Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With Acute Lymphoblastic Leukemia

May 28, 2013 updated by: Martin Schrappe, University Hospital Schleswig-Holstein

ALL-BFM 2000 Multi-Center Study for the Treatment of Children and Adolescents With Acute Lymphoblastic Leukemia

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. It is not yet known which combination chemotherapy regimen is more effective in treating young patients with acute lymphoblastic leukemia.

PURPOSE: Thisphase III trial is studying several different combination chemotherapy regimens to compare how well they work in treating young patients with acute lymphoblastic leukemia.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES:

  • Compare the relative efficacy of induction therapy comprising dexamethasone or prednisone, in terms of a higher rate of event-free survival (EFS) and overall survival and a reduced rate of relapse, in pediatric patients with intermediate-risk or high-risk acute lymphoblastic leukemia (ALL).
  • Compare the relative safety of a reduced-intensity reintensification regimen comprising dexamethasone, vincristine, cyclophosphamide, and anthracyclines vs a standard treatment regimen in pediatric patients with standard-risk ALL identified by fast clearance of leukemic cells.
  • Compare the efficacy of a second delayed reintensification regimen vs standard reintensification therapy, in terms of improved EFS, in pediatric patients with intermediate-risk ALL.
  • Compare the efficacy of extended reintensification therapy (triple reinduction) vs standard reintensification therapy (intensive pulses and one reintensification) in pediatric patients with high-risk ALL.

OUTLINE: This is a randomized, multicenter study.

  • Prednisone prephase therapy: Patients receive oral prednisone on days 1-7 and one dose of methotrexate (MTX) intrathecally (IT) on day 1.

  • Induction/consolidation therapy, protocol I: Patients are randomized to 1 of 2 treatment arms.

    • Arm I (closed to accrual as of 6/30/2006): Patients receive prednisone (PRED) on days 8-28.
    • Arm II (closed to accrual as of 6/30/2006): Patients receive dexamethasone (DEXA) on days 8-28.

Patients in both arms also receive vincristine (VCR) and daunorubicin hydrochloride (DNR) once weekly in weeks 2-5; asparaginase (ASP) on days 12-33; cyclophosphamide (CPM) on days 36 and 64; cytarabine (ARA-C) in weeks 6-9; mercaptopurine (MP) on days 36-63; and MTX IT on days 1, 12, 33, 45, and 59.*

NOTE: *Patients with CNS disease also receive MTX IT on days 18 and 27.

After completion of induction/consolidation therapy, patients are stratified according to risk group based on disease response (standard-risk [SR] group [negative minimal residual disease (MRD) on day 33 and before protocol M, day 78] vs high-risk [HR] group [MRD ≥ 10^-³ on day 78] vs intermediate-risk [IR] group [all nonSR/nonHR]).* Patients with SR and IR disease proceed to extracompartment therapy. Patients with HR disease proceed to reintensification therapy.

NOTE: *Patients meeting any of the following criteria are placed in the HR group regardless of MRD response: Philadelphia chromosome-positive disease (BCR/ABL or t[9;22]; translocations [t4;11][q11;q23] or MLL/AF4); "prednisone-poor-response" (≥ 1,000 blasts/mm³ in the peripheral blood on day 8 after prednisone prephase therapy); or no response to study induction therapy (M2/3 at day 33).

  • Extracompartment therapy, protocol M: Patients receive MP on days 1-56 and MTX on days 8, 22, 36, and 50.

After completion of extracompartment therapy, SR and IR patients proceed to reintensification therapy. SR patients are randomized to arms I or II. IR patients are randomized to arms I or III. HR patients who have completed induction/consolidation therapy are randomized to arms IV or V.

  • Reintensification therapy:

    • Arm I (standard reinduction therapy, protocol II [closed to accrual as of 6/30/2006]): SR and IR patients receive DEXA on days 1-22; VCR and doxorubicin hydrochloride (DOX) in weeks 2-5; ASP on days 8, 11, 15, and 18; CPM on day 36; ARA-C and thioguanine (TG) on days 36-49; and MTX IT on days 38 and 45.* Patients then proceed to maintenance therapy.

