PD-1 Inhibitors +Venetoclax+CAG Regimens in R/R T-ALL (PD1-VEN-CAG)

A Prospective, Multicenter Clinical Study on the Efficacy and Safety of PD-1 Inhibitors Combined With Venetoclax+CAG Regimens in the Treatment of Adult Refractory/Relapsed Acute T-lymphoblastic Leukemia (T-ALL)

This prospective multicenter study evaluates the efficacy and safety of PD-1 inhibitor combined with venetoclax and HAG/CAG chemotherapy in refractory/relapsed T-ALL (R/R T-ALL). Despite standard chemotherapy, R/R T-ALL remains challenging, with low salvage remission rates (~40%) and poor survival. Preclinical data suggest PD-1 blockade enhances leukemic stem cell eradication, while venetoclax (BCL-2 inhibitor) synergizes with chemotherapy. Eligible patients receive 1-2 cycles of PD-1 inhibitor + venetoclax + CAG, with responders proceeding to allo-HSCT or MRD-guided consolidation. The trial aims to improve CR rates and survival, offering a novel immunochemotherapy approach for this high-risk population.

Study Overview

• Status: Active, not recruiting
• Conditions: Acute T Lymphoblastic Leukemia (T-ALL)
• Intervention / Treatment: Drug: PD-1 Inhibitors

Detailed Description

I. Research Objectives and Background According to the definition and classification by the World Health Organization (WHO), T-cell acute lymphoblastic leukemia (T-ALL) is a precursor lymphoid neoplasm arising from the accumulation of genetic alterations during T-cell development in the thymus, leading to differentiation arrest and abnormal proliferation of immature progenitor cells. It represents a highly heterogeneous group of diseases. The annual incidence of ALL is approximately 1.8 per 100,000 individuals, with T-ALL accounting for about 25% of adult ALL cases.

Despite significant advances in understanding the molecular pathogenesis of T-ALL over the past four decades, its treatment remains predominantly based on standard chemotherapy, which has improved outcomes in newly diagnosed ALL. However, refractory/relapsed T-ALL (R/R T-ALL) still exhibits poor long-term efficacy, with allogeneic hematopoietic stem cell transplantation (allo-HSCT) remaining the primary curative approach. Multiple studies worldwide have confirmed that T-ALL patients achieving remission after intensive chemotherapy still face a high relapse rate. In R/R T-ALL cases, the composite complete remission rate (CRc) following multi-agent salvage chemotherapy remains low (approximately 40%), and the prognosis is dismal. Multivariate analysis of prognostic factors has shown that disease biology (e.g., immunophenotype or cytogenetic abnormalities) does not significantly impact survival in R/R T-ALL. The only predictive factor for long-term survival in this population is whether early salvage therapy is administered. Current international and domestic treatment guidelines recommend clinical trials as the first-line option for R/R ALL patients, including novel drug trials, CAR-T cell therapy targeting various antigens, and investigator-initiated studies (e.g., BCL-2 inhibitor combined with chemotherapy).

Recent pivotal studies have revealed that leukemia stem cells (LSCs) in T-ALL express the immune checkpoint receptor programmed cell death protein 1 (PD-1). Depleting PD-1-expressing cells, genetically deleting PD-1 in T-ALL cells, or blocking PD-1/receptor interactions significantly eradicates LSCs and suppresses disease progression. Combined treatment with PD-1 blockade and chemotherapy markedly prolonged survival in mice transplanted with T-ALL cells. Additionally, venetoclax, an oral selective small-molecule BCL-2 inhibitor, has demonstrated promising efficacy as monotherapy or in combination regimens across various hematologic malignancies. Several studies indicate that T-ALL exhibits sensitivity to venetoclax, and its therapeutic effect can be enhanced when combined with conventional chemotherapeutic agents or targeted therapies.

These findings support the clinical application of PD-1 inhibitor combined with BCL-2 inhibitor (venetoclax) in R/R T-ALL. However, prospective clinical studies are warranted to determine whether this combination can improve outcomes in R/R T-ALL patients.

Based on the above theoretical and clinical evidence, we designed a prospective, multicenter clinical trial for R/R T-ALL patients, evaluating the efficacy and safety of PD-1 inhibitor plus venetoclax combined with HAG regimen (homoharringtonine, cytarabine, and granulocyte colony-stimulating factor). This study aims to enhance overall survival and contribute to the advancement of therapeutic strategies for R/R T-ALL.

II. Study Protocol

Screening Phase:

Patients diagnosed with R/R T-ALL will undergo screening, including bone marrow morphology, immunophenotyping, cytogenetics, fusion gene analysis, and mutation profiling.

Additional assessments: complete blood count, biochemistry, infectious disease screening, chest CT, and ultrasonography (cardiac, lymph node, abdominal). Eligible patients will be enrolled.

Treatment Phase (Cycle 1):

Enrolled patients will receive one course of PD-1 inhibitor + venetoclax + CAG regimen (cytarabine, aclarubicin, granulocyte colony-stimulating factor).

Efficacy evaluation will be performed at ~4 weeks post-treatment.

Response-Adapted Therapy:

Patients achieving morphologic CR with incomplete hematologic recovery (mCRc): Proceed to allo-HSCT as soon as possible. Repeat the regimen if transplant is delayed.

