Lupus-like manifestations in MDS/CMML: Evidence for clonal origin and therapeutic implications

Abstract Background Myelodysplastic neoplasms (MDS) and Chronic myelomonocytic leukemia (CMML) can be associated with immune-mediated inflammatory diseases (IMIDs), often displaying atypical features, including some cases of lupus erythematosus (LE). However, the association between LE and MDS/CMML has not been described in detail. This study aimed to characterize features of LE - either systemic lupus erythematosus (SLE) or cutaneous lupus erythematosus (CLE) - occurring in combination with MDS/CMML. Methods Retrospective multicenter study was conducted in French centers of the MINHEMON group, in cooperation with the French MDS group (GFM). Patients included had both LE and MDS/CMML, with an interval of less than 10 years between diagnoses. A 2:1 case control study was performed with patients having idiopathic SLE. Skin biopsies were centrally reviewed by pathologists specialized in cutaneous manifestations of MDS/CMML. Hematological responses were assessed according to IWG 2018 and IWG 2023 criteria. Results Twenty-four patients with MDS/CMML-associated LE were included: 19 with SLE and 5 with isolated CLE. LE was diagnosed before MDS in 10 patients, concomitantly (less than 3 months apart) in 10 patients, and after MDS diagnosis in 4 patients. Median age at LE diagnosis was 65 years [range 32-85]; 9 (46%) were females. Skin involvement was observed in 17 patients, with predominant chilblain CLE (n= 6): a rare chronic cutaneous lupus characterized by painful erythematous or violaceous lesions typically affecting acral areas such as fingers, toes, nose and ears. Lupus nephritis was rare (n=2). Median lupus activity SLEDAI-2K score at diagnosis was 9 [5-16]. Antinuclear antibodies (ANA) were positive in 20 patients, anti-dsDNA antibodies in 6 patients, and decreased C3 level in 10 patients. Sixteen (66%) patients had MDS including 8 MDS-MLD, 4 MDS-IB1, 2 MDS-SLD, 2 MDS unclassifiable. Eight patients (33%) had CMML, including 5 CMML-0, 2 CMML-1, 1 CMML-2. Only 4 patients had marrow blasts ≥5%. Karyotype was normal in 13 cases and del 20q was observed in 6 cases. The most frequent somatic mutations (in the 19 patients with NGS data) were TET2 (n=8), KRAS (n=7), ASXL1 (n=5), SRSF2 (n=4), CBL (n=3), and NRAS (n=2). Twenty-two patients had lower-risk MDS/CMML (IPSS-R score ≤ 3.5). Median follow-up was 4.5 years [1-31], during which 7 patients died, 2 patients progressed to AML, one to MDS-IB2, and one from CMML-0 to CMML-1. S kin biopsies from 12 patients were reviewed, all displaying typical LE features, 6/12 shared characteristics of both CLE and MDS-associated cutaneous infiltration (MDS cutis). Similar mutations were detected in bone marrow and skin samples in 6/8 patients who had NGS assessment at both sites. Compared with idiopathic SLE, patients with MDS/CMML-associated SLE were significantly older (p<0.001) more frequently males (p<0.01), and had less renal (p<0.001) and articular (p<0.001) involvement. They also had lower ANA titers (p<0.001) and reduced anti-dsDNA positivity (p=0.001). For lupus manifestations, 15 patients received hydroxychloroquine (HCQ) alone and 4 achieved compplete remission (CR); 12 patients received HCQ in combination with oral corticosteroids and 6 achieved CR. Seven patients with active LE received specific treatment for MDS/CMML: 1 with MDS-IB2 received allo-SCT, achieving hematology and LE CR.; 1 with AML received azacytidine (AZA) and venetoclax, achieving hematological and LE CR. One patient with MDS-IB1, two with CMML-1, one with CMML-2 and one with MDS-MLD received AZA alone: 2 achieved LE CR and hematological partial response (PR), 1 had clinical LE improvement with stable hematological disease, and 2 had hematological progression without LE improvement. One patient (moderate MDS-MLD) received AZA exclusively for refractory CLE, achieving LE CR. Conclusion : MDS/CMML-associated LE represents a distinct inflammatory syndrome. Rather than true autoimmune LE, these patients probably have a clonal inflammatory phenotype mimicking LE, driven by dysregulated myeloid clones infiltrating target tissues such as the skin. Improvement of systemic manifestations following hematologic treatment suggests that clinical features may be clone-dependent. In patients with atypical or treatment-resistant lupus, especially in older adults, men, or those with chilblain CLE, cytopenia, a myeloid neoplasm should be systematically considered, and clone-directed hematologic therapy may be considered.