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.
