Chemotherapy With Targeted-Immunotherapy for Newly Diagnosed Ph+ ALL

Institute of Hematology & Blood Diseases Hospital, China110 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

110

Conditions

Ph+ ALL

Interventions

OlverembatinibDRUG

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.

VenetoclaxDRUG

BCL-2 inhibitor. Used only in the experimental arm.Induction: Ramp-up: 100mg D1, 200mg D2, 400mg D3-28. Consolidation: 400mg D1-7.

BlinatumomabDRUG

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.

Chemotherapy Backbone RegimensDRUG

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.

Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)OTHER

Recommended for patients with MRD ≥0.01% after two treatment blocks.

Inotuzumab ozogamicinDRUG

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.

Eligibility

Sex: ALLMin age: 14 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Rate of BCR::ABL1 ≤0.01% at 90 days (after three cycles of treatment)

Time frame: up to 90 days

Modified Event-Free Survival (mEFS) from start of InO consolidation

Time frame: From the start of InO consolidation therapy up to 2 years

Secondary Outcomes

Overall Survival

Time frame: up to 5 years

Relapse-Free Survival

Time frame: up to 5 years

Cumulative incidence of molecular relapse

Time frame: up to 5 years

Cumulative incidence of hematologic relapse

Time frame: up to 5 years

Proportion of patients with next-generation sequencing minimal residual disease <0.01% after three cycles of treatment (90 days)

Time frame: up to 90 days

Proportion of patients with next-generation sequencing minimal residual disease <0.01% at the end of consolidation therapy

Time frame: up to 1 year

Incidence of treatment-related cardiovascular events

Time frame: up to 5 years from the initiation of treatment

Proportion of patients with BCR::ABL1 ≤0.01% at completion of consolidation therapy

Time frame: up to 9 months

Incidence of SOS/VOD

Time frame: From the start of InO consolidation therapy up to 6 months post-treatment

Hematopoietic Stem Cell Transplantation (HSCT) rate

Time frame: up to 5 years

Chemotherapy With Targeted-Immunotherapy for Newly Diagnosed Ph+ ALL

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts