Combination Chemotherapy Followed by Bone Marrow or Peripheral Stem Cell Transplantation in Treating Patients With Acute Myelogenous Leukemia

NCT ID: NCT00002549

Last Updated: 2009-12-23

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE3
• Total Enrollment: 1520 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 1993-11-30

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell or bone marrow transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells.

PURPOSE: Randomized phase III trial to compare the effectiveness of combination chemotherapy followed by bone marrow or peripheral stem cell transplantation in treating patients with acute myelogenous leukemia.

Detailed Description

OBJECTIVES: I. Determine the complete remission (CR) rate following 1 or 2 courses of ICE (idarubicin/cytarabine/etoposide) vs. MICE (mitoxantrone/cytarabine/etoposide) vs. DCE (daunorubicin/cytarabine/etoposide) in patients with newly diagnosed acute myeloid leukemia. II. Compare disease-free survival and overall survival achieved with each anthracycline on the above induction regimens and with intermediate-dose cytarabine (IDIA vs. NOVIA vs. DIA) as consolidation therapy. III. Compare disease-free survival, relapse rate, death in first CR, and overall survival in patients who receive peripheral blood stem cells (PBSC) vs. autologous bone marrow transplant (AuBMT) vs. allogeneic bone marrow transplant (AlBMT) as rescue from myeloablative therapy following remission consolidation. IV. Assess the time to recovery of normal or acceptable polymorphonuclear leukocyte and platelet counts following each treatment step. V. Determine the incidence and type of grade 4 toxicity and treatment-related mortality. VI. Evaluate the quality of life during each step of treatment using self-administered questionnaires. VII. Compare stem cell mobilization after IDIA vs. NOVIA vs. DIA, each using granulocyte colony-stimulating factor as the mobilizing growth factor. VIII. Assess the rate of completion of stem cell transplantation using PBSC vs. AlBMT vs. AuBMT as the last step of therapy. IX. Compare the costs of treatment (e.g., antibiotics and transfusion requirements) and hospitalization duration between the AuBMT vs. PBSC.

OUTLINE: Randomized study. All patients are randomized to Arms I, II, and III for Induction/Consolidation. Patients in CR following Consolidation who have an HLA-identical sibling, are less than 45 or 55 years of age (depending on center policy), and have adequate organ function are nonrandomly assigned to AlBMT on Regimen A; those in CR who are without an available sibling donor and who have adequate organ function proceed to Regimen B, then are randomized to Arms IV and V. The following acronyms are used: AlBMT Allogeneic Bone Marrow Transplant ARA-C Cytarabine, NSC-63878 AuBMT Autologous Bone Marrow Transplant BU Busulfan, NSC-750 CTX Cyclophosphamide, NSC-26271 DCE DNR/ARA-C/VP-16 DHAD Mitoxantrone, NSC-301739 DIA DNR/ID ARA-C DNR Daunorubicin, NSC-82151 G-CSF Granulocyte Colony-Stimulating Factor (Rhone-Poulenc-Rorer) ICE IDA/ARA-C/VP-16 IDA Idarubicin, NSC-256439 ID Intermediate Dose IDIA IDA/ID ARA-C Mesna Mercaptoethane sulfonate, NSC-113891 MICE DHAD/ARA-C/VP-16 NOVIA DHAD/ID ARA-C PBSC Peripheral Blood Stem Cells TBI Total-Body Irradiation VP-16 Etoposide, NSC-141540 INDUCTION/CONSOLIDATION: Arm I: 3-Drug Combination Chemotherapy followed by 2-Drug Combination Chemotherapy. ICE; followed by IDIA. Arm II: 3-Drug Combination Chemotherapy followed by 2-Drug Combination Chemotherapy. MICE; followed by NOVIA. Arm III: 3-Drug Combination Chemotherapy followed by 2-Drug Combination Chemotherapy. DCE; followed by DIA. POSTCONSOLIDATION THERAPY: Regimen A: Single-Agent Chemoablation plus Radioablation or 2-Drug Chemoablation followed by Hematopoietic Rescue. CTX; plus TBI (equipment unspecified); or CTX/BU; followed by AlBMT. Entry on EORTC study comparing CI IDA with standard CTX/TBI or CTX/BU encouraged. Regimen B: Stem cell Mobilization and Harvest. G-CSF or CTX/G-CSF. Arm IV: Single-Agent Chemoablation plus Radioablation or 2-Drug Chemoablation followed by Hematopoietic Rescue. CTX/TBI or CTX/BU; followed by PBSC. Arm V: Single-Agent Chemoablation plus Radioablation or 2-Drug Chemoablation followed by Hematopoietic Rescue. CTX/TBI or CTX/BU; followed by AuBMT.

PROJECTED ACCRUAL: 1,520 patients will be randomized for Induction/Consolidation over about 5 years; if excessive deaths are found at interim analyses, the inferior arm will close. It is expected that 744 patients will be randomized for Postconsolidation therapy, with 345 patients followed until relapse/death.

Conditions

Leukemia

Keywords

untreated adult acute myeloid leukemia; adult acute erythroid leukemia (M6); adult acute myeloblastic leukemia without maturation (M1); adult acute myeloblastic leukemia with maturation (M2); adult acute myelomonocytic leukemia (M4); adult acute monoblastic leukemia (M5a); adult acute megakaryoblastic leukemia (M7); secondary acute myeloid leukemia; adult acute monocytic leukemia (M5b)

Study Design

• Allocation Method: RANDOMIZED
• Primary Study Purpose: TREATMENT

Interventions

filgrastim

Intervention Type: BIOLOGICAL

busulfan

Intervention Type: DRUG

cyclophosphamide

Intervention Type: DRUG

cytarabine

Intervention Type: DRUG

daunorubicin hydrochloride

Intervention Type: DRUG

etoposide

Intervention Type: DRUG

idarubicin

Intervention Type: DRUG

mesna

Intervention Type: DRUG

mitoxantrone hydrochloride

Intervention Type: DRUG

allogeneic bone marrow transplantation

Intervention Type: PROCEDURE

autologous bone marrow transplantation

Intervention Type: PROCEDURE

peripheral blood stem cell transplantation

Intervention Type: PROCEDURE

radiation therapy

Intervention Type: RADIATION

Eligibility Criteria

Inclusion Criteria

PATIENT CHARACTERISTICS: Age: 15 to 60 Performance status: Not specified Hematopoietic: Not applicable Hepatic: Bilirubin no greater than 1.5 x ULN Renal: Creatinine no greater than 1.5 x ULN Cardiovascular: No severe heart failure requiring diuretics or with an LVEF less than 50% Other: No severe concomitant neurologic disease No severe concomitant psychologic disease

PRIOR CONCURRENT THERAPY: No prior therapy for AML (chemotherapy, radiotherapy, or more than 7 days of corticosteroids)

• Minimum Eligible Age: 15 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

European Organisation for Research and Treatment of Cancer - EORTC

NETWORK

Sponsor Role: lead

Principal Investigators

Robert A. Zittoun, MD

Role: STUDY_CHAIR

Hotel Dieu de Paris

Locations

Universitaetsklinik

Innsbruck, , Austria

Algemeen Ziekenhuis Middelheim

Antwerp, , Belgium

A.Z. St. Jan

Bruges, , Belgium

Hopital Universitaire Erasme

Brussels, , Belgium

Institut Jules Bordet

Brussels (Bruxelles), , Belgium

Universitair Ziekenhuis Antwerpen

Edegem, , Belgium

CHU Sart-Tilman

Liège, , Belgium

University Hospital Rebro

Zagreb, , Croatia

Medical School/University of Zagreb

Zagreb (Agram), , Croatia

University Hospital - Olomouc

Olomouc, , Czechia

Institute of Hematology and Blood Transfusion

Prague, , Czechia

Hopital Edouard Herriot

Lyon, , France

Centre Antoine Lacassagne

Nice, , France

Hotel Dieu de Paris

Paris, , France

Hopital Cochin

Paris, , France

Hopital Necker

Paris, , France

Centre Medico-Chirurgical Foch

Suresnes, , France

Institut Gustave Roussy

Villejuif, , France

Staedtische Kliniken Duisburg

Duisburg, , Germany

Klinikum Grosshadern

Munich (Muenchen), , Germany

County Hospital

Kecskemét, , Hungary

Ospedale Civile Alessandria

Alessandria, , Italy

Ospedale Torrette University Ancona

Ancona, , Italy

Ospedale Civile Avellino

Avellino, , Italy

Universita Degli Studi di Bari Policlinico

Bari, , Italy

Ospedale Regionale A. Di Summa

Brindisi, , Italy

Ospedale Oncologico A. Businco

Cagliari, , Italy

Ospedale Ferrarotto

Catania, , Italy

Ospedale Regionale A. Pugliese

Catanzaro, , Italy

Centro Trapianti di Midollo Osseo

Cremona, , Italy

Ospedale Santa Croce

Cuneo, , Italy

Universita Degli Studi di Firenze - Policlin. di Careggi

Firenze (Florence), , Italy

Ospedali Riuniti Foggia

Foggia, , Italy

Ospedale S. Antonio Abate

Gallarate Varese, , Italy

Ospedale San Martino/Cliniche Universitarie Convenzionale

Genoa (Genova), , Italy

Ospedale Gen. Provinciale Santa Maria Goretti

Latina, , Italy

Ospedale Maggiore Lodi

Lodi, , Italy

Instituto Scientifico H.S. Raffaele

Milano (Milan), , Italy

Ospedale Maggiore Ca Granda

Milano (Milan), , Italy

Universita di Modena

Modena, , Italy

Azienda Ospedaliera "A. Cardarelli"

