Ph+ ALL
Conditions
Brief summary
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.
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 1.Start from 4 cycle. 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.
Recommended for patients with MRD ≥0.01% after two treatment blocks.
DRUGInotuzumab ozogamicin
Optional add-on therapy 2. Start from 4 cycle. at a total dose of 2 mg per cycle. TKI should be discontinued 5 days prior to InO administration, and olverembatinib oral therapy should be resumed one week after InO administration. For patients who remain NGS MRD-positive after one cycle of InO, a repeat cycle of InO may be considered. Note: If 2 cycles given,cycle 9 are omitted.
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 |
| Modified Event-Free Survival (mEFS) from start of InO consolidation | From the start of InO consolidation therapy up to 2 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 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 |
Countries
China
Contacts
CONTACTHui Wei, MD
Outcome results
None listed