PD-1 Inhibitors +Venetoclax+CAG Regimens in R/R T-ALL

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.

Inclusion criteria

• Age >=18 years old;
• Met the T-ALL diagnosis before enrollment (for specific diagnostic criteria, see the attachment);
• 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);
• The performance status score of the Eastern Cooperative Oncology Group (ECOG) in the United States ranges from 0 to 2 points.
• Expected survival period >=3 months;
• During the screening period, there were no organ function abnormalities that restricted the use of this scheme.
• Understand this study and sign the informed consent form.

Exclusion criteria

• 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;
• 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.);
• There has been a history of other malignant tumors within the past five years;
• 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;
• Inability to understand or comply with the research protocol;
• Patients under 18 years old.