Safety and efficacy of low-intensity chemotherapy combined with sequential blinatumomab and inotuzumab ozogamicin immunotherapy in newly diagnosed B-ALL patients unfit/fit-declined for intensive chemotherapy: A prospective, open-label, single-arm Phase II trial in progress Free

Intensive, multiagent chemotherapy remains the cornerstone of conventional therapy for B-cell acute lymphoblastic leukemia (B-ALL), but is poorly tolerated by older adults or those with major comorbidities. Dose reductions or omissions in chemotherapy alone are significantly associated with a higher risk of relapse. Novel immunotherapies, especially inotuzumab ozogamicin (InO) and blinatumomab (BiTE), delivered alongside or sequentially after low-intensity chemotherapy achieve high complete remission (CR) rates of 90-97% and deep molecular responses, with 1-year overall survival (OS) of 84-100% in older or high-risk patients (pts) and manageable toxicity (NCT01371630; NCT03739814). However, antigen escape-mediated resistance and optimal regimen sequencing/dosing still compromise long-term benefit. We hypothesize that sequential delivery of BiTE followed by InO may preempt resistance by eliminating antigen-loss variants through complementary mechanisms, while low-intensity chemotherapy primes the microenvironment for enhanced immunotherapy.

This single-arm trial (NCT06985485) at the First Affiliated Hospital of Soochow University in China will evaluate the safety and efficacy of low-intensity chemotherapy combined with full-course sequential immunotherapy in B-ALL. The study will enroll 26 newly diagnosed B-ALL pts aged ≥60 years or 15-60 years, who are either unfit for intensive chemotherapy or fit but have declined it (fit-declined). Unfit pts must have Eastern Cooperative Oncology Group performance status ≥2 or at least one of: 1) congestive heart failure requiring therapy or left ventricular ejection fraction of ≤50%, 2) diffusing capacity of carbon monoxide of ≤65% or forced expiratory volume in the first second of ≤65%, 3) creatinine >2×the upper limit of normal [ULN] or creatinine clearance <45 mL/min), 4) total bilirubin >1.5×ULN or aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3×ULN), 5) active uncontrolled infection, 6), cognitive impairment, 7) other chemotherapy-contraindicated comorbidities.

Induction therapy consists of low-intensity chemotherapy combined with BiTE with or without TKIs. Regimen included dexamethasone 8 mg/m²/day intravenously injection (IV), days 1-14, vindesine 4 mg, IV, day 7, followed by blinatumomab dosed by body weight: pts ≥45 kg receive fixed dosing (9 µg/day days 1-7, 28 µg/day days 8-28), pts <45 kg receive BSA-adjusted dosing (5 µg/m²/day days 1-7, 15 µg/m²/day days 8-28). Philadelphia chromosome-positive ALL pts receive second-generation TKIs, with subsequent switch to third-generation TKIs upon resistance.If morphologic remission is not achieved after initial therapy, a salvage cycle with InO (0.8 mg/m², day 1, IV) will be administered. Those with persistent treatment failure will discontinue protocol therapy and transition to alternative therapies (e.g. hematopoietic stem cell transplantation, or clinical trials). Post-remission consolidation chemotherapy includes high-dose methotrexate followed by sequential immunotherapy: BiTE (per weight-stratified dosing), then after a 2-week break, InO (0.8 mg/m² on day 1), followed by another 2-week break. This sequence is repeated for 4 cycles. Each cycle includes two lumbar punctures for central nervous system prophylaxis, administered before BiTE and before InO, respectively. Pts then enter long-term follow-up, and those who relapse are withdrawn from the study.

The primary endpoint is OS, analyzed using the Kaplan-Meier method to estimate median survival time and corresponding 95% confidence intervals (CI). Secondary endpoints include: CR rate and objective response rate, assessed by the Clopper-Pearson method for 95% CIs; event-free survival and relapse-free survival, estimated via Kaplan-Meier; non-relapse mortality and cumulative incidence of relapse, calculated using competing risks analysis; and safety endpoints.

This study aims to establish a full-course immunotherapy approach potentially reducing chemotherapy in this population while addressing challenges like antigen escape via sequential CD19/CD22 targeting.