The main goal of this study is to improve the outcome of children and adolescents with acute lymphoblastic leukemia with high risk first relapse by optimization of treatment strategies within a large international trial and the integration of new agents.
Morphologically confirmed diagnosis of 1st relapsed precursor B-cell or T-cell ALL
Children less than 18 years of age at date of inclusion into the study
Meeting HR criteria any BM relapse, early/very early isolated BM relapse, very early isolated/combined extramedullary relapse)
Patient enrolled in a participating centre
Breakpoint cluster region-Abelson (BCR-ABL)/ t(9;22) positive ALL
Pregnancy or positive pregnancy test (urine sample positive for β-humane choriongonadotropin (HCG) > 10 U/l)
Sexually active adolescents not willing to use highly effective contraceptive method (pearl index <1) until 12 months after end of anti-leukemic therapy
Breast feeding
Parallel
Bortezomib
DrugPatients randomised to the HR-B arm receive induction, consolidation with the modified ALL R3 protocol. In this arm, patients are randomized to receive Bortezomib together with the ALL R3 protocol during induction. Administration of Bortezomib: 1.3 mg/m2 as intravenous bolus or subcutaneously (SC, at the discretion of the treating physician) on days 1 and 4 of weeks 1 and 3.
Rate of Complete Remission
Rate of complete second remission (CR2) quantified by cytology after induction with standard chemotherapy + bortezomib (arm B) compared with standard chemotherapy (arm A).
Event-free Survival
Improvement of three years event-free survival (EFS)
Overall Survival
Improvement of three years overall survival (OS)
Minimal Residual Disease Reduction (MRD)
Improvement of Minimal Residual Disease (MRD) reduction after induction with versus without bortezomib
Minimal Residual Disease Load
Improvement of MRD load prior to stem cell transplantation (SCT).
Minimal Residual Disease in Isolated Extramedullary Relapse
The rate and extent of sub-microscopic bone marrow (BM) involvement in extramedullary leukemia will be investigated prospectively.
Extended Genetic Characterization
Extension of genetic characterization and correlation with clinical data
In-vitro drug response profile
Generation of primografts from patient samples for bio-banking and drug testing by using immunodeficient mice. The outcome measure is the in-vitro drug response profile using the primograft of primary patient sample. The in-vitro drug response profile will be compared to the in-vivo drug response of a patient. In order to get an "in-vitro drug response profile" apoptosis/viability of the primary patient sample or patient-derived xenograft sample is measured using different concentrations of novel drugs normally after 48 hours of treatment. These drugs could be potentially given to a patient, when there will be no response to conventional protocol treatment. Apoptosis/viability is measured by live cell imaging microscopy or/and by flow cytometry. The report will include half maximal inhibitory concentration (IC50), the concentration of a drug which kills half of the cell after a defined time (normally 48h) for a variety of potential drugs.
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Charite University, Berlin, Germany
Lead sponsor
Australian & New Zealand Children's Haematology/Oncology Group
Collaborator
St. Anna Kinderkrebsforschung, CCRI (co-sponsor, Austria)
Collaborator
European Organisation for Research and Treatment of Cancer - EORTC
Collaborator
University Hospital, Motol
Collaborator
Rigshospitalet, Denmark
Collaborator
Turku University Central Hospital (co-sponsor, Finland)
Collaborator
Centre Hospitalier Universitaire de Nice
Collaborator
Our Lady's Chilrden's Hospital (Co-Sponsor Ireland)
Collaborator
Tel Aviv Sourasky Medical Centre (Co-Sponsor Israel)
Collaborator
Ospedale Pediatrico Bambino (co-sponsor, Italy)
Collaborator
Prinses Máxima Centrum (Co-Sponsor Netherlands)
Collaborator
Oslo University Hospital (co-sponsor, Norway)
Collaborator
Wroclaw Medical University
Collaborator
Instituto Português de Oncologia de Lisboa (co-sponsor, Portugal)
Collaborator
Karolinska University Hospital Stockholm (co-sponsor, Sweden)
Collaborator
Spanish Society of Pediatric Hematology and Oncology (SEHOP) (Co-Sponsor Spain)
Collaborator
University Children's Hospital, Zurich
Collaborator
Manchester University NHS Foundation Trust
Collaborator
