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

Sponsor

Martin Schrappe (Other)

Overall Status

Recruiting

CT.gov ID

NCT03643276

Collaborator

Deutsche Krebshilfe e.V., Bonn (Germany) (Other)

5,000

Enrollment

115

Locations

Arms

120

Anticipated Duration (Months)

43.5

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia, Pediatric	Drug: Blinatumomab Drug: Bortezomib Drug: Cyclophosphamide Drug: Cytarabine Drug: Daunorubicin Drug: Myocet Drug: Dexamethasone Drug: Doxorubicin Drug: Etoposide Drug: Fludarabine Phosphate Drug: Ifosfamide Drug: 6-Mercaptopurine Drug: Methotrexate Drug: Pegaspargase Drug: Prednisolone Drug: Tioguanin Drug: Vincristine Drug: Vindesine Drug: Erwinase	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

5000 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Intervention Model Description:

pB-ALL/MR: 2 parallel groups (R-MR) or 2x2 factorial design (R-eHR, R-MR) depending on early risk group assignment. pB-ALL/HR: 2 parallel groups (R-HR) or 2x2 factorial design (R-eHR, R-HR) depending on early risk group assignment. T-ALL/early non-SR: 2 parallel groups (R-T). pB-ALL/SR: Single group. T-ALL/early SR: Single group.pB-ALL/MR: 2 parallel groups (R-MR) or 2x2 factorial design (R-eHR, R-MR) depending on early risk group assignment. pB-ALL/HR: 2 parallel groups (R-HR) or 2x2 factorial design (R-eHR, R-HR) depending on early risk group assignment. T-ALL/early non-SR: 2 parallel groups (R-T). pB-ALL/SR: Single group. T-ALL/early SR: Single group.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jul 15, 2018

Anticipated Primary Completion Date :

Jul 14, 2028

Anticipated Study Completion Date :

