Overview

This trial is a non-blinded, single-center, open-label, single-arm clinical study to evaluate a full-course immunotherapy regimen in patients with B-cell acute lymphoblastic leukemia (B-ALL). The study population includes newly diagnosed patients who are unfit for or decline intensive chemotherapy, as well as patients with relapsed/refractory disease or with measurable residual disease (MRD) positivity following prior chemotherapy. The trial aims to explore the efficacy and safety of sequential therapy with a CD19-directed CD3 T-cell engager and inotuzumab ozogamicin. The primary endpoint is overall survival (OS), while secondary endpoints include complete remission rate (CRR)、Objective Response Rate (ORR)、Event-free survival (EFS)、Relapse-free survival (RFS)、Cumulative incidence of relapse (CIR)、Non-relapse mortality (NRM) and safety.

Eligibility

Inclusion Criteria:

1. Newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL) patients aged ≥60 years, as per NCCN guidelines.
2. Newly diagnosed B-ALL patients aged ≥15 to \<60 years who are unfit for intensive chemotherapy (Unfit), as per NCCN guidelines, meeting at least one of the following criteria:

1、ECOG score ≥2 2、Severe cardiac comorbidities (e.g., congestive heart failure requiring treatment, left ventricular ejection fraction ≤50%, unstable angina) 3、Severe pulmonary comorbidities (e.g., DLCO ≤65%, FEV1 ≤65%) 4、Severe renal comorbidities (e.g., serum creatinine \>2×upper limit of normal (ULN), creatinine clearance \<45 mL/min by any formula) 5、Severe hepatic comorbidities (e.g., total bilirubin \>1.5×ULN, AST/ALT/ALP \>3×ULN) 6、Active infection refractory to antimicrobial therapy 7、Documented cognitive impairment 8、Other comorbidities contraindicating intensive chemotherapy (3) Newly diagnosed B-ALL patients aged ≥15 to \<60 years with good performance status and adequate organ function who decline intensive chemotherapy for subjective reasons (Fit-Declined), as per NCCN guidelines (e.g., fear of toxicity, financial/social/psychological factors, preference for quality of life).

(4) Patients aged ≥15 years with relapsed/refractory B-ALL or MRD positivity after prior chemotherapy (5) All patients must meet the following organ function requirements:

1. Left ventricular ejection fraction (LVEF) ≥40% by echocardiogram
2. Creatinine clearance ≥30 mL/min (by any formula)
3. ALT and AST ≤3×ULN, total bilirubin ≤2×ULN (unless attributed to leukemia)
4. ≤Grade 1 dyspnea and oxygen saturation \>91% without supplemental oxygen (6) Ability to understand and voluntarily sign the informed consent form. (7) Life expectancy ≥3 months.

Exclusion Criteria:

1. Presence of central nervous system (CNS) or other extramedullary disease.
2. Concurrent other active malignancies or malignancies requiring treatment.
3. Prior exposure to CD19- or CD22-targeted therapies (including but not limited to CD19-directed CD3 T-cell engager, inotuzumab ozogamicin, CD19 or/and CD22 CAR-T).
4. Use of immunosuppressive agents within 2 weeks prior to signing informed consent, or planned long-term immunosuppressive therapy after enrollment.
5. Active cardiac disease (NYHA Class ≥3 as assessed by medical history and physical examination).
6. Severe chronic liver disease (e.g., cirrhosis, nodular regenerative hyperplasia, active hepatitis \[HBsAb-positive, HCVAb-positive\]).

1、Patients with occult or prior HBV infection (defined as HBcAb-positive, HBsAg-negative) are eligible only if HBV DNA PCR is negative, and require monthly HBV DNA monitoring with prophylactic antiviral therapy.

2、HCV antibody-positive patients are eligible only if HCV RNA PCR is negative. 3、History of confirmed severe or persistent veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS).

(7) Bacterial, fungal, viral, mycoplasma, or other infections that are uncontrolled as judged by the investigator; HIV, syphilis, or SARS-CoV-2 infection.

(8) Past or current CNS disorders, such as seizures, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any CNS-related autoimmune disease.

(9) Primary immunodeficiency or active autoimmune disease. (10) History of severe immediate hypersensitivity to any study drugs. (11) Receipt of live vaccine within 6 weeks prior to screening. (12) Psychiatric disorders or other conditions that may compromise compliance with study requirements, treatment, or monitoring.

(13) Pregnant or breastfeeding women, or fertile patients unwilling to use contraception.

(14) Any other condition deemed unsuitable for study participation by the investigator.