IntReAll SR 2010

Late isolated B-cell precursor (BCP) bone marrow (BM) relapse, late/early combined BCP BM relapse, any late/early isolated extramedullary (EM) relapse. End of recruitment: July 2020

Intergroup, international multicentre, phase III treatment optimisation trial

Though survival of children with acute lymphoblastic leukemia (ALL) has considerably improved over the past few decades, relapsed ALL remains a leading cause of mortality in children with cancer. Given the rarity of the disease, prospective clinical trials need to be coordinated within an international cooperative group such as the International BFM Study Group (I-BFM-SG). Within the group, over the last few years two different treatment protocols, ALL-REZ BFM 2002 and ALL R3 have been used by most study groups for treatment of relapsed ALL. Both trials have produced comparable results.
For non-HR or standard risk (SR) patients both ALL-REZ BFM 2002 and ALL R3 have achieved better results than previous trials.
Both protocols have however been primarily used in patients relapsing off different frontline protocols. Thus there is need for a prospective randomized controlled comparison across the study groups, before a uniform backbone for further trials can be developed.
In SR patients, survival may be improved by modifying the consolidation therapy using the targeted non-myelotoxic drug Epratuzumab (humanised chimeric anti CD22 antibody). Epratuzumap will be randomized.

Primary objevtives

• Overall: Improvement of event-free survival (EFS) probabilities in childhood relapsed ALL
• Randomization 1: EFS of Arm A (ALL-REZ BFM 2002) versus B (ALLR3) in SR patients
• Randomization 2: Influence of epratuzumab on EFS in consolidation of SR patients

Before the start of the treatment the first ramdomization into the study-arms A (ALL-REZ BFM 2002) or B (UK-ALL-R3) has to take place. After the end of the induction therapy all patient with a response (M1 or M2) to the therapy will be randomized into the study-arms "With Epratuzumab" or "Without Epratuzumab".
Depending of the site of relapse the result of the MRD before the consolidation therapy decides, if the patient is eligible for Stem cell transplantation (SCT) and what donor-type is aceptable:

-patients of arm A (ALL-REZ BFM 2002) are eligible for allogeneic SCT if MRD after induction at week 5 is ≥ 10-3;
-patients of arm B (ALLR3) are eligible for allogeneic SCT if MRD after induction at day 35 is ≥ 10-4.

• Morphologically confirmed diagnosis of 1st relapsed precursor B-cell or T-cell ALL
• Children less than 18 years of age at inclusion
• Meeting SR criteria: late isolated or late/early combined BCP BM relapse, any late/early isolated extramedullary relapse
• Patient enrolled in a participating centre
• Written informed consent
• Start of treatment falling into the study period
• No participation in other clinical trials 30 days prior to study enrolment that interfere with this protocol, except trials for primary ALL

Inclusion criteria specific for the epratuzumab randomization

• Precursor B-cell Immunophenotype of ALL
• M1 or M2 bone marrow status after induction

• Sexually active adolescents not willing to use highly effective contraceptive method (pearl index <1) until 2 years after end of antileukemic therapy
• Breast feeding
• Relapse post allogeneic stem-cell transplantation
• The whole protocol or essential parts are declined either by patient himself/herself or the respective legal guardian
• No consent is given for saving and propagation of pseudonymized medical data for study reasons
• Severe concomitant disease that does not allow treatment according to the protocol at the investigator’s discretion (e.g. malformation syndromes, cardiac malformations, metabolic disorders)
• Karnovsky / Lansky score < 50%
• Subjects unwilling or unable to comply with the study procedures
• Subjects who are legally detained in an official institute