Low-intensity Chemotherapy Combined With Targeted-Immunotherapy for Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Prospective Clinical Cohort Study
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 110
- 试验地点
- 1
- 主要终点
- Rate of BCR::ABL1 ≤0.01% at 90 days (after three cycles of treatment)
研究概览
简要总结
This is an open-label, prospective clinical cohort study evaluating the efficacy and safety of reduced-intensity chemotherapy combined with targeted therapy and immunotherapy in adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The study consists of two integrated parts. The first part is a randomized controlled comparison to investigate the role of venetoclax, a BCL2 inhibitor, when added to a backbone of olverembatinib (a third-generation TKI) and reduced-intensity chemotherapy (VPVO regimen) during the first three cycles of induction/consolidation therapy. The second part is a single-arm exploration of inotuzumab ozogamicin (InO) combined with TKI and chemotherapy as a consolidation strategy for patients who complete the 90-day primary endpoint assessment but do not receive blinatumomab, offering an alternative to blinatumomab-based regimens. The primary endpoint for the venetoclax part is the rate of BCR-ABL < 0.01% at day 90. The primary endpoint for the InO consolidation part is modified event-free survival (EFS) from the start of InO treatment. Key secondary endpoints include overall survival (OS), relapse-free survival (RFS), cumulative incidence of molecular and hematologic relapse, NGS MRD negativity rates, and safety profiles including cardiovascular events and SOS/VOD. The study aims to enroll 110 patients in the initial phase and an additional 78 patients for the InO consolidation phase.
详细描述
Background: Ph+ ALL is a high-risk subtype of adult ALL. Although outcomes have improved with TKI-based therapy, achieving early deep molecular response remains critical for long-term survival. Novel combinations with BCL2 inhibitor venetoclax and CD3-CD19 bispecific antibody blinatumomab may further deepen responses.
Objective
To determine whether adding venetoclax to a low-intensity chemotherapy backbone (vincristine, prednisone, olverembatinib) improves early molecular response and survival, and to explore the impact of different cycles of blinatumomab.
Design: This is a single-center, open-label, randomized controlled trial. Eligible patients are newly diagnosed Ph+ ALL aged ≥14 years, with ECOG ≤2 and adequate organ function. Patients will be randomized 1:1 to Arm A (control) or Arm B (venetoclax) during the first three cycles.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Newly diagnosed ALL with t(9;22)(q34;q11) or BCR::ABL1 positivity (by PCR or FISH).
- •Age ≥ 14 years.
- •ECOG performance status ≤
- •Adequate organ function: Total bilirubin <1.5x ULN; AST/ALT ≤2.5x ULN; Serum creatinine <2x ULN; Cardiac enzymes <2x ULN; Serum amylase ≤1.5x ULN; Left ventricular ejection fraction (LVEF) >45%.
- •Male and female patients of childbearing potential must agree to use effective contraception.
- •Signed informed consent.
排除标准
- •Diagnosis of chronic myeloid leukemia in chronic, accelerated, or blast phase.
- •Prior systemic anti-leukemic therapy for ALL (except corticosteroids or hydroxyurea for cytoreduction prior to enrollment).
- •Myocardial infarction within 12 months prior to enrollment; uncontrolled/unstable angina, congestive heart failure, uncontrolled hypertension or arrhythmia.
- •Uncontrolled active severe infection.
- •Active psychiatric illness that may hinder treatment completion or informed consent.
- •Any other condition deemed unsuitable for the study by the investigator.
研究组 & 干预措施
Venetoclax-Added Therapy (Chemotherapy + Olverembatinib + Venetoclax)
Patients receive the same backbone as the Control Arm plus the BCL2 inhibitor venetoclax for the first three treatment blocks.
Consolidation 1 & 2 (OP, 4 weeks each): Olverembatinib (40mg every other day) D1-28; Prednisone D1-14；Vincristine (VCR) D1,8. OVB dose is reduced to 20mg every other day for patients achieving CMR after Consolidation 1.
Subsequent Chemotherapy: Includes High-Dose Methotrexate (cycles 4, 6, and 8 )and Intermediate-Dose Cytarabine( cycles 5, 7, and 9) with dosing adjusted based on age.
Maintenance therapy:MM and VP regimen with venetoclax for 2 years. Olverembatinib therapy for at least 5 years.
Optional Add-on 1: Patients with financial means may receive 1-4 cycles of blinatumomab starting from Cycle 4.
Optional Add-on 2: Patients who do not receive blinatumomab will receive inotuzumab ozogamicin (InO) starting from Cycle 4.