NOTE: *Patients with CNS disease also receive MTX IT on days 1 and 18.

  • Arm II (reduced-intensity reinduction therapy, protocol III [closed to accrual as of 6/30/2006]): SR patients receive DEXA on days 1-15; VCR and DOX on days 1 and 8; ASP on days 1, 4, 8, and 11; CPM on day 15; ARA-C and TG on days 15-28; and MTX IT on days 17 and 24.* Patients then proceed to maintenance therapy.

NOTE: *Patients with CNS disease also receive MTX on day 1.

  • Arm III (reduced-intensity reinduction/second delayed reinduction therapy [double reintensification therapy] [closed to accrual as of 6/30/2006]): IR patients receive reduced-intensity reintensification therapy as in arm II. After a 10-week interim maintenance phase, treatment repeats once for a second delayed course of reintensification therapy. Patients then proceed to maintenance therapy.

  • Arm IV (standard reintensification therapy [closed to accrual as of 6/30/2006]): HR patients receive two sequences of the following HR therapy elements (i.e., in this order: 1, 2, 3, 1, 2, 3) following reintensification therapy as in arm I. Patients then proceed to maintenance therapy.

    • Element HR-1: Patients receive DEXA on days 1-5; VCR on days 1 and 6; ARA-C twice on day 5; MTX and CPM every 12 hours on days 2-4 (5 doses); ASP on days 6 and 11; and MTX/ARA-C/PRED IT on day 1.
    • Element HR-2: Patients receive DEXA on days 1-5; vindesine on days 1 and 6; DNR on day 5; MTX and ifosfamide every 12 hours on days 2-4 (5 doses); ASP on days 6 and 11; and MTX/ARA-C/PRED IT on day 1.* NOTE: *HR patients with CNS disease also receive IT therapy on day 5.
    • Element HR-3: Patients receive DEXA on days 1-5; ARA-C every 12 hours on days 1-2 (4 doses); etoposide five times daily on days 3-5; ASP on days 6 and 11; and MTX/ARA-C/PRED IT on day 1.

  • Arm V (extended reintensification therapy [triple protocol III] [closed to accrual as of 6/30/2006]): HR patients receive HR therapy elements 3, 2, and 1 as in arm IV following reintensification therapy as in arm II repeated the therapy element twice with 4-week interim maintenance phases in between. Patients then proceed to maintenance therapy.

    • Interim maintenance/maintenance therapy: Patients receive MTX once weekly and MP daily until week 104.
    • Radiotherapy: HR patients or patients with T-cell acute lymphoblastic leukemia or CNS disease undergo CNS radiotherapy.

PROJECTED ACCRUAL: A total of 2,000 patients will be accrued for this study.

Study Type

Interventional

Enrollment (Actual)

