Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Active	1 to 18	Other	ALL-BFM-2000 EU-20682, NCT00430118

Objectives

1. 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).
2. 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.
3. 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.
4. 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.

Entry Criteria

Disease Characteristics:

• Histologically confirmed acute lymphoblastic leukemia (ALL)



• No secondary ALL

Prior/Concurrent Therapy:

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

Patient Characteristics:

• No prior disease that would preclude treatment with chemotherapy

Expected Enrollment

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

Outcomes

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

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.

Dworzak MN, Schumich A, Printz D, et al.: CD20 up-regulation in pediatric B-cell precursor acute lymphoblastic leukemia during induction treatment: setting the stage for anti-CD20 directed immunotherapy. Blood 112 (10): 3982-8, 2008.[PUBMED Abstract]

Flohr T, Schrauder A, Cazzaniga G, et al.: Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia 22 (4): 771-82, 2008.[PUBMED Abstract]

Attarbaschi A, Mann G, Panzer-Grümayer R, et al.: Minimal residual disease values discriminate between low and high relapse risk in children with B-cell precursor acute lymphoblastic leukemia and an intrachromosomal amplification of chromosome 21: the Austrian and German acute lymphoblastic leukemia Berlin-Frankfurt-Munster (ALL-BFM) trials. J Clin Oncol 26 (18): 3046-50, 2008.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

