Combination Chemotherapy With or Without Bone Marrow Transplantation in Treating Patients With Acute Promyelocytic Leukemia

NCT ID: NCT00002701

Last Updated: 2013-09-20

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE3
• Total Enrollment: 750 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 1995-10-31

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Bone marrow transplantation may be able to replace immune cells that were destroyed by chemotherapy to kill tumor cells. It is not yet known which regimen of combination chemotherapy with or without bone marrow transplantation is more effective in treating promyelocytic leukemia

PURPOSE: Randomized phase III trial to compare the effectiveness of different combination chemotherapy regimens with or without bone marrow transplantation in treating patients who have promyelocytic leukemia.

Detailed Description

OBJECTIVES:

• Determine the complete remission (CR) rate in patients with acute promyelocytic leukemia treated with induction comprising tretinoin (ATRA) and idarubicin (IDA).
• Determine the presence of the promyelocyte-retinoic acid receptor alpha (PML-RARa) transcript using polymerase chain reaction (PCR) in patients with CR after 3 sequential consolidation regimens comprising cytarabine (ARA-C) plus IDA, followed by mitoxantrone plus etoposide, and then IDA, ARA-C, and thioguanine.
• Determine the percentage of patients who complete the protocol, including PML-RARa-positive patients treated with post-consolidation bone marrow transplantation (BMT) and PML-RARa-negative patients treated with maintenance comprising mercaptopurine (MP) plus methotrexate (MTX) vs ATRA only vs MP plus MTX alternating with ATRA vs observation only.
• Compare the disease-free survival (DFS) and overall survival of these patients treated with these regimens.
• Determine the rate and type of grade 4 toxicity, treatment-related mortality, and time to granulocyte and platelet recovery associated with each phase of treatment in these patients.
• Determine the DFS and overall survival of PML-RARa-positive patients who are ineligible for BMT and are treated with maintenance comprising MP plus MTX alternating with ATRA.
• Compare the quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study.

• Induction: Patients receive oral tretinoin (ATRA) twice daily beginning on day 1 and continuing for 30-90 days and idarubicin (IDA) IV over 15 minutes on days 2, 4, and 8. ATRA is discontinued before day 90 in the presence of complete remission (CR) at day 30 or 60, unacceptable toxicity, or disease progression or in the absence of at least a partial remission at day 60. Patients who achieve CR during induction proceed to consolidation.
• Consolidation:

• First consolidation: Within 2 weeks after achieving CR, patients receive cytarabine (ARA-C) IV over 6 hours followed 3 hours later by IDA IV over 15 minutes on days 1-4.
• Second consolidation:Within 4-6 weeks after initiation of first consolidation, patients receive mitoxantrone IV over 30 minutes and etoposide IV over 1 hour (beginning 12 hours after initiation of mitoxantrone infusion) on days 1-5.
• Third consolidation:Within 4-6 weeks after initiation of second consolidation, patients receive ARA-C subcutaneously every 8 hours and oral thioguanine every 8 hours on days 1-5 and IDA IV over 15 minutes on day 1.

Patients proceed to group A if they are promyelocyte-retinoic acid receptor alpha (PML-RARa)-negative after recovery from third consolidation. Patients proceed to allogeneic bone marrow transplantation (BMT) on group B if they are PML-RARa-positive, achieve CR, are under age 55, and have an HLA-A, -B, and -DR identical, chronic myelomonocytic leukemia nonreactive, family donor after recovery from third consolidation. Patients proceed to autologous BMT on group B if they are PML-RARa-positive, achieve CR, and have no identical family donor or are age 55 and over after recovery from third consolidation. Patients proceed to arm III of group A if they are PML-RARa-positive and ineligible for BMT after recovery from third consolidation.

• Group A (maintenance): Patients are stratified according to participating center and initial white blood cell count. Patients are randomized to 1 of 4 treatment arms.

• Arm I: Patients receive oral mercaptopurine (MP) daily and oral methotrexate (MTX) weekly.
• Arm II: Beginning 3 months after recovery from third consolidation, patients receive oral ATRA on days 1-15.

Treatment on arms I and II continues every 3 months for 2 years in the absence of disease progression or unacceptable toxicity.

• Arm III: Patients receive 1 course of arm I treatment, alternated by 1 course of arm II treatment. Alternating treatment continues every 3 months for 2 years in the absence of disease progression or unacceptable toxicity.
• Arm IV: Patients undergo observation only.

• Group B: Eligible patients receive conditioning comprising cyclophosphamide (CTX) IV for 2 days followed by total body irradiation or oral busulfan on days -9 to -6 and CTX on days -5 to -2. Autologous or allogeneic bone marrow is infused on day 0 (within 4 months after initiation of third consolidation).

Quality of life is assessed at baseline, after induction, after each consolidation regimen, and then every 3 months beginning after treatment on group A or B.

Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 750 patients will be accrued for this study within 7.5 years.

Conditions

Leukemia

Keywords

untreated adult acute myeloid leukemia; adult acute promyelocytic leukemia (M3)

Study Design

• Allocation Method: RANDOMIZED
• Primary Study Purpose: TREATMENT

Interventions

busulfan

Intervention Type: DRUG

cyclophosphamide

Intervention Type: DRUG

cytarabine

Intervention Type: DRUG

etoposide

Intervention Type: DRUG

idarubicin

Intervention Type: DRUG

mercaptopurine

Intervention Type: DRUG

methotrexate

Intervention Type: DRUG

mitoxantrone hydrochloride

Intervention Type: DRUG

thioguanine

Intervention Type: DRUG

tretinoin

Intervention Type: DRUG

allogeneic bone marrow transplantation

Intervention Type: PROCEDURE

autologous bone marrow transplantation

Intervention Type: PROCEDURE

radiation therapy

Intervention Type: RADIATION

Eligibility Criteria

Inclusion Criteria

DISEASE CHARACTERISTICS:

• Newly diagnosed acute promyelocytic leukemia
• Must have promyelocyte-retinoic acid receptor alpha transcript at disease presentation

PATIENT CHARACTERISTICS:

Age:

• 16 to 74

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Bilirubin no greater than 3 times upper limit of normal (ULN)
• AST no greater than 3 times ULN
• Alkaline phosphatase no greater than 3 times ULN

Renal:

• Creatinine no greater than 2.5 mg/dL

Cardiovascular:

• No cardiac contraindication to anthracycline chemotherapy

Other:

• No active serious infection not controlled by antibiotics
• No severe concurrent psychiatric disease
• No other malignancy except basal cell carcinoma
• Not pregnant or nursing
• Negative pregnancy test

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No concurrent cytotoxic chemotherapy

Endocrine therapy:

• Prior corticosteroids for leukemia allowed

Radiotherapy:

• No concurrent radiotherapy

Surgery:

• Not specified

Other:

• No prior antileukemic therapy

• Minimum Eligible Age: 16 Years
• Maximum Eligible Age: 74 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Gruppo Italiano Malattie EMatologiche dell'Adulto

OTHER

Sponsor Role: collaborator

European Organisation for Research and Treatment of Cancer - EORTC

NETWORK

Sponsor Role: lead

Principal Investigators

Petra Muus, MD, PhD

Role: STUDY_CHAIR

Universitair Medisch Centrum St. Radboud - Nijmegen

Franco Mandelli, MD

Role: STUDY_CHAIR

Azienda Policlinico Umberto Primo

Locations

Innsbruck Universitaetsklinik

Innsbruck, , Austria

Algemeen Ziekenhuis Middelheim

Antwerp, , Belgium

A.Z. St. Jan

Bruges, , Belgium

Hopital Universitaire Erasme

Brussels, , Belgium

C.H.U. Saint-Pierre

Brussels (Bruxelles), , Belgium

Institut Jules Bordet

Brussels (Bruxelles), , Belgium

Universitair Ziekenhuis Antwerpen

Edegem, , Belgium

U.Z. Gasthuisberg

Leuven, , Belgium

CHU Sart-Tilman

Liège, , Belgium

Centre Hospitalier Peltzer-La Tourelle

Verviers, , Belgium

University Hospital Rebro

Zagreb, , Croatia

Medical School/University of Zagreb

Zagreb (Agram), , Croatia

Onkologicka Klinka A Onkologicka Lab

Prague, , Czechia

Centre Hospitalier Regional de Lille

Lille, , France

Hopital Edouard Herriot

Lyon, , France

Centre Antoine Lacassagne

Nice, , France

Hotel Dieu de Paris

Paris, , France

Hopital Necker

Paris, , France

Centre Medico-Chirurgical Foch

Suresnes, , France

Institut Gustave Roussy

Villejuif, , France

Klinikum Duisburg

Duisburg, , Germany

Klinikum Grosshadern

Munich (Muenchen), , Germany

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

Policlinico di Careggi

Firenze (Florence), , Italy

Ospedali Riuniti Foggia

Foggia, , Italy

Ospedale S. Antonio Abate

Gallarate Varese, , Italy

Ospedale San Martino/Cliniche Universitarie Convenzionate

Genoa (Genova), , Italy

Ospedale Gen. Provinciale Santa Maria Goretti

Latina, , Italy

Ospedale Maggiore Lodi

Lodi, , Italy

Istituto Scientifico H.S. Raffaele

Milan, , Italy

Ospedale Maggiore Ca Granda

Milano (Milan), , Italy

Ospedale Di Montefiascone

Montefiascone, , 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 San Francesco

Nuoro, , Italy

Azienda Ospedaliera di Padova

Padova (Padua), , Italy

Policlinico - Cattedra di Ematologia

Palermo, , Italy

Ospedale Cervello

Palermo, , Italy

Azienda Ospedaliera Di Parma

Parma, , Italy

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

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

Ospedal SS Annunziata

Taranto, , Italy

Cattedra di Immunologia Clinica

Turin (TO), , Italy

Ospedale Molinette

Turin (Torino), , Italy

Leyenburg Ziekenhuis

's-Gravenhage (Den Haag, the Hague), , Netherlands

Groot Ziekengasthuis 's-Hertogenbosch

's-Hertogenbosch, , Netherlands

Academisch Medisch Centrum

Amsterdam, , Netherlands

Academisch Ziekenhuis Groningen

Groningen, , Netherlands

Leiden University Medical Center

Leiden, , Netherlands

University Medical Center Nijmegen

Nijmegen, , Netherlands

University Hospital - Rotterdam Dijkzigt

Rotterdam, , Netherlands

Ibn-i Sina Hospital, Ankara University

Ankara, , Turkey (Türkiye)

Countries

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

Other Identifiers

EORTC-06952

Identifier Type: -

Identifier Source: secondary_id

ITA-GIMEMA-AIEOP-1

Identifier Type: -

Identifier Source: secondary_id

CDR0000064499

Identifier Type: -

Identifier Source: org_study_id