International Cooperative Treatment Protocol for Children and Adolescents With Lymphoblastic Lymphoma

Study Overview
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Brief Summary
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Primary objectives: Randomization R1, all patients eligible: To examine, whether the cumulative incidence of relapses with involvement of the CNS (CNS relapse, pCICR) can be decreased by a modified induction therapy including dexamethasone (experimental arm) instead of prednisone (standard arm) Randomization R2, only patients with high risk LBL eligible: to examine, whether the probability of event-free survival (pEFS) in these patients can be improved by receiving an intensified treatment arm versus a standard treatment arm (as used in the EURO-LB 02)

Detailed Description
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The trial LBL 2018 is a collaborative prospective, multi-national, multi-center, randomized clinical trial for the treatment of children and adolescents with newly diagnosed lymphoblastic lymphoma. The LBL 2018 trial will be open for the qualified centers of following participating study Groups (core study cohort): AIEOP (Italy), BFM (Austria, Czech Republic, Germany, Switzerland), BSPHO (Belgium), CoALL (Germany), DCOG (The Netherlands), NOPHO (Denmark, Finland, Norway, Sweden), PPLLSG (Poland), SEHOP (Spain) and SFCE (France). HKPHOSG (Hong Kong), HPOG (Hungary), ISPHO (Israel), NSPHO (Moscow), SHOP (Portugal) and SPS (Slovak Republic) start patient recruitment into the extended study cohort (without randomization). Over the trial period study groups may switch from the extended study cohort to the core study cohort. Primary objectives: Randomization R1, all patients eligible: To examine, whether the cumulative incidence of relapses with involvement of the CNS (CNS relapse, pCICR) can be decreased by a modified induction therapy including dexamethasone (experimental arm) instead of prednisone (standard arm) Randomization R2, only patients with high risk LBL eligible: to examine, whether the probability of event-free survival (pEFS) in these patients can be improved by receiving an intensified treatment arm versus a standard treatment arm (as used in the EURO-LB 02) Patients are stratified into 3 different risk groups according to CNS status, immunophenotype, genetic markers and stage of disease at diagnosis: high risk group (HR), standard risk group I/II (SR I/II) and standard risk group (SR). Patients in the risk groups SR I/II and SR are randomized (R1) in two arms after a cytoreductive prephase with prednisone. Patients in standard arm receive the standard induction phase with prednisone. Patients in the experimental arm receive an induction phase with dexamethasone instead of prednisone. In SR group, induction phase is followed by the consolidation phase, the non-HR extra-compartment phase with HD-MTX (high-dose methotrexate), the reintensification phase and the maintenance therapy for the total therapy duration of 24 months. In SR I/II group, patients receive no reintensification phase. The Induction phase is followed by the consolidation phase, the non-HR extra-compartment phase and the maintenance therapy for the total therapy duration of 24 months. Patients in the HR group are eligible for randomization (R1) as outlined above. In addition high risk patients are eligible for second randomization (R2) at the end of induction phase. In the standard arm, HR-patients receive the consolidation phase and the non-HR extra-compartment phase. In the experimental arm, HR-patients receive a consolidation phase including two additional doses of PEG asparaginase and the HR-intensified extra-compartment phase consisting of two high risk courses alternating with two HD-MTX courses. Either phase is followed by the reintensification phase and the maintenance therapy for the total therapy duration of 24 months. Patients with involvement of the CNS (CNS positive) are stratified to the high risk group (HR) and are eligible for both randomizations (R1 and R2). Additionally, patients with CNS involvement (CNS positive) receive intensified intrathecal therapy. Intrathecal therapy consists of TIT (triple intrathecal therapy) after diagnosis of CNS involvement. TIT is administered twice weekly until clearance of blasts in the cerebrospinal fluid is achieved. Further intrathecal therapy is provided at the same points of time as for patients without CNS involvement, but TIT instead of MTX IT. In addition, patients receive four additional doses of TIT during maintenance. Cranial irradiation is omitted for patients with CNS involvement.

