Reduced‑intensity post‑induction chemotherapy plus blinatumomab versus standard post‑induction therapy in pediatric standard‑risk B‑ALL (AIEOP‑BFM ALL 2025)

• To improve the outcome of children and adolescents with acute lymphoblastic leukemia by incorporating targeted therapies—either immunotherapy or pathway‑specific small molecules—delivered as randomized or non‑randomized modular interventions within an enhanced risk‑adapted stratification that integrates clinical features, genetic profiling, and in‑vivo treatment response.
• In the Standard‑Risk B‑ALL sub‑protocol, to assess whether a reduced‑intensity post‑induction chemotherapy combined with a single 28‑day cycle of blinatumomab can lower treatment burden without compromising disease control compared with standard post‑induction therapy.

The trial enrolled 900 participants diagnosed with acute lymphoblastic leukemia (including mixed phenotype acute leukemia meeting specified criteria). Eligible individuals were children and adolescents younger than 18 years at diagnosis, encompassing both male and female patients. All participants were newly diagnosed and had received standard induction and early consolidation therapy according to current treatment recommendations before enrollment. Inclusion required written informed consent from guardians, assent from the child when appropriate, and classification as standard‑risk B‑ALL or meeting B‑cell immunology criteria for the sub‑protocol. No specific dietary, physical‑activity, or other lifestyle restrictions were stipulated. The cohort was recognized as vulnerable due to its pediatric nature.

The study is a phase III, randomized, controlled trial evaluating a reduced‑intensity post‑induction chemotherapy combined with a 28‑day cycle of blinatumomab in patients with acute lymphoblastic leukemia who meet standard‑risk B‑cell criteria. Recruitment is planned to begin on 1 September 2026 and continue until 31 August 2036. After obtaining informed consent, participants undergo a screening visit to confirm eligibility, followed by baseline assessments prior to randomization. Subsequent study visits are scheduled at the end of each treatment phase (post‑induction, consolidation, and maintenance) to monitor disease status, administer study drugs, and record safety and efficacy parameters. An end‑of‑study visit is performed after completion of the treatment regimen and final follow‑up assessments. Participants remain in the trial from the screening visit through the end‑of‑study visit, with the total period of involvement determined by the individual treatment schedule and follow‑up requirements. Individual participation may be discontinued in accordance with protocol‑specified criteria, such as predefined safety thresholds, withdrawal of consent, or disease progression.

The experimental immunotherapy component consists of blinatumomab supplied as a powder for concentrate and solution for infusion, administered by continuous intravenous infusion at a dose of 28 µg daily for 28 days, substituting the standard post‑induction chemotherapy cycle.

Methotrexate sodium is provided in the pharmaceutical form PHF00231MIG for intravenous administration at a dose of 5000 mg/m² per infusion, given according to the protocol‑defined schedule.

Cyclophosphamide is supplied in the pharmaceutical form PHF00231MIG for intravenous infusion at a dose of 500 mg/m² per administration, administered on the designated treatment days.

Mercaptopurine is supplied in the pharmaceutical form PHF00245MIG for oral administration at a dose of 100 mg/m² per day, taken as prescribed in the treatment regimen.

Vinorelbine (listed under the name VINCRISTINE) is provided in the pharmaceutical form PHF00007MIG for intravenous infusion at a dose of 2 mg per infusion, administered on the scheduled chemotherapy days.

Pegaspargase is administered intravenously at a dose of 3750 IU per infusion, given on the protocol‑specified day.

Cytarabine is supplied in the pharmaceutical form PHF00230MIG for intravenous infusion at a dose of 75 mg/m² per administration, delivered according to the treatment schedule.

Dexamethasone acetate is provided in the pharmaceutical form PHF00245MIG for oral administration at a dose of 10 mg/m² per day, taken as directed.

Tioguanine is supplied in the pharmaceutical form PHF00245MIG for oral administration at a dose of 60 mg/m² per day, administered according to the protocol.

Recombinant L‑asparaginase (Enrylaze) is supplied as a solution for injection/infusion at a dose of 50 mg/m² per intravenous infusion, given on the assigned treatment day.

Doxorubicin hydrochloride is provided in the pharmaceutical form PHF00231MIG for intravenous infusion at a dose of 30 mg/m² per administration, administered on the scheduled chemotherapy days.

All investigational and standard‑of‑care agents are administered according to the defined dosing schedule, with dosing times recorded in the study case report form. Compliance is monitored by site personnel through direct observation of administration, verification of dose calculations based on body surface area, and documentation of any dose modifications or missed doses.

Efficacy will be evaluated using time‑to‑event and incidence endpoints. The primary efficacy parameter is Disease‑free survival, defined as the interval from randomization to the earliest occurrence of relapse, second malignancy, or death from any cause, or to the date of last follow‑up if no event occurs. Secondary efficacy assessments include overall survival (time from randomization to death from any cause or last follow‑up), cumulative incidence of treatment‑related mortality, cumulative incidence of relapse, frequency of adverse events of interest and serious adverse events, total number of inpatient treatment days, and quality‑of‑life outcomes collected in a separate add‑on study.

All time‑to‑event endpoints will be calculated using standard survival analysis methods, with censoring at the date of last follow‑up for participants without an event. Incidence rates will be estimated using competing‑risk analyses where appropriate. Adverse‑event data and inpatient days will be extracted from the clinical trial case report forms, and quality‑of‑life will be measured with validated patient‑reported outcome instruments specified in the ancillary protocol.