Ph+ ALL
Conditions
Brief summary
This is a prospective, open-label, randomized controlled trial to evaluate the efficacy and safety of low-intensity chemotherapy combined with targeted agents (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.
Detailed description
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.
Interventions
DRUGOlverembatinib
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.
DRUGVenetoclax
BCL-2 inhibitor. Used only in the experimental arm.Induction: Ramp-up: 100mg D1, 200mg D2, 400mg D3-28. Consolidation: 400mg D1-7.
DRUGBlinatumomab
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.
DRUGChemotherapy Backbone Regimens
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.
OTHERCAR-T Cell Therapy
After second consolidation (optional pathway).
Recommended for patients with MRD ≥0.01% after two treatment blocks.
Sponsors
Institute of Hematology & Blood Diseases Hospital, China
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
14 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Newly diagnosed ALL with t(9;22)(q34;q11) or BCR::ABL1 positivity (by PCR or FISH). * Age ≥ 14 years. * ECOG performance status ≤ 2. * 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.
Exclusion criteria
* 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.
Design outcomes
Primary
| Measure | 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 |
Secondary
| Measure | Time frame |
|---|---|
| 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 |
| 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 |
Contacts
CONTACTHui Wei, MD
Outcome results
None listed