Clinical trial NCT00002549: Combination Chemotherapy Followed by Bone Marrow or Peripheral Stem Cell Transplantation in Treating Patients With Acute Myelogenous Leukemia
Official title: RANDOMIZED PHASE III STUDY OF INDUCTION (ICE VS MICE VS DCE) AND INTENSIVE CONSOLIDATION (IDIA VS NOVIA VS DIA) FOLLOWED BY BONE MARROW TRANSPLANTATION IN ACUTE MYELOGENOUS LEUKEMIA: AML 10 PROTOCOL
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
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)
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2004-07-19
Enrollment: 1520
Sex: ALL
Minimum age (years): 15
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

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.

Eligibility criteria: DISEASE CHARACTERISTICS: Newly diagnosed acute myeloid leukemia (AML) of any FAB histology (M1-M7) except M3 At least 30% blast cells in bone marrow smears Secondary leukemias eligible, as follows: Following cured malignancies, including Hodgkin's disease Following exposure to alkylating agents or radiotherapy for other reasons The following leukemias are excluded: Blast crisis of chronic myeloid leukemia Leukemia secondary to other myeloproliferative disease Leukemia secondary to myelodysplastic syndrome of more than 6 months' duration No other progressive malignant disease

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)

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Universitaetsklinik
city: Antwerp
country: Belgium
facility: Algemeen Ziekenhuis Middelheim
city: Brugge
country: Belgium
facility: A.Z. St. Jan
city: Brussels (Bruxelles)
country: Belgium
facility: Institut Jules Bordet
city: Brussels
country: Belgium
facility: Hopital Universitaire Erasme
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Liege
country: Belgium
facility: CHU Sart-Tilman
city: Zagreb (Agram)
country: Croatia
facility: Medical School/University of Zagreb
city: Zagreb
country: Croatia
facility: University Hospital Rebro
city: Olomouc
country: Czech Republic
facility: University Hospital - Olomouc
city: Prague
country: Czech Republic
facility: Institute of Hematology and Blood Transfusion
city: Lyon
country: France
facility: Hopital Edouard Herriot
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Hotel Dieu de Paris
city: Paris
country: France
facility: Hopital Cochin
city: Paris
country: France
facility: Hopital Necker
city: Suresnes
country: France
facility: Centre Medico-Chirurgical Foch
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Duisburg
country: Germany
facility: Staedtische Kliniken Duisburg
city: Munich (Muenchen)
country: Germany
facility: Klinikum Grosshadern
city: Kecskemet
country: Hungary
facility: County Hospital
city: Alessandria
country: Italy
facility: Ospedale Civile Alessandria
city: Ancona
country: Italy
facility: Ospedale Torrette University Ancona
city: Avellino
country: Italy
facility: Ospedale Civile Avellino
city: Bari
country: Italy
facility: Universita Degli Studi di Bari Policlinico
city: Brindisi
country: Italy
facility: Ospedale Regionale A. Di Summa
city: Cagliari
country: Italy
facility: Ospedale Oncologico A. Businco
city: Catania
country: Italy
facility: Ospedale Ferrarotto
city: Catanzaro
country: Italy
facility: Ospedale Regionale A. Pugliese
city: Cremona
country: Italy
facility: Centro Trapianti di Midollo Osseo
city: Cuneo
country: Italy
facility: Ospedale Santa Croce
city: Firenze (Florence)
country: Italy
facility: Universita Degli Studi di Firenze - Policlin. di Careggi
city: Foggia
country: Italy
facility: Ospedali Riuniti Foggia
city: Gallarate Varese
country: Italy
facility: Ospedale S. Antonio Abate
city: Genoa (Genova)
country: Italy
facility: Ospedale San Martino/Cliniche Universitarie Convenzionale
city: Latina
country: Italy
facility: Ospedale Gen. Provinciale Santa Maria Goretti
city: Lodi
country: Italy
facility: Ospedale Maggiore Lodi
city: Milano (Milan)
country: Italy
facility: Instituto Scientifico H.S. Raffaele
city: Milano (Milan)
country: Italy
facility: Ospedale Maggiore Ca Granda
city: Modena
country: Italy
facility: Universita di Modena
city: Naples (Napoli)
country: Italy
facility: Azienda Ospedaliera "A. Cardarelli"
city: Naples (Napoli)
country: Italy
facility: Federico II University Medical School
city: Naples (Napoli)
country: Italy
facility: Ospedale S. Gennora USL 42
city: Naples (Napoli)
country: Italy
facility: Ospedale Nuovo Pellegrini
city: Novara
country: Italy
facility: Ospedale Maggiore
city: Nuoro
country: Italy
facility: Ospedale San Francesco
city: Orbassano, (Torino)
country: Italy
facility: Azienda Ospedale S. Luigi - Universita Di Torino
city: Palermo
country: Italy
facility: Policlinico - Cattedra di Ematologia
city: Palermo
country: Italy
facility: Policlinico P. Giaccone - Universita Di Palermo
city: Palermo
country: Italy
facility: Ospedale Cervello
city: Parma
country: Italy
facility: Azienda Ospedaliera Di Parma
city: Pavia
country: Italy
facility: University and I.R.C.C.S. Policlinico San Matteo
city: Perugia
country: Italy
facility: Policlinico Monteluce
city: Pesaro
country: Italy
facility: Ospedale San Salvatore
city: Pescara
country: Italy
facility: Ospedale Civile Pescara
city: Potenza
country: Italy
facility: Ospedale San Carlo
city: Reggio Calabria
country: Italy
facility: Ospedali Riuniti
city: Reggio Emilia
country: Italy
facility: Arcispedale S. Maria Nuova
city: Rome
country: Italy
facility: Ospedale San Eugenio
city: Rome
country: Italy
facility: Azienda Policlinico Umberto Primo
city: Rome
country: Italy
facility: Policlinico A. Gemelli - Universita Cattolica del Sacro Cuore
city: San Giovanni - Rotondo
country: Italy
facility: Ospedale Casa Sollievo della Sofferenza
city: Sassari
country: Italy
facility: Istituto di Ematologia Universita - University di Sassari
city: Sondalo (so)
country: Italy
facility: Azienda Ospedaliera Ospedale E. Mortelli
city: Taranto
country: Italy
facility: Ospedal SS Annunziata
city: Turin (Torino)
country: Italy
facility: Ospedale Molinette
city: 's-Hertogenbosch
country: Netherlands
facility: Groot Ziekengasthuis 's-Hertogenbosch
city: Amsterdam
country: Netherlands
facility: Onze Lieve Vrouwe Gasthuis
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Nijmegen
country: Netherlands
facility: University Medical Center Nijmegen
city: Veldhoven
country: Netherlands
facility: Sint Joseph Ziekenhuis
city: Coimbra
country: Portugal
facility: Hospitais da Universidade de Coimbra (HUC)
city: Porto
country: Portugal
facility: Hospital Escolar San Joao
city: Ankara
country: Turkey
facility: Ibn-i Sina Hospital, Ankara Univeristy
Study officials:
affiliation: Hotel Dieu de Paris
name: Robert A. Zittoun, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.