Efficacy and Safety of Low-dose Chemotherapy Plus Immuno-targeted Drugs in Newly Diagnosed Elderly/Unfit Ph- B-ALL

In the treatment of Ph-negative (Ph-) B-cell acute lymphoblastic leukemia (B-ALL), despite the achievements of chemotherapy and immunotherapy, the therapeutic outcomes are unsatisfactory in elderly or unfit patients. In recent years, tumor immunotherapy has demonstrated a high safety and efficacy profile in refractory Ph- B-ALL patients. These findings suggest that the advancement of immunotherapy application may be an important approach to improve patient survival. In this study, we propose a treatment approach that combines immuno-targeted drugs with low-dose chemotherapy for newly diagnosed elderly or unfit patients with Ph- B-ALL, aiming to enhance the measurable residual disease (MRD)-negative complete remission (CR) rate measured through flow cytometry following induction therapy, reduce the risk of relapse, and ultimately improve patients' overall survival.

In this open-label, single-arm, Phase II study, prospective clinical trial, a total of 53 Ph-negative (Ph-) B-cell acute lymphoblastic leukemia (B-ALL) patients will be enrolled. The primary endpoint is measurable residual disease (MRD)-negative complete remission (CR) rate after induction therapy.

The first cycle of induction therapy is administered with Inotuzumab ozogamicin (INO), Venetoclax (VEN), and a combination of low-dose chemotherapy. The second cycle of induction therapy is Blinatumomab (Blino) plus VEN regimen. Alternatively, the first cycle of induction therapy is a combination of VEN and low-dose chemotherapy, and the second cycle of induction therapy is methotrexate (MTX) plus cytarabine (Ara-C) plus VEN regimen. Subsequent consolidation and maintenance therapy consist of low-dose chemotherapy, Blino, and VEN. Patients can receive chimeric antigen receptor T-Cell (CAR-T) Immunotherapy or allogeneic hematopoietic stem cell transplantation (HSCT) or receive autologous HSCT whenever possible during their first CR. Otherwise, they will finish the consolidation chemotherapy. Study patients are scheduled for follow-up for at least 5 years after the end of maintenance therapy.

The purpose of current study is to determine the efficacy and safety of low-dose chemotherapy combined with immuno-targeted drugs in newly diagnosed elderly or unfit patients with Ph- B-ALL.

Eligibility Criteria:
Inclusion Criteria:

1. Newly diagnosed Ph-negative B-cell acute lymphoblastic leukemia according to World Health Organization (WHO) 2016 criteria
2. CD22 positive tumor cells
3. ≥60 years of age, or 18 to 59 years of age, with at least one of the following: Eastern Cooperative Oncology Group (ECOG) performance status of 2 - 3; severe heart, lung, liver, or kidney disease; presence of comorbidities that are not suitable for intensive chemotherapy in the physician's judgment
4. Estimated survival ≥3 months
5. Consent and effective contraception for men and women of childbearing potential
6. Understanding and signing of informed consent forms and agreement to comply with study requirements.

Exclusion Criteria:

1. Burkitt lymphoma/leukemia
2. acute leukemias of ambiguous lineage
3. pregnant women
4. severe uncontrolled active infection
5. previous history of chronic liver disease (e.g. cirrhosis) or venous occlusive liver disease (VOD) or sinus obstruction syndrome (SOS)
6. History of clinically significant ventricular arrhythmia, syncope of unknown origin (not vasovagal) or sinoatrial block or higher degree atrioventricular (AV) block Chronic bradycardia state (unless permanent pacemaker implanted)
7. New or chronic hepatitis B or C infection (positive for hepatitis B surface antigen and anti-hepatitis C antibody, respectively) or known HIV seropositivity. HIV testing may need to be performed according to local regulations or practices
8. Psychiatric disorders likely to prevent the subject from completing treatment or informed consent
9. Other conditions considered unsuitable for the study by the investigator.