This prospective, multi-center, randomized, controlled Phase II study is to compare the therapeutic efficacy and side effect of VACl (Venetoclax,Azacitidine,Cladribine) alternating with VACh (Venetoclax,Azacitidine,Chidamide), VACl, VACh and VA in newly diagnosed adult acute myeloid leukemia (AML) patients ineligible for intensive therapy or declining. Cladribine is a purine analogue widely used in hematologic malignancies. The monocytic leukemia stem cell is selective sensitivity to Cladribine. Chidamide, a newly designed selective histone deacetylase inhibitor, could down regulate myeloid cell leukaemia 1 (MCL1) expression in Venetoclax resistant AML cells. Chidamide or Cladribine have synergistic anti-leukemia effects with VA through their unique mechanisms, which can eradicate leukemia stem cells and prevent the occurrence of drug resistance.
AML is a clonal myelopoietic stem cell disorder characterized by the accumulation of neoplastic cells in the bone marrow and in the peripheral circulation. The median age of AML patients is 68 years. Although intensive chemotherapy and allogeneic stem cell transplant (allo-HSCT) are standard approaches for newly diagnosed patients, they are associated with higher rates of treatment related complications and inferior outcomes in older patients. Venetoclax, a newly orally available and selective B cell lymphoma-2 (BCL2) inhibitor, Venetoclax in combination with hypomethylation agents or cytarabine has been approved by the Food and Drug Administration (FDA) for the treatment of patients with newly diagnosed AML unfit for intensive chemotherapy. However, the emergence of resistance to Venetoclax based combinations has become an important clinical dilemma. Resistance to Venetoclax can be acquired through the up regulation of anti-apoptotic proteins, such as myeloid cell leukaemia 1 (MCL1). Chidamide, a newly designed selective histone deacetylase inhibitor, Chidamide could down Bregulate MCL1 expression in Venetoclax resistant AML cells. Our experience showed that the Chidamide+VA could improve the condition of R/R AML patients who are resistant to VA. Cladribine is a purine analogue widely used in hematologic malignancies. It was demonstrated that addition of Cladribine to the VA regimen increases eradication of primary AML containing monocytic leukemia stem cell activity in both in vitro and in vivo preclinical models. Chidamide or Cladribine have synergistic anti-leukemia effects with VA through their unique mechanisms, which can eradicate leukemia stem cells and prevent the occurrence of drug resistance, thereby increasing response rate, prolonging patient survival, reducing recurrence, and improving prognosis without increasing treatment-related complications. Therefore, this prospective, multi-center, randomized, controlled Phase II study is to compare the therapeutic efficacy and side effect of VACl (Venetoclax,Azacitidine,Cladribine) alternating with VACh (Venetoclax,Azacitidine,Chidamide), VACl, VACh and VA in newly diagnosed adult AML patients ineligible for intensive therapy or declining.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
172
Azacitidine:75mg/m2 Subcutaneous daily for 7 days Venetoclax: orally once daily (100 mg d1, 200mg d2, 400mg d3-28) Cladribine: 5mg/m2 IV over approximately 1 to 2 hours, daily on days 1-3.
Azacitidine: 75mg/m2 Subcutaneous daily for 7 days Venetoclax: orally once daily (100mg d1, 200mg d2, 400mg d3-28) Chidamide: 10mg orally daily for 12 days
VACl: Azacitidine:75mg/m2 Subcutaneous daily for 7 days Venetoclax: orally once daily (100 mg d1, 200mg d2, 400mg d3-28) Cladribine: 5mg/m2 IV over approximately 1 to 2 hours, daily on days 1-3. VACh: Azacitidine: 75mg/m2 Subcutaneous daily for 7 days Venetoclax: orally once daily (100mg d1, 200mg d2, 400mg d3-28) Chidamide: 10mg orally daily for 12 days
Azacitidine: 75mg/m2 Subcutaneous (SC) daily for 7 days Venetoclax: orally once daily (100mg d1, 200mg d2, 400mg d3-28).
The First Affliated Hospital of Soochow University
Suzhou, Jiangsu, China
RECRUITINGEvent-free survival (EFS)
It is defined as the number of days from the date of randomization to the date of earliest evidence of relapse, subsequent treatment other than stem cell transplant while in composite complete remission (CR+CRi), or death. If the specified event (relapse, start of subsequent treatment, or death) does not occur, subjects will be censored at the date of last disease assessment.
Time frame: 1 year
Cumulative incidence of relapse (CIR)
Time from CR to disease recurrence or progression
Time frame: 1 year
Composite complete response (CRc)
CRc rate was defifined as patients achieving a CR or CRi
Time frame: At the end of Cycle 1 (each cycle is 21-28 days)
Overall Survival (OS)
Time from date of treatment start until date of death due to any cause
Time frame: 1 year
Adverse reactions in hematology
Record of adverse events in hematological system during and after VA,VACl,VACh,VACl alternating with VACh regimen induction (agranulocytosis days, platelet(PLT)/red blood cell (RBC) transfusion units)
Time frame: At the end of Cycle 1 (each cycle is 21-28 days)
Nonhematological adverse reactions
Record of adverse events in other organs or systmes during and after VA,VACl,VACh,VACl alternating with VACh regimen induction (infection and organ injury)
Time frame: At the end of Cycle 1 (each cycle is 21-28 days)
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