Clinical Outcome Of Treatment With A Combined Regimen Of Decitabine Followed By Low-dose Idarubicin And Cytarabine For Patients With High-risk Myelodysplastic Syndromes And AML Transformed From Myelodysplastic Syndromes(MDS/AML)

Purposes.To evaluate the efficacy and safety of the combined regimen of decitabine followed by low-dose idarubicin and cytarabine for patients with high-risk myelodysplastic syndromes and AML transformed from myelodysplastic syndromes and investigate the effects of MDS-related mutations on the efficacy and long-term survival of this program.Patients and Methods.A total of 44 high-risk MDS and MDS/AML patients were prospectively enrolled,who were from the First Affiliated Hospital of Zhejiang University, Sir Run Run Shaw Hospital, Zhejiang Provincial People’s Hospital and Yuhang City First People’s Hospital.Patients were administered DAC at 20 mg/m2 daily via intravenous infusion for 3 consecutive days. Idarubicin was administered 6 mg/m2 via a continuous infusion from the fourth day for 3 consecutive days. Idarubicin was combined simultaneously with cytarabine at 25 mg/m2 bid via subcutaneous injection for 5 days. They were DAC combination group.The 15 of MDS-related genes were tested in 24 patients. Observating the overall response rate(ORR), complete remission(CR) and survival of combination therapy and exploring the impact of molecular genetics on efficacy and long-term survival.A total of 35 high-risk MDS and MDS/AML patients who had received traditional chemotherapy in our hospital were analyzed.Traditional chemotherapy, including improved AA program (Acla + Ara-c), improved IA program (IDA + Ara-c) and CAG Programme (G-CSF + Acla + Ara-c). The differences of efficacy, safety and survival between traditional chemotherapy group and DAC combination group were retrospectively analyzed and compared.Results.The overall response rate(ORR) of DAC combination group was 88.6%(39/44),24 out of 44 patients(54.5%) achieved CR+CRi, the traditional chemotherapy group achieved 57.1%ORR, CR+CRi was 31.4%(11/35), compared with traditional chemotherapy group, the patients in DAC combination group achieved higher CR rate (P=0.040).In DAC combination group, the CR+CRi rate of untreated patients is significantly higher than the patients who have received other regimens(63.6% vs.27.3%, P<0.05), the CR+CRi was the highest in patients with AML evolving from MDS who was untreated.23 of the 44 patients (52.3%)can achieve CR/CRi after receving only the initial course. There were no differences between patients with intermediate/poor cytogenetic abnormalities and patients with good cytogenetic abnormalities (50.0% vs.58.6%, P> 0.05).Meanwhile previous treatment history was an independent prognostic factor of efficacy.In DAC combination group,median overall survival time was 10 months(0-26months),which had obvious advantage of patients who received traditional chemotherapy(10 vs. 9month,p=0.045).Meanwhile, either patients who had lower ferritin count or patients without underlying diseases had survial advantages.24 patients were tested the MDS-related genes,41.7% patients had at least one kind of gene mutation,5 TP53 mutations were detected in 10 patient samples.There was a non-significant trend toward better ORR in patients with gene mutation than patients without gene mutation.However, TP53-mutated patients showed significantly worse overall survival (OS) compared to no TP53-mutated patients (8 vs.19.5months, P=0.013).Although a good therapeutic effect was achieved in all patients, patients who achieved CR/CRi all experienced grade Ⅳ hematologic toxicity, median duration of absolute neutrophil counts(ANC)< 1.0×109/L and blood platelet counts (PLT)< 50x109/L was respectively 21.8 days(range=8-53days) and 21.7 days(range=8-40days).The median duration of hemoglobin< 65g/L was 18.3 days(range=2-35days).The most common non-hematologic toxicity induced febrile neutropenia, followed by gastrointestinal reactions.Mortality rate of first course of treatment was 4.5% (2/44), no significant differences of mortality at 6 months were observed rate between DAC combination group and traditional chemotherapy group.The 2 year mortality in DAC combination group was significantly lower than traditional chemotherapy group.Conclusions.The study demonstrates that combination treatment with DAC in patients with MDS and AML can improve the response rate,have survival advantage, shorten the duration of thrombocytopenia after chemotherapy and reduce the 2 year mortality.It show that patients without treatment history chould achieve higher CR+CRi rate, especially in the MDS/AML patients who had not been treated. Patients with intermediate/poor cytogenetic abnormalities also can achieve good response. Meanwhile, previous treatment history were independent prognostic factors of efficacy.Patients who had lower ferritin count or patients without underlying diseases had survial advantages.In this study, MDS-related gene mutation positive rate was 4.7%(10/24), in which the most common mutations is TP53 gene, TP53 mutations can affect overall survival. Patients who achieved CR/CRi all experienced grade IV hematologic toxicity and the most common non-hematologic toxicity induced febrile neutropenia, followed by gastrointestinal reactions.Mortality rate of first course treatment was 4.5%. Most patients can well tolerate the bone marrow suppression, the treatment-related mortality was not significantly increased.