Allogeneic HSCT is an option for patients with NGS MRD ≥0.01% after two cycles of treatment.
干预措施: Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) (Other)
Standard Therapy (Chemotherapy + Olverembatinib)
Patients receive a backbone of low-intensity chemotherapy combined with olverembatinib(OVB) .
Induction : Vincristine D1,8,15,22; Prednisone D1-28; Olverembatinib D1-28；
Consolidation 1 & 2: Olverembatinib D1-28; Prednisone D1-14；Vincristine D1,8. OVB dose is reduced to 20mg every other day for patients achieving CMR after Consolidation 1.
Subsequent Chemotherapy: Includes High-Dose Methotrexate (cycles 4, 6, and 8 )and Intermediate-Dose Cytarabine( cycles 5, 7, and 9) with dosing adjusted based on age .
Maintenance therapy: MM and VP regimen for 2 years. OVB maintenance therapy continues for at least 5 years.
Optional Add-on 1: Patients may receive 1-4 cycles of blinatumomab starting from Cycle 4.
Optional Add-on 2: Patients who do not receive blinatumomab will receive inotuzumab ozogamicin (InO) starting from Cycle 4
Allogeneic HSCT is an option for patients with NGS MRD ≥0.01% after two cycles of treatment.
干预措施: Blinatumomab (Drug)
Venetoclax-Added Therapy (Chemotherapy + Olverembatinib + Venetoclax)
Patients receive the same backbone as the Control Arm plus the BCL2 inhibitor venetoclax for the first three treatment blocks.
Consolidation 1 & 2 (OP, 4 weeks each): Olverembatinib (40mg every other day) D1-28; Prednisone D1-14；Vincristine (VCR) D1,8. OVB dose is reduced to 20mg every other day for patients achieving CMR after Consolidation 1.
Subsequent Chemotherapy: Includes High-Dose Methotrexate (cycles 4, 6, and 8 )and Intermediate-Dose Cytarabine( cycles 5, 7, and 9) with dosing adjusted based on age.
Maintenance therapy:MM and VP regimen with venetoclax for 2 years. Olverembatinib therapy for at least 5 years.
Optional Add-on 1: Patients with financial means may receive 1-4 cycles of blinatumomab starting from Cycle 4.
Optional Add-on 2: Patients who do not receive blinatumomab will receive inotuzumab ozogamicin (InO) starting from Cycle 4.
Allogeneic HSCT is an option for patients with NGS MRD ≥0.01% after two cycles of treatment.
干预措施: Blinatumomab (Drug)
Standard Therapy (Chemotherapy + Olverembatinib)
Patients receive a backbone of low-intensity chemotherapy combined with olverembatinib(OVB) .
Induction : Vincristine D1,8,15,22; Prednisone D1-28; Olverembatinib D1-28；
Consolidation 1 & 2: Olverembatinib D1-28; Prednisone D1-14；Vincristine D1,8. OVB dose is reduced to 20mg every other day for patients achieving CMR after Consolidation 1.
Subsequent Chemotherapy: Includes High-Dose Methotrexate (cycles 4, 6, and 8 )and Intermediate-Dose Cytarabine( cycles 5, 7, and 9) with dosing adjusted based on age .
Maintenance therapy: MM and VP regimen for 2 years. OVB maintenance therapy continues for at least 5 years.
Optional Add-on 1: Patients may receive 1-4 cycles of blinatumomab starting from Cycle 4.
Optional Add-on 2: Patients who do not receive blinatumomab will receive inotuzumab ozogamicin (InO) starting from Cycle 4
Allogeneic HSCT is an option for patients with NGS MRD ≥0.01% after two cycles of treatment.
干预措施: Inotuzumab ozogamicin (Drug)
Venetoclax-Added Therapy (Chemotherapy + Olverembatinib + Venetoclax)
Patients receive the same backbone as the Control Arm plus the BCL2 inhibitor venetoclax for the first three treatment blocks.
Consolidation 1 & 2 (OP, 4 weeks each): Olverembatinib (40mg every other day) D1-28; Prednisone D1-14；Vincristine (VCR) D1,8. OVB dose is reduced to 20mg every other day for patients achieving CMR after Consolidation 1.
Subsequent Chemotherapy: Includes High-Dose Methotrexate (cycles 4, 6, and 8 )and Intermediate-Dose Cytarabine( cycles 5, 7, and 9) with dosing adjusted based on age.
Maintenance therapy:MM and VP regimen with venetoclax for 2 years. Olverembatinib therapy for at least 5 years.
Optional Add-on 1: Patients with financial means may receive 1-4 cycles of blinatumomab starting from Cycle 4.
Optional Add-on 2: Patients who do not receive blinatumomab will receive inotuzumab ozogamicin (InO) starting from Cycle 4.
Allogeneic HSCT is an option for patients with NGS MRD ≥0.01% after two cycles of treatment.
干预措施: Inotuzumab ozogamicin (Drug)
Standard Therapy (Chemotherapy + Olverembatinib)
Patients receive a backbone of low-intensity chemotherapy combined with olverembatinib(OVB) .
Induction : Vincristine D1,8,15,22; Prednisone D1-28; Olverembatinib D1-28；
Consolidation 1 & 2: Olverembatinib D1-28; Prednisone D1-14；Vincristine D1,8. OVB dose is reduced to 20mg every other day for patients achieving CMR after Consolidation 1.
Subsequent Chemotherapy: Includes High-Dose Methotrexate (cycles 4, 6, and 8 )and Intermediate-Dose Cytarabine( cycles 5, 7, and 9) with dosing adjusted based on age .
Maintenance therapy: MM and VP regimen for 2 years. OVB maintenance therapy continues for at least 5 years.
Optional Add-on 1: Patients may receive 1-4 cycles of blinatumomab starting from Cycle 4.
Optional Add-on 2: Patients who do not receive blinatumomab will receive inotuzumab ozogamicin (InO) starting from Cycle 4
Allogeneic HSCT is an option for patients with NGS MRD ≥0.01% after two cycles of treatment.
干预措施: Olverembatinib (Drug)
Venetoclax-Added Therapy (Chemotherapy + Olverembatinib + Venetoclax)
Patients receive the same backbone as the Control Arm plus the BCL2 inhibitor venetoclax for the first three treatment blocks.
Consolidation 1 & 2 (OP, 4 weeks each): Olverembatinib (40mg every other day) D1-28; Prednisone D1-14；Vincristine (VCR) D1,8. OVB dose is reduced to 20mg every other day for patients achieving CMR after Consolidation 1.
Subsequent Chemotherapy: Includes High-Dose Methotrexate (cycles 4, 6, and 8 )and Intermediate-Dose Cytarabine( cycles 5, 7, and 9) with dosing adjusted based on age.
Maintenance therapy:MM and VP regimen with venetoclax for 2 years. Olverembatinib therapy for at least 5 years.
Optional Add-on 1: Patients with financial means may receive 1-4 cycles of blinatumomab starting from Cycle 4.
Optional Add-on 2: Patients who do not receive blinatumomab will receive inotuzumab ozogamicin (InO) starting from Cycle 4.
Allogeneic HSCT is an option for patients with NGS MRD ≥0.01% after two cycles of treatment.
干预措施: Olverembatinib (Drug)
Venetoclax-Added Therapy (Chemotherapy + Olverembatinib + Venetoclax)
Patients receive the same backbone as the Control Arm plus the BCL2 inhibitor venetoclax for the first three treatment blocks.
Consolidation 1 & 2 (OP, 4 weeks each): Olverembatinib (40mg every other day) D1-28; Prednisone D1-14；Vincristine (VCR) D1,8. OVB dose is reduced to 20mg every other day for patients achieving CMR after Consolidation 1.
Subsequent Chemotherapy: Includes High-Dose Methotrexate (cycles 4, 6, and 8 )and Intermediate-Dose Cytarabine( cycles 5, 7, and 9) with dosing adjusted based on age.
Maintenance therapy:MM and VP regimen with venetoclax for 2 years. Olverembatinib therapy for at least 5 years.
Optional Add-on 1: Patients with financial means may receive 1-4 cycles of blinatumomab starting from Cycle 4.
Optional Add-on 2: Patients who do not receive blinatumomab will receive inotuzumab ozogamicin (InO) starting from Cycle 4.
Allogeneic HSCT is an option for patients with NGS MRD ≥0.01% after two cycles of treatment.
干预措施: Venetoclax (Drug)
Standard Therapy (Chemotherapy + Olverembatinib)
Patients receive a backbone of low-intensity chemotherapy combined with olverembatinib(OVB) .
Induction : Vincristine D1,8,15,22; Prednisone D1-28; Olverembatinib D1-28；
Consolidation 1 & 2: Olverembatinib D1-28; Prednisone D1-14；Vincristine D1,8. OVB dose is reduced to 20mg every other day for patients achieving CMR after Consolidation 1.
