Blinatumomab and Combination Therapy Versus Standard of Care in Older Adults With Newly Diagnosed Philadelphia-Negative B-Cell Precursor Acute Lymphoblastic Leukemia

The primary objective of this phase 3 study is to compare event-free survival (EFS) in older adults with newly diagnosed Philadelphia-negative B-cell precursor acute lymphoblastic leukemia receiving blinatumomab alternating with low-intensity chemotherapy versus those receiving standard of care (SOC) chemotherapy. Additionally, overall survival (OS) will be evaluated as a primary clinical outcome. A safety run-in phase is also conducted to assess the safety and tolerability of the alternating regimen.

Secondary objectives include:

• Evaluation of additional efficacy endpoints and pharmacokinetics (PK) during the safety run-in.
• Comparison of patient-reported outcomes (PROs), specifically fatigue and pain, and assessment of global health status using the EORTC QLQ-C30.
• Analysis of safety profiles and non-relapse mortality.
• Characterization of relapses based on CD19 expression, lineage switch, and relapse localization.
• Evaluation of the proportion of patients undergoing allogeneic or autologous hematopoietic stem cell transplantation (HSCT) during the first continuous complete remission (CR), and subsequent relapse and mortality rates following HSCT.

This study involves 134 participants diagnosed with newly diagnosed Philadelphia-negative B-cell precursor acute lymphoblastic leukemia. The study population includes both male and female patients, categorized within specific age ranges. The cohort consists of older adults aged 55 years or older, or individuals aged 40 to 54 years presenting with specific comorbidities such as diabetes mellitus with end-organ damage, severe liver disease, or a body mass index of 40 or greater. Participants must exhibit an Eastern Cooperative Oncology Group performance status of 2 or less, unless a higher score is attributed to the underlying leukemia. Inclusion requires adequate organ function, specifically a renal estimated glomerular filtration rate of at least 50 mL/min/1.73 m2, a left ventricular ejection fraction of at least 50%, and appropriate hepatic function. The primary objectives are:

• To evaluate the safety and tolerability of blinatumomab alternating with low-intensity chemotherapy.
• To compare event-free survival between the experimental regimen and standard of care chemotherapy.
• To compare overall survival between the experimental regimen and standard of care chemotherapy.

This Phase 3 randomized, controlled study evaluates the efficacy and safety of blinatumomab alternating with low-intensity chemotherapy compared to the standard of care for older adults with newly diagnosed Philadelphia-negative B-cell precursor acute lymphoblastic leukemia. The study includes a safety run-in period to assess the tolerability of the experimental regimen. The primary objectives are to compare event-free survival and overall survival between the two treatment arms. Study procedures begin with a screening visit to confirm eligibility based on age, performance status, and organ function. Following randomization, participants undergo treatment consisting of various therapeutic agents, including rituximab, cytarabine, and vincristine sulfate. Clinical assessments are conducted to monitor complete remission, minimal residual disease, and patient-reported outcomes such as fatigue and pain. The trial is expected to continue through approximately April 2031. Early termination may occur based on safety concerns or clinical criteria defined within the protocol.

The experimental treatment regimen consists of several investigational components. Blinatumomab is administered via intravenous use at a dose of 28 µg. Rituximab is administered via intravenous use at a dose of 375 mg/m². Cytarabine is administered via intravenous use at a dose of 1000 mg/m². Cyclophosphamide is administered via intravenous use at a dose of 150 mg/m². Dexamethasone is administered either via oral use at 10 mg/m² or via intravenous use at 10 mg/m². Methotrexate sodium is administered via intravenous use at 1 mg/m² or via oral use at 20 mg/m². Mercaptopurine is administered via oral use at 60 mg/m². Vincristine sulfate is administered via intravenous use at 8 mg.

The comparator treatment group receives standard-of-care therapies. Dexamethasone is administered via oral use at 40 mg/m² or via intravenous use at 40 mg. Rituximab is administered via intravenous use at 375 mg/m². Blinatumomab is administered via intravenous use at 28 µg. Cyclophosphamide is administered via intravenous use at 500 mg/m². Prednisone is administered via oral use at 200 mg. Idarubicin is administered via intravenous use at 10 mg. Prednisolone is administered via oral use at 200 mg. Pegaspargase is administered via intravenous use at 1000 U. Doxorubicin is administered via intravenous use at 50 mg/m². Cytarabine is administered via intravenous use at 60 mg/m². Mercaptopurine is administered via oral use at 60 mg/m². Vincristine sulfate is administered via intravenous use at 2 mg. Asparaginase is administered via intravenous use at 6000 U. Crisantaspase is administered via intravenous use at 50 mg/m². Methotrexate sodium is administered via intravenous use at 1 mg/m² or via oral use at 20 mg.

The efficacy of the investigational regimen in patients with Philadelphia-negative B-cell precursor Acute Lymphoblastic Leukemia will be evaluated through several primary and secondary endpoints. The primary efficacy endpoints for the Phase 3 component include event-free survival (EFS), defined as the time from randomization to treatment failure, relapse, or death from any cause, and overall survival (OS), defined as the time from randomization to death due to any cause. During the safety run-in, efficacy is assessed via complete remission (CR), minimal residual disease (MRD) response levels, and relapse-free survival (RFS).

Secondary efficacy assessments include:

• MRD RFS, which tracks the time from achieving CR with MRD response to the first occurrence of molecular, hematologic, or extramedullary relapse, or death.
• Pharmacokinetic (PK) parameters for blinatumomab, specifically steady state concentration (Css) and clearance (CL).
• Patient-reported outcomes, including changes from baseline in fatigue scores via the PROMIS Fatigue – Short Form 7a, pain scores via the Brief Pain Inventory – Short Form (BPI-SF), and various quality of life measures using the QLQ-C30 scale, such as global health status, physical function, and nausea/vomiting.
• Analysis of relapse characteristics, including lineage switch to acute myeloid leukemia (AML), localization of relapse, and CD19 positive or negative relapse identified through flow cytometry or immunohistochemistry in bone marrow and cerebrospinal fluid.
• Clinical outcomes related to hematopoietic stem cell transplantation (HSCT) and mortality rates in CR.