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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Acute Lymphoblastic Leukemia, Pediatric

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: pB: early (non-)HR-standard/MR-standard<br>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<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Cytarabine<br>* 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<br>Drug: Daunorubicin<br>* Part of standard chemotherapy<br>Drug: Dexamethasone<br>* Part of standard chemotherapy<br>Drug: Doxorubicin<br>* Part of standard chemotherapy<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Methotrexate<br>* Part of standard chemotherapy<br>Drug: Pegaspargase<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* Part of standard chemotherapy<br>* Other names: Prednisone;Drug: Tioguanin<br>* Part of standard chemotherapy<br>Drug: Vincristine<br>* Part of standard chemotherapy<br>Drug: Erwinase<br>* Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction<br>|
| Experimental: pB: early HR-exp./MR-standard<br>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<br>* Experimental therapy in randomization R-eHR<br>Drug: Cyclophosphamide<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Cytarabine<br>* 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<br>Drug: Daunorubicin<br>* Part of standard chemotherapy<br>Drug: Dexamethasone<br>* Part of standard chemotherapy<br>Drug: Doxorubicin<br>* Part of standard chemotherapy<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Methotrexate<br>* Part of standard chemotherapy<br>Drug: Pegaspargase<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* Part of standard chemotherapy<br>* Other names: Prednisone;Drug: Tioguanin<br>* Part of standard chemotherapy<br>Drug: Vincristine<br>* Part of standard chemotherapy<br>Drug: Erwinase<br>* Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction<br>|
| Experimental: pB: early (non)HR-standard/MR-exp.<br>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<br>* Experimental therapy in randomizations R-HR and R-MR<br>Drug: Cyclophosphamide<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Cytarabine<br>* 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<br>Drug: Daunorubicin<br>* Part of standard chemotherapy<br>Drug: Dexamethasone<br>* Part of standard chemotherapy<br>Drug: Doxorubicin<br>* Part of standard chemotherapy<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Methotrexate<br>* Part of standard chemotherapy<br>Drug: Pegaspargase<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* Part of standard chemotherapy<br>* Other names: Prednisone;Drug: Tioguanin<br>* Part of standard chemotherapy<br>Drug: Vincristine<br>* Part of standard chemotherapy<br>Drug: Erwinase<br>* Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction<br>|
| Experimental: pB: early HR-exp./MR-exp.<br>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<br>* Experimental therapy in randomizations R-HR and R-MR<br>Drug: Bortezomib<br>* Experimental therapy in randomization R-eHR<br>Drug: Cyclophosphamide<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Cytarabine<br>* 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<br>Drug: Daunorubicin<br>* Part of standard chemotherapy<br>Drug: Dexamethasone<br>* Part of standard chemotherapy<br>Drug: Doxorubicin<br>* Part of standard chemotherapy<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Methotrexate<br>* Part of standard chemotherapy<br>Drug: Pegaspargase<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* Part of standard chemotherapy<br>* Other names: Prednisone;Drug: Tioguanin<br>* Part of standard chemotherapy<br>Drug: Vincristine<br>* Part of standard chemotherapy<br>Drug: Erwinase<br>* Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction<br>|
| Active Comparator: pB: early (non-)HR-standard/HR-standard<br>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<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Cytarabine<br>* 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<br>Drug: Daunorubicin<br>* Part of standard chemotherapy<br>Drug: Myocet<br>* Part of intensification block Myocet-FLA for patients with very high relapse risk<br>Drug: Dexamethasone<br>* Part of standard chemotherapy<br>Drug: Doxorubicin<br>* Part of standard chemotherapy<br>Drug: Etoposide<br>* Part of standard chemotherapy<br>Drug: Fludarabine Phosphate<br>* Part of intensification block Myocet-FLA for patients with very high relapse risk<br>Drug: Ifosfamide<br>* Part of standard chemotherapy<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Methotrexate<br>* Part of standard chemotherapy<br>Drug: Pegaspargase<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* Part of standard chemotherapy<br>* Other names: Prednisone;Drug: Tioguanin<br>* Part of standard chemotherapy<br>Drug: Vincristine<br>* Part of standard chemotherapy<br>Drug: Vindesine<br>* Part of standard chemotherapy<br>Drug: Erwinase<br>* Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction<br>|
