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This is a prospective, open-label, randomized controlled trial to evaluate the efficacy of low-intensity chemotherapy combined with venetoclax and blinatumomab in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Patients will be randomized to receive or not receive venetoclax during the first three cycles of induction and consolidation therapy. All patients receive olverembatinib (a third-generation TKI) continuously and may receive up to 4 cycles of blinatumomab starting from the fourth cycle. The primary endpoint is the rate of BCR::ABL1 ≤0.01% at 90 days and event-free survival (EFS). Secondary endpoints include overall survival (OS), relapse-free survival (RFS), molecular relapse rate, MRD negativity rate by NGS, and cardiovascular events.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Standard Therapy (Chemotherapy + Olverembatinib) | Active Comparator | 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 with or without venetoclax according to the study groups for 2 years. OVB maintenance therapy continues for at least 5 years. Optional Add-on: Patients may receive 1-4 cycles of blinatumomab starting after Consolidation 1.If the patient undergoes CAR-T therapy, the following conditioning regimen will be administered in cycle 4. Allogeneic HSCT is an option for patients with NGS MRD ≥0.01% after two cycles of treatment. |
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| Venetoclax-Added Therapy (Chemotherapy + Olverembatinib + Venetoclax) | Experimental | 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 or without venetoclax according to the study groups for 2 years. Olverembatinib therapy for at least 5 years. Optional Add-on: Patients with financial means may receive 1-4 cycles of blinatumomab starting after Consolidation 1.If the patient undergoes CAR-T therapy, the following conditioning regimen will be administered in cycle 4. Allogeneic HSCT is an option for patients with NGS MRD ≥0.01% after two cycles of treatment. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Olverembatinib | Drug | Third-generation tyrosine kinase inhibitor (TKI) targeting BCR-ABL1, including T315I mutation.nduction & Consolidation: 40mg every other day. After achieving CMR: Reduced to 20mg every other day during maintenance. |
| Measure | Description | Time Frame |
|---|---|---|
| Rate of BCR::ABL1 ≤0.01% at 90 days (after three cycles of treatment) | up to 90 days | |
| Event-Free Survival | up to 5 years |
| Measure | Description | Time Frame |
|---|---|---|
| Overall Survival | up to 5 years | |
| Relapse-Free Survival | up to 5 years | |
| Cumulative incidence of molecular relapse |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Hui Wei, MD | Contact | 13132507161 | weihui@ihcams.ac.cn |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Blood Diseases Hospital | Recruiting | Tianjin | Tianjin Municipality | 300020 | China |
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| ID | Term |
|---|---|
| C579813 | olverembatinib |
| C579720 | venetoclax |
| C510808 | blinatumomab |
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| Venetoclax | Drug | BCL-2 inhibitor. Used only in the experimental arm.Induction: Ramp-up: 100mg D1, 200mg D2, 400mg D3-28. Consolidation: 400mg D1-7. |
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| Blinatumomab | Drug | CD19/CD3 bispecific T-cell engager (BiTE). Optional add-on therapy.Start: After first consolidation. Duration: 1-4 cycles (each cycle = 28 days), intercalated with chemotherapy cycles. Note: If ≥3 cycles given,cycle 8 and 9 are omitted. |
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| Chemotherapy Backbone Regimens | Drug | Induction (VPO/VPVO): Vincristine + Prednisone + Olverembatinib (± Venetoclax). Consolidation (VOVP/OVP): Vincristine +Olverembatinib + Prednisone (± Venetoclax). HD-MTX: High-dose methotrexate with leucovorin rescue in cycle 4,6,8. ID-AraC: Intermediate-dose cytarabine in cycle 5,7,9. |
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| Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) | Other | Recommended for patients with MRD ≥0.01% after two treatment blocks. |
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| 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 |
| 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 |