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

Condition(s) targeted: Leukemia

Intervention: busulfan (Drug); cyclophosphamide (Drug); cytarabine (Drug); etoposide (Drug); idarubicin (Drug); mercaptopurine (Drug); methotrexate (Drug); mitoxantrone hydrochloride (Drug); thioguanine (Drug); tretinoin (Drug); allogeneic bone marrow transplantation (Procedure); autologous bone marrow transplantation (Procedure); radiation therapy (Procedure)

Phase: Phase 3

Status: Active, not recruiting

Sponsored by: European Organization for Research and Treatment of Cancer

Official(s) and/or principal investigator(s):
Petra Muus, MD, PhD, Study Chair, Affiliation: Universitair Medisch Centrum St. Radboud - Nijmegen
Franco Mandelli, MD, Study Chair, Affiliation: Azienda Policlinico Umberto Primo

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.

Official title: INDUCTION WITH ALL-TRANS RETINOIC ACID IN COMBINATION WITH IDARUBICIN AND INTENