Comparison of the Efficacy and Safety of Venetoclax in Combination With 3 Days Decitabine (DEC3-VEN) vs. Venetoclax in Combination With Azacitidine (VIALE-A) in the Treatment of Elderly Patients or Unfit, New-diagnosis Acute Myeloid Leukemia Patients

Department of Hematology, The Second Affiliated Hospital of Kunming Medical University.

Combining the results of previous studies and based on the clinical practice in our center, we designed the Venetoclax in combination with 3days-Decitabine regimen for induction therapy in elderly or unfit AML patients with a primary diagnosis, and set Venetoclax in combination with Azacitidine (VIALE-A) as a control group to compare the efficacy and safety and to provide evidence for the optimal selection of the clinical treatment regimen.

PRIMARY ENDPOINT: To assess whether Venetoclax in combination with 3 days-diascitabine versus standard dose Venetoclax in combination with azacitidine improves event-free survival (EFS) in elderly or adult patients with unfit AML during the maximum follow-up period. Event-free survival was defined as the absence of events such as treatment failure, intolerance withdrawal, all-cause death, or achievement of CR or CRi, or relapse after MLFS, whichever occurred first, between patients' randomization and the maximum follow-up period. Treatment failure was defined as failure to achieve CR or CRi, MLFS after 2 courses of induction therapy.

Induction therapy regimen:

A: Experimental group: Venetoclax in combination with Decitabine (+-sorafenib) Venetoclax (VEN) 100mg d1, 200mg d2, 400mg d3-14 Decitabine (DEC) 20mg/m2/q8h, d4-6 (infusion time >2h) Sorafenib 600mg/d, d8-14 (FLT3/ITD mutation positive patients) B: Control: standard dose of Venetoclax + Azacitidine Venetoclax (VEN) 100mg d1, 200mg d2, 400mg d3-28 Azacitidine (AZA) 75mg/m2/d, d3-9

Post-remission treatment regimen:

A: Experimental group: Venetoclax combined with Decitabine Venetoclax (VEN ) 400mg/d, d1-7 Decitabine (DEC) 20mg/m2/q8h, d2-3 (this regimen is repeated every 4-6 weeks) B: Control Group: Venetoclax combined with Azacitidine Venetoclax (VEN ) 100mg d1, 200mg d2, 400mg/d d3-28 Azacitidine (AZA) 75mg/m2/d, d3-9 (this regimen is repeated every 4-6 weeks)

Inclusion Criteria:

• Subjects suitable for enrollment in this study must meet all of the following criteria.

  1. meet the World Health Organization diagnostic criteria (WHO2022 criteria) except APL or carry one of the abnormal karyotypes such as t(8;21)/(RUNX1::RUNX1TI), inv(16)(p13.1q22), t(16;16) (p13.1q22), t(16;16)/CBFβ::myh11), etc. Patients with acute myeloid leukemia other than those with one of the abnormal karyotypes such as t(16;16)/CBFβ::myh11
  2. Patients with AML not otherwise classified under the World Health Organization AML classification, except for acute myeloproliferative disorder with myelofibrosis and myeloid sarcoma.
  3. Male or female, A: Elderly patients aged > or = 60 years (unwilling to undergo intense chemotherapy); B: Patients aged > 18 years who are not candidates for standard-dose chemotherapy, defined as those with at least one of the following comorbidities: 1) Eastern Collaborative Oncology Group Physical Conditioning Grading (ECOG) score of 2 or 3; 2) Chronic heart failure (CHF) requiring treatment or with a left ventricular ejection fraction (LVEF) of ≤ 50%; 3) Chronic heart failure (CHF) requiring treatment or with a left ventricular ejection fraction (LVEF) of ≤ 50%. heart failure (CHF) cardiac history or chronic unstable angina; 3) carbon monoxide diffusing capacity (DLCO) ≤65% or forced expiratory volume in 1 second (FEV1) ≤65%; 4) creatinine clearance of ≥30 mL/min to ≤45 mL/min; and 5) any other condition deemed by the investigator to be incompatible with standard-dose chemotherapy must be reviewed with the study chair prior to study enrollment ;
  4. patients have not received prior treatment for AML (except hydroxyurea and Ara-C <1.0 g/d).
  5. Eastern Cooperative Oncology Group Physical Status Assessment (ECOG-PS) score of <=3.
  6. pass the requirements for the following laboratory test indices (performed within 7 days prior to treatment):
  1. Aspartate aminotransferase (ALT), alanine aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 x upper limit of normal (ULN), serum bilirubin ≤ 2 x ULN; and serum cardiac enzymes < 2.0 x ULN; unless considered to be leukemic organ involvement.
  2. Creatinine ≥ 30 mL/min, calculated by the Cockcroft Gault formula or measured by 24-hour urine collection.

  7.Subjects of childbearing potential must have a negative pregnancy test result within 72 hours prior to the start of treatment, and participating patients must use contraception during trial treatment and for 3 years after completion of treatment.

  8. life expectancy greater than 2 months. 9. Informed consent must be signed prior to the start of all specific study procedures, either by the patient himself/herself or by a member of his/her immediate family; in view of the patient's condition, if the patient's own signature would not be conducive to the treatment of his/her condition, the informed consent will be signed by the legal guardian or by a member of the patient's immediate family.

Exclusion Criteria:

Subjects may not be enrolled in this study if they meet any of the following criteria:

1. AML with BCR-ABL1; or CML bone marrow acute stage.
2. Treatment-naïve patients (is defined as having received induction chemotherapy in the past, regardless of efficacy).
3. Secondary leukemia (mainly refers to those whose World Health Organization (WHO) AML classification belongs to the subcategory of treatment-related AML and those with a history of prior MDS and/or MPD).
4. concomitant other hematologic diseases (such as hemophilia, myelofibrosis and other investigators considered unsuitable for enrollment; previous blood abnormalities, but ever bone marrow examination except MDS and MPD allowed enrollment).

5、Pregnant or lactating patients. 6, Allergic to any of the drugs involved in this study. 7, Have used strong or moderate CYP7A inducers within 3 days before the start of study treatment.

8, Concomitant malignant tumors of other organs (those requiring treatment). 9, Significantly abnormal hepatic or renal function beyond the enrollment criteria.

10, Active heart disease, defined as one or more of the following:

1. Myocardial infarction less than 6 months from study entry;
2. A history of arrhythmia requiring drug therapy or severe clinical symptoms;
3. Uncontrolled or symptomatic congestive heart failure (> NYHA class 2); 10, patients with severe infectious diseases (untreated tuberculosis, pulmonary aspergillosis), known infection with human immunodeficiency virus (HIV) or active hepatitis B or C.

11. Subjects with evidence of central nervous system leukemia prior to treatment.

Subjects with epilepsy, dementia, or other abnormal mental states that require medication and who are unable to understand or follow the regimen.

13, Conditions that limit oral drug intake or gastrointestinal absorption. 14, Subjects who, in the opinion of the investigator, are not suitable for enrollment