with MAP2K1 mutations (23.1% vs. 8%, p=0.08). Two patients with pathogenic CSF1R mutations both had central nervous system (CNS) involvement. Among C-ECD patients, BRAFV600E conferred a higher rate of CNS involvement (50.9% vs. 25%, p=0.01). No significant difference was observed in NC-ECD patients (71.4% vs 36%, p=0.09). Among NC-ECD cases, MAP2K1 mutations conferred a reduced risk of cardiac involvement (37.5% vs. 79.2%, p=0.03) and no such difference was observed in patients with C-ECD (40% vs 34.1%, p=0.79). The median numbers of organs involved in patients with BRAF, MAP2K1, and KRAS/NRAS mutations were 5, 3, and 3, respectively, with no significant difference.

Conclusions:

C-ECD affects more organs and more frequently involves bones, adrenal glands, and sinuses. AVP-D was exclusively observed in C-ECD. Conversely, NC-ECD showed a higher prevalence of cardiac involvement. BRAFV600E was more commonly identified in C-ECD, whereas non-V600 mutations and MAP2K1 mutations were more prevalent in NC-ECD. Among C-ECD patients, BRAFV600E was correlated with a greater likelihood of CNS involvement. Conversely, NC-ECD patients with MAP2K1 mutations had a reduced risk of cardiac involvement. This study highlights the distinct clinical and molecular features of C-ECD and NC-ECD, underscoring the importance of subclassifying ECD into classical and non-classical forms. Further studies are needed to explore differences in the clinical outcomes between the 2 forms.

Disclosures: Bennani: Acrotech Biopharma LLC: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Pfizer: Membership on an entity's Board of Directors or advisory committees. Vassallo: Pfizer: Research Funding; BMS: Research Funding; Sun Pharma: Research Funding; Rion: Consultancy; Sanofi: Consultancy. Tobin: National institutes of Health: Research Funding; Mayo Clinic Center: Research Funding. Hilal: BeiGene: Consultancy, Research Funding. Alhaj Moustafa: AbbVie: Consultancy. Ahmed: Agios: Current Employment. Goyal: Opna Bio, Seagen: Membership on an entity's Board of Directors or advisory committees; Recordati: Consultancy.

*signifies non-member of ASH