NCT03643276

Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia - AIEOP-BFM ALL 2017

International Collaborative Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia - AIEOP-BFM ALL 2017

• Status: Recruiting
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 5,000 (estimated)
• Sponsor: Martin Schrappe · Academic / Other
• Sex: All
• Age: 17 Years
• Healthy volunteers: Not accepted

Summary

The understanding of acute lymphoblastic leukemia (ALL) in childhood and adolescence has largely changed due to extensive genetic research in recent years: ALL is now considered to be a very heterogeneous disease group. The leukemia cells present themselves with quite differently activated regulatory mechanisms of the malignant phenotype. The introduction of more accurate methods of assessing therapy response ("minimal residual disease \[MRD\] tests") has provided new insights into very different mechanisms of action, including factors influenced by host factors; this has had practical clinical consequences for the use of more individualized therapy. Multimodal therapies have enabled a cure level of over 80% for ALL in this age group. However, the own and international study data show that the therapy toxicity of the contemporary chemotherapy concepts has become unacceptably high, in particular with respect to those intensified therapies used for the treatment of patients at high risk of ALL relapse. The AIEOP-BFM ALL 2017 study therefore aims for an innovative integrated approach that will not only adapt the risk stratification to new prognostic markers using more comprehensive diagnostics, but above all, qualitatively reorient the therapy. The most important consequence will be that this study is testing immunotherapy with the bispecific antibody blinatumomab as an alternative to particularly intensive and toxic chemotherapy elements in precursor B-cell ALL (pB-ALL) patients with detectable chemotherapy resistance and at high risk of relapse. With the aim to complement the effects of the conventional chemotherapy, Blinatumomab is in addition tested in the large group of pB-ALL patients at intermediate relapse risk with seemingly unremarkable leukemia, but who account for a large proportion of all relapses. Targeted therapy is also used in the form of the proteasome inhibitor bortezomib for patients with pB-ALL and slow response to the drugs of the induction chemotherapy with the aim to overcome intrinsic chemotherapy resistance of the ALL cells. In patients with T-lineage ALL, who have particularly poor chances for cure after relapse, the established consolidation chemotherapy has proved to be particularly effective. This chemotherapy phase is therefore tested in a longer and more intensive form in such T-ALL patients with intermediate or slow early treatment response with the aim to reduce the relapses rate in this subgroup.

Detailed description

Patients are stratified into 4 early risk groups for therapy during the consolidation phase (T/early SR, T/early non-SR, pB/early non-HR, pB/early HR) and 5 risk groups for post-consolidation therapy (T/non-HR, T/HR, pB/SR, pB/MR, pB/HR). Risk stratification is based on immunophenotypic lineage, genetics of leukemic cells and treatment response on the basis of cytomorphology and methods for detection minimal residual disease. The trial includes four randomized study questions testing experimental treatments on top of the risk-stratified standard chemotherapy backbone: Primary study questions: Randomization R-eHR: Early High-risk (early HR) pB-ALL defined by genetics and/or inadequate treatment response over the course of induction: Can the probability of event-free survival (pEFS) from time of randomization be improved by additional therapy with the proteasome inhibitor bortezomib during an extended consolidation treatment phase compared with standard extended consolidation? Randomization R-HR: High-risk (HR) pB-ALL defined by genetics and/or inadequate treatment response by the end of consolidation: Can the pEFS from time of randomization be improved by a treatment concept including two cycles of post-consolidation immunotherapy with blinatumomab (15 µg/m²/d for 28 days per cycle) plus 4 doses intrathecal Methotrexate replacing two conventional highly intensive chemotherapy courses? Randomization R-MR: Intermediate risk (MR) pB-ALL defined by genetics and intermediate MRD response: Can the probability of disease-free survival (pDFS) from time of randomization be improved by additional therapy with one cycle of post-reintensification immunotherapy with blinatumomab (15 µg/m²/d for 28 days)? Randomization R-T: Early non-standard risk (early non-SR) T-ALL patients defined by treatment response over the course of induction: Can the pEFS from time of randomization be improved by the extension of the standard of care consolidation phase by 14 days with an increase of the consolidation cumulative doses of Cyclophosphamide, Cytarabine and 6-Mercaptopurine by 50%? Secondary study questions: All randomizations: Can the overall survival be improved by the treatment in the experimental arm? All randomizations: What is the incidence of treatment-related toxicities and mortality in the experimental arm compared to the standard arm? Randomization R-eHR: Can the MRD load after consolidation treatment be reduced by the additional treatment with bortezomib? Randomization R-HR: Can treatment-related life-threatening complications and mortality during the intensified consolidation phase of high-risk treatment be reduced when replacing two intensive chemotherapy courses by two cycles of immunotherapy with blinatumomab? Randomization R-HR: What is the proportion of patients with insufficient MRD response to blinatumomab as defined in the protocol as compared to the MRD response after the HR-2' block in the control arm? Randomization R-HR: Can the MRD load after the first treatment cycle (HR 2'/blinatumomab) and the second cycle (HR-3'/blinatumomab) be reduced in the experimental arm when compared with conventional intensive chemotherapy? Randomization R-MR: What is the proportion of patients with positive MRD after reintensification Protocol II who become MRD-negative over the blinatumomab cycle compared to 4 weeks of standard maintenance therapy? Randomization R-T: Can the MRD load after consolidation treatment be reduced by extension of the consolidation phase? Standard-risk patients: Is the clinical outcome comparable to that obtained for standard-risk patients in study AIEOP-BFM ALL 2009? A small subgroup of patients at very high relapse risk is eligible for allogeneic hematopoietic stem cell transplantation after the intensified consolidation therapy phase. Patients with T-ALL and hyperleukocytosis (\>=100,000/µL) and patients with CNS involvement at diagnosis (CNS3 status) are eligible for cranial irradiation with 12 Gy if age at time of irradiation is at least 4 years.

Conditions

• Acute Lymphoblastic Leukemia, Pediatric

Interventions

Type	Name	Description
DRUG	Blinatumomab	Experimental therapy in randomizations R-HR and R-MR
DRUG	Bortezomib	Experimental therapy in randomization R-eHR
DRUG	Cyclophosphamide	Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T
DRUG	Cytarabine	Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T and in the intensification block Myocet-FLA for patients with very high relapse risk
DRUG	Daunorubicin	Part of standard chemotherapy
DRUG	Myocet	Part of intensification block Myocet-FLA for patients with very high relapse risk
DRUG	Dexamethasone	Part of standard chemotherapy
DRUG	Doxorubicin	Part of standard chemotherapy
DRUG	Etoposide	Part of standard chemotherapy
DRUG	Fludarabine Phosphate	Part of intensification block Myocet-FLA for patients with very high relapse risk
DRUG	Ifosfamide	Part of standard chemotherapy
DRUG	6-Mercaptopurine	Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T
DRUG	Methotrexate	Part of standard chemotherapy
DRUG	Pegaspargase	Part of standard chemotherapy
DRUG	Prednisolone	Part of standard chemotherapy
DRUG	Tioguanin	Part of standard chemotherapy
DRUG	Vincristine	Part of standard chemotherapy
DRUG	Vindesine	Part of standard chemotherapy
DRUG	Erwinase	Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction

Timeline

• Start date: 2018-07-15
• Primary completion: 2028-07-14
• Completion: 2028-07-14
• First posted: 2018-08-22
• Last updated: 2025-04-06

Locations

115 sites across 8 countries: Australia, Austria, Czechia, Germany, Israel, Italy, Slovakia, Switzerland