Chemotherapy With Targeted-Immunotherapy for Newly Diagnosed Ph+ ALL

Low-intensity Chemotherapy Combined With Targeted-Immunotherapy for Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Prospective Clinical Cohort Study

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 Overview

• Status: Recruiting
• Conditions: Ph+ ALL
• Intervention / Treatment: Drug: Olverembatinib; Drug: Chemotherapy Backbone Regimens; Other: Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT); Drug: Venetoclax; Drug: Blinatumomab; Drug: Inotuzumab ozogamicin

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.

• Study Type: Interventional
• Enrollment (Estimated): 110
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Hui Wei, MD; Phone Number: 13132507161; Email: weihui@ihcams.ac.cn

Study Locations

• China
  • Tianjin Municipality
    • Tianjin, Tianjin Municipality, China, 300020
      • Recruiting
      • Blood Diseases Hospital
      • Contact: hui wei, MD; Phone Number: 86-13132507161; Email: weihui@ihcams.ac.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: Olverembatinib; 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.; Drug: Chemotherapy 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.; Other: Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT); Recommended for patients with MRD ≥0.01% after two treatment blocks.; Drug: Blinatumomab; 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.; Drug: Inotuzumab 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.
Experimental: 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.	Drug: Olverembatinib; 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.; Drug: Chemotherapy 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.; Other: Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT); Recommended for patients with MRD ≥0.01% after two treatment blocks.; Drug: Venetoclax; BCL-2 inhibitor. Used only in the experimental arm.Induction: Ramp-up: 100mg D1, 200mg D2, 400mg D3-28. Consolidation: 400mg D1-7.; Drug: Blinatumomab; 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.; Drug: Inotuzumab 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.

What is the study measuring?

Primary Outcome Measures

Outcome 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 Outcome Measures

Outcome 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

Collaborators and Investigators

• Sponsor: Institute of Hematology & Blood Diseases Hospital, China

Study record dates

Study Major Dates

• Study Start (Actual): April 10, 2026
• Primary Completion (Estimated): March 31, 2028
• Study Completion (Estimated): March 30, 2030

Study Registration Dates

• First Submitted: March 19, 2026
• First Submitted That Met QC Criteria: March 19, 2026
• First Posted (Actual): March 25, 2026

Study Record Updates

• Last Update Posted (Actual): July 23, 2026
• Last Update Submitted That Met QC Criteria: July 21, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Amino Acids, Peptides, and Proteins; Proteins; Carbohydrates; Glycosides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Aminoglycosides; Calicheamicins; Inotuzumab Ozogamicin; venetoclax; blinatumomab; olverembatinib
• Other Study ID Numbers: IIT2026022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No