Evaluating the Efficacy of Venetoclax Combined With Azacitidine Induction Therapy of Early T-cell Precursor-like Acute Lymphoblastic Leukemia and T-ALL With Myeloid Mutations
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- Overall response rate (ORR) after two treatment cycles of induction therapy
研究概览
简要总结
The goal of this clinical trial is to evaluate the efficacy and safety of venetoclax combined with azacitidine in treating newly diagnosed early T-cell precursor (ETP)-like acute lymphoblastic leukemia (ALL), T-ALL with myeloid mutations, or T/myeloid mixed-phenotype acute leukemia (T/My-MPAL).
Participant population: Patients aged ≥14 years diagnosed with ETP-like leukemia, T-ALL with myeloid mutations, or T/My-MPAL, regardless of sex/gender.
The main question it aims to answer: Does venetoclax plus azacitidine achieve a significantly higher overall response rate (ORR: CR + CRi) compared to historical controls (54% vs. 90%) after two induction cycles?
Comparison group: Researchers will compare ORR outcomes to historical data from conventional chemotherapy regimens to assess treatment superiority.
Participants will:
- Receive two 28-day cycles of venetoclax (oral, 100 mg D1, 200 mg D2, 400 mg D3-28) and azacitidine (75 mg/m²/day SC, D1-7).
- Undergo serial bone marrow biopsies, blood tests, and imaging (e.g., PET-CT) for response assessment.
- Follow dose adjustment protocols for toxicity management (e.g., neutropenia, thrombocytopenia).
详细描述
This study addresses the unmet need for effective therapies in high-risk T-ALL subtypes, including ETP-like leukemia and T/My-MPAL, which exhibit myeloid-like genetic profiles (e.g., FLT3, DNMT3A, RUNX1 mutations) and poor outcomes under conventional chemotherapy (5-year OS <40%). Preclinical and pilot clinical data demonstrate that venetoclax, a BCL-2 inhibitor, synergizes with azacitidine, a hypomethylating agent, to induce apoptosis in leukemia stem cells by targeting oxidative phosphorylation and epigenetic dysregulation. Building on a pilot study, this Phase II trial employs a single-arm design to validate efficacy in a larger cohort.
Patients receive two induction cycles of venetoclax (oral, 100 mg D1, 200 mg D2, 400 mg D3-28) and azacitidine (75 mg/m² SC D1-7), with response assessed via bone marrow morphology, flow cytometry, and molecular testing (Days 22-35).
Early Efficacy Evaluation: After the first induction cycle (Days 22-35), response is assessed via bone marrow morphology, flow cytometry, and molecular profiling.
Stopping Criteria:
Patients failing to achieve at least partial remission (PR) after Cycle 1 will be withdrawn from the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 14 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •No gender restrictions
- •Age ≥ 14 years
- •Confirmed diagnosis of one of the following:
- •ETP-like leukemia (CD7⁺, CD1a-, CD8-, with CD5 expression stratified as ETP-ALL ≤75% or Near-ETP-ALL >75%) T-cell acute lymphoblastic leukemia (T-ALL) with myeloid mutations (including FLT3, DNMT3A, STAG2, IDH1/2, RUNX1, EZH2, WT1, ASXL1/2, SF3B1, TET2, BCOR, BCORL1, and MLL-PTD) T/myeloid mixed phenotype acute leukemia (T/My-MPAL) (with concurrent T-lineage and myeloid markers, e.g., cCD3⁺/mCD3⁺, CD7⁺, MPO⁺)
- •Newly diagnosed patients without prior induction therapy Limited prior therapy allowed: hydroxyurea, dexamethasone, or low-dose cytarabine/venetoclax (cumulative dose <0.5g), and leukocytapheresis
- •Expected survival time ≥ 3 months
- •Liver function: total bilirubin ≤ 2× ULN; ALT/AST ≤ 3× ULN (or ≤ 5× ULN if liver infiltration by leukemia is present) ; Renal function: endogenous creatinine clearance ≥ 30 ml/min; Cardiac function: left ventricular ejection fraction > 45%