Patients achieving partial remission (PR): Administer a second cycle of PD-1 inhibitor + venetoclax + CAG, followed by re-evaluation at ~4 weeks.

If mCRc is achieved: Proceed to allo-HSCT.

If mCRc is not achieved: Discontinue study treatment and switch to alternative therapies.

Maintenance and Follow-up:

Patients in remission but ineligible for allo-HSCT will continue the regimen until minimal residual disease (MRD)-negative status is achieved, followed by two additional cycles of PD-1 inhibitor + CAG before entering the follow-up phase.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Fujian
    • Fuzhou, Fujian, China, 350001
      • Fujian Medical University Union Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age >=18 years old;
2. Met the T-ALL diagnosis before enrollment (for specific diagnostic criteria, see the attachment);
3. Refractory T-ALL (newly diagnosed T-ALL that fails to achieve remission after treatment with one standard regimen) or recurrent T-ALL (bone marrow blasts exceed 5% again after remission, and the morphology and immunophenotype of leukemia cells are consistent with T-ALL);
4. The performance status score of the Eastern Cooperative Oncology Group (ECOG) in the United States ranges from 0 to 2 points.
5. Expected survival period >=3 months;
6. During the screening period, there were no organ function abnormalities that restricted the use of this scheme.
7. Understand this study and sign the informed consent form.

Exclusion Criteria:

1. Patients with refractory/relapsed T-ALL who are not suitable for or whose economic conditions restrict the use of PD-1 and venetoclax for treatment;
2. Diseases that may limit patients' participation in this trial due to abnormal functions of organs such as the heart, lungs, liver, and kidneys (such as advanced infections, uncontrolled diabetes, severe heart failure or angina pectoris, active pulmonary tuberculosis, asthma, COPD, bronchiectasis, severe renal insufficiency, etc.);
3. There has been a history of other malignant tumors within the past five years;
4. Known HIV infection, active hepatitis B virus (HbsAg positive and HBV-DNA higher than the upper limit of the detection value) or active hepatitis C virus (anti-HCV antibody positive or HCV RNA positive) infection;
5. Inability to understand or comply with the research protocol;
6. Patients under 18 years old.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PD-1+venetoclax+CAG treatment group; PD-1 inhibitor combined with venetoclax and CAG regimen (cytarabine, aclarubicin, G-CSF) for up to 2 cycles of 21 days each in patients with relapsed/refractory T-ALL.	Drug: PD-1 Inhibitors; PD-1 inhibitor+venetoclax+Cytarabine+Aclarubicin+G-CSF regimen; Other Names: G-CSF; Cytarabine; Aclarubicin; venetocalx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mCRc	CR+CRi+MLFS	At the end of Cycle 2 (each cycle is 21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		After 2 years
Side effect	Hematological and non-hematological adverse reactions	At the end of every Cycle (each cycle is 21 days)
minimal residual disease, MRD		At the end of every Cycle (each cycle is 21 days)

Collaborators and Investigators

• Sponsor: Fujian Medical University Union Hospital
• Investigators: Principal Investigator: Shaoyuan Wang, Pro, Fujian Institute of Hematology,Fujian Provincial Key Laboratory on Hematology,Fujian Medical University Union Hospital

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2025
• Primary Completion (Estimated): January 31, 2027
• Study Completion (Estimated): January 31, 2029

Study Registration Dates

• First Submitted: January 15, 2026
• First Submitted That Met QC Criteria: April 14, 2026
• First Posted (Actual): April 21, 2026

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 14, 2026
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: venetoclax; PD-1 inhibitor; CAG; acute T-lymphoblastic leukemia
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, Lymphoid; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hemic and Lymphatic Diseases; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Antineoplastic Agents, Immunological; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Pharmacologic Actions; Chemical Actions and Uses; Therapeutic Uses; Hydrocarbons; Hydrocarbons, Cyclic; Biological Factors; Carbohydrates; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glycosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Intercellular Signaling Peptides and Proteins; Arabinonucleosides; Anthracyclines; Naphthacenes; Aminoglycosides; Glycoproteins; Glycoconjugates; Colony-Stimulating Factors; Hematopoietic Cell Growth Factors; Cytokines; Immune Checkpoint Inhibitors; Cytarabine; Granulocyte Colony-Stimulating Factor; Aclarubicin
• Other Study ID Numbers: FujianUnionH-XYK2025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The anonymized raw data generated in this study will be shared within six months after the publication of the main research results. The shared data include baseline characteristics of the subjects, efficacy evaluation results and safety data. The data will be provided through the following channels: 1. Public database: Upload to the "Results" section of ClinicalTrials.gov. 2. On-demand application: Researchers can contact the corresponding author by email, submit the research plan and data usage agreement, and obtain the data after approval by the ethics committee. The use of data must meet the following conditions: - Only for non-commercial academic research; Do not attempt to identify the identity of the subjects; When citing data, the source must be indicated.
• IPD Sharing Time Frame: Within 6 months after the publication of the main results.
• IPD Sharing Access Criteria: Data will be accessible through two channels: (1) Publicly available in the "Results" section of ClinicalTrials.gov; (2) Upon reasonable request to the corresponding author. For channel (2), researchers must submit a research plan and data use agreement. Access is granted after approval by the ethics committee. Data use is restricted to non-commercial academic research. Users must not attempt to identify participants and must cite the source.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No