4559

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Austria
      • Dornbirn, Austria, A-6850
        • Krankenhaus Dornbirn
      • Feldkirch-Tisis, Austria, A-6807
        • Landeskrankenhaus Feldkirch
      • Graz, Austria, 8036
        • Universitaet Kinderklinik
      • Innsbruck, Austria, A-6020
        • Innsbruck Universitaetsklinik
      • Klagenfurt, Austria, 9026
        • Landeskrankenhaus Klagenfurt
      • Leoben, Austria, A-8700
        • LKH Leoben
      • Linz, Austria, 4010
        • A. oe. Krankenhaus der Barmherzigen Schwestern Kinderabteilung
      • Linz, Austria, A-4020
        • Landes-Kinderkrankenhaus
      • Salzburg, Austria, A-5020
        • St. Johanns-Spital
      • Vienna, Austria, A-1090
        • St. Anna Children's Hospital
  • Germany
      • Aachen, Germany, D-52074
        • Kinderklinik - Universitaetsklinikum Aachen
      • Augsburg, Germany, DOH-86156
        • Klinikum Augsburg
      • Bad Mergentheim, Germany, D-97980
        • Caritas-Krankenhaus Bad Mergentheim
      • Bayreuth, Germany, D-95445
        • Klinikum Bayreuth
      • Berlin, Germany, D-13353
        • Charite University Hospital - Campus Virchow Klinikum
      • Berlin, Germany, 13125
        • Helios Klinikum Berlin
      • Bonn, Germany, D-53113
        • Kinderklinik der Universitaet Bonn
      • Braunschweig, Germany, 38118
        • Staedtisches Klinikum - Howedestrase
      • Chemnitz, Germany, D-09116
        • Klinikum Chemnitz gGmbH
      • Coburg, Germany, 96450
        • Klinikum Coburg
      • Cologne, Germany, D-50924
        • Children's Hospital
      • Cologne, Germany, D-50735
        • Kliniken der Stadt Koeln gGmbH - Kinderkrankenhaus Riehl
      • Cottbus, Germany, D-03048
        • Carl - Thiem - Klinkum Cottbus
      • Datteln, Germany, 45711
        • Vestische Kinderklinik Universitaetsklinik Witten/Herdecke
      • Detmold, Germany, D-32756
        • Klinikum Lippe - Detmold
      • Dortmund, Germany, D-44137
        • Klinikum Dortmund
      • Dresden, Germany, D-01307
        • Universitatsklinikum Carl Gustav Carus
      • Duisburg, Germany, D-47055
        • Klinikum Duisburg
      • Erfurt, Germany, 99089
        • HELIOS Klinikum Erfurt
      • Erlangen, Germany, 91054
        • Universitaets - Kinderklinik
      • Essen, Germany, D-45147
        • Universitaetsklinikum Essen
      • Frankfurt, Germany, D-60590
        • Klinikum der J.W. Goethe Universitaet
      • Freiburg, Germany, D-79106
        • Universitaetskinderklinik - Universitaetsklinikum Freiburg
      • Giessen, Germany, D-35385
        • Kinderklinik
      • Goettingen, Germany, D-37075
        • Universitaetsklinikum Goettingen
      • Halle, Germany, D-06097
        • Universitaetsklinikum Halle
      • Hannover, Germany, D-30625
        • Medizinische Hochschule Hannover
      • Heidelberg, Germany, D-69120
        • Universitaets-Kinderklinik Heidelberg
      • Heilbronn, Germany, D-74064
        • SLK - Kliniken Heilbronn GmbH - Klinikum am Gesundbrunnen
