Exploratory Study of CD22/CD19 Dual-Target CAR-T Cell Therapy as Consolidation Treatment After First Remission in High-Risk B-Cell Acute Lymphoblastic Leukemia

An Exploratory Study on Targeted CD22/CD19 Chimeric Antigen Receptor (CAR)-T Cell Immunotherapy for Enhanced Consolidation Therapy After Initial Remission in High-risk B-cell Acute Lymphoblastic Leukemia

This single-center, open-label, single-arm, prospective study will evaluate the safety, tolerability, and efficacy of CD22/CD19 dual-target chimeric antigen receptor T-cell (CAR-T) therapy as consolidation treatment in patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) who have achieved first remission after standard induction therapy and consolidation chemotherapy. Approximately 30 patients will be enrolled. Participants will undergo screening, cell collection for CAR-T manufacturing, lymphodepleting chemotherapy, and subsequent CAR-T cell infusion, followed by scheduled safety and efficacy follow-up. Safety assessments will include monitoring for cytokine release syndrome (CRS), neurotoxicity, hematologic toxicity, organ toxicity, infections, and other adverse events. Efficacy assessments will include event-free survival (EFS), overall survival (OS), progression-free survival (PFS), duration of response(DOR), relapse, and mortality. Exploratory analyses will assess CAR-T cell kinetic characteristics and clonal evolution after treatment.

Inclusion Criteria:

1. Patients who have provided written informed consent and are willing and able to comply with study procedures, including scheduled visits, treatment, laboratory tests, and other study-related assessments.

2. Patients with cytologically or histologically confirmed B-cell acute lymphoblastic leukemia/lymphoma (B-ALL/LBL) according to WHO 2022 criteria, with CD19-positive and/or CD22-positive disease. Patients must have achieved first morphological complete remission (CR1; bone marrow blasts <5%) after standard induction chemotherapy. Patients may or may not have achieved deep remission, defined as minimal residual disease (MRD) negativity assessed by flow cytometry and/or molecular methods (e.g., quantitative PCR or next-generation sequencing).

3. Patients who are eligible for enhanced consolidation therapy. Patients with high-risk disease defined as:

   High-risk group based on cytogenetic and molecular features, regardless of MRD status after consolidation; or Standard-risk group with persistent MRD positivity after two cycles of consolidation therapy, indicating a high risk of relapse.

   In addition, patients are unwilling or ineligible to allogeneic hematopoietic stem cell transplantation, and are planned to receive CAR-T cell therapy as consolidation treatment.

4. Age between 18 and 85 years, regardless of sex.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

6. Estimated life expectancy ≥3 months.

7. Hemoglobin ≥60 g/L (transfusion allowed).

8. Absolute neutrophil count ≥1,000/μL and platelet count ≥45,000/μL.

9. Adequate organ function, defined as:

   Total bilirubin ≤1.5 × upper limit of normal (ULN) (except Gilbert's syndrome); ALT and AST ≤2.5 × ULN; Serum creatinine ≤1.5 × ULN or creatinine clearance ≥60 mL/min (Cockcroft-Gault formula); Left ventricular ejection fraction (LVEF) ≥50%, no clinically significant arrhythmia, and no pericardial effusion; Baseline oxygen saturation >92% on room air; No clinically significant pleural effusion.

10. Subjects of reproductive potential must agree to use effective contraception from enrollment until at least 6 months after completion of the study. Subjects who are pregnant or suspected to be pregnant must notify the investigator immediately.

Exclusion Criteria:

1. Patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), or with risk factors indicating the need for allogeneic hematopoietic stem cell transplantation (meeting any of the following), who are planned to receive allogeneic hematopoietic stem cell transplantation or CD19/CD3 bispecific antibody (blinatumomab) therapy and refuse CAR-T cell immunotherapy as consolidation treatment, including any of the following conditions:

   ① Early relapse within 6 months after achieving first complete remission;

   ② Primary refractory disease, defined as failure to achieve first morphological complete remission after two cycles of standard first-line induction chemotherapy;

   ③ Failure to achieve complete remission or relapse after first-line or multiple lines of salvage chemotherapy;

   ④ Relapse after allogeneic hematopoietic stem cell transplantation.

2. Prior treatment with any CAR-T cell therapy or other genetically modified T-cell therapies.

3. Known history of HIV infection, active hepatitis B virus (HBV) infection, or any uncontrolled active systemic infection requiring intravenous antibiotics.

   (Active HBV infection is defined as: HBV DNA ≥2000 IU/mL, ALT ≥2×ULN, and exclusion of other causes of hepatitis.)

4. Non-disease-related hepatic or renal dysfunction defined as:

   ALT or AST >3×ULN; Total bilirubin >2×ULN; Creatinine clearance <30 mL/min.

5. History of significant cardiovascular disease within 12 months prior to enrollment, including myocardial infarction, coronary intervention, unstable angina, or clinically significant arrhythmia.

6. Other severe or uncontrolled medical conditions that may interfere with study participation or outcomes, including but not limited to uncontrolled diabetes, severe gastrointestinal disease, severe cardiopulmonary disease, autoimmune disease, immunodeficiency, or uncontrolled infections.

7. History of severe immediate hypersensitivity reactions to study-related drugs, aminoglycosides, or biologic agents.

8. Pregnant or breastfeeding women.

9. Patients who are unable or unwilling to comply with study procedures or follow-up, or who have poor adherence as judged by the investigator.

10. History of other malignancies unless disease-free for at least 3 years without active treatment (except for adequately treated non-melanoma skin cancer or carcinoma in situ).

11. Receipt of live vaccines within 6 weeks prior to initiation of lymphodepleting chemotherapy.

12. Major surgery within 14 days prior to enrollment or planned major surgery during the study period.

13. Any other condition that, in the investigator's judgment, may increase risk, interfere with study results, or make the patient unsuitable for the study.