Jul 14, 2028

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: pB: early (non-)HR-standard/MR-standard Induction (5 wks): "Protocol IA" with prednisolone, vincristine, daunorubicin, pegaspargase, IT methotrexate (MTX) Consolidation (6 w/4 w): "Consolidation extended" (control arm of randomization R-eHR) with cyclophosphamide, cytarabine, 6-mercaptopurine (6-MP), IT MTX, dexamethasone, vincristine, pegaspargase or "Consolidation short" (standard arm of early non-HR group) with cyclophosphamide, cytarabine, 6-mercaptopurine, IT MTX Extra-compartment phase (8 wks): "Protocol M" with 6-MP, HD-MTX, IT MTX Reinduction (6 wks): "Protocol II" with dexamethasone, vincristine, doxorubicin, pegaspargase, IT MTX, cyclophosphamide, tioguanine, cytarabine Maintenance (until 2 years after initial diagnosis): 6-MP, MTX [without preceding blinatumomab (control arm of randomization R-MR)] Erwinase is given in case of allergy to pegaspargase.	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: Dexamethasone Part of standard chemotherapy Drug: Doxorubicin 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 Other Names: Prednisone Drug: Tioguanin Part of standard chemotherapy Drug: Vincristine Part of standard chemotherapy Drug: Erwinase Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction
Experimental: pB: early HR-exp./MR-standard Induction (5 w): "Protocol IA" with prednisolone, vincristine, daunorubicin, pegaspargase, IT MTX Consolidation (6 w): "Consolidation extended+BZM" (experimental arm of randomization R-eHR) with cyclophosphamide, cytarabine, 6-MP, IT MTX, dexamethasone, vincristine, pegaspargase, bortezomib (given at 1.3 mg/m²/dose on days 50, 53, 56 and 59) Extra-compartment phase (8 wks): "Protocol M" with 6-MP, HD-MTX, IT MTX Reinduction (6 wks): "Protocol II" with dexamethasone, vincristine, doxorubicin, pegaspargase, IT MTX, cyclophosphamide, tioguanine, cytarabine Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX [without preceding blinatumomab (control arm of randomization R-MR)] Erwinase is given in case of allergy to pegaspargase.	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: Dexamethasone Part of standard chemotherapy Drug: Doxorubicin 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 Other Names: Prednisone Drug: Tioguanin Part of standard chemotherapy Drug: Vincristine Part of standard chemotherapy Drug: Erwinase Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction
Experimental: pB: early (non)HR-standard/MR-exp. Induction (5 w): "Protocol IA" with prednisolone, vincristine, daunorubicin, pegaspargase, IT MTX Consolidation (6 w/4 w): "Consolidation extended" (control arm in randomization R-eHR) with cyclophosphamide, cytarabine, 6-MP, IT MTX, dexamethasone, vincristine, pegaspargase or "Consolidation short" (standard arm of early non-HR group) with cyclophosphamide, cytarabine, 6-mercaptopurine, IT MTX Extra-compartment phase (8 w): "Protocol M" with 6-MP, HD-MTX, IT MTX Reinduction (6 w): "Protocol II" with dexamethasone, vincristine, doxorubicin, pegaspargase, IT MTX, cyclophosphamide, tioguanine, cytarabine Blinatumomab (4 w): 1 cycle blinatumomab given at 15 µg/m²/day for 28 days (experimental arm of randomization R-MR) Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX Erwinase is given in case of allergy to pegaspargase.	Drug: Blinatumomab Experimental therapy in randomizations R-HR and R-MR 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: Dexamethasone Part of standard chemotherapy Drug: Doxorubicin 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 Other Names: Prednisone Drug: Tioguanin Part of standard chemotherapy Drug: Vincristine Part of standard chemotherapy Drug: Erwinase Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction
Experimental: pB: early HR-exp./MR-exp. Induction (5 w): "Protocol IA" with prednisolone, vincristine, daunorubicin, pegaspargase, IT MTX Consolidation (6 w): "Consolidation extended+BZM" (experimental arm of randomization R-eHR) with cyclophosphamide, cytarabine, 6-MP, IT MTX, dexamethasone, vincristine, pegaspargase, bortezomib (given at 1.3 mg/m²/dose on days 50, 53, 56 and 59) Extra-compartment phase (8 w): "Protocol M" with 6-MP, HD-MTX,IT MTX Reinduction (6 weeks): "Protocol II" with dexamethasone, vincristine, doxorubicin, PEG-L-asparaginase, IT MTX, cyclophosphamide, tioguanine, cytarabine Blinatumomab (4 w): 1 cycle blinatumomab given at 15 µg/m²/day for 28 days (experimental arm of randomization R-MR) Maintenance phase (until 2 yrs after initial diagnosis): 6-MP, MTX Erwinase is given in case of allergy to pegaspargase.	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: Dexamethasone Part of standard chemotherapy Drug: Doxorubicin 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 Other Names: Prednisone Drug: Tioguanin Part of standard chemotherapy Drug: Vincristine Part of standard chemotherapy Drug: Erwinase Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction
Active Comparator: pB: early (non-)HR-standard/HR-standard Induction (5 w): as in other pB arms Consolidation (6 w/4 w): "Consolidation extended" (control arm in randomization R-eHR) with cyclophosphamide, cytarabine, 6-MP, IT methotrexate, dexamethasone, vincristine, pegaspargase or "Consolidation short" (standard arm of early non-HR group) with cyclophosphamide, cytarabine, 6-MP, IT MTX Intensified consolidation (3x5 d): Block HR-1' followed by HR-2' and HR-3' (control arm in randomization R-HR) with dexamethasone, vincristine, vindesine, daunorubicin, HD-MTX, IT MTX, HD-cytarabine, cyclophosphamide, ifosfamide, pegaspargase, etoposide Reinduction (3x4 w): "Protocol III" given 3 times with dexamethasone, vincristine, doxorubicin, pegaspargase, IT MTX, cyclophosphamide, tioguanine, cytarabine Maintenance (until 2 yrs after init. diagnosis): 6-MP, MTX Erwinase is given in case pegaspargase allergy. Pts with poor response to intensified consolidation receive Myocet-FLA (Myocet, fludarabine, HD-cytarabine, IT-MTX).	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 Other Names: Prednisone 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
Experimental: pB: early HR-exp./HR-standard Induction (5 w): as in other pB arms Consolidation (6 w): "Consolidation extended+BZM" (experimental arm of randomization R-eHR) with cyclophosphamide, cytarabine, 6-MP, IT MTX, dexamethasone, vincristine, pegaspargase, bortezomib (1.3 mg/m²/dose on days 50, 53, 56 and 59) Intensified consolidation (3x5 d): Block HR-1' followed by HR-2' and HR-3' (control arm in randomization R-HR) with dexamethasone, vincristine, vindesine, daunorubicin, HD-MTX, IT MTX, HD-cytarabine, cyclophosphamide, ifosfamide, pegaspargase, etoposide Reinduction (3x4 w): as in arm "pB: early (non-)HR-standard/HR-standard" Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX Erwinase is given in case of allergy to pegaspargase. Pts with poor response to intensified consolidation receive Myocet-FLA (Myocet, fludarabine, HD-cytarabine, IT-MTX)	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 Other Names: Prednisone 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