Naples (Napoli), , Italy

Federico II University Medical School

Naples (Napoli), , Italy

Ospedale S. Gennora USL 42

Naples (Napoli), , Italy

Ospedale Nuovo Pellegrini

Naples (Napoli), , Italy

Ospedale Maggiore

Novara, , Italy

Ospedale San Francesco

Nuoro, , Italy

Azienda Ospedale S. Luigi - Universita Di Torino

Orbassano, (Torino), , Italy

Policlinico - Cattedra di Ematologia

Palermo, , Italy

Policlinico P. Giaccone - Universita Di Palermo

Palermo, , Italy

Ospedale Cervello

Palermo, , Italy

Azienda Ospedaliera Di Parma

Parma, , Italy

University and I.R.C.C.S. Policlinico San Matteo

Pavia, , Italy

Policlinico Monteluce

Perugia, , Italy

Ospedale San Salvatore

Pesaro, , Italy

Ospedale Civile Pescara

Pescara, , Italy

Ospedale San Carlo

Potenza, , Italy

Ospedali Riuniti

Reggio Calabria, , Italy

Arcispedale S. Maria Nuova

Reggio Emilia, , Italy

Ospedale San Eugenio

Rome, , Italy

Azienda Policlinico Umberto Primo

Rome, , Italy

Policlinico A. Gemelli - Universita Cattolica del Sacro Cuore

Rome, , Italy

Ospedale Casa Sollievo della Sofferenza

San Giovanni Rotondo, , Italy

Istituto di Ematologia Universita - University di Sassari

Sassari, , Italy

Azienda Ospedaliera Ospedale E. Mortelli

Sondalo (so), , Italy

Ospedal SS Annunziata

Taranto, , Italy

Ospedale Molinette

Turin (Torino), , Italy

Groot Ziekengasthuis 's-Hertogenbosch

's-Hertogenbosch, , Netherlands

Onze Lieve Vrouwe Gasthuis

Amsterdam, , Netherlands

Medisch Spectrum Twente

Enschede, , Netherlands

Leiden University Medical Center

Leiden, , Netherlands

University Medical Center Nijmegen

Nijmegen, , Netherlands

Sint Joseph Ziekenhuis

Veldhoven, , Netherlands

Hospitais da Universidade de Coimbra (HUC)

Coimbra, , Portugal

Hospital Escolar San Joao

Porto, , Portugal

Ibn-i Sina Hospital, Ankara Univeristy

Ankara, , Turkey (Türkiye)

Countries

Austria; Belgium; Croatia; Czechia; France; Germany; Hungary; Italy; Netherlands; Portugal; Turkey (Türkiye)

References

Maurillo L, Buccisano F, Spagnoli A, et al.: In acute myeloid leukemia, the use in induction of standard dose arac is associated with a better quality of response as compared to an induction regimen containing high dose arac. [Abstract] Blood 114 (22): A-1584, 2009.

Reference Type: BACKGROUND

Oosterveld, M, Suciu S, Muus P, et al.: A new prognostic disease specific model to predict survival after intensive antileukemic treatment for young patients with poor-risk MDS and AML: results of the CRIANT and AML-10 studies conducted by the EORTC/GIMEMA/SAKK/HOVON/EBMT groups. [Abstract] Blood 104 (11): A-2020, 2004.

Reference Type: BACKGROUND

Mandelli F, Vignetti M, Suciu S, Stasi R, Petti MC, Meloni G, Muus P, Marmont F, Marie JP, Labar B, Thomas X, Di Raimondo F, Willemze R, Liso V, Ferrara F, Baila L, Fazi P, Zittoun R, Amadori S, de Witte T. Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10. J Clin Oncol. 2009 Nov 10;27(32):5397-403. doi: 10.1200/JCO.2008.20.6490. Epub 2009 Oct 13.

Reference Type: RESULT

PMID: 19826132 (View on PubMed)

Baron F, Stevens-Kroef M, Kicinski M, Meloni G, Muus P, Marie JP, Halkes CJM, Thomas X, Vrhovac R, Albano F, Lefrere F Sr, Sica S, Mancini M, Venditti A, Hagemeijer A, Jansen JH, Amadori S, de Witte T, Willemze R, Suciu S. Impact of induction regimen and allogeneic hematopoietic cell transplantation on outcome in younger adults with acute myeloid leukemia with a monosomal karyotype. Haematologica. 2019 Jun;104(6):1168-1175. doi: 10.3324/haematol.2018.204826. Epub 2018 Dec 6.

Reference Type: DERIVED

PMID: 30523055 (View on PubMed)

Baron F, Stevens-Kroef M, Kicinski M, Meloni G, Muus P, Marie JP, Halkes CJM, Thomas X, Vrhovac R, Specchia G, Lefrere F Sr, Sica S, Mancini M, Venditti A, Hagemeijer A, Becker H, Jansen JH, Amadori S, de Witte T, Willemze R, Suciu S. Cytogenetic clonal heterogeneity is not an independent prognosis factor in 15-60-year-old AML patients: results on 1291 patients included in the EORTC/GIMEMA AML-10 and AML-12 trials. Ann Hematol. 2018 Oct;97(10):1785-1795. doi: 10.1007/s00277-018-3396-4. Epub 2018 Jun 20.

Reference Type: DERIVED

PMID: 29926156 (View on PubMed)

Other Identifiers

EORTC-06931

Identifier Type: -

Identifier Source: secondary_id

CDR0000063311

Identifier Type: -

Identifier Source: org_study_id