Childhood Acute Lymphoblastic Leukemia Treatment Protocol Moscow-Berlin 2008 (ALL-MB 2008)

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

QUESTIONS AND OBJECTIVES OF ALL-MB-2008 STUDY

1. 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?
2. Whether the use of PEG-asparaginase in induction will allow to avoid the anthracyclines in standard risk group patients and to reduce treatment myelotoxicity?
3. 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?
4. 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?
5. 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?
6. Will the new risk group stratification to improve overall and event-free survival?

Study Overview

• Status: Unknown
• Conditions: Childhood Acute Lymphoblastic Leukemia
• Intervention / Treatment: Radiation: Cranial irradiation; Drug: Triple intrathecal therapy; Drug: High-dose Methotrexate; Drug: Low-dose Methotrexate; Drug: PEG-L-asparaginase cons; Drug: E.coli L-asparaginase; Drug: Daunorubicin; Drug: PEG-L-asparaginase ind

• Study Type: Interventional
• Enrollment (Anticipated): 3000
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belarus
  • Gomel, Belarus
    • Republican Research and Practical Center of Radiation Medicine
  • Minsk, Belarus
    • Republic Research and Practical Center of Pediatric Oncology and Hematology
  • Mogilev, Belarus
    • Mogilev Regional Children's Hospital
• Russian Federation
  • Arkhangelsk, Russian Federation
    • Arkhangelsk Regional Children's Hospital
  • Astrakhan, Russian Federation
    • Regional Children's Hospital
  • Balashikha, Russian Federation
    • Moscow Regional Cancer Dispensary
  • Blagoveshchensk, Russian Federation
    • Amur Regional Children's Hospital
  • Chelyabinsk, Russian Federation
    • Chelyabinsk Regional Children's Clinical Hospital
  • Irkutsk, Russian Federation
    • Irkutsk Regional Children Clinical Hospital
  • Ivanovo, Russian Federation
    • Regional Clinical Hospital
  • Khabarovsk, Russian Federation
    • Regional Children's Clinical Hospital
  • Kirov, Russian Federation
    • Kirov Research Institute of Hematology and Blood Transfusion
  • Krasnodar, Russian Federation
    • Regional Children's Hospital
  • Krasnoyarsk, Russian Federation
    • Krasnoyarsk Territorial Clinical Children Hospital
  • Kursk, Russian Federation
    • Regional Children's Hospital
  • Makhachkala, Russian Federation
    • Republic Children's Clinical Hospital
  • Moscow, Russian Federation
    • Morozov Children's Clinical Hospital
  • Moscow, Russian Federation
    • Research Institute of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev
  • Moscow, Russian Federation
    • Russian Children's Clinic Hospital
  • Nalchik, Russian Federation
    • Republic Children's Clinical Hospital
  • Nizhnevartovsk, Russian Federation
    • District Children's Clinic Hospital
  • Nizhny Novgorod, Russian Federation
    • Regional Children's Clinic Hospital
  • Novokuznetsk, Russian Federation
    • Municipal Children's Clinic Hospital №4
  • Novosibirsk, Russian Federation
    • Novosibirsk Central District Hospital
  • Orenburg, Russian Federation
    • Regional Clinical Oncology Dispensary
  • Perm, Russian Federation
    • Perm Regional Children's Clinic Hospital
  • Rostov-on-Don, Russian Federation
    • Regional Children's Hospital
  • Rostov-on-Don, Russian Federation
    • Rostov Research Institute of Oncology
  • Ryazan, Russian Federation
    • N. Dmitrieva Ryazan Regional Children's Hospital
  • Saint Petersburg, Russian Federation
    • Children's Municipal Hospital №1
  • Saint Petersburg, Russian Federation
    • Municipal Hospital №31
  • Saint Petersburg, Russian Federation
    • R. Gorbacheva Research Institute of Pediatric Hematology and Transfusiology; Pavlov State Medical University of Saint-Petersburg
  • Samara, Russian Federation
    • Children's Municipal Clinical Hospital №1
  • Saratov, Russian Federation
    • Profpathology and Hematology Clinic; Saratov State Medical University
  • Stavropol, Russian Federation
    • Regional Children's Clinical Hospital
  • Surgut, Russian Federation
    • Surgut Central District Clinical Hospital
  • Tomsk, Russian Federation
    • Tomsk Regional Clinical Hospital
  • Tula, Russian Federation
    • Tula Regional Children's Hospital
  • Ulan-Ude, Russian Federation
    • Republic Children's Clinical Hospital
  • Ulyanovsk, Russian Federation
    • Ulyanovsk Regional Children's Clinical Hospital
  • Vladivostok, Russian Federation
    • Municipal Children's City Hospital, Territorial Children's Hematological Center
  • Voronezh, Russian Federation
    • Voronezh Regional Children Clinical Hospital №1
  • Yakutsk, Russian Federation
    • Republic Hospital №1 - National Medicine Centre
  • Yaroslavl, Russian Federation
    • Regional Children's Clinical Hospital
  • Yekaterinburg, Russian Federation
    • Regional Children's Clinical Hospital № 1
• Uzbekistan
  • Tashkent, Uzbekistan
    • Research Institute of Hematology and Blood Transfusion