University Hospital Schleswig-Holstein - Kiel Campus

Martin Schrappe, MD, PhD, Protocol chair		Ph: 49-431-597-1620

Austria
	Dornbirn
	Krankenhaus Dornbirn
		B. Ausserer, MD	Ph:  43-5572-303-2301
	Feldkirch-Tisis
	Landeskrankenhaus Feldkirch
		Contact Person	Ph:  43-5522-303-2900
	Graz
	Universitaet Kinderklinik
		Christian Urban	Ph:  43-316-385-3485
	Innsbruck
	Innsbruck Universitaetsklinik
		Contact Person	Ph:  43-512-5048-1570
	Klagenfurt
	Landeskrankenhaus Klagenfurt
		Wilhelm Kaulfersch	Ph:  43-463-5380
	Leoben
	LKH Leoben
		Ingomar Mutz, MD	Ph:  43-3842-401-2438
	Linz
	A. oe. Krankenhaus der Barmherzigen Schwestern Kinderabteilung
		Contact Person	Ph:  43-7327-6770
	Landes-Kinderkrankenhaus
		K. Schmitt	Ph:  43-7326-9230
	Salzburg
	St. Johanns-Spital
		Contact Person	Ph:  43-661-4482-2690
	Vienna
	St. Anna Children's Hospital
		Helmut Gadner, MD, FRCPG	Ph:  43-140-4700
Germany
	Aachen
	Kinderklinik - Universitaetsklinikum Aachen
		R. Mertens, MD, PhD	Ph:  49-241-818-9902
			Email: rmertens@ukaachen.de
	Augsburg
	Klinikum Augsburg
		Astrid Gnekow	Ph:  49-821-400-3631
	Bad Mergentheim
	Caritas-Krankenhaus Bad Mergentheim
		Buchhorn	Ph:  49-7931-582-370
	Bayreuth
	Klinikum Bayreuth
		T. Rupprecht	Ph:  49-921-400-6200
	Berlin
	Charite University Hospital - Campus Virchow Klinikum
		Gunter Henze	Ph:  49-304-5056-6032
	Helios Klinikum Berlin
		A. Liebeskind	Ph:  49-30-9401-2367
	Bonn
	Kinderklinik der Universitaet Bonn
		Udo Bode, MD	Ph:  49-228-2873-3215
			Email: udo.bode@ukb.uni-bonn.de
	Braunschweig
	Staedtisches Klinikum - Howedestrase
		Contact Person	Ph:  49-531-595-1424
	Chemnitz
	Klinikum Chemnitz gGmbH
		Krause, MD	Ph:  49-371-3332-4281
	Coburg
	Klinikum Coburg
		Roland Frank, MD	Ph:  49-9561-223-3803
	Cologne
	Children's Hospital
		Frank Berthold, MD	Ph:  49-221-478-4380
			Email: frank.berthold@uk-koeln.de
	Kliniken der Stadt Koeln gGmbH - Kinderkrankenhaus Riehl
		Contact Person	Ph:  49-221-8907-5243
	Cottbus
	Carl - Thiem - Klinkum Cottbus
		E. Holfeld	Ph:  49-355-46-2332
	Datteln
	Vestische Kinderklinik Universitaetsklinik Witten/Herdecke
		Contact Person	Ph:  49-2363-975-846
	Detmold
	Klinikum Lippe - Detmold
		Klaus Wesseler, MD	Ph:  49-5231-72-4511
	Dortmund
	Klinikum Dortmund
		Heidi Olscheswski, MD	Ph:  49-231-9532-1050
	Dresden
	Universitatsklinikum Carl Gustav Carus
		M. Suttorp, MD	Ph:  49-351-458-3522
			Email: meinolf.suttorp@uniklinikum-dresden.de
	Duisburg
	Klinikum Duisburg
		Contact Person	Ph:  49-203-7330
	Erfurt
	Helios Klinikum Erfurt
		Axel Sauerbrey, MD	Ph:  49-361-781-4501
			Email: asauerbrey@erfurt.helios-kliniken.de
	Erlangen
	Universitaets - Kinderklinik
		W. Holter, MD	Ph:  49-9131-853-4759
	Essen
	Universitaetsklinikum Essen
		Bernhard Kremens, MD	Ph:  49-201-723-2503
	Frankfurt
	Klinikum der J.W. Goethe Universitaet
		Thomas Klingebiel, MD	Ph:  49-69-6301-5094
			Email: thomas.klingebiel@kgu.de
	Freiburg
	Universitaetskinderklinik - Universitaetsklinikum Freiburg
		Charlotte Niemeyer, MD	Ph:  49-761-270-4506
			Email: charlotte.niemeyer@uniklinik-freiburg.de
	Giessen
	Kinderklinik
		Alfred Reiter, MD	Ph:  49-641-994-3420
	Goettingen
	Universitaetsklinikum Goettingen
		M. Lakomek, MD	Ph:  49-551-396-201
	Halle
	Universitaetsklinikum Halle
		Dieter Koerholz, MD	Ph:  49-345-557-3257
	Hannover
	Medizinische Hochschule Hannover
		Karl Welte, MD	Ph:  49-511-532-6710
			Email: welte.karl.h@mh-hannover.de
	Heidelberg
	Universitaets-Kinderklinik Heidelberg
		Andreas Kulozik, MD, PhD	Ph:  49-6621-56-4555
			Email: andreas.kulozik@med.uni-heidelberg.de
	Heilbronn
	SLK - Kliniken Heilbronn GmbH - Klinikum am Gesundbrunnen
		Walter Kachel	Ph:  49-7131-493-702
	Herdecke
	Gemeinschaftskrankenhaus
		Contact Person	Ph:  49-2330-62-3893
	Homburg
