Background/Purpose: Clonal hematopoiesis has emerged as a key contributor to systemic inflammation, bridging hematologic and immune-mediated inflammatory disorders (IMIDs). Isocitrate dehydrogenase 1 and 2 (IDH1/2) somatic mutations, typically found in myeloid neoplasms (MN), may be overrepresented in patients with both MN and IMIDs. This study aimed to characterize the clinical, immunological, and molecular features of IDH-mutated MN associated with IMIDs, and to assess outcomes and treatment responses, particularly to IDH inhibitors.

Methods: We conducted a multicenter retrospective cohort study of 50 patients with IDH-mutated MN and IMIDs (IDHmut group), compared to 61 patients with MN and IMIDs without IDH mutations (IDHwt group). Clinical and biological characteristics, survival outcomes, therapeutic responses, cytokine profiles, and circulating immune cell populations were assessed.

Results: Fifty patients (25 (50%) male, median age 73 (54-85) years) with IDH-mutated MN and IMID (MN-IMID-IDHmut group) were included. Twenty-seven (54%), 22 (44%) and 1 (2%) patients respectively displayed IDH1, IDH2, both mutations. Thirty-six (72%) had MDS and 14 (28%) patients had CMML. The most common inflammatory manifestations were musculoskeletal in 39 (78%) patients, cutaneous in 22 (44%) and vascular in 12 (24%). Musculoskeletal involvement was inflammatory arthralgia without synovitis in 20 (51%) patients and arthritis in 19 (49%). These symptoms were predominantly symmetrical (92%) and polyarticular (56%), with common involvement of both proximal and distal joints such as the shoulders (55%), hands (53%), and wrists (34%). Erosive lesions were infrequent (10%). The most frequent underlying IMIDs diagnosis were seronegative arthritis in 17 (34%) patients, polymyalgia rheumatica in 13 (26%) and giant cell arteritis in 8 (16%).Compared to the IDHwt group, patients in the IDHmut group were more frequently female (50% vs 25%, p = 0.006) and older (73 (54-85) vs 69 (20-86) years, p=0.038). Musculoskeletal manifestations were significantly more common in the IDH-mutated group (78% vs 54%, p=0.009), whereas cutaneous, digestive, and renal manifestations were significantly less frequent. Polymyalgia rheumatica was significantly more common in the IDHmut group (26% vs 8%, p=0.011). A specific cytokine signature with significant higher expression of several chemokines implicated in monocyte and dendritic cells recruitment to inflamed tissues was identified.Inflammatory efficacy of biologics targeting inflammation and azacitidine were limited with an overall response rate below 25% at 3 months and below 10% at 12 months. Seven patients with active inflammatory disease received IDH inhibitors. The iORR was 86% at 3 months, 83% at 6 months and 66% at 12 months. All of the 7 patients displayed a hematological response.

Conclusion: This study suggests that IDH mutations may contribute to a distinct disease phenotype, marked by a predominance of inflammatory rheumatologic manifestations, particularly polymyalgia rheumatica. These findings highlight new therapeutic opportunities, including the use of targeted anti-IDH therapies.

Figure 1: Rheumatologic involvement in IDH-mutated myeloid neoplasms

Figure 2: Efficacy of anti-IDH inhibitors on IMID patients with IDH-mutated myeloid neoplasm

Legend: (A) Hematological parameters (hemoglobin, platelets, neutrophils, and bone marrow blasts) during follow-up (M0, M1, M3, M6 and M12). Each dot represents an individual patient; (B) Proportion of patients with active versus inactive IMID at anti-IDH onset (left), evolution of inflammatory response rates over time (middle), and longitudinal changes in steroid dosage (mg/day) and C-reactive protein (mg/L) in 7 patients with active IMID (right); (C) Cytokine profile pre- and post-ivosidenib (anti-IDH1) in one patient showing log2 fold changes in circulating cytokines and chemokines, with upregulated (red) and down-regulated (blue) markers; (D) D-2-HG and CRP levels evolution under anti-IDH1 inhibitor in one patient.

CRP: C-reactive protein; IMID: immune-mediated inflammatory disorder; VAF: variant allele frequency

Table: Characteristics of IMID patients with IDH-mutated versus IDH-wild type myeloid neoplasms

Continuous variables are presented as medians (range), while categorical variables are presented as counts (percentage).

Abbreviations: IMID: immune-mediated inflammatory disorders; MN: myeloid neoplasm; SD: standard deviation;

Footnote: * complex karyotype (i.e. >= 3 anomalies) ; ** other (n=4) including del20q (n=2), del5p (n=1),+19+21 (n=1) ; *** other (n=10) including del20q (n=3), -Y (n=2), del5q (n=1), -7 (n=1), del7q (n=1), del4q (n=1); **** inflammatory backpain; ***** other (n=7) including inflammatory back pain (n=2); myalgia (n=5)

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inflammatory-rheumatic-diseases-in-idh-mutated-myeloid-neoplasms-clinical-spectrum-and-response-to-idh-inhibitors/