      • Herdecke, Germany, 58313
        • Gemeinschaftskrankenhaus
      • Homburg, Germany, 66421
        • Universitaetsklinikum des Saarlandes
      • Jena, Germany, D-07745
        • Universitaets - Kinderklinik
      • Karlsruhe, Germany, 76133
        • Staedtisches Klinikum Karlsruhe gGmbH
      • Kassel, Germany, D-34125
        • Klinikum Kassel
      • Kiel, Germany, D-24105
        • University Hospital Schleswig-Holstein - Kiel Campus
      • Koblenz, Germany, D-56065
        • Klinikum Kemperhof Koblenz
      • Ludwigshafen, Germany, 67065
        • St. Annastift Krankenhaus
      • Luebeck, Germany, D-23538
        • Universitaets - Kinderklinik - Luebeck
      • Magdeburg, Germany, 39120
        • Universitatsklinikum der MA
      • Mannheim, Germany, D-68167
        • Staedtisches Klinik - Kinderklinik
      • Marburg, Germany, D-35043
        • Universitaetsklinikum Giessen und Marburg GmbH - Marburg
      • Minden, Germany, D-32423
        • Klinikum Minden
      • Muenster, Germany, D-48149
        • Klinik und Poliklinik fuer Kinder und Jugendmedizin - Universitaetsklinikum Muenster
      • Munich, Germany, 80804
        • Krankenhaus Muenchen Schwabing
      • Neunkirchen, Germany, D-66539
        • Kinderklinik Kohlhof
      • Nuremberg, Germany, 90419
        • Cnopf'sche Kinderklinik
      • Oldenburg, Germany, 26133
        • Klinikum Oldenburg
      • Rostock, Germany, D-18057
        • Kinderklinik - Universitaetsklinikum Rostock
      • Saarbrucken, Germany, 66119
        • Saarbrucker Winterbergkliniken
      • Schwerin, Germany, D-19049
        • Klinikum Schwerin
      • Siegen, Germany, D-57072
        • Kinderklink Siegen Deutsches Rotes Kreuz
      • St. Augustin, Germany, 53757
        • Johanniter-Kinderklinik
      • Stuttgart, Germany, D-70176
        • Olgahospital
      • Trier, Germany, D-54290
        • Krankenanstalt Mutterhaus der Borromaerinnen
      • Tuebingen, Germany, D-72076
        • Universitaetsklinikum Tuebingen
      • Ulm, Germany, D-89075
        • Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm
      • Vechta, Germany, D-49377
        • St. Marienhospital - Vechta
      • Wilhelmshaven, Germany, D-26389
        • Reinhard-Nieter-Krankenhaus
      • Wolfsburg, Germany, D-38440
        • Klinikum der Stadt Wolfsburg
      • Wuerzburg, Germany, D-97080
        • Universitaets - Kinderklinik Wuerzburg
  • Switzerland
      • Aarau, Switzerland, CH-5001
        • Kantonsspital Aarau
      • Basel, Switzerland, CH-4005
        • Universitaets-Kinderspital beider Basel
      • Locarno, Switzerland, 6600
        • Ospedale "la Carita", Locarno
      • Lucerne 16, Switzerland, CH-6000
        • Kinderspital Luzern
      • St. Gallen, Switzerland, CH-9006
        • Ostschweizer Kinderspital
      • Zurich, Switzerland, CH-8032
        • University Children's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 18 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

DISEASE CHARACTERISTICS:

  • Histologically confirmed acute lymphoblastic leukemia (ALL)
  • No secondary ALL

PATIENT CHARACTERISTICS:

  • No prior disease that would preclude treatment with chemotherapy

PRIOR CONCURRENT THERAPY:

  • More than 4 weeks since prior chemotherapy
  • More than 4 weeks since prior steroids

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Induction Prot I/Dexa - reinduction Prot III
Drug: cyclophosphamide
Radiation: radiation therapy
Drug: prednisone
Drug: asparaginase
Drug: cytarabine
Drug: daunorubicin hydrochloride
Drug: dexamethasone
Drug: methotrexate
Drug: vincristine sulfate
Drug: mercaptopurine
Drug: thioguanine
Drug: doxorubicin hydrochloride
Drug: ifosfamide
Drug: vindesine
Experimental: Induction Prot I/Pred - reinduction Prot III
Drug: cyclophosphamide
Radiation: radiation therapy
Drug: prednisone
Drug: asparaginase
Drug: cytarabine
Drug: daunorubicin hydrochloride
Drug: dexamethasone
Drug: methotrexate
Drug: vincristine sulfate
Drug: mercaptopurine
Drug: thioguanine
Drug: doxorubicin hydrochloride
Drug: ifosfamide
Drug: vindesine
Experimental: Induction Prot I/Dexa - reinduction Prot II
Drug: cyclophosphamide
Radiation: radiation therapy
Drug: prednisone
Drug: asparaginase
Drug: cytarabine
Drug: daunorubicin hydrochloride
Drug: dexamethasone
Drug: methotrexate
Drug: vincristine sulfate
Drug: mercaptopurine
Drug: thioguanine
Drug: doxorubicin hydrochloride
Drug: ifosfamide
Drug: vindesine
Active Comparator: Induction Prot I/Pred - reinduction Prot II
Drug: cyclophosphamide
Radiation: radiation therapy
Drug: prednisone
Drug: asparaginase
Drug: cytarabine
Drug: daunorubicin hydrochloride
Drug: dexamethasone
Drug: methotrexate
Drug: vincristine sulfate
Drug: mercaptopurine
Drug: thioguanine
Drug: doxorubicin hydrochloride
Drug: ifosfamide
Drug: vindesine
Experimental: Induction Prot I/Dexa - reinduction 2x Prot III
Drug: cyclophosphamide
Radiation: radiation therapy
Drug: prednisone
Drug: asparaginase
Drug: cytarabine
Drug: daunorubicin hydrochloride
Drug: dexamethasone
Drug: methotrexate
Drug: vincristine sulfate
Drug: mercaptopurine
Drug: thioguanine
Drug: doxorubicin hydrochloride
Drug: ifosfamide
Drug: vindesine
Experimental: Induction Prot I/Pred - reinduction 2x Prot III
Drug: cyclophosphamide
Radiation: radiation therapy
Drug: prednisone
Drug: asparaginase
Drug: cytarabine
Drug: daunorubicin hydrochloride
Drug: dexamethasone
Drug: methotrexate
Drug: vincristine sulfate
Drug: mercaptopurine
Drug: thioguanine
Drug: doxorubicin hydrochloride
Drug: ifosfamide
Drug: vindesine
Experimental: Induction Prot I/Dexa - reinduction 3 HR courses + 3x Prot III
Drug: cyclophosphamide
Radiation: radiation therapy
Drug: prednisone
Drug: asparaginase
Drug: cytarabine
Drug: daunorubicin hydrochloride
Drug: dexamethasone
Drug: etoposide
Drug: methotrexate
Drug: vincristine sulfate
Drug: mercaptopurine
Drug: thioguanine
Drug: doxorubicin hydrochloride
Drug: ifosfamide
Drug: vindesine
Experimental: Induction Prot I/Pred - reinduction 3 HR courses + 3x Prot III
Drug: cyclophosphamide
Radiation: radiation therapy
Drug: prednisone
Drug: asparaginase
Drug: cytarabine
Drug: daunorubicin hydrochloride
Drug: dexamethasone
Drug: etoposide
Drug: methotrexate
Drug: vincristine sulfate
Drug: mercaptopurine
Drug: thioguanine
Drug: doxorubicin hydrochloride
Drug: ifosfamide
Drug: vindesine
Experimental: Induction Prot I/Dexa - reinduction 6 HR courses + Prot II
Drug: cyclophosphamide
Radiation: radiation therapy
Drug: prednisone
Drug: asparaginase
Drug: cytarabine
Drug: daunorubicin hydrochloride
Drug: dexamethasone
Drug: etoposide
Drug: methotrexate
Drug: vincristine sulfate
Drug: mercaptopurine
Drug: thioguanine
Drug: doxorubicin hydrochloride
Drug: ifosfamide
Drug: vindesine
Active Comparator: Induction Prot I/Pred - reinduction 6 HR courses + Prot II
Drug: cyclophosphamide
Radiation: radiation therapy
Drug: prednisone
Drug: asparaginase
Drug: cytarabine
Drug: daunorubicin hydrochloride
Drug: dexamethasone
Drug: etoposide
Drug: methotrexate
Drug: vincristine sulfate
Drug: mercaptopurine
Drug: thioguanine
Drug: doxorubicin hydrochloride
Drug: ifosfamide
Drug: vindesine

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Efficacy of dexamethasone vs prednisone during the induction phase
Time Frame: End of Trial
End of Trial
Event-free survival (EFS) and overall survival after initial remission in intermediate-risk and high-risk patients
Time Frame: End of Trial
End of Trial
Safety and efficacy of treatment reduction during reintensification in standard-risk patients
Time Frame: End of Trial
End of Trial
EFS after second delayed reintensification in intermediate-risk patients
Time Frame: End of Trial
End of Trial
Outcome after extended reintensification therapy in high-risk patients
Time Frame: End of Trial
End of Trial

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital Schleswig-Holstein

Investigators

  • Study Chair: Martin Schrappe, MD, PhD, University Hospital Schleswig-Holstein

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2000

Primary Completion (Actual)

January 1, 2012

Study Completion (Actual)

January 1, 2012

Study Registration Dates

First Submitted

January 30, 2007

First Submitted That Met QC Criteria

January 30, 2007

First Posted (Estimate)

February 1, 2007

Study Record Updates

Last Update Posted (Estimate)

May 29, 2013

Last Update Submitted That Met QC Criteria

May 28, 2013

Last Verified

May 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CDR0000528029
  • ALL-BFM-2000
  • EU-20682

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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