Epigenetic Priming with Decitabine Followed By Low-Dose Idarubicin Plus Cytarabine in AML Evolving from MDS or Higher Risk MDS: A Multicentre Phase 2 Single-Arm Trial

Background: DNA methyltransferase inhibitors sensitize leukemia cells to chemotherapeutics. Previous studies have indicated decitabine sequentially combined with idarubicin was an effective treatment for myeloid neoplasms. We therefore conducted a phase 2 study of combination of decitabine followed by low-dose idarubicin plus cytarabine in acute myeloid leukemia (AML) evolving from myelodysplastic syndrome (MDS) and higher risk MDS. Methods: The study was a single-arm, prospective, multicenter study. Patients with AML evolving from MDS and refractory anemia with excess blasts (RAEB-2) high-risk MDS based on the 2008 WHO classification were included. The treatment plan consisted of decitabine 20 mg/m2 daily for 3 consecutive days on days 1-3, followed by idarubicin 6mg/m2 for 3 consecutive days on days 4-6, and cytarabine 25mg/m2 every 12 hours for 5 days on days 4-8. Granulocyte colony stimulating factor ( G-CSF) was given from day 4 and discontinued when neutrophil count increased to 1.0 × 109/L. In case remission was achieved after the first course, a similar second remission-induction course was given, to be followed by either an allogeneic hematopoietic stem cell transplantation (allo-HSCT) or subsequent consolidation courses, which was at the investigator's discretion. Results: A total of 71 patients were enrolled and treated, among whom 44 (62.0%) had AML evolving from MDS, 55 (77.5%) were previously untreated, 12 (16.9%) had an adverse karyotype, and 6 (10.0%) had TP53 mutations. 40 (56.3%) patients achieved a major response, including 20 (28.2%) patients with complete remission (CR) and 20 (28.2%) patients with complete remission with incomplete blood count recovery (CRi). The major response (CR+CRi) rate was 63.6% in AML patients and 44.4% in MDS patients (p=0.142). The median overall survival (OS) was 22.4 months (95% confidence interval (CI) ,17.8-27.0). The median OS was 24.2 months (95% CI 18.0-30.4) and 20.0 months (95% CI 11.2-28.7) for patients with AML and MDS (p=0.347), respectively. The median progress free survival (PFS) for the entire cohort was 12.1 months (95% CI 3.9-20.4). The median PFS was 17.6 months ( 95% CI 13.3-22.0) and 6.8 months (95% CI 0.1-13.6) for patients with AML and MDS (p=0.151), respectively. Patients who achieved CR/CRi had superior OS: 26.4 months ( 95% CI 17.6-35.2) vs. 20.0 months (95% CI 6.2-33.8) in non CR/CRi patients (p=0.042). Also patients who achieved CR/CRi had prolonged PFS: 17.8 months (95% CI 8.6-27.0) vs. 8.6 months (95% CI 3.5-13.8) in those not achieving CR. Patients with platelet doubling achieved significantly higher CR/CRi rate (24/24(100%) vs. 16/47(34.0%), p 50×109/L of 25 days (range: 8-41). Conclusions: The regimen of decitabine priming followed by low-dose idarubicin plus cytarabine appears to be highly effective and has an acceptable safety profile in patients with AML evolving from MDS or RAEB-2. Further controlled studies are needed to confirm the activity of this regimen, and could help to provide an alternative option for induction therapy in this population. Download : Download high-res image (417KB) Download : Download full-size image Disclosures No relevant conflicts of interest to declare.