Childhood Acute Lymphoblastic Leukemia Treatment Protocol Moscow-Berlin 2008

Study Overview
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Brief Summary
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QUESTIONS AND OBJECTIVES OF ALL-MB-2008 STUDY Whether the early PEG-asparaginase in induction will lead to the earlier achievement of remission, improvement of days 8 and 15 responses leading to an earlier reconstitution of bone marrow and immunocompetence, decrease of severe infections and early mortality rate? Whether the use of PEG-asparaginase in induction will allow to avoid the anthracyclines in standard risk group patients and to reduce treatment myelotoxicity? Whether the administration of 9 doses of PEG-asparaginase 1,000 U/m2 instead of 18 doses of E.coli L-asparaginase 5,000 U/m2 in standard risk patients will improve treatment outcome? Whether the administrations of high dose methotrexate (2 g/m2 in 24 hours) during 1-st consolidation in intermediate risk patients will result in decrease of central nervous system relapse incidence and improvement of event-free and overall survival? Whether the increase of 6-mercaptopurine starting dose up to 50 mg/m2 in 1-st consolidation phase (instead of 25 mg/m2) will decrease in relapse risk, but would not be accompanied with enhanced toxicity? Is it possible to completely avoid the cranial irradiation in intermediate risk patients? In some subgroup of intermediate risk patients? Is it enough to control neuroleukemia in these patients to introduce additional TIT in the consolidation phase of treatment? How will change the possible late effects in these patients according to the third arm of randomization? Will the new risk group stratification to improve overall and event-free survival?

Official Title
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Moscow-Berlin 2008 Multicenter Randomised Study for Treatment of Acute Lymphoblastic Leukemia in Children and Adolescents

Conditions
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Childhood Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: PEG-L-asparaginase ind
* Drug: PEG-L-asparaginase cons
* Drug: E.coli L-asparaginase
* Drug: High-dose Methotrexate
* Drug: Low-dose Methotrexate
* Drug: Triple intrathecal therapy
* Radiation: Cranial irradiation
* Drug: Daunorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age at diagnosis at 1 to 18 years. The start of induction therapy within a time interval of study recruitment phase. The diagnosis of ALL is to be proved by the morphological, cytochemical, and immunological analysis of tumor cells in bone marrow. Informed consent of the parents (guardians) of the patient to be treated in one of the clinics included in this multicenter study. Exclusion Criteria: ALL is a second malignant tumor; The disease is a relapse of previously misdiagnosed and, therefore, inadequately treated ALL; There is severe concomitant disease, which significantly impedes chemotherapy protocol (such as multiple malformations, heart diseases, metabolic disorders, etc.); There is a lack of important basic data needed for the exact adherence to the cytostatic therapy according to a specific protocol of chemotherapy (differential diagnosis of acute lymphoblastic/myeloid leukemia is not possible, stratification according to risk group is not possible); The patient was treated before for a long time with cytotoxic drugs; There were deviations in the treatment not covered by the protocol and/or not due to side effects of treatment and/or complications of the disease

Ages Eligible for Study
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Minimum Age: 1 Year
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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cranial irradiation<br>Consolidation therapy with cranial irradiation in intermediate risk group patients | Radiation: Cranial irradiation<br>* 12 Gy cranial irradiation is conducted at weeks 31-32 of the Protocol in patients >3 years of age<br>|
| Experimental: Additional TIT<br>Consolidation therapy with additional triple intrathecal therapy (N6) and without cranial irradiation in intermediate risk group patients | Drug: Triple intrathecal therapy<br>* Intrathecal injection of 3 drugs is additionally given three times during phase S-2 (weeks 15, 17, and 19 - days 99, 113, and 127), and three times during phase S-3 (weeks 23, 25, and 27 - days 155, 169, and 183).<br>* Other names: Methotrexate/Cytarabine/Prednisone i.th.;|
| Experimental: MTX 2,000 mg/m2<br>Consolidation therapy with High-dose Methotrexate 2,000 mg/m2/24 h i.v. biweekly in intermediate risk group patients | Drug: High-dose Methotrexate<br>* 2,000 mg/m2 per 24 hours is given at days 43, 57, and 71 (weeks 7, 9, and 11). 1/5 of the total dose is given as slow intravenous bolus over 3-5 minutes. 4/5 of the total dose of methotrexate is injected as continuous 24 hours infusion.<br>|
| Active Comparator: MTX 30 mg/m2<br>Consolidation therapy with Low-dose Methotrexate 30 mg/m2 i.m. weekly in intermediate risk group patients | Drug: Low-dose Methotrexate<br>* 30 mg/м2 is given intramuscularly 1 time weekly - days 43, 50, 57, 64, 71, and 78 (weeks 7, 8, 9, 10, 11, and 12).<br>|
| Experimental: PEG-asp 1,000 U/m2<br>Consolidation therapy with PEG-L-asparaginase cons 1,000 U/m2 biweekly in standard risk group patients | Drug: PEG-L-asparaginase cons<br>* 1,000 U/m2 intravenously, in 200 ml of saline, during 1 hour, 24 hours after methotrexate on weeks 7, 9, and 11 - days 44, 58, and 72 (phase S1), weeks 15, 17, and 19 - days 100, 114, 128 (phase S2), weeks 23, 25, and 27 - days 156, 170, 184 (phase S3).<br>|
| Active Comparator: L-asp 5,000 U/m2<br>Consolidation therapy with E.coli L-asparaginase 5,000 U/m2 weekly in standard risk group patients | Drug: E.coli L-asparaginase<br>* E.coli L-asparaginase (asparaginase medac) 5,000 U/m2 intramuscularly weekly, 24 hours after methotrexate dose, from week 7 to week 12 - days 44, 51, 58. 65, 72, 79 (phase S1), from week 15 to week 20 - days 100, 107, 114, 121, 128, 135 (phase S2), from week 23 to week 28 - days 156, 163, 170, 177, 184, 191 (phase S3).<br>* Other names: Asparaginase Medac;|
| Active Comparator: PEG-DNR+<br>Induction therapy without PEG-L-asparaginase and with Daunorubicin 45 mg/m2 in standard and intermediate risk group patients | Drug: Daunorubicin<br>* Daunorubicin at a dose of 45 mg/m2 i.v. for 6 hours on day 8 of induction therapy<br>|
| Experimental: PEG+DNR+<br>Induction therapy with PEG-L-asparaginase ind (1,000 U/m2 on day 3 of therapy)and daunorubicin 45 mg/m2 in standard and intermediate risk group patients | Drug: PEG-L-asparaginase ind<br>* 1,000 U/m2 on day 3 of induction therapy, intravenously, in 200 ml of saline, during 1 hour<br>Drug: Daunorubicin<br>* Daunorubicin at a dose of 45 mg/m2 i.v. for 6 hours on day 8 of induction therapy<br>|
| Experimental: PEG+DNR-<br>Induction therapy with PEG-L-asparaginase ind (1,000 U/m2 on day 3 of therapy) without daunorubicin on day 8 in standard risk group patients | Drug: PEG-L-asparaginase ind<br>* 1,000 U/m2 on day 3 of induction therapy, intravenously, in 200 ml of saline, during 1 hour<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival |  | 3 years, 5 years and 10 years after study start | 
| overall survival |  | 3 years, 5 years and 10 years after study start | 
| cumulative incidence of relapse |  | 3 years, 5 years and 10 years after study start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| early death rate |  | 3 years, 5 years and 10 years after study start | 
| remission death rate |  | 3 years, 5 years and 10 years after study start | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute lymphoblastic leukemia, children, adolescents, L-asparaginase, methotrexate