IntReALL HR 2010

Primary objectives
To improve the rates of complete remission (CR) in HR ALL relapse patients
Secondary objectives:
Improve rates of event-free survival (EFS) and overall survival (OS)
Improvement in MRD reduction after induction with versus without bortezomib
Evaluation of the toxicity of induction with versus without bortezomib
Evaluation of the efficacy of the consolidation elements with regard to reducing the MRD burden until to allo-HSCT

The IntReALL HR 2010 study is an international multicenter, unblinded, randomized therapy optimization study.
It includes the following treatment arms:

• Induction: prospective, adaptive, unblinded randomized phase II study comparing arm A (modified ALL R3 protocol) with arm B (modified ALL R3 protocol + bortezomib)
• Post-induction: Single-arm post-induction observational study with intensive polychemotherapy with the blocks HC1 (modified AIEOP-BFM ALL 2009 HR1 block) and HC2 (modified HR3 block).
• NEW September 2019: 3rd post-induction block: as the interim analysis of the Amgen Blinatumomab study showed superiority of the Blinatumomab cycle over the HC3 block, the study was terminated early and all patients can receive the Blinatumomab cycle.
• All patients in morphologically complete 2nd remission will undergo allogeneic HSCT.
• Termination of the study after completion of the second or third consolidation block prior to the investigational window study and/or allo-HSCT. Follow-up will continue until the secondary EFS/OS endpoints are reached
• Patients with an inadequate response to therapy (MRD ≥ 10-3 after induction) may receive individualized consolidation therapy based on individual biological characteristics of the leukemia (if such treatment is available)

• Morphologically confirmed diagnosis of a first relapse of B-precursor or T-cell ALL
• Children under 18 years of age at the time of inclusion in the study
• Fulfillment of all HR criteria
• Inclusion of the patient in a participating study center
• Written informed consent available
• Start of treatment during ongoing study
• No participation in other clinical studies that interfere with this study protocol (except ALL first disease studies) within 30 days prior to inclusion in the study

• BCR-ABL/ t(9;22) positive ALL
• Pregnancy or positive pregnancy test (urine sample positive for β-HCG over 10 U/l)
• Sexually active adolescents who do not consent to the use of highly effective contraception (Pearl Index under 1) until 12 months after the end of antileukemic therapy
• Breastfeeding
• Recurrence after allogeneic HSCT
• Neuropathy higher II°
• Refusal of the entire protocol or significant parts by the patient themselves, their parents/guardians or their legal guardian
• No consent for storage and transfer of pseudonymized medical data for study reasons
• Serious concomitant diseases which, in the opinion of the investigator, do not allow treatment in accordance with the protocol (e.g. malformation syndromes, cardiac malformations, metabolic disorders)
• Patients who are unwilling or unable to comply with the study procedures
• Placement in an institution by court or official order