An interventional study of Azacitidine and Dasatinib in Acute Myeloid Leukemia, sponsored by LanZhou University. Status unknown at 1 site in China. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-04-25.
Sponsored by LanZhou University · Not applicable, Interventional, and Treatment
This project is a prospective, single-center study to evaluate the efficacy, safety and related mechanisms of azacitidine combined with low-dose dasatinib in maintenance therapy in patients with intermediate and high-risk acute myeloid leukemia(AML). The patients were randomly divided into azacitidine group and azacitidine combined with low-dose dasatinib group. The overall survival and disease-free survival were taken as the main end points, and the mortality and recurrence rate were taken as the secondary end points, meanwhile, the incidence of adverse events were evaluated. At the same time, the mRNA expressions of DNA methyltransferase (DNMT1, DNMT3a, DNMT3b), tumor suppressor genes (TP53, P15, P16, P21, CDH1, DOK6, SHP1, PTPN11) and differentiation genes (pu.1, C/EBP α, C/EBP β) were detected. Pyrophosphate sequencing was used to detect the methylation level of the promoter region of these tumor suppressor genes. Western Blot was used to detect apoptosis proteins (caspase3, caspase8) and phosphorylated proteins (pSTAT3, pSTAT5, pAKT). The proportion of apoptotic population of bone marrow cells was determined by flow cytometry. Therefore, the data in this study will reflect the efficacy and safety of azacitidine or azacitidine combined with low-dose dasatinib in real-world maintenance therapy in patients with medium and high-risk AML.
In addition to studying the overall survival, disease-free survival and recurrence rates, mortality and incidence of adverse events of patients treated with azacitidine or azacitidine combined with low-dose dasatinib, we will also study its related mechanisms. One of the pathogenesis of AML is that abnormal DNA methylation makes the cell cycle out of control and carcinogenesis by inhibiting the expression of tumor suppressor genes. In addition, the abnormal activation of tyrosine kinase signal pathway also promotes the development of leukemia. Azacitidine, the hypomethylating agents, can not only inhibit the DNA methyltransferase family, but also activate tumor suppressor genes to inhibit a variety of tyrosine kinase signaling pathways, including JAK-STAT. NaShen et al have directly demonstrated that tyrosine kinase inhibitors (TKIs) can not only inhibit the abnormal activation of tyrosine kinase pathway, but also reduce DNA methylation. This study found that the combination of the second generation TKIs and hypomethylating agents can reduce has a synergistic effect on promoting apoptosis and reducing DNA methylation. In addition, TKIs often produces drug resistance due to long exposure time, and the main mechanisms of drug resistance is due to DNA methylation and abnormal reactivation of tyrosine kinase signal pathway. The combination of TKI and azacitidine reduces DNA methylation and inhibits the reactivation of abnormal tyrosine kinase signal pathway, which is helpful to improve TKI drug resistance. Based on the above theory, we assume that patients treated with azacitidine and dasatinib may have more obvious demethylation effect, increased expression of tumor suppressive genes, more obvious apoptosis, and inhibition of phosphorylated protein expression.So we did the lab tests of these mechanisms.We innovatively used azacitidine and TKIs in the treatment of patients with AML maintenance, in order to reduce drug toxicity, enhance drug efficacy, improve patient prognosis and reduce the financial burden of patients.
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The heart, pulmonary, liver and kidneys have sufficient organ functions:
Exclusion Criteria:
HCV positive; or HIV positive; or one of the following HBV test results:
Patients with intermediate and high risk AML were negative for minimal residual disease after intensive induction and consolidation chemotherapy,the patients were randomly divided into two groups, and one group was given azacitidine(75mg/m2, per day on day 1-7\]. Dasatinib 100 mg p.o. qd was administered on days 1-28 of each consolidation cycle.
Drug: Azacitidine · Drug: Dasatinib
Patients with intermediate and high risk AML were negative for minimal residual disease after intensive induction and consolidation chemotherapy,the patients were randomly divided into two groups, and the other group was given azacitidine(75mg/m2, per day on day 1-7)on days 1-28 of each consolidation cycle.
Drug: Azacitidine
Azacitidine, 75mg/m2,d1-7;Treatment cycles every 28 days
dasatinib,20mg,po,qd,treatment cycles every 28 days
overall survival
OS is defined as the time from the date of enrollment until the date of death from any cause.
Time frame: up to 30 months.
disease-free survival
Event-free survival is defined as the time from enrollment until documented refractory disease, relapse after complete remission(CR) or CR with incomplete recovery of blood counts(CRi), or death from any cause.
Time frame: up to 30 months.
mortality
The proportion of patients from enrollment to death was recorded.
Time frame: mortality rate at 30 months.
recurrence rate
Record the proportion of patients with recurrence in the study.
Time frame: recurrence rate at 30 months.
adverse events
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.
Time frame: Adverse events were assessed weekly during the first and second cycles, and every two cycles thereafter (each cycle is 28 days), up to 30 months.
apoptotic protein and phosphorylated protein
The relative expression of apoptotic protein(caspase3, caspase8) and phosphorylated protein(pSTAT3, pSTAT5, pAKT) were detected by western blot with bone marrow aspirate.
Time frame: once before enrollment and once after the completion of the study, up to 30 months.
DNA methyltransferase, tumor suppressor genes and differentiation genes
To detect the mRNA expression of DNA methyltransferase(DNMT1, DNMT3a, DNMT3b), tumor suppressor genes(TP53,P15, P16, P21, CDH1, DOK6, SHP1, PTPN11) and differentiation gene(pu.1, C/EBPα, C/EBPβ) with bone marrow aspirate by Q-PCR.
Time frame: once before enrollment and once after the completion of the study, up to 30 months.
methylation level in the promoter region of some tumor suppressor genes.
Detection of methylation level in the promoter region of the above tumor suppressor genes by pyrophosphate sequencing using patient bone marrow aspirate.
Time frame: once before enrollment and once after the completion of the study, up to 30 months.
Percentage of bone marrow cell apoptosis population
The percentage of apoptotic population of bone marrow cells was determined by flow cytometry.
Time frame: once before enrollment and once after the completion of the study, up to 30 months.
Plan to share: No — After the completion of the clinical trial, we will choose whether to disclose the result according to the relevant regulations of the Chinese Genetic Office.
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LanZhou University