Official Title
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LBL 2018 - International Cooperative Treatment Protocol for Children and Adolescents With Lymphoblastic Lymphoma

Conditions
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Lymphoblastic Lymphoma, Childhood

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Cytarabine
* Drug: Dexamethasone
* Drug: Daunorubicin
* Drug: Doxorubicin
* Drug: Ifosfamide
* Drug: 6-Mercaptopurine
* Drug: Methotrexate
* Drug: PEG asparaginase
* Drug: Prednisone
* Drug: Prednisolone
* Drug: Thioguanine
* Drug: Vincristine
* Drug: Vindesine


Participation Criteria
=================
Eligibility Criteria
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Inclusion criteria: newly diagnosed lymphoblastic lymphoma age <18 years patient enrolled in a participating center written informed consent of patient (>14 years of age or according to local law and regulation) and parents to trial participation and transfer and processing of data willingness of patients and the investigator/pathologist to provide adequate slides/blocks for reference (molecular) pathology and international pathology panel and/or fresh or fresh frozen samples for genetic risk group stratification if these samples are available after standard diagnostic procedures. Exclusion criteria: lymphoblastic lymphoma as secondary malignancy non-lymphoma related relevant medical, psychiatric or social conditions incompatible with trial treatment, including among others prior organ transplant severe immunodeficiency demyelinating Charcot-Marie Tooth syndrome serious acute or chronic infections, such as HIV, VZV and tuberculosis urinary tract infection, cystitis, urinary outflow obstruction, severe renal impairment (creatinine clearance less than 20 ml/min) severe hepatic impairment (bilirubin >3 times ULN, transaminases >10 times ULN) myocardial insufficiency, severe arrhythmias ulcers of the oral cavity and known active gastrointestinal ulcer disease known hypersensitivity to any IMP and to any excipient (listed in section 6.1 of the respective SmPC) steroid pre-treatment with ≥ 1 mg/kg/d for more than two weeks during the last month before diagnosis vaccination with live vaccines within 2 weeks before start of protocol treatment treatment started according to another protocol or pre-treatment with cytostatic drugs participation in another clinical trial that interferes with the protocol, except NHL-BFM Registry 2012 and trials with different endpoints, involving aspects of supportive treatment, which can run parallel to LBL 2018 without influencing the outcome of this trial (e.g. trials on antiemetics, antibiotics, strategies for psychosocial support) 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 cytostatic therapy

