Azacitidine (AZA) and venetoclax (VEN) combination for the treatment of immune mediate inflammatory diseases (IMID) associated with myeloid neoplasms (MN)

Abstract

Abstract Background: IMID occurring in patients with MN, particularly studied in France by our MINHEMON group, are associated with substantial morbidity and represent a significant therapeutic challenge, due to a high frequency of steroid dependence and frequent refractoriness to conventional immunosuppressive therapies. We previously showed that AZA can induce parallel hematologic and inflammatory responses in VEXAS and other IMIDs associated with MDS and CMML (Mekinian et al., Leukemia 2022). In VEXAS, a recent study showed up to 60% inflammatory response rate with AZA (Jachiet et al., Blood 2025). With VEN-AZA combination now established as a standard treatment in elderly AML and gaining use in other MN settings, we aimed to evaluate its efficacy on IMID, in patients with coexisting IMID and MN. Methods: Nationwide multicenter retrospective study between 2020 and 2025 within MINHEMON network, including patients with MDS, CMML, or AML who received VEN-AZA and had active IMID within 3 months before treatment initiation, defined by clinical inflammatory flare (new or worsening symptoms with organ involvement) and CRP >10 mg/L. As in our previous experience, inflammatory complete response (CR) was defined as full clinical resolution, CRP <10 mg/L, and steroid dose <10 mg/day or discontinued. Partial response (PR) as full clinical resolution and >50% reduction in CRP, still > 10 mg/l and steroid dose >50% reduction, still >10mg/d. Hematologic responses were assessed according to ELN 2022 and IWG 2023 criteria. Results: 11 patients were included (8 males/3 females; median age 70 [range 64–81]). WHO 2022, diagnoses were: de novo AML (n=4), AML post MDS-IB1 (n=1), TP53-mutated higher risk MDS (n=2), CMML 1 (n=2), CMML 2 (n=1), and MDS-IB2 (n=1). Cytogenetic abnormalities were found in 10 (91%) patients, most frequently trisomy 8 (n=3), del(5q) (n=3), -7/del(7p) (n=3), and complex karyotype (n=2). Most frequent mutations were ASXL1 (n=4), IDH2 (n=4), TP53 (n=2), U2AF1 (n=2), RUNX1 (n=2), and SRSF2 (n=2). No patient had UBA1 mutation. IMID included fever (9/11), inflammatory arthritis (5/11), skin lesions (5/11), interstitial pneumonia (2/11), documented gastrointestinal ulcerations (2/11), muscle involvement (2/11), systemic granulomatosis (1/11), aortitis (1/11). 5 (45%) had involvement of ≥ 2 organ systems. Median interval between IMID and MN diagnoses was 2 months (IQR 1–9). VEN-AZA, rather in particular than AZA alone, was initiated for hematologic indications in all patients. At VEN-AZA initiation, 8 (76%) patients were receiving steroids (median dose 40 mg/day [range 7.5–70]), and the median CRP level was 93 mg/L [range 30–190]. VEN-AZA was used as first-line therapy in 10 (91%) patients (1 patient previously exposed to AZA alone). 2 patients received prior treatment with tocilizumab but were switched to VEN-AZA because of their hematologic disease The inflammatory ORR was 82% (9/11:6 CR, 3 PR), with a median time to response of 3 months [range 1-6 months]. Steroids were successfully discontinued in all responders, when they had steroid therapy. The hematologic ORR was 82% (9/11: 6 CR, 1 MLFS, 2 PR). A concordant CR was observed in 5 patients, 2 patients with no inflammatory response were also hematological non-responders. With a median follow-up of 10 months [range 1-47]. 3 (27%) patients died from hematologic disease progression. 5 (45%) were still on treatment, with response durations of 1, 5, 20, 23 and 42 months. 8 (76%) had grade 3-4 neutropenia, and 6 had severe non-fatal infections, leading to dose reduction. 1 patient received allo SCT after 6 cycles of AZA-VEN and was in PR of both diseases after 6 months Conclusion: In this preliminary study in patients with severe MN and concurrent active IMID, VEN-AZA achieved inflammatory and hematological response with clinical efficacy on both disorders. Inflammatory responses were possibly somewhat higher than with AZA monotherapy, but with a higher incidence of early neutropenia, and patient numbers are too small for any conclusion. Future studies are needed to determine if, in some situations, VEN-AZA could be superior to AZA alone on severe IMID associated with MN.