Experimental: pB: early (non-)HR-standard/HR-exp. Induction (5 w): as in other pB arms Consolidation (6 w/4 w): "Consolidation extended" (control arm in randomization R-eHR) with cyclophosphamide, cytarabine, 6-MP, IT MTX, dexamethasone, vincristine, pegaspargase or "Consolidation short" (standard arm of early non-HR group) with cyclophosphamide, cytarabine, 6-MP, IT MTX Intensified consolidation (1x5 d + 2x28 d): Block HR-1' with dexamethasone, vincristine, HD-MTX, IT MTX, HD-cytarabine, cyclophosphamide, pegaspargase followed by 2 cycles blinatumomab at 15 µg/m²/day for 28 days per cycle plus 2x2 doses IT MTX (experimental arm of randomization R-HR) Reinduction (3x4 weeks): as in arm "pB: early (non-)HR-standard/HR-standard" Maintenance (until 2 yrs after init. diagnosis): 6-MP, MTX Erwinase is given in case of pegaspargase allergy. Pts with poor response to intensified consolidation receive Myocet-FLA (Myocet, fludarabine, HD-cytarabine, IT-MTX)	Drug: Blinatumomab Experimental therapy in randomizations R-HR and R-MR 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: 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 Other Names: Prednisone Drug: Tioguanin Part of standard chemotherapy Drug: Vincristine Part of standard chemotherapy Drug: Erwinase Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction
Experimental: pB: early HR-exp./HR-exp. Induction (5 w): as in other pB arms Consolidation (6 w): "Consolidation extended+BZM" (experimental arm of randomization R-eHR) with cyclophosphamide, cytarabine, 6-MP, IT MTX, dexamethasone, vincristine, pegaspargase, bortezomib (1.3 mg/m²/dose on days 50, 53, 56 and 59) Intensified consolidation (1x5 d + 2x28 d): Block HR-1' with dexamethasone, vincristine, HD-MTX, IT MTX, HD-cytarabine, cyclophosphamide, pegaspargase followed by 2 cycles blinatumomab at 15 µg/m²/day for 28 days per cycle plus 2x2 doses IT MTX (experimental arm of randomization R-HR) Reinduction (3x4 weeks): as in arm "pB: early (non-)HR-standard/HR-standard" Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX Erwinase is given in case of allergy to pegaspargase. Pts with poor response to intensified consolidation receive Myocet-FLA (Myocet, fludarabine, HD-cytarabine, IT-MTX)	Drug: Blinatumomab Experimental therapy in randomizations R-HR and R-MR 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: 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 Other Names: Prednisone Drug: Tioguanin Part of standard chemotherapy Drug: Vincristine Part of standard chemotherapy Drug: Erwinase Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction
Other: pB: early non-HR/SR Induction (5 w): "Protocol IA" with prednisolone, vincristine, daunorubicin, pegaspargase, IT MTX Consolidation (4 w): "Consolidation short" with cyclophosphamide, cytarabine, 6-mercaptopurine, IT MTX Extra-compartment phase (8 w): "Protocol M" with 6-MP, HD-MTX, IT MTX Reinduction (6 w): "Protocol II" with dexamethasone, vincristine, doxorubicin, pegaspargase, IT MTX, cyclophosphamide, tioguanine, cytarabine Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX Erwinase is given in case of allergy to pegaspargase.	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: Dexamethasone Part of standard chemotherapy Drug: Doxorubicin 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 Other Names: Prednisone Drug: Tioguanin Part of standard chemotherapy Drug: Vincristine Part of standard chemotherapy Drug: Erwinase Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction
Active Comparator: T: early non-SR-standard/(non-)HR Induction (5 w): "Protocol IA-Dexa" with prednisolone/dexamethasone, vincristine, daunorubicin, pegaspargase, IT MTX or "Protocol IA-CPM" with prednisolone instead of dexamethasone and additional CPM Consolidation (4 w): "Protocol IB regular" (control arm in randomization. R-T) with cyclophosphamide, cytarabine, 6-mercaptopurine, IT MTX non-HR extra-compartment phase and reinduction: as in arm "pB: early non-HR/SR" HR intensified consolidation and reinduction: as in arm "pB: early (non-)HR-standard/HR-standard" Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX Erwinase is given in case of allergy to pegaspargase. Pts with poor response to intensified consolidation receive Myocet-FLA (Myocet, fludarabine, HD-cytarabine, IT-MTX)	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 Other Names: Prednisone 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
Experimental: T: early non-SR-exp/(non-)HR Induction (5 w): "Protocol IA-Dexa" with prednisolone/dexamethasone, vincristine, daunorubicin, pegaspargase, IT MTX or "Protocol IA-CPM" with prednisolone instead of dexamethasone and additional CPM Consolidation (6 w): "Protocol IB long" (experimental arm in randomization R-T) with cyclophosphamide, cytarabine, 6-mercaptopurine, IT MTX non-HR extra-compartment phase and reinduction: as in arm "pB: early non-HR/SR" HR intensified consolidation and reinduction: as in arm "pB: early (non-)HR-standard/HR-standard" Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX Erwinase is given in case of allergy to pegaspargase. Pts with poor response to intensified consolidation receive Myocet-FLA (Myocet, fludarabine, HD-cytarabine, IT-MTX)	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 Other Names: Prednisone 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
Other: T: early SR/non-HR Induction (5 w): "Protocol IA-Dexa" with prednisolone/dexamethasone, vincristine, daunorubicin, pegaspargase, IT MTX Consolidation (4 w): "Protocol IB regular" with cyclophosphamide, cytarabine, 6-mercaptopurine, IT MTX Extra-compartment phase (8 w): "Protocol M" with 6-MP, HD-MTX, IT MTX Reinduction (6 w): "Protocol II" with dexamethasone, vincristine, doxorubicin, pegaspargase, IT MTX, cyclophosphamide, tioguanine, cytarabine Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX Erwinase is given in case of allergy to pegaspargase.	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: Dexamethasone Part of standard chemotherapy Drug: Doxorubicin 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 Other Names: Prednisone Drug: Tioguanin Part of standard chemotherapy Drug: Vincristine Part of standard chemotherapy Drug: Erwinase Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction

Outcome Measures

Primary Outcome Measures

Event-free survival [Assessed up to 120 months from start of study]
Randomization R-eHR, R-HR and R-T: Time from randomization until the first event defined as follow: cytomorphological or molecular non-response (resistance to protocol treatment, considered as event at day zero), relapse, second malignancy or death from any cause. This will be called EFS time.
Disease-free survival [Assessed up to 120 months from start of study]
Randomization R-MR: Time from randomization until the first event defined as follow: Relapse, second malignancy or death from any cause. This will be called DFS time.

Secondary Outcome Measures

Survival [Assessed up to 120 months from start of study]
All patients/randomizations: Time until death from any cause, starting at the same time point as the EFS/DFS.
Treatment-related mortality [Assessed up to 120 months from start of study]
Frequency and incidence of treatment-related mortality in induction or continuous complete remission
Adverse Events of interest/Serious Adverse Events [Assessed up to 120 months from start of study]
Frequency and incidence of adverse events of interest and serious adverse events in specific protocol phases, randomized arms and overall during follow-up
MRD response [Measurements of MRD response at end of randomized treatments (intended time frame 13 weeks in R-eHR/R-T, 26 weeks in R-HR, 34 weeks in R-MR).]
MRD load after the randomized treatment phases (R-eHR, R-HR, R-MR and R-T) as well as after the first/second cycle of Blinatumomab or after the HR 2'/HR 3' block (R-HR)
Proportion of patients with Blina Poor-Response [Measurements of MRD response intended after 30 weeks from individual start of treatment, assessment of proportion at 120 months from start of study]
Proportion of patients with poor MRD response to the first Blinatumomab cycle ("Blinatumomab Poor-Response") (R-HR)