Subsequent Chemotherapy: Includes High-Dose Methotrexate (cycles 4, 6, and 8 )and Intermediate-Dose Cytarabine( cycles 5, 7, and 9) with dosing adjusted based on age .
Maintenance therapy: MM and VP regimen for 2 years. OVB maintenance therapy continues for at least 5 years.
Optional Add-on 1: Patients may receive 1-4 cycles of blinatumomab starting from Cycle 4.
Optional Add-on 2: Patients who do not receive blinatumomab will receive inotuzumab ozogamicin (InO) starting from Cycle 4
Allogeneic HSCT is an option for patients with NGS MRD ≥0.01% after two cycles of treatment.
干预措施: Chemotherapy Backbone Regimens (Drug)
Standard Therapy (Chemotherapy + Olverembatinib)
Patients receive a backbone of low-intensity chemotherapy combined with olverembatinib(OVB) .
Induction : Vincristine D1,8,15,22; Prednisone D1-28; Olverembatinib D1-28；
Consolidation 1 & 2: Olverembatinib D1-28; Prednisone D1-14；Vincristine D1,8. OVB dose is reduced to 20mg every other day for patients achieving CMR after Consolidation 1.
Subsequent Chemotherapy: Includes High-Dose Methotrexate (cycles 4, 6, and 8 )and Intermediate-Dose Cytarabine( cycles 5, 7, and 9) with dosing adjusted based on age .
Maintenance therapy: MM and VP regimen for 2 years. OVB maintenance therapy continues for at least 5 years.
Optional Add-on 1: Patients may receive 1-4 cycles of blinatumomab starting from Cycle 4.
Optional Add-on 2: Patients who do not receive blinatumomab will receive inotuzumab ozogamicin (InO) starting from Cycle 4
Allogeneic HSCT is an option for patients with NGS MRD ≥0.01% after two cycles of treatment.
干预措施: Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) (Other)
Venetoclax-Added Therapy (Chemotherapy + Olverembatinib + Venetoclax)
Patients receive the same backbone as the Control Arm plus the BCL2 inhibitor venetoclax for the first three treatment blocks.
Consolidation 1 & 2 (OP, 4 weeks each): Olverembatinib (40mg every other day) D1-28; Prednisone D1-14；Vincristine (VCR) D1,8. OVB dose is reduced to 20mg every other day for patients achieving CMR after Consolidation 1.
Subsequent Chemotherapy: Includes High-Dose Methotrexate (cycles 4, 6, and 8 )and Intermediate-Dose Cytarabine( cycles 5, 7, and 9) with dosing adjusted based on age.
Maintenance therapy:MM and VP regimen with venetoclax for 2 years. Olverembatinib therapy for at least 5 years.
Optional Add-on 1: Patients with financial means may receive 1-4 cycles of blinatumomab starting from Cycle 4.
Optional Add-on 2: Patients who do not receive blinatumomab will receive inotuzumab ozogamicin (InO) starting from Cycle 4.
Allogeneic HSCT is an option for patients with NGS MRD ≥0.01% after two cycles of treatment.
干预措施: Chemotherapy Backbone Regimens (Drug)
结局指标
主要结局
Rate of BCR::ABL1 ≤0.01% at 90 days (after three cycles of treatment)
时间窗: up to 90 days
Event-Free Survival
时间窗: up to 5 years
Modified Event-Free Survival (mEFS) from start of InO consolidation
时间窗: From the start of InO consolidation therapy up to 2 years
次要结局
- Incidence of treatment-related cardiovascular events(up to 5 years from the initiation of treatment)
- Proportion of patients with BCR::ABL1 ≤0.01% at completion of consolidation therapy(up to 90 days)
- Overall Survival(up to 5 years)
- Relapse-Free Survival(up to 5 years)
- Cumulative incidence of molecular relapse(up to 5 years)
- Cumulative incidence of hematologic relapse(up to 5 years)
- Proportion of patients with next-generation sequencing minimal residual disease <0.01% after three cycles of treatment (90 days)(up to 90 days)
- Proportion of patients with next-generation sequencing minimal residual disease <0.01% at the end of consolidation therapy(up to 1 year)
- Proportion of patients with BCR::ABL1 ≤0.01% at completion of consolidation therapy(up to 9 months)
- Incidence of SOS/VOD(From the start of InO consolidation therapy up to 6 months post-treatment)
- Hematopoietic Stem Cell Transplantation (HSCT) rate(up to 5 years)