Ages Eligible for Study
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Maximum Age: 18 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: SR I/II: R1 into protocol Ia-Pred<br>cytoreductive prephase with prednisone standard induction phase (protocol Ia-prednisone) consolidation phase (protocol Ib) non-HR extra-compartment phase (protocol M) maintenance therapy | Drug: Cyclophosphamide<br>* Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Cytarabine<br>* No involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2). Involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Daunorubicin<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Methotrexate<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: PEG asparaginase<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1) and in the experimental treatment phase Protocol Ib* (Randomization R2)<br>Drug: Prednisone<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* No involvement of CNS: Part of standard chemotherapy. Involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2<br>Drug: Vincristine<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>|
| Experimental: SR I/II: R1 into protocol Ia-Dexa<br>cytoreductive prephase with prednisone experimental induction phase (protocol Ia-dexamethasone) consolidation phase (protocol Ib) non-HR extra-compartment Phase (protocol M) maintenance therapy | Drug: Cyclophosphamide<br>* Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Cytarabine<br>* No involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2). Involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Dexamethasone<br>* Part of the experimental therapy in Randomization R1 (Protocol Ia-Dexamethasone) and in Randomization R2 (Intensified Protocol M)<br>Drug: Daunorubicin<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Methotrexate<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: PEG asparaginase<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1) and in the experimental treatment phase Protocol Ib* (Randomization R2)<br>Drug: Prednisone<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* No involvement of CNS: Part of standard chemotherapy. Involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2<br>Drug: Vincristine<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>|
| Other: SR: R1 into protocol Ia-Pred<br>cytoreductive prephase with prednisone standard induction phase (protocol Ia-prednisone) consolidation phase (protocol Ib) non-HR extra-compartment phase (protocol M) reintensification phase (protocol II) maintenance therapy | Drug: Cyclophosphamide<br>* Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Cytarabine<br>* No involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2). Involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Dexamethasone<br>* Part of the experimental therapy in Randomization R1 (Protocol Ia-Dexamethasone) and in Randomization R2 (Intensified Protocol M)<br>Drug: Daunorubicin<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Doxorubicin<br>* Part of standard chemotherapy<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Methotrexate<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: PEG asparaginase<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1) and in the experimental treatment phase Protocol Ib* (Randomization R2)<br>Drug: Prednisone<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* No involvement of CNS: Part of standard chemotherapy. Involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2<br>Drug: Thioguanine<br>* Part of standard chemotherapy<br>Drug: Vincristine<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>|
| Experimental: SR: R1 into protocol Ia-Dexa<br>cytoreductive prephase with prednisone experimental induction phase (protocol Ia-dexamethasone) consolidation phase (protocol Ib) non-HR extra-compartment phase (protocol M) reintensification phase (protocol II) maintenance therapy | Drug: Cyclophosphamide<br>* Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Cytarabine<br>* No involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2). Involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Dexamethasone<br>* Part of the experimental therapy in Randomization R1 (Protocol Ia-Dexamethasone) and in Randomization R2 (Intensified Protocol M)<br>Drug: Daunorubicin<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Doxorubicin<br>* Part of standard chemotherapy<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Methotrexate<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: PEG asparaginase<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1) and in the experimental treatment phase Protocol Ib* (Randomization R2)<br>Drug: Prednisone<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* No involvement of CNS: Part of standard chemotherapy. Involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2<br>Drug: Thioguanine<br>* Part of standard chemotherapy<br>Drug: Vincristine<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>|
| Other: HR: R1 into Pred and R2 into non-HR extra-compartment phase<br>cytoreductive prephase with prednisone standard induction phase (protocol Ia-prednisone) consolidation phase (protocol Ib) non-HR extra-compartment phase (protocol M) reintensification phase (protocol II) maintenance therapy | Drug: Cyclophosphamide<br>* Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Cytarabine<br>* No involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2). Involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Dexamethasone<br>* Part of the experimental therapy in Randomization R1 (Protocol Ia-Dexamethasone) and in Randomization R2 (Intensified Protocol M)<br>Drug: Daunorubicin<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Doxorubicin<br>* Part of standard chemotherapy<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Methotrexate<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: PEG asparaginase<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1) and in the experimental treatment phase Protocol Ib* (Randomization R2)<br>Drug: Prednisone<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* No involvement of CNS: Part of standard chemotherapy. Involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2<br>Drug: Thioguanine<br>* Part of standard chemotherapy<br>Drug: Vincristine<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>|