- •Demonstrated capacity to understand the study and willingness to provide informed consent
排除标准
- •Presence of recurrent genetic abnormalities such as t(8;21), t(15;17), inv(16)/t(16;16) leukemia
- •Prior hypersensitivity to study drugs or compounds of similar chemical structure
- •Active uncontrolled infections as determined by the investigator
- •Active bleeding
- •Recent history (within 1 year) of thrombosis, embolism, or cerebral hemorrhage
- •Pregnancy, breastfeeding, or unwillingness to use contraception in women of childbearing potential
- •Drug addiction or chronic alcoholism that could interfere with trial evaluation
- •Psychiatric disorders or other conditions that would prevent obtaining informed consent or compliance with trial requirements
- •Any condition deemed unsuitable for trial participation by the investigator
研究组 & 干预措施
Investigational ( venetoclax, azacytidine)
Two cycles induction as venetoclax (oral, 100 mg D1, 200 mg D2, 400 mg D3-28) and azacitidine (75 mg/m² SC D1-7); Consolidation: For fit patients, if those with MRD (Minimal Residual Disease) are negative or refuse to undergo allo-HSCT (Hematopoietic stem-cell transplantation), intermediate-dose (2g/m² q12h, days 1-3) cytarabine-based therapy is administered for 3-4 cycles; if patients are MRD-positive, they undergo allo-HSCT.
For unfit patients, each venetoclax combined with azacitidine treatment cycle is anticipated to be 28 days in length until progression of disease, although cycle delays may occur due to delayed blood count recovery.
干预措施: Venetoclax (Drug)
Investigational ( venetoclax, azacytidine)
Two cycles induction as venetoclax (oral, 100 mg D1, 200 mg D2, 400 mg D3-28) and azacitidine (75 mg/m² SC D1-7); Consolidation: For fit patients, if those with MRD (Minimal Residual Disease) are negative or refuse to undergo allo-HSCT (Hematopoietic stem-cell transplantation), intermediate-dose (2g/m² q12h, days 1-3) cytarabine-based therapy is administered for 3-4 cycles; if patients are MRD-positive, they undergo allo-HSCT.
For unfit patients, each venetoclax combined with azacitidine treatment cycle is anticipated to be 28 days in length until progression of disease, although cycle delays may occur due to delayed blood count recovery.
干预措施: Azacitidine (Drug)
Investigational ( venetoclax, azacytidine)
Two cycles induction as venetoclax (oral, 100 mg D1, 200 mg D2, 400 mg D3-28) and azacitidine (75 mg/m² SC D1-7); Consolidation: For fit patients, if those with MRD (Minimal Residual Disease) are negative or refuse to undergo allo-HSCT (Hematopoietic stem-cell transplantation), intermediate-dose (2g/m² q12h, days 1-3) cytarabine-based therapy is administered for 3-4 cycles; if patients are MRD-positive, they undergo allo-HSCT.
For unfit patients, each venetoclax combined with azacitidine treatment cycle is anticipated to be 28 days in length until progression of disease, although cycle delays may occur due to delayed blood count recovery.
干预措施: Cytarabine (Drug)
结局指标
主要结局
Overall response rate (ORR) after two treatment cycles of induction therapy
时间窗: time from the date of enrollment to 2 cycles of induction before consolidation therapy（100 days）
Rates of complete remission (CR), and complete remission with incomplete hematologic recovery (CRi)
次要结局
- OS: overall survival(2 years)
- LFS：leukemia-free survival(2 years)
- DOR: duration of remission(2 years)
- AE(Within 60 days after treatment)
- Volume of infused blood products(Within 60 days)
研究者
yuejun Liu
Physician
The First Affiliated Hospital of Soochow University