Introduction The topline results from the randomized phase 3 VERONA trial evaluating venetoclax in combination with azacitidine for the treatment of newly diagnosed higher-risk myelodysplastic syndromes (HR-MDS) did not meet the primary endpoint of overall survival (OS) with a reported hazard ratio (HR) of 0.908; log-rank, p=0.3772. As future pivotal HR-MDS trials will likely require molecular biomarker strategies for success, we examined our real-world data exploring role of venetoclax in HR-MDS identifying subsets of patients (pts) who could potentially benefit from the combination therapy.

Methods Following VERONA study eligibility criteria, we identified pts who were treated with hypomethylating agents monotherapy (HMAm) or HMA+Venetoclax (HMAv) as 1st therapy for HR-MDS (defined by IPSS-R) at our institution. Comparative analyses were performed regarding response rates, transformation to acute myeloid leukemia (AML), leukemia free survival (LFS) and Overall Survival (OS).

Results We identified 1259 HR-MDS pts, 94 of whom received HMAv and 1165 HMAm. The baseline characteristics were similar between the 2 groups except more pts with MDS-IB2 being in the combination arm (46% vs 27%; p=0.026). A higher % of pts in the combination arm proceeded to allogeneic hematopoietic stem cell transplant (AHSCT; n=35; 37.2%) as compared to HMAm (n=241; 20.7%; p<0.005. Molecular subsets were balanced except for more IDH-1 (7.6% vs 2.7%, p=0.004), IDH-2 (8.7% vs 5%, p=0.03) being more frequent in the HMAv arm and ZRSR2 more in HMAm arm (4% vs 1%, p= 0.038).TP53 was observed in 36% and 40%, respectively in the HMAv and HMAm (p =0.15).

Response rates based on IWG 2006 criteria were: CR 19.1% vs 14.5%, mCR 46.8% vs 13.8%, PR 2.1% vs 1.2%, and HI 1.1% vs 13.7% respectively for HMAv and HMAm. The ORR (HI+) was 69.1% compared to 43.2% (p < 0.001). Among 554 pts with known IWG 2022 response, CR was 29.6% vs 19.5% and composite CR (CR + CR-L + CRh) was 58% vs 38.3%, respectively for HMAv and HMAm, p=0.001.

The rate of AML transformation was 30.9% for HMAv and 42.1% for HMAm (p=0.032). The LFS was not reached for the HMAv compared to 21.6 mo with HMAm (95%CI 17.9-25.3) (p=0.086)

The median OS from start of therapy was 17.2 mo (95%CI 9.1-25.4) for HMAv compared to 15.5 mo (95%CI 14.8-16.3) for HMAm (HR 0.79 (95%CI 0.6-1.04; p=0.098). The 5-year OS was 22.9% vs 10.8% (p=0.008). Using propensity matching score accounting for age, IPSS-M, blast%, AHSCT, and TP53; the median OS was similar (17.2 mo vs 16.5 mo, HR 0.98 (95% CI 0.72-1.34); p=0.9).

Among pts with ASXL-1 mutation, there was a median OS advantage observed for pts receiving combination therapy (n=19), 44.9 mo compared to 18.7 for HMAm (n=126), p=0.039. HR 0.43 (95% CI 0.19-0.98) (p=0.045)

There was a trend for improved OS among pts who proceeded to AHSCT. Among 276 pts who proceeded to AHSCT, 35 pts were treated with HMAv. The baseline characteristics were comparable between HMAv and HMAm treated pts prior AHSCT with the exception of more complex cytogenetics in HMAm arm (38% vs 14%, p 0.006) but no difference in prevalence of TP53. The median OS was not reached for the HMAv group as compared to 32.6 mo (95%CI 22-43.3) for HMAm, (HR 0.61; 95%CI 0.32-1.16; p=0.13). The 3-year OS rate was 66.4% for HMAv compared to 48.9% for HMAm prior to AHSCT; p=0.13). There was no survival advantage among non-transplanted pts with HMAv. Among 983 pts, 59 pts were treated with HMAv. The baseline characteristics were similar between HMAv and HMAm alone for non-transplanted pts except for more pts with MDS-IB2 among HMAv group. The median OS was 11.3 mo (95%CI 8.2-14.4) for HMAv compared to 14.18 (95% CI 13.39-14.94) for HMAm. HR 1.15 (95% CI 0.84-1.56; p=0.38).

Among pts with wild-type TP53, there was a trend for better OS with HMAv compared to HMAm with median OS 27.6 mo (95% CI 17.8-37.4) compared to 19.4 (95%CI 17.5-21.3) (p=0.083), this was mainly driven by higher AHSCT rate among HMAv 46% compared to 21% for HMAm.

There was no survival advantage for HMAv among pts defined as MDS/AML by ICC 2022 criteria (blasts 10-19%).

Conclusion There was no survival advantage in our cohort for using combination HMAv in all-comer HR-MDS pts consistent with the topline results from VERONA study. However, our data indicate potential benefit among pts proceeding to AHSCT and in those with ASXL-1 mutations. It will be crucial to analyze those subsets in the VERONA trial to help guide any potential future clinical trial design.

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2025
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