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Long Term Survival Results and Prognostic Factors Results of Higher Risk MDS and CMML treated with guadecitabine
Background: Guadecitabine SC (SGI-110) is a dinucleotide next generation hypomethylating agent (HMA) resistant to degradation by cytidine deaminase resulting in extended in vivo exposure to its active metabolite decitabine.
Methods: Int, or HR MDS, and CMML patients who were either treatment-naïve (TN) or relapsed/refractory (r/r) to other HMAs were randomized to either 60 mg/m2 or 90 mg/m2 QDx5 every 28 days.
Results: We randomized 102 patients with a median follow up of 3.2 years: 53 to 60 mg/m2 and 49 patients to 90 mg/m2 QDx5. Of those, 53 patients were TN and 49 patients were r/r MDS/CMML. Median age was 71 and 72 years for TN MDS and r/r respectively. Most baseline patient characteristics were well balanced between the 2 treatment dose groups except that more CMML patients were randomized to the 60 mg/m2 group (28%) vs. 14% in the 90 mg/m2 group, and more patients with baseline BM blasts >5% were in the 90 mg/m2 group (67%) vs. 38% in the 60 mg/m2 group. Most patients were RBC transfusion-dependent at baseline (57%). In the r/r MDS cohort, most patients (77%) received ≥6 months of prior HMA treatment.
In the TN MDS cohort the median Overall Survival (OS) was 23.4 months (25.7 months for 60 mg/m2 dose group and 18.6 months for 90 mg/m2 dose group). In the r/r MDS cohort, the median OS was 11.7 months. No statistically significant difference in response or OS was observed between the 2 dose groups. In the overall population of 102 TN and r/r MDS patients there were no major differences in OS based on DNMT3A or TET2 mutation status while patients with TP53 mutations had worse median OS (7.4 months) compared to those without TP53 mutations (22.6 months). Other baseline prognostic factors associated with worse OS were BM blasts >5%; RBC transfusion-dependence; IPSS High Risk; and ECOG Performance Status of 2 or higher.
Conclusions: The median OS of 23.4 months (25.7 months for the 60 mg/m2 dose group) in TN MDS, and 11.7 months in r/r MDS signals a promising clinical activity of guadecitabine in the treatment of higher risk MDS/CMML. A phase 3 trial (ASTRAL-3) of guadecitabine vs Physician Treatment Choice in r/r MDS and CMML patients previously treated with other HMAs is actively enrolling (ClinicalTrials.gov ID: NCT02907359).