A PHASE II PROSPECTIVE TRIAL OF AZACITIDINE IN STEROID-DEPENDENT OR REFRACTORY SYSTEMIC AUTOIMMUNE/INFLAMMATORY DISORDERS AND VEXAS SYNDROME ASSOCIATED WITH MDS AND CMML

A. Mekinian, P. FenauxSorbonne University, Internal Medicine, Paris, France Saint Antoine, Internal Medicine, Paris, France  Background Systemic autoimmune and inflammatory disorders (SAID) are underestimated, and potentially life-threatening complications observed in 15-25% of myelodysplastic neoplasms (MDS) and chronic myelomonocytic leukemia (CMML), although pathophysiological links between both types of disorders remain uncertain. In 2020, Beck et al. described VEXAS (Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome (OMIM #301054, defined by the presence of UBA1 mutations, in patients with severe systemic inflammation, chronic fever, 30% of whom had concurrent MDS. VEXAS is typically associated with refractoriness to conventional immunosuppressive therapies (IST) and dismal prognosis, and prospectively evaluated effective treatment strategies remain to be established. In MDS/CMML patients with concomitant SAID, but no UBA1 mutation, we and others observed a high incidence of mutations of the epigenetic regulators TET2 and IDH1/2, whose presence correlated with defects in adaptive T lymphocyte homeostasis. Objectives This led us to launch a prospective phase II trial of AZA in patients with MDS/CMML and steroid dependent/refractory SAID. Methods This prospective open-label, single-arm multicenter, phase II study trial (ClinicalTrials.gov identifier: NCT02985190) was sponsored by the Groupe Francophone des Myélodysplasies (GFM, French MDS group). Celgene Corporation supplied the study drug but did not contribute to data collection or analysis. Eligible criteria were: (1) age ≥18 years (2) revised IPSS (IPSS-R) intermediate 2 or high, or IPSS-R low or intermediate-1 with significant cytopenia (i.e., transfusion dependent anemia resistant to erythropoietin-stimulating agents and/or platelets below 30 G/L or below 50 G/L with bleeding, and/or ANC < 0.5 G/l with infectious complications), (3) SAID defined according to usual international criteria for each SAID (all cases were centrally reviewed by expert internists AM and VJ) (4) steroid resistance or dependence of SAID, defined as the inability to decrease the dose of steroids below 15 mg/day during at least 2 months. Results Thirty patients were included between July 2017 and June 2020 in 18 centers, 29 of whom received at least one cycle of AZA and were considered evaluable. Twelve of the 29 patients (41%) were retrospectively found positive for UBA1 mutation (VEXAS syndrome), while in the remaining cases SAID included inflammatory arthritis (n=6) (rheumatoid arthritis (n=3), undifferentiated (n=2) and psoriasis arthritis (n=1)), unclassified vasculitis (n=3), neutrophilic dermatosis (n=3), unclassified SAID (n=2), systemic lupus erythematosus (SLE), relapsing scleritis and immune thrombocytopenia in one case each. After 6 cycles, 19 patients (66%) had obtained SAID response (including 8 CR and 11 PR), while 10 SAID remained stable and none had progressed. The daily dose of steroids decreased from a median of 50 mg/day (95% CI [40-71]) at AZA onset to 15 mg/day (95% CI [13-31]) (p<0.0001) and 10 mg/day (95% CI [5-10]) (p<0.0001) of prednisone equivalent after 3 and 6 cycles respectively. Median steroid daily dose was lower in SAID responders compared to non-responders after 3 (15 mg/day [12-25] versus 50 mg/day [46-60], p=0.04) and 6 (8 [4-10] versus 33 [21-35], p=0.05) cycles of AZA. Median steroid daily dose did not decrease after 6 cycles of AZA. Conclusion Thus, in this prospective trial, 66% of MDS/CMML patients with SAID obtained SAID complete or partial response after 6 cycles of AZA. We observed an important and sustained steroid-sparing effect of AZA, with reduction to a median dose below 10 mg/day of prednisone equivalent after 6 cycles. AZA also yielded hematological response in 59% of the patients, and 88% of hematological responders had concomitant SAID response. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests None Declared. Keywords: Vasculitis, Treat to target, Randomized control trial DOI: 10.1136/annrheumdis-2023-eular.127Citation: , volume 82, supplement 1, year 2023, page 165Session: New evidence on IgG4-related and rare autoinflammatory diseases (Oral Presentations)