| Experimental: HR: R1 into Dexa and R2 into non-HR extra-compartment phase<br>cytoreductive prephase with prednisone experimental induction phase (protocol Ia-dexamethasone) consolidation phase (protocol Ib) non-HR extra-compartment phase (protocol M) reintensification phase (protocol II) maintenance therapy | Drug: Cyclophosphamide<br>* Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Cytarabine<br>* No involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2). Involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Dexamethasone<br>* Part of the experimental therapy in Randomization R1 (Protocol Ia-Dexamethasone) and in Randomization R2 (Intensified Protocol M)<br>Drug: Daunorubicin<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Doxorubicin<br>* Part of standard chemotherapy<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Methotrexate<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: PEG asparaginase<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1) and in the experimental treatment phase Protocol Ib* (Randomization R2)<br>Drug: Prednisone<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* No involvement of CNS: Part of standard chemotherapy. Involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2<br>Drug: Thioguanine<br>* Part of standard chemotherapy<br>Drug: Vincristine<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>|
| Experimental: HR: R1 into Pred and R2 into HR extra-compartment phase<br>cytoreductive prephase with prednisone standard induction phase (protocol Ia-prednisone) consolidation phase (protocol Ib*) HR extra-compartment phase (intensified protocol M) reintensification phase (protocol II) maintenance therapy | Drug: Cyclophosphamide<br>* Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Cytarabine<br>* No involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2). Involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Dexamethasone<br>* Part of the experimental therapy in Randomization R1 (Protocol Ia-Dexamethasone) and in Randomization R2 (Intensified Protocol M)<br>Drug: Daunorubicin<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Doxorubicin<br>* Part of standard chemotherapy<br>Drug: Ifosfamide<br>* Part of the experimental therapy in Randomization R2 (Intensified Protocol M)<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Methotrexate<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: PEG asparaginase<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1) and in the experimental treatment phase Protocol Ib* (Randomization R2)<br>Drug: Prednisone<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* No involvement of CNS: Part of standard chemotherapy. Involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2<br>Drug: Thioguanine<br>* Part of standard chemotherapy<br>Drug: Vincristine<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Vindesine<br>* Part of the experimental therapy in Randomization R2 (Intensified Protocol M)<br>|
| Experimental: HR: R1 into Dexa and R2 into HR extra-compartment phase<br>cytoreductive prephase with prednisone experimental induction phase (protocol Ia-dexamethasone) consolidation phase (protocol Ib*) HR extra-compartment phase (intensified protocol M) reintensification phase (protocol II) maintenance therapy | Drug: Cyclophosphamide<br>* Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Cytarabine<br>* No involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2). Involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Dexamethasone<br>* Part of the experimental therapy in Randomization R1 (Protocol Ia-Dexamethasone) and in Randomization R2 (Intensified Protocol M)<br>Drug: Daunorubicin<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Doxorubicin<br>* Part of standard chemotherapy<br>Drug: Ifosfamide<br>* Part of the experimental therapy in Randomization R2 (Intensified Protocol M)<br>Drug: 6-Mercaptopurine<br>* Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Methotrexate<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: PEG asparaginase<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1) and in the experimental treatment phase Protocol Ib* (Randomization R2)<br>Drug: Prednisone<br>* Part of standard chemotherapy<br>Drug: Prednisolone<br>* No involvement of CNS: Part of standard chemotherapy. Involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2<br>Drug: Thioguanine<br>* Part of standard chemotherapy<br>Drug: Vincristine<br>* Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1) and in the experimental treatment phase Intensified Protocol M (Randomization R2)<br>Drug: Vindesine<br>* Part of the experimental therapy in Randomization R2 (Intensified Protocol M)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of relapse with involvement of the CNS (CNS-relapse, pCICR) | The time to relapse is defined as the time from randomization to the first relapse or the date of last follow-up. Other events (non-response, progressive disease, relapse, second malignancy or death before and in CR) will be taken into account as competing events. | through study completion, maximal 7.25 years | 
| Estimated probability of event-free survival (pEFS) | The pEFS is defined as the time from randomization to the first event (non-response, progressive disease, relapse, second malignancy or death from any cause) or date of last follow-up. | through study completion, maximal 7.25 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival (pOS) | Survival (pOS) is defined as time from diagnosis to death due to any cause or to the date of last contact for patients alive | through study completion, maximal 7.25 years | 
| Frequency of treatment-related toxicity overall and in specific protocol elements, randomized arms and during follow up |  | through study completion, maximal 7.25 years | 
| Frequency of treatment-related mortality overall and in specific protocol elements, randomized arms and during follow up |  | through study completion, maximal 7.25 years | 
| Frequency of adverse events of interest and severe adverse events overall |  | through study completion, maximal 7.25 years | 
| Rate of evaluable patients for risk group stratification |  | during recruitment | 
| Cumulative incidence of relapses in association with molecular markers |  | through study completion, maximal 7.25 years | 
| Cumulative incidence of relapses in association with minimal residual disease results |  | through study completion, maximal 7.25 years |