	Universitaetsklinikum des Saarlandes
		Norbert Graf	Ph:  49-6841-168-8397
	Jena
	Universitaets - Kinderklinik
		Felix Zintl, MD	Ph:  49-3641-938-220
	Karlsruhe
	Staedtisches Klinikum Karlsruhe gGmbH
		A. Leipold	Ph:  49-721-9740
	Kassel
	Klinikum Kassel
		Martina Rodehueser, MD	Ph:  49-561-980-3382
	Kiel
	University Hospital Schleswig-Holstein - Kiel Campus
		Martin Schrappe, MD, PhD	Ph:  49-431-597-1620
	Koblenz
	Klinikum Kemperhof Koblenz
		M. Rister, MD	Ph:  49-261-499-2602
	Ludwigshafen
	St. Annastift Krankenhaus
		Barbara Selle, MD	Ph:  49-621-5702-4450
	Luebeck
	Universitaets - Kinderklinik - Luebeck
		Peter Bucsky, MD	Ph:  49-451-500-2557
			Email: bucsky@paedia.ukl.mu-luebeck.de
	Magdeburg
	Universitatsklinikum der MA
		Uwe Mittler, MD	Ph:  49-391-671-7210
	Mannheim
	Staedtisches Klinik - Kinderklinik
		M. Duerken	Ph:  49-621-383-2244
	Marburg
	Universitaetsklinikum Giessen und Marburg GmbH - Marburg
		H. Christiansen, MD	Ph:  49-6421-286-2671
	Minden
	Klinikum Minden
		Contact Person	Ph:  49-571-8010
	Muenster
	Klinik und Poliklinik fuer Kinder und Jugendmedizin - Universitaetsklinikum Muenster
		Heribert Juergens, MD	Ph:  49-251-834-7742
			Email: jurgh@uni-muenster.de
	Munich
	Krankenhaus Muenchen Schwabing
		Stefan Burdach, MD, PhD	Ph:  49-89-3068-2261
	Neunkirchen
	Kinderklinik Kohlhof
		Contact Person	Ph:  49-6821-3630
	Nuremberg
	Cnopf'sche Kinderklinik
		W. Scheurlen	Ph:  49-911-3340-323
	Oldenburg
	Klinikum Oldenburg
		Hermann Mueller, MD	Ph:  49-441-403-2013
			Email: mueller.hermann@klinikum-oldenburg.de
	Rostock
	Kinderklinik - Universitaetsklinikum Rostock
		Carl Friedrich Classen, MD, PD	Ph:  49-381-494-7000
			Email: carl-friedrich.classen@med.uni-rostock.de
	Saarbrucken
	Saarbrucker Winterbergkliniken
		Contact Person	Ph:  49-681-963-2161
	Schwerin
	Klinikum Schwerin
		Contact Person	Ph:  49-385-520-2710
	Siegen
	Kinderklink Siegen Deutsches Rotes Kreuz
		Rainer Burghard, MD	Ph:  49-2712-3450
			Email: rainer.burghard@drk-kinderklinik.de
	St. Augustin
	Johanniter-Kinderklinik
		Roswitha Dickerhoff, MD	Ph:  49-2241-249-304
			Email: roswitha.dickerhoft@uni-bonn.de
	Stuttgart
	Olgahospital
		Stefan Bielack, MD	Ph:  49-711-992-2461
			Email: st.bielack@olgahospital.de
	Trier
	Krankenanstalt Mutterhaus der Borromaerinnen
		Wolfgang Rauh, MD	Ph:  49-651-947-2654
	Tuebingen
	Universitaetsklinikum Tuebingen
		Rupert Handgretinger, MD	Ph:  49-7071-298-4744
	Ulm
	Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm
		Klaus Debatin, MD	Ph:  49-731-5000
			Email: klaus-michael.debatin@medizin.uni-ulm.de
	Vechta
	St. Marienhospital - Vechta
		Contact Person	Ph:  49-4441-990
	Wilhelmshaven
	Reinhard-Nieter-Krankenhaus
		Liebner, MD	Ph:  49-4421-89-1843
	Wolfsburg
	Klinikum der Stadt Wolfsburg
		Contact Person	Ph:  49-5361-8000
	Wuerzburg
	Universitaets - Kinderklinik Wuerzburg
		P. G. Schlegel, MD	Ph:  49-931-2012-7856
			Email: schlegel@mail.uni-wuerzburg.de
Switzerland
	Aarau
	Kantonspital Aarau
		R. Angst	Ph:  41-62-838-4906
	Basel
	Universitaets-Kinderspital beider Basel
		Michael Paulussen, MD	Ph:  41-61-685-6565
	Locarno
	Ospedale "la Carita", Locarno
		Luisa Nobile Buetti, MD	Ph:  41-91-811-4552
	Lucerne 16
	Kinderspital Luzern
		U. Caflisch, MD	Ph:  41-41-205-3172
	St. Gallen
	Ostschweizer Kinderspital
		Jeanette Greiner, MD	Ph:  41-712-431-360
			Email: jeanette.greiner@kispisg.ch
	Zurich
	University Children's Hospital
		Felix Niggli, MD	Ph:  41-44-266-7111

Registry Information
Official Title		ALL-BFM 2000 Multi-Center Study for the Treatment of Children and Adolescents with Acute Lymphoblastic Leukemia
Trial Start Date		2000-07-01
Registered in ClinicalTrials.gov		NCT00430118
Date Submitted to PDQ		2006-12-18
Information Last Verified		2009-01-09