Real-World Data Show Suboptimal Efficacy With AZA in Treatment-Naïve High-Risk MDS

Real-world data is bolstering previous findings suggesting a need for more effective treatment options for previously untreated patients with higher-risk myelodysplastic syndromes (HR-MDS).

Pulling data from a US electronic health record–based database, researchers found low rates of complete remission (CR) and poor overall survival (OS) among 382 patients receiving first-line azacytidine (AZA), a hypomethylating agent (HMA). They published their findings in Clinical Lymphoma, Myeloma & Leukemia.

Approved 2 decades ago, AZA is considered standard of care for frontline treatment of high-risk MDS, a disease characterized by poor OS and an increased risk of progression to acute myeloid leukemia. Currently, several novel treatments, including an anti-CD47 monoclonal antibody and an anti–TIM-3 monoclonal antibody, are being assessed in combination with AZA.

Among the patients included in the retrospective study, the CR rate—the study’s primary end point—was 7.9% (n = 30), and median duration of CR—a secondary end point—was 12 (95% CI, 7.7-15.6) months.

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Patients were treated a median 1 month following their diagnosis, and median follow-up was 12.9 months. Across patients, median OS—another secondary end point—was 17.9 (95% CI, 15.5-21.7) months. At 1 year, 67.3% (95% CI, 62%-72%) of patients were still alive, but this dropped to 40.9% (95% CI, 35.1%-46.6%) at 2 years and 30.6% (95% CI, 24.6%-36.7%) at 3 years.

“Regardless of confirmation of responses with IWG [International Working Group] 2006 criteria, real-world outcomes in patients treated with AZA monotherapy were poorer in this study than those achieved in the initial phase 3 clinical trials, underscoring the limited clinical benefit of HMA therapy in routine clinical practice. The CR rate was 17% and median OS was 24.5 months in the landmark randomized phase 3 clinical trial,” wrote the researchers. “In addition, other real-world studies in HR-MDS have reported variations in clinical outcomes in routine practice, thought to be due to differences in receipt and continuation of HMA therapy. Baseline patient and disease characteristics are often dissimilar between clinical trial and real-world populations, and this may play a role in the discrepant outcomes for AZA observed in these 2 settings.”

Compared with the landmark phase 3 AZA trial, the real-world study included more patients 65 years and older (86.1% vs 68.2%) and more patients with Eastern Cooperative Oncology Group performance status scores of 2 or higher (15.9% vs 7%).

All patients included in the real-world study were 18 years and older, treatment naïve, and had received at least 1 dose of AZA in accordance with its approved indication. Additional inclusion criteria to better enable a comparable patient population to that from the clinical trials included adequate liver and renal function.

The researchers noted that the stringent selection criteria may have limited generalizability of their findings, and they highlighted the inherent limitation stemming from the retrospective nature of their study.

Throughout follow-up, 95.3% (n = 364) of patients discontinued treatment, most commonly due to disease progression (35.3%). Other reasons for discontinuation included adverse events (14.4%) and death (10.7%). Among all patients, 62.8% responded to treatment.

Study data also included response rates for 2 subgroups of patients, those with poor cytogenetic risk and those withTP53 mutation, finding similar efficacy as the full patient population. Although a surprising finding, the researchers explained the comparable efficacy results were likely due to small sample sizes in the subgroups. Among the 101 patients with poor cytogenetic risk, overall response rate (ORR) was 60.4%, with 7.9% of patients achieving CR. Among the 46 patients with a TP53 mutation, ORR was 63%, with 8.7% achieving CR.

Reference

RajakumaraswamyN, Gandhi M, Wei AH, et al. Real-world effectiveness of azacytidine in treatment-naïve patients with higher risk myelodysplastic syndromes. Clin Lymphoma Myeloma Leuk. Published online December 19, 2023. doi:10.1016/j.clml.2023.12.008