P744: a real-world study of multiple-cycle hypomethylating agents monotherapy in myelodysplastic syndromes

Background: Hypomethylating agents(HMAs) were the most common initial treatment in patients with higher-risk MDS who were ineligible for transplantation. However, the survival benefit of patients treated with HMAs monotherapy observed in real-world studies was limited, which was shorter than the survival in the registration studies. Either azacitidine or decitabine needed some time to take effect, we therefore retrospectively enrolled patients treated with HMAs monotherapy for at least 4 consecutive cycles. Aims: To explore the therapeutic effect and prognostic factors of Hypomethylating agents(HMAs) in the treatment of patients with myelodysplastic syndromes (MDS) in the real world. Methods: 409 patients with newly diagnosed MDS who received HMAs monotherapy for at least 4 consecutive cycles from March 2010 to June 2021 from 45 hospitals in China were retrospectively analyzed. And a subset of 171 patients were sequenced by next generation sequencing (NGS) before first-line HMAs therapy. Results: 409 patients were enrolled. After a median follow up of 22 months, the median number of cycles was 6 (range,4-25). For the total cohort(N=409),the CR rate was 33.98%, and the ORR was 77.02%.The median OS was 25.97 months. 187 (187/409,45.70%) patients developed disease progression. Among them, 253 patients received decitabine monotherapy. The CR rate was 37.15%,and the ORR was 79.45%.The median OS was 29.77 months. 156 patients received azacitidine monotherapy. The CR rate was 28.85%, and the ORR was 73.08%.The median OS time was 20.17 months. Compared with the azacitidine group, patients in the decitabine group had longer survival(P=0.005). Multivariate analysis showed that complex karyotypes (P=0.012) and the cycles (P<0.001) were independent factors for the increased CR rate; the cycles (P<0.001) were also predictive of the higher ORR. Age (≥ vs ＜65y, HR=1.89, P=0.001), hemoglobin ((<80 vs ≥80 g/L, HR=1.52, P=0.03), complex karyotypes (HR=2.26; P=0.002), and drug (azacitidine vs decitabine, HR=1.68, P=0.004) retained independent adverse significance in the OS multivariable cox model. However, only the cycles (HR=0.86, P<0.001) was protective factor. Patients who responded to HMAs also had improved OS(P=0.0248). Survival was not obviously related to the regimens of HMAs (decitabine P=0.7872; azacitidine P=0.3734,respectively), but to the cycles (P<0.001). The optimal cut-off for the cycles was 10. Patients treated with HMAs for 10 or more cycles had significantly longer OS than that less than 10 cycles (P<0.0001). The most frequently mutated genes included TP53 (25.00%), ASXL1 (24.00%), TET2 (22.00%), SRSF2 (13.00%), RUNX1 (11.00%), and SF3B1(11.00%). Patients with TP53 mutations had higher CR rate to HMAs (53.7%), but significantly worse OS (P=0.0131). Among hematological adverse reactions, the proportion of grade 3/4 adverse reactions was slightly higher in decitabine group than in azacitidine group, and leukopenia was statistically significant(P=0.012). Grade 3/4 pneumonia occurred in 52 patients(20.6%) in decitabine group, and 10 (6.4%) in azacitidine group (p<0.001). Myelosuppression is more pronounced with decitabine than with azacitidine. Summary/Conclusion Continuous and regular use of HMAs in the treatment of MDS patients is beneficial to improve the effectiveness and prognosis. Decitabine is superior to azacitidine in terms of efficacy and prognosis.Keywords: Hypomethylating agents, Myelodysplastic syndrome