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

newly diagnosed acute lymphoblastic leukemia or
newly diagnosed mixed phenotype acute leukemia (MPAL) meeting one of the following criteria:
biphenotypic with a dominant T or B lineage assignment
bilineal either with a dominant lymphoblastic population or if another reasonable rationale exists to treat the patient with an ALL-based therapy regimen
newly diagnosed acute undifferentiated leukemia
age < 18 years (up to 17 years and 365 days) at the day of diagnosis
patient enrolled in a participating center
written informed consent to trial participation and transfer and processing of data A subsequent removal from the study is only allowed if the inclusion criteria turn out not to be fulfilled or in the case of pregnancy of the patient.

Exclusion Criteria:

Ph+ (BCR-ABL1 or t(9;22)-positive) ALL
bilineal leukemia with a lymphoblastic and a separate non-lymphoblastic (≥ 10% of total cells) blast subset
pre-treatment with cytostatic drugs
glucocorticoid pre-treatment with ≥ 1 mg/kg/d for more than two weeks during the last month before diagnosis
treatment started according to another protocol
underlying disease that does not allow treatment according to the protocol (e.g. severe congenital heart disease, Charcot-Marie Syndrome, Ataxia-teleangiectasia…)
ALL diagnosed as second malignancy and preceding chemotherapy and/or radiotherapy
evidence of pregnancy or lactation period
Sexually active adolescents not willing to use highly effective contraceptive method (pearl index <1) until 12 months after end of anti-leukemic therapy
participation in another clinical trial except for add-on trials within the scope of supportive care approved by the sponsor
live vaccine immunization within 2 weeks before start of protocol treatment

