Introduction: Hypomethylating agents (HMAs) remain the only approved standard-of-care therapy shown to improve overall survival (OS) in higher-risk myelodysplastic syndromes (HR-MDS). OS is the gold standard endpoint in phase III clinical trials. However, complete response (CR) has been commonly used as a surrogate endpoint in phase I and II trials to support advancement to phase III. Recent data show high CR rates in early-phase trials do not consistently improve OS. For instance, patients (pts) with TP53-mutated HR-MDS may achieve CR with HMAs, but responses are short-lived with limited survival benefit. These findings suggest response durability, rather than CR alone, may better reflect clinical benefit. We aimed to evaluate whether a durable CR could serve as a more reliable surrogate endpoint for drug development in HR-MDS.

Methods: We retrospectively analyzed adults (≥18 years) with HR-MDS (Intermediate or higher IPSS-R risk) treated with first-line HMA-based therapy at Moffitt Cancer Center (MCC). Pts undergoing allogeneic transplant were excluded. Responses were assessed using IWG 2006 and 2022 criteria. Durable CR was defined as CR >6 months. OS was assessed using Cox regression. To account for guarantee-time bias, we used both time-independent Cox models and a 6-month landmark analysis. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to assess associations between CR status, duration, and OS.

Results: We identified 980 pts. Median age was 72; 91% were White. MDS-IB2 was the most common WHO 2022 subtype (28%), and 30% had therapy-related MDS. At HMA start, 54% were RBC or platelet transfusion dependent. Median OS for the cohort was 14.0 months (95% CI, 13.2–14.7).

By IWG 2006, best responses were CR in 114 (12%), marrow CR in 149 (15%), PR in 11 (1%), HI in 138 (14%), SD in 364 (37%), and PD in 184 (19%). Median OS was 20.0 months (95% CI, 18.4–21.9) in CR pts, vs. 13.0 months (95% CI, 12.3–13.9) for others (p<0.001).

Using IWG 2022 (357 evaluable pts): CR/CR-equivalent in 67 (19%), CR uni in 24 (7%), CR bi in 36 (10%), CRh in 8 (3%), PR in 4 (1%), HI in 30 (9%), NR in 130 (37%), PD in 51 (14%). Median OS was 24.2 months (95% CI, 18.5–29.8) for CR/CR-equivalent, vs. 13.7 months (95% CI, 12.9–14.4) for others (p<0.001).

Although achieving a CR was associated with a 42% reduction in the hazard of death (HR 0.58; 95% CI 0.47–0.72; p < 0.0001), this was dependent on the duration of CR. Durable CR showed a 44% reduction in death hazard compared to all other pts (HR 0.56; 95% CI 0.45–0.70; p < 0.0001). In contrast, short-duration CR (≤ 6 months) did not reduce mortality risk (HR 0.79; 95% CI 0.46–1.36; p = 0.39). Landmark analysis restricted to 775 pts alive at 6 months confirmed that durable CR was associated with a 34% reduction in death hazard from the landmark time forward (HR 0.66; 95% CI 0.53–0.82; p < 0.001), while short CR conferred no significant survival benefit (HR 0.92; 95% CI 0.52–1.63; p = 0.77).

Among pts treated at MCC, clinical trial participants had higher overall response rates compared to those receiving HMA alone or HMA plus venetoclax; however, rates of durable CR were similar across groups. We also assessed response and its durability across 3 cohorts treated with HMA based therapy. Pts receiving HMA monotherapy (n=921) had a CR rate of 11.6% (107/921), with 10% achieving a durable CR (93/921), representing 87% (93/107) of CRs as durable. The HMA plus venetoclax cohort (n=59) had a CR rate of 11.9% (7/59) with 8.5% (5/59) durable CR, equating to 71% (5/7) of CRs durable. Clinical trial pts (n=41) receiving HMA plus novel agents (magrolimab, eprenetapopt, or tamibarotene) had a higher CR rate of 29.3% (12/41) with 24.4% (10/41) durable CR, translating into 83% (10/12) of CRs being durable.

In subgroup analysis of pts with TP53-mutated MDS treated with HMA alone (n=242), achieving a durable CR was associated with a 38% reduction in risk of death (HR 0.62; 95% CI 0.39–0.97; p=0.037). Pts with TP53-mutated MDS treated with HMA plus eprenetapopt on trial (n=16), attaining a durable CR was associated with an even greater survival benefit, demonstrating a 73% reduction in hazard of death (HR 0.27; 95% CI 0.07–0.99; p=0.048).

Conclusion: Only durable CR translates into a survival benefit in HR-MDS. CR >6 months is a practical, clinically meaningful surrogate endpoint and may improve assessment of treatment efficacy and accelerate drug development in HR-MDS.

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2025
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