Combination Chemotherapy Plus Steroid Therapy in Treating Children With Acute Lymphoblastic Leukemia or Lymphoblastic Non-Hodgkin's Lymphoma

NCT00003728 | Unknown Phase 3

• 2 other identifiers: CDR0000066840EORTC-58951
• Study Type: interventional
• Target: 1,500
• Locations: 3 countries
• Sites: 23

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. It is not yet known which regimen of combination chemotherapy plus steroid therapy is more effective for acute lymphoblastic leukemia or lymphoblastic non-Hodgkin's lymphoma. PURPOSE: Randomized phase III trial to compare the effectiveness of different regimens of combination chemotherapy plus steroid therapy in treating children who have acute lymphoblastic leukemia or lymphoblastic non-Hodgkin's lymphoma.

Conditions

Leukemia; Lymphoma

Keywords

stage I childhood lymphoblastic lymphoma; stage II childhood lymphoblastic lymphoma; stage III childhood lymphoblastic lymphoma; stage IV childhood lymphoblastic lymphoma; untreated childhood acute lymphoblastic leukemia; L1 childhood acute lymphoblastic leukemia; L2 childhood acute lymphoblastic leukemia; T-cell childhood acute lymphoblastic leukemia; B-cell childhood acute lymphoblastic leukemia; acute undifferentiated leukemia

Outcome Measures

Primary Outcomes (2)

• Event-free survival after first randomization

• Disease-free survival after second and third randomization

Secondary Outcomes (4)

• Overall survival

• Response to prephase as assessed by number of blasts/mm³ in peripheral blood (< 1,000 vs ≥ 1,000) after randomization

• Response as assessed by bone marrow (BM) blasts after first randomization, at evaluation of prephase, and on day 15 of induction

• Toxicity and long-term toxicity as assessed by CTC v2

Interventions

asparaginase DRUG

cyclophosphamide DRUG

cytarabine DRUG

daunorubicin hydrochloride DRUG

dexamethasone DRUG

doxorubicin hydrochloride DRUG

etoposide DRUG

leucovorin calcium DRUG

mercaptopurine DRUG

methotrexate DRUG

methylprednisolone DRUG

mitoxantrone hydrochloride DRUG

prednisolone DRUG

therapeutic hydrocortisone DRUG

thioguanine DRUG

vincristine sulfate DRUG

vindesine DRUG

allogeneic bone marrow transplantation PROCEDURE

peripheral blood stem cell transplantation PROCEDURE

Eligibility Criteria

• Age: Up to 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

DISEASE CHARACTERISTICS: * Histologically confirmed acute lymphoblastic leukemia (ALL) of FAB L1 or L2 morphology * Positive SIg allowed OR * Histologically confirmed precursor B or precursor T lymphoblastic non-Hodgkin's lymphoma (NHL) * No diffuse large cell B-cell lymphoma, Burkitt's lymphoma, or high-grade B-cell lymphoma (Burkitt-like) * Very low-risk (VLR) patients meeting 1 of the following criteria: * ALL of B-cell lineage * WBC less than 10,000/mm\^3 * Must meet 1 of the following conditions: * DNA index greater than 1.16 and less than 1.50 and chromosome number 51-66 or unknown * DNA index not assessed and chromosome number 51-66 * DNA index greater than 1.16 and less than 1.50 and chromosome number is unknown * Good response to prephase therapy * Absence of t(9;22) or BCR/ABL, t(4;11)/MLL-AF4, or 11q23/MLL rearrangement * No acute undifferentiated leukemia (AUL) * No CNS or gonadal involvement * Precursor B-lymphoblastic NHL stage I or II OR * Average risk (AR) patients: * Must meet 1 of the following criteria: * ALL with good response to prephase therapy who are neither VLR or very high risk (VHR) * VLR ALL with CNS involvement (CSF positive or negative) * Precursor B-lymphoblastic NHL stage III or IV without any VHR feature * Precursor T-lymphoblastic NHL * AR patients substratified in: * AR1: B-cell lineage ALL with WBC less than 100,000/mm\^3 * Surreptitious or hemorrhagic CSF becoming negative at D4 of prephase therapy * Precursor B-lymphoblastic NHL stage III or IV * Precursor T-lymphoblastic NHL stage I or II * AR2: B-cell lineage ALL with WBC at least 100,000/mm\^3 * T-cell lineage ALL regardless of the WBC * Overt or non-equivocal CNS involvement at D0 or any CSF involvement at D4 * Gonadal involvement * Precursor T-lymphoblastic NHL stage III or IV * Newborn Down syndrome patients with AR2 features are assigned to the AR1 group OR * VHR patients: * Must meet 1 of the following criteria: * ALL patients meeting 1 of the following conditions: * Poor response to prephase therapy (at least 1,000/mm\^3 blasts in peripheral blood after completion of prephase therapy) * t(9;22) or BCR/ABL * t(4;11)/MLL-AF4 = 11q23/MLL rearrangement * Near haploidy (no more than 34 chromosomes or DNA index less than 0.7) * Hypodiploid (35-40 chromosomes or DNA index 0.7 to 0.8) * AUL * For B lineage ALL: failure to achieve complete response (CR) after completion of protocol IA * For T lineage ALL: failure to achieve CR or good partial response (GPR) after completion of protocol IA * Minimal-residual disease (greater than 1,000 blasts/100,000 mononuclear bone marrow cells) at evaluation of IA (day 35) * NHL patients who failed to achieve CR or GPR after completion of protocol IA * All VHR patients are eligible for stem cell transplantation except those whose sole VHR criterion is a poor response to prephase therapy and who have none of the following features: * T-cell immunophenotype * Early B ALL (CD10 negative) * WBC at least 100,000/mm\^3 * Newborn Down syndrome patients with VHR features are assigned to AR1 group NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology. PATIENT CHARACTERISTICS: Age: * Under 18 Performance status: * Not specified Life expectancy: * Not specified Hematopoietic: * See Disease Characteristics Hepatic: * Not specified Renal: * Not specified PRIOR CONCURRENT THERAPY: Biologic therapy: * See Disease Characteristics Chemotherapy: * Not specified Endocrine therapy: * Not specified Radiotherapy: * Not specified Surgery: * Not specified Other: * No prior therapy