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age at diagnosis at 1 to 18 years.
2. The start of induction therapy within a time interval of study recruitment phase.
3. The diagnosis of ALL is to be proved by the morphological, cytochemical, and immunological analysis of tumor cells in bone marrow.
4. Informed consent of the parents (guardians) of the patient to be treated in one of the clinics included in this multicenter study.

Exclusion Criteria:

1. ALL is a second malignant tumor;
2. The disease is a relapse of previously misdiagnosed and, therefore, inadequately treated ALL;
3. There is severe concomitant disease, which significantly impedes chemotherapy protocol (such as multiple malformations, heart diseases, metabolic disorders, etc.);
4. 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);
5. The patient was treated before for a long time with cytotoxic drugs;
6. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Cranial irradiation; Consolidation therapy with cranial irradiation in intermediate risk group patients	Radiation: Cranial irradiation; 12 Gy cranial irradiation is conducted at weeks 31-32 of the Protocol in patients >3 years of age
Experimental: Additional TIT; Consolidation therapy with additional triple intrathecal therapy (N6) and without cranial irradiation in intermediate risk group patients	Drug: Triple intrathecal therapy; 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).; Other Names: Methotrexate/Cytarabine/Prednisone i.th.
Experimental: MTX 2,000 mg/m2; Consolidation therapy with High-dose Methotrexate 2,000 mg/m2/24 h i.v. biweekly in intermediate risk group patients	Drug: High-dose Methotrexate; 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.
Active Comparator: MTX 30 mg/m2; Consolidation therapy with Low-dose Methotrexate 30 mg/m2 i.m. weekly in intermediate risk group patients	Drug: Low-dose Methotrexate; 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).
Experimental: PEG-asp 1,000 U/m2; Consolidation therapy with PEG-L-asparaginase cons 1,000 U/m2 biweekly in standard risk group patients	Drug: PEG-L-asparaginase cons; 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).
Active Comparator: L-asp 5,000 U/m2; Consolidation therapy with E.coli L-asparaginase 5,000 U/m2 weekly in standard risk group patients	Drug: E.coli L-asparaginase; 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).; Other Names: Asparaginase Medac
Active Comparator: PEG-DNR+; Induction therapy without PEG-L-asparaginase and with Daunorubicin 45 mg/m2 in standard and intermediate risk group patients	Drug: Daunorubicin; Daunorubicin at a dose of 45 mg/m2 i.v. for 6 hours on day 8 of induction therapy
Experimental: PEG+DNR+; 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: Daunorubicin; Daunorubicin at a dose of 45 mg/m2 i.v. for 6 hours on day 8 of induction therapy; Drug: PEG-L-asparaginase ind; 1,000 U/m2 on day 3 of induction therapy, intravenously, in 200 ml of saline, during 1 hour
Experimental: PEG+DNR-; 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; 1,000 U/m2 on day 3 of induction therapy, intravenously, in 200 ml of saline, during 1 hour

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Federal Research Institute of Pediatric Hematology, Oncology and Immunology
• Investigators: Principal Investigator: Alexander I. Karachunskiy, Professor, Research Institute of Pediatric Hematology, Oncology and Immunology

Publications and helpful links

Helpful Links

• Study web-site

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2008
• Primary Completion (Actual): January 1, 2015
• Study Completion (Anticipated): July 1, 2020

Study Registration Dates

• First Submitted: September 26, 2013
• First Submitted That Met QC Criteria: September 26, 2013
• First Posted (Estimate): October 1, 2013

Study Record Updates

• Last Update Posted (Actual): February 5, 2020
• Last Update Submitted That Met QC Criteria: February 4, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Acute lymphoblastic leukemia, children, adolescents, L-asparaginase, methotrexate
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Antibiotics, Antineoplastic; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Prednisone; Cytarabine; Methotrexate; Daunorubicin; Asparaginase; Pegaspargase
• Other Study ID Numbers: ALL-MB 2008