| Experimental: pB: early HR-exp./HR-standard<br>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<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Cytarabine<br>* 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<br>Drug: Daunorubicin<br>* Part of standard chemotherapy<br>Drug: Myocet<br>* Part of intensification block Myocet-FLA for patients with very high relapse risk<br>Drug: Dexamethasone<br>* Part of standard chemotherapy<br>Drug: Doxorubicin<br>* Part of standard chemotherapy<br>Drug: Etoposide<br>* Part of standard chemotherapy<br>Drug: Fludarabine Phosphate<br>* Part of intensification block Myocet-FLA for patients with very high relapse risk<br>Drug: Ifosfamide<br>* Part of standard chemotherapy<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Methotrexate<br>* Part of standard chemotherapy<br>Drug: Pegaspargase<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* Part of standard chemotherapy<br>* Other names: Prednisone;Drug: Tioguanin<br>* Part of standard chemotherapy<br>Drug: Vincristine<br>* Part of standard chemotherapy<br>Drug: Vindesine<br>* Part of standard chemotherapy<br>Drug: Erwinase<br>* Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction<br>|
| Experimental: pB: early (non-)HR-standard/HR-exp.<br>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<br>* Experimental therapy in randomizations R-HR and R-MR<br>Drug: Cyclophosphamide<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Cytarabine<br>* 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<br>Drug: Daunorubicin<br>* Part of standard chemotherapy<br>Drug: Myocet<br>* Part of intensification block Myocet-FLA for patients with very high relapse risk<br>Drug: Dexamethasone<br>* Part of standard chemotherapy<br>Drug: Doxorubicin<br>* Part of standard chemotherapy<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Methotrexate<br>* Part of standard chemotherapy<br>Drug: Pegaspargase<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* Part of standard chemotherapy<br>* Other names: Prednisone;Drug: Tioguanin<br>* Part of standard chemotherapy<br>Drug: Vincristine<br>* Part of standard chemotherapy<br>Drug: Erwinase<br>* Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction<br>|
| Experimental: pB: early HR-exp./HR-exp.<br>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<br>* Experimental therapy in randomizations R-HR and R-MR<br>Drug: Cyclophosphamide<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Cytarabine<br>* 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<br>Drug: Daunorubicin<br>* Part of standard chemotherapy<br>Drug: Myocet<br>* Part of intensification block Myocet-FLA for patients with very high relapse risk<br>Drug: Dexamethasone<br>* Part of standard chemotherapy<br>Drug: Doxorubicin<br>* Part of standard chemotherapy<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Methotrexate<br>* Part of standard chemotherapy<br>Drug: Pegaspargase<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* Part of standard chemotherapy<br>* Other names: Prednisone;Drug: Tioguanin<br>* Part of standard chemotherapy<br>Drug: Vincristine<br>* Part of standard chemotherapy<br>Drug: Erwinase<br>* Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction<br>|
| Other: pB: early non-HR/SR<br>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<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Cytarabine<br>* 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<br>Drug: Daunorubicin<br>* Part of standard chemotherapy<br>Drug: Dexamethasone<br>* Part of standard chemotherapy<br>Drug: Doxorubicin<br>* Part of standard chemotherapy<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Methotrexate<br>* Part of standard chemotherapy<br>Drug: Pegaspargase<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* Part of standard chemotherapy<br>* Other names: Prednisone;Drug: Tioguanin<br>* Part of standard chemotherapy<br>Drug: Vincristine<br>* Part of standard chemotherapy<br>Drug: Erwinase<br>* Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction<br>|