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• European Organisation for Research and Treatment of Cancer - EORTC: lead

Study Sites (23)

Ziekenhuis Netwerk Antwerpen Middelheim

Antwerp, 2020, Belgium

Location

Hopital Universitaire Des Enfants Reine Fabiola

Brussels, 1020, Belgium

Location

Academisch Ziekenhuis der Vrije Universiteit Brussel

Brussels, 1090, Belgium

Location

Ghent University

Ghent, B-9000, Belgium

Location

Universitair Ziekenhuis Gent

Ghent, B-9000, Belgium

Location

U.Z. Gasthuisberg

Leuven, B-3000, Belgium

Location

Centre Hospitalier Regional de la Citadelle

Liège, 4000, Belgium

Location

Clinique de l'Esperance

Montegnée, 4420, Belgium

Location

Centre Hospitalier Regional et Universitaire d'Angers

Angers, 49033, France

Location

CHR de Besancon - Hopital Saint-Jacques

Besançon, 25030, France

Location

CHU de Caen

Caen, 14033, France

Location

CHU de Grenoble - Hopital de la Tronche

Grenoble, 38043, France

Location

Hopital Debrousse

Lyon, 69322, France

Location

Hopital Arnaud de Villeneuve

Montpellier, 34059, France

Location

CHR Hotel Dieu

Nantes, 44035, France

Location

Hopital de l'Archet CHU de Nice

Nice, F-06202, France

Location

CHU - Hopital Robert Debre

Paris, 75019, France

Location

Hopital Jean Bernard

Poitiers, 86021, France

Location

Hopital Americain

Reims, 51092, France

Location

Hopital Universitaire Hautepierre

Strasbourg, 67098, France

Location

Hopital des Enfants

Toulouse, 31026, France

Location

Hospital Escolar San Joao

Porto, 4200, Portugal

Location

Instituto Portugues de Oncologia Centro do Porto, SA

Porto, 4200, Portugal

Location

Related Publications (17)

• Ducassou S, Ferlay C, Bergeron C, Girard S, Laureys G, Pacquement H, Plantaz D, Lutz P, Vannier JP, Uyttebroeck A, Bertrand Y. Clinical presentation, evolution, and prognosis of precursor B-cell lymphoblastic lymphoma in trials LMT96, EORTC 58881, and EORTC 58951. Br J Haematol. 2011 Feb;152(4):441-51. doi: 10.1111/j.1365-2141.2010.08541.x. Epub 2011 Jan 7.

  PMID: 21210776 BACKGROUND

• Clappier E, Collette S, Grardel N, Girard S, Suarez L, Brunie G, Kaltenbach S, Yakouben K, Mazingue F, Robert A, Boutard P, Plantaz D, Rohrlich P, van Vlierberghe P, Preudhomme C, Otten J, Speleman F, Dastugue N, Suciu S, Benoit Y, Bertrand Y, Cave H; EORTC-CLG. NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951. Leukemia. 2010 Dec;24(12):2023-31. doi: 10.1038/leu.2010.205. Epub 2010 Sep 23.

  PMID: 20861920 BACKGROUND

• Clappier E, Collette S, Grardel N, et al.: Prognostic significance of NOTCH1 and FBXW7 mutations in childhood T-cell acute lymphoblastic leukemia (T-ALL): results from the EORTC Children Leukemia Group. [Abstract] Blood 114 (22): A-909, 2009.

  BACKGROUND

• Renneville A, Kaltenbach S, Clappier E, Collette S, Micol JB, Nelken B, Lepelley P, Dastugue N, Benoit Y, Bertrand Y, Preudhomme C, Cave H. Wilms tumor 1 (WT1) gene mutations in pediatric T-cell malignancies. Leukemia. 2010 Feb;24(2):476-80. doi: 10.1038/leu.2009.221. Epub 2009 Oct 22. No abstract available.

  PMID: 19847202 BACKGROUND

• Cave H, Suciu S, Preudhomme C, Poppe B, Robert A, Uyttebroeck A, Malet M, Boutard P, Benoit Y, Mauvieux L, Lutz P, Mechinaud F, Grardel N, Mazingue F, Dupont M, Margueritte G, Pages MP, Bertrand Y, Plouvier E, Brunie G, Bastard C, Plantaz D, Vande Velde I, Hagemeijer A, Speleman F, Lessard M, Otten J, Vilmer E, Dastugue N; EORTC-CLG. Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951. Blood. 2004 Jan 15;103(2):442-50. doi: 10.1182/blood-2003-05-1495. Epub 2003 Sep 22.

  PMID: 14504110 BACKGROUND

• Mirebeau D, Acquaviva C, Suciu S, Bertin R, Dastugue N, Robert A, Boutard P, Mechinaud F, Plouvier E, Otten J, Vilmer E, Cave H; EORTC-CLG. The prognostic significance of CDKN2A, CDKN2B and MTAP inactivation in B-lineage acute lymphoblastic leukemia of childhood. Results of the EORTC studies 58881 and 58951. Haematologica. 2006 Jul;91(7):881-5.

  PMID: 16818274 BACKGROUND

• Cavé H, Suciu S, Preudhomme C, et al.: HOX11L2 expression linked to t(5;14)(q35;q32) is not associated with poor prognosis in childhood T-ALL treated in EORTC trials 58 881 and 58 951. [Abstract] Blood 100(11 pt 1): A-576, 153a, 2002.

  BACKGROUND

• De Moerloose B, Suciu S, Bertrand Y, Mazingue F, Robert A, Uyttebroeck A, Yakouben K, Ferster A, Margueritte G, Lutz P, Munzer M, Sirvent N, Norton L, Boutard P, Plantaz D, Millot F, Philippet P, Baila L, Benoit Y, Otten J; Children's Leukemia Group of the European Organisation for Research and Treatment of Cancer (EORTC). Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951. Blood. 2010 Jul 8;116(1):36-44. doi: 10.1182/blood-2009-10-247965. Epub 2010 Apr 20.

  PMID: 20407035 RESULT

• Bertrand Y, Suciu S, Benoit Y, et al.: Dexamethasone(DEX)(6mg/sm/d) and prednisolone(PRED)(60mg/sm/d) in induction therapy of childhood ALL are equally effective: results of the 2nd interim analysis of EORTC trial 58951. [Abstract] Blood 112 (11): A-8, 2008.

  RESULT

• Sirvent N, Suciu S, Benoit Y, et al.: Prognostic significance of central nervous system (CNS) status of children with acute lymphoblastic leukemia (ALL) treated without cranial irradiation: results of European Organization for Research and Treatment of Cancer (EORTC) Children Leukemia Group study 58951. [Abstract] Blood 112 (11): A-303, 2008.

  RESULT

• Bertrand Y, Goutagny MP, Poulat AL, et al.: Asparagine depletion, safety and antibody production after E coli asparaginase treatment in children with newly diagnosed acute lymphoblastic leukaemia treated with EORTC 58951 protocol: a single center report. [Abstract] Blood 110 (11): A-4337, 2007.

  RESULT

• Sirvent N, Suciu S, De Moerloose B, Ferster A, Mazingue F, Plat G, Yakouben K, Uyttebroeck A, Paillard C, Costa V, Simon P, Pluchart C, Poiree M, Minckes O, Millot F, Freycon C, Maes P, Hoyoux C, Cave H, Rohrlich P, Bertrand Y, Benoit Y; Children's Leukemia Group of the European Organisation for Research Treatment of Cancer. CNS-3 status remains an independent adverse prognosis factor in children with acute lymphoblastic leukemia (ALL) treated without cranial irradiation: Results of EORTC Children Leukemia Group study 58951. Arch Pediatr. 2021 Jul;28(5):411-416. doi: 10.1016/j.arcped.2021.04.009. Epub 2021 May 24.