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Sydney Children's Hospital	Sydney	Australia
2	The Children's Hospital at Westmead	Westmead	Australia
3	Univ.Klinik für Kinder- und Jugendheilkunde Graz	Graz	Austria
4	Univ.Klinik für Kinder- und Jugendheilkunde Innsbruck	Innsbruck	Austria
5	Kepler Universitätsklinikum	Linz	Austria
6	LKH Salzburg	Salzburg	Austria
7	St. Anna Kinderspital	Vienna	Austria
8	University Hospital Brno	Brno	Czechia
9	University Hospital Hradec Králové	Hradec Králové	Czechia
10	University Hospital Olomouc	Olomouc	Czechia
11	University Hospital Ostrava-Poruba	Ostrava-Poruba	Czechia
12	University Hospital Plzeň	Plzeň	Czechia
13	University Hospital Motol	Praha	Czechia
14	Masaryk´s Hospital Ústí nad Labem	Ústí nad Labem	Czechia
15	Regional Hospital České Budějovice	České Budějovice	Czechia
16	Kinderklinik der med. Fakultät der RWTH, Bereich Hämatologie/Onkologie	Aachen	Germany	52074
17	I. Klinik für Kinder u. Jugendliche, Klinikum Augsburg, Hämatologie/ Onkologie	Augsburg	Germany	86156
18	Klinikum Berlin-Buch II. Kinderklinik, Bereich Onkologie/Allg. Pädiatrie	Berlin	Germany	13125
19	Kinderklinik der Charité, Campus Virchow Klinikum (CVK), Abt.: Kinderhämatologie	Berlin	Germany	13353
20	Städtisches Krankenhaus, Kinderklinik	Braunschweig	Germany	38118
21	Klinikum Chemnitz gGmbH, Klinik für Kinder- und Jugendmedizin, Hämatologie / Onkologie	Chemnitz	Germany	09009
22	Carl-Thiem-Klinikum, Kinderklinik, Abt. Hämatologie/Onkologie	Cottbus	Germany	03048
23	Vestische Kinder- u. Jugendklinik, Universitätsklinik Witten/Herdecke	Datteln	Germany	45711
24	Klinikum Dortmund, Klinik f. Kinder- und Jugendmedizin	Dortmund	Germany	44137
25	Universitatsklinikum Carl Gustav Carus	Dresden	Germany	D-01307
26	Universitätsklinik	Düsseldorf	Germany
27	Helios Klinikum Erfurt GmbH, Klinik für Kinderheilkunde	Erfurt	Germany	99089
28	Universitaets - Kinderklinik	Erlangen	Germany	91054
29	Universitaetsklinikum Essen	Essen	Germany	D-45147
30	Klinikum der J.W. Goethe Universitaet	Frankfurt	Germany	D-60590
31	Universitaetskinderklinik - Universitaetsklinikum Freiburg	Freiburg	Germany	D-79106
32	Klinikum der Justus-Liebig-Universität, Zentrum für Kinderheilkunde, Abt. Hämatologie/Onkologie	Gießen	Germany	35385
33	Klinik und Poliklinik für Kinder und Jugendmedizin, Allgemeine Pädiatrie mit Poliklinik/Pädiatrische Onkologie und Hämatologie	Greifswald	Germany	17475
34	Universitäts-Kinderklinik Päd. I, Hämatologie/Onkologie	Göttingen	Germany	37099
35	Medizinische Hochschule Hannover, Zentrum Kinderheilkunde u. Jugendmedizin	Hannover	Germany	30625
36	Universitäts-Kinderklinik, Päd. Onkologie, Hämatologie, und Immunologie	Heidelberg	Germany	69120
37	Klinikum Heilbronn GmbH, Klinik für Kinderheilkunde und Jugendmedizin/Perinatalzentrum	Heilbronn	Germany	74078
38	Gemeinschaftskrankenhaus Herdecke, Kinderabteilung	Herdecke	Germany	58313
39	Universitaetsklinikum des Saarlandes	Homburg	Germany	66421
40	Klinikum, der Friedrich-Schiller-Universität, Klinik für Kinder- und Jugendmedizin	Jena	Germany	7740
41	Staedtisches Klinikum Karlsruhe gGmbH	Karlsruhe	Germany	76133
42	Klinikum Kassel	Kassel	Germany	D-34125
43	Klinik für Allgemeine Paediatrie, Univ.-Klinikum Schleswig-Holstein, Campus Kiel	Kiel	Germany	24105
44	Kliniken der Stadt Köln GmbH, Kinderkrankenhaus Riehl	Köln	Germany	50735
45	Med. Einrichtungen der Universität zu Köln, Klinik für Allg. Kinderheilkunde, Onkologisch-hämatologische Station	Köln	Germany	50937
46	Department für Frauen- und Kindermedizin, Abteilung für Pädiatrische Onkologie, Hämatologie und Hämostaseologie	Leipzig	Germany	04103
47	Universität zu Lübeck, Klinik für Kinder- u. Jugendmedizin, Abt. Hämatologie/ Onkologie/Immunologie	Lübeck	Germany	23538
48	Universitätsklinikum Magdeburg, Klinik für Päd. Hämatologie/Onkologie	Magdeburg	Germany	39120
49	Klinikum Mannheim gGmbH, Kinderklinik, Abt. Hämatologie/Onkologie	Mannheim	Germany	68167
50	Universitätsklinikum	Mannheim	Germany
51	Johannes Wesling Klinikum Minden	Minden	Germany	32429
52	Städt. Krankenhaus München GmbH, Krankenhaus München-Schwabingen, Kinderklinik d. TU	München	Germany	80804
53	Ludwig-Maximilian-Universität, Dr. von Haunersches Kinderspital	München	Germany
54	Universitäts-Kinderklinik, Päd. Hämatologie und Onkologie	Münster	Germany	48149
55	Cnopf'sche Kinderklinik, Onkologie	Nürnberg	Germany	90419
56	Klinikum Oldenburg gGmbH, Zentrum für Kinder- u. Jugendmedizin, (Elisabeth Kinderkrankenhaus)	Oldenburg	Germany	26133
57	Universitätsklinikum	Regensburg	Germany
58	Universitäts-Kinderklinik	Rostock	Germany	18055
59	Asklepios-Klinik, Sankt Augustin GmbH	Sankt Augustin	Germany	53757
60	HELIOS Kliniken Schwerin, Klinik f. Kinder-u. Jugendmedizin	Schwerin	Germany	19049
61	Olga-Hospital, Kinderklinik, Pädiatrisches Zentrum, Abt. Hämatologie/Onkologie	Stuttgart	Germany	70176
62	Krankenanstalt Trier, Mutterhaus der Borromaeerinnen, Pädiatrische Abteilung	Trier	Germany	54290
63	Universitaetsklinikum Tuebingen	Tuebingen	Germany	D-72076
64	Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm	Ulm	Germany	D-89075
65	Stadtkrankenhaus, Kinderklinik	Wolfsburg	Germany	38440
66	Universitaets - Kinderklinik Wuerzburg	Wuerzburg	Germany	D-97080
67	Soroka University Medical Center	Beer Sheva	Israel
68	Rambam Health Care Campus	Haifa	Israel
69	Hadassah Medical center	Jerusalem	Israel
70	Schneider Children Medical Center of Israel	Petach-Tikva	Israel
71	Sheba Medical Center Tel-Hashomer	Ramat Gan	Israel
72	Dana children hospital	Tel-Aviv	Israel
73	Azienda ospedali riuniti	Ancona	Italy
74	AOUC Policlinico Bari	Bari	Italy
75	A.O. Papa Giovanni XXIII	Bergamo	Italy
76	Università di Bologna	Bologna	Italy
77	ASST Spedali Civili di Brescia	Brescia	Italy
78	Ospedale Businco	Cagliari	Italy
79	Azienda ospedaliero universitaria	Catania	Italy
80	AO Pugliese Ciaccio	Catanzaro	Italy
81	S.O. Annunziata - A. O. Cosenza	Cosenza	Italy
82	Ospedale Meyer	Firenze	Italy
83	Istituto Giannina Gaslini	Genova	Italy
84	Policlinico di Modena Azienda Ospedaliero-Universitaria	Modena	Italy
85	Clinica pediatrica Fondazione MBBM	Monza	Italy
86	A.O.U. Vanvitelli	Napoli	Italy
87	AORN Santobono Pausilipon	Napoli	Italy
88	Azienda ospedaliera di Padova	Padova	Italy
89	Ospedale Civico ARNAS Civico e Di Cristina	Palermo	Italy
90	Azienda ospedaliero-universitaria di Parma	Parma	Italy
91	Fondazione IRCCS Policlinico San Matteo	Pavia	Italy
92	Ospedale S. Maria della misericordia	Perugia	Italy
93	Ospedale Civile di Pescara	Pescara	Italy
94	Ospedale Santa Chiara Pisa	Pisa	Italy
95	Grande ospedale metropolitano B-M-M	Reggio Calabria	Italy
96	Ospedale infermi	Rimini	Italy
97	Fondazione Policlinico Gemelli	Roma	Italy
98	Ospedale Bambino Gesù	Roma	Italy
99	Policlinico Umberto I Università Sapienza di Roma	Roma	Italy
100	Ospedale "Casa sollievo della sofferenza"	San Giovanni Rotondo	Italy
101	A.O.U. Città della salute e della scienza di Torino	Torino	Italy
102	IRCCS Burlo Garofolo	Trieste	Italy
103	AOU Verona	Verona	Italy
104	Klinika pediatrickej hematológie a onkológie SZU a DFNsP	Banská Bystrica	Slovakia
105	Comenius University Children's Hospital	Bratislava	Slovakia
106	Detská fakultná nemocnica Košice	Košice	Slovakia
107	Kantonsspital Aarau	Aarau	Switzerland
108	Universitäts-Kinderspital beider Basel	Basel	Switzerland
109	Ospedale San Giovanni Bellinzona	Bellinzona	Switzerland
110	Inselspital Bern	Bern	Switzerland
111	HUG Hôpitaux Universitaires de Gèneve	Genève	Switzerland
112	CHUV Centre Hospitalier Universitaire Vaudois	Lausanne	Switzerland
113	Luzerner Kantonsspital-Kinderspital Luzern	Luzern	Switzerland
114	Ostschweizer Kinderspital	St. Gallen	Switzerland
115	Universitäts-Kinderspital Zürich	Zürich	Switzerland