Chemotherapy With Targeted-Immunotherapy for Newly Diagnosed Ph+ ALL

Official title

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

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.

Interventions

• 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 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 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 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.

Primary outcome measures

• 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 outcome measures (10)

• 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]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Blood Diseases Hospital — Tianjin

Identifiers

NCT: NCT07493161 · IIT2026022

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