Real world treatment outcome with azacytidine (AZA)-tocilizumab (TCZ) for reducing steroid dependence in vexas syndrome with myelodysplastic syndrome (MDS): A single-center, 1.5-year longitudinal observational study

Abstract

Abstract Background: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a rare, adult-onset autoinflammatory disorder caused by somatic UBA1 mutations, first described in 2020, primarily affects biological males and presents with multisystemic inflammation and hematological abnormalities. The disease is notably steroid-dependent, with frequent relapses occurring upon tapering of glucocorticoids, making long-term discontinuation challenging. Given its recent discovery, treatment guidelines remain undefined. This study evaluates the real-world outcomes and safety of combined AZA and TCZ in a patient with VEXAS syndrome and concurrent MDS, aiming to reduce steroid dependence. Case description: An 89 year old Caucasian male with a history of relapsing pulmonary infiltrates and recurrent inflammatory episodes (including dacryocystitis and pan-uveitis) presented with fatigue, weight loss, pleuritic chest pain, and symptomatic anemia. Labs showed macrocytic anemia (Hb 9g/dl, MCV 102.3 fL), leucopenia (2800/μL), eosinophilia (13.7%) and elevated inflammatory markers (CRP 82.2 mg/L, ESR 113 mm/hr, ferritin 733 ng/mL). ANA was positive (1:160, speckled pattern) with elevated dsDNA (48 IU/mL). Bone marrow biopsy showed hypercellular marrow with 5–7% blasts, multilineage dysplasia, and vacuolization of erythroid and myeloid precursors. Cytogenetic and FISH were normal. Findings were consistent with MDS-EB1 (IPSS-R 4, intermediate risk). Given the combination of systemic autoinflammatory findings and vacuolated precursors in marrow, next-generation sequencing for VEXAS syndrome was pursued and confirmed the presence of a somatic UBA1 mutation (p.Met41Val) with a variant allele frequency (VAF) of 70%. Treatment and outcome: The patient was initiated on high-dose prednisone (PRD) at 40 mg daily and Erythropoiesis-Stimulating Agent, leading to clinical improvement. Attempts to taper PRD resulted in multiple outbreaks of inflammatory flares (pan-uveitis, elevated CRP/ESR/Ferritin), confirming steroid-dependent VEXAS phenotype. Due to coexisting MDS, AZA was initiated (6 cycles, Day 1-4 every 28 days) with good tolerability aside from grade 2 anemia and neutropenia. Acyclovir, atovaquone and voriconazole were used for anti-microbial prophylaxis. Day +90 evaluation revealed inflammatory markers reduction (CRP 0.8 mg/L, ESR 7 mm/hr, ferritin 654 ng/mL), PRD reduced to 10 mg, consistent with complete remission CR (clinical remission, CRP ≤10mg/L, glucocorticoid ≤10mg/day). Day +180, inflammatory markers rose (CRP 204.6 mg/L, ESR 82 mm/hr, ferritin 914 ng/ml), prompting PRD escalation to 30 mg and continuation of AZA. By Day +280, inflammatory markers again declined (CRP 2.9 mg/L, ESR 12 mm/hr, ferritin 300ng/mL), bone marrow biopsy showed normocellularity, no blast, maturing cell lines, and UBA1 VAF decreased to 24%, PRD reduced to 15mg/day, indicating partial remission (clinical remission with ≥50% reductions in both CRP and glucocorticoid from baseline). The patient experienced multiple steroid-related complications including diffuse osteopenia with vertebral and sternal stress fractures, central retinal vein obstruction and rupture, renal impairment, pedal edema and weight gain. A request for compassionate use of a JAK inhibitor was denied, but monthly TCZ was initiated off-label to decrease the steroid burden. This led to sustained symptom control, reduced systemic inflammation (CRP <0.2 mg/L, ESR 1 mm/hr, ferritin 238 ng/mL), and successful tapering of PRD to 5 mg/day, with the patient remaining in CR and flare-free for over six months till date. Discussion: This case demonstrates that combined AZA-TCZ therapy may be effective in managing steroid-refractory VEXAS syndrome with concurrent MDS. While AZA alone has shown better outcomes than TCZ in prior studies, our study demonstrates that the addition of TCZ in the setting of persistent inflammation improves clinical response. Also, the sustained improvements in inflammatory markers, UBA1 VAF, and marrow function suggest a potential disease-modifying benefit beyond symptom control. Conclusion: As VEXAS syndrome is a novel disease, there is absence of standardized treatment guidelines. This case highlights the promise of AZA-TCZ combination therapy in steroid dependent VEXAS syndrome with MDS. Further investigation into targeted steroid-sparing regimens along with patient specific guidelines is warranted for durable disease control and improved outcomes.