| Active Comparator: T: early non-SR-standard/(non-)HR<br>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<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Cytarabine<br>* 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<br>Drug: Daunorubicin<br>* Part of standard chemotherapy<br>Drug: Myocet<br>* Part of intensification block Myocet-FLA for patients with very high relapse risk<br>Drug: Dexamethasone<br>* Part of standard chemotherapy<br>Drug: Doxorubicin<br>* Part of standard chemotherapy<br>Drug: Etoposide<br>* Part of standard chemotherapy<br>Drug: Fludarabine Phosphate<br>* Part of intensification block Myocet-FLA for patients with very high relapse risk<br>Drug: Ifosfamide<br>* Part of standard chemotherapy<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Methotrexate<br>* Part of standard chemotherapy<br>Drug: Pegaspargase<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* Part of standard chemotherapy<br>* Other names: Prednisone;Drug: Tioguanin<br>* Part of standard chemotherapy<br>Drug: Vincristine<br>* Part of standard chemotherapy<br>Drug: Vindesine<br>* Part of standard chemotherapy<br>Drug: Erwinase<br>* Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction<br>|
| Experimental: T: early non-SR-exp/(non-)HR<br>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<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Cytarabine<br>* 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<br>Drug: Daunorubicin<br>* Part of standard chemotherapy<br>Drug: Myocet<br>* Part of intensification block Myocet-FLA for patients with very high relapse risk<br>Drug: Dexamethasone<br>* Part of standard chemotherapy<br>Drug: Doxorubicin<br>* Part of standard chemotherapy<br>Drug: Etoposide<br>* Part of standard chemotherapy<br>Drug: Fludarabine Phosphate<br>* Part of intensification block Myocet-FLA for patients with very high relapse risk<br>Drug: Ifosfamide<br>* Part of standard chemotherapy<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Methotrexate<br>* Part of standard chemotherapy<br>Drug: Pegaspargase<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* Part of standard chemotherapy<br>* Other names: Prednisone;Drug: Tioguanin<br>* Part of standard chemotherapy<br>Drug: Vincristine<br>* Part of standard chemotherapy<br>Drug: Vindesine<br>* Part of standard chemotherapy<br>Drug: Erwinase<br>* Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction<br>|
| Other: T: early SR/non-HR<br>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<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Cytarabine<br>* 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<br>Drug: Daunorubicin<br>* Part of standard chemotherapy<br>Drug: Dexamethasone<br>* Part of standard chemotherapy<br>Drug: Doxorubicin<br>* Part of standard chemotherapy<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T<br>Drug: Methotrexate<br>* Part of standard chemotherapy<br>Drug: Pegaspargase<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* Part of standard chemotherapy<br>* Other names: Prednisone;Drug: Tioguanin<br>* Part of standard chemotherapy<br>Drug: Vincristine<br>* Part of standard chemotherapy<br>Drug: Erwinase<br>* Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | 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. | Assessed up to 120 months from start of study | 
| Disease-free survival | 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. | Assessed up to 120 months from start of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | All patients/randomizations: Time until death from any cause, starting at the same time point as the EFS/DFS. | Assessed up to 120 months from start of study | 
| Treatment-related mortality | Frequency and incidence of treatment-related mortality in induction or continuous complete remission | Assessed up to 120 months from start of study | 
| Adverse Events of interest/Serious Adverse Events | Frequency and incidence of adverse events of interest and serious adverse events in specific protocol phases, randomized arms and overall during follow-up | Assessed up to 120 months from start of study | 
| MRD response | 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) | 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). | 
| Proportion of patients with Blina Poor-Response | Proportion of patients with poor MRD response to the first Blinatumomab cycle (Blinatumomab Poor-Response) (R-HR) | Measurements of MRD response intended after 30 weeks from individual start of treatment, assessment of proportion at 120 months from start of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomized trial, Acute Lymphoblastic Leukemia, Childhood, Pediatric, Immunotherapy, Blinatumomab, Proteasome Inhibitor, Bispecific antibody, Bortezomib, Chemotherapy