  PMID: 34034929 DERIVED

• Mondelaers V, Suciu S, De Moerloose B, Ferster A, Mazingue F, Plat G, Yakouben K, Uyttebroeck A, Lutz P, Costa V, Sirvent N, Plouvier E, Munzer M, Poiree M, Minckes O, Millot F, Plantaz D, Maes P, Hoyoux C, Cave H, Rohrlich P, Bertrand Y, Benoit Y; Children-s Leukemia Group (CLG) of the European Organization for Research and Treatment of Cancer (EORTC). Prolonged versus standard native E. coli asparaginase therapy in childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma: final results of the EORTC-CLG randomized phase III trial 58951. Haematologica. 2017 Oct;102(10):1727-1738. doi: 10.3324/haematol.2017.165845. Epub 2017 Jul 27.

  PMID: 28751566 DERIVED

• Ghazavi F, Clappier E, Lammens T, Suciu S, Caye A, Zegrari S, Bakkus M, Grardel N, Benoit Y, Bertrand Y, Minckes O, Costa V, Ferster A, Mazingue F, Plat G, Plouvier E, Poiree M, Uyttebroeck A, van der Werff-Ten Bosch J, Yakouben K, Helsmoortel H, Meul M, Van Roy N, Philippe J, Speleman F, Cave H, Van Vlierberghe P, De Moerloose B. CD200/BTLA deletions in pediatric precursor B-cell acute lymphoblastic leukemia treated according to the EORTC-CLG 58951 protocol. Haematologica. 2015 Oct;100(10):1311-9. doi: 10.3324/haematol.2015.126953. Epub 2015 Jul 2.

  PMID: 26137961 DERIVED

• Clappier E, Grardel N, Bakkus M, Rapion J, De Moerloose B, Kastner P, Caye A, Vivent J, Costa V, Ferster A, Lutz P, Mazingue F, Millot F, Plantaz D, Plat G, Plouvier E, Poiree M, Sirvent N, Uyttebroeck A, Yakouben K, Girard S, Dastugue N, Suciu S, Benoit Y, Bertrand Y, Cave H; European Organisation for Research and Treatment of Cancer, Children's Leukemia Group (EORTC-CLG). IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children's Leukemia Group study 58951. Leukemia. 2015 Nov;29(11):2154-61. doi: 10.1038/leu.2015.134. Epub 2015 Jun 8.

  PMID: 26050650 DERIVED

• Domenech C, Suciu S, De Moerloose B, Mazingue F, Plat G, Ferster A, Uyttebroeck A, Sirvent N, Lutz P, Yakouben K, Munzer M, Rohrlich P, Plantaz D, Millot F, Philippet P, Dastugue N, Girard S, Cave H, Benoit Y, Bertrandfor Y; Children's Leukemia Group (CLG) of European Organisation for Research and Treatment of Cancer (EORTC). Dexamethasone (6 mg/m2/day) and prednisolone (60 mg/m2/day) were equally effective as induction therapy for childhood acute lymphoblastic leukemia in the EORTC CLG 58951 randomized trial. Haematologica. 2014 Jul;99(7):1220-7. doi: 10.3324/haematol.2014.103507. Epub 2014 Apr 11.

  PMID: 24727815 DERIVED

• Dastugue N, Suciu S, Plat G, Speleman F, Cave H, Girard S, Bakkus M, Pages MP, Yakouben K, Nelken B, Uyttebroeck A, Gervais C, Lutz P, Teixeira MR, Heimann P, Ferster A, Rohrlich P, Collonge MA, Munzer M, Luquet I, Boutard P, Sirvent N, Karrasch M, Bertrand Y, Benoit Y. Hyperdiploidy with 58-66 chromosomes in childhood B-acute lymphoblastic leukemia is highly curable: 58951 CLG-EORTC results. Blood. 2013 Mar 28;121(13):2415-23. doi: 10.1182/blood-2012-06-437681. Epub 2013 Jan 15.

  PMID: 23321258 DERIVED

MeSH Terms

Conditions

Leukemia; Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Biphenotypic, Acute

Interventions

Asparaginase; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Doxorubicin; Etoposide; Leucovorin; Mercaptopurine; Methotrexate; Methylprednisolone; Mitoxantrone; Prednisolone; Hydrocortisone; Thioguanine; Vincristine; Vindesine; Peripheral Blood Stem Cell Transplantation

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Lymphoid

Intervention Hierarchy (Ancestors)

Amidohydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Sulfhydryl Compounds; Sulfur Compounds; Purines; Aminopterin; Anthraquinones; Anthrones; Anthracenes; Quinones; Pregnenediones; Pregnenes; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Indolizidines; Indolizines; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative

Study Officials

• Jacques Otten, MD

  Academisch Ziekenhuis der Vrije Universiteit Brussel

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Purpose: TREATMENT
• Sponsor Type: NETWORK

Study Record Dates

• First Submitted: November 1, 1999
• First Posted: January 27, 2003
• Study Start: December 1, 1998
• Primary Completion: May 1, 2008
• Last Updated: January 21, 2011

Record last verified: 2009-06

Locations

FR (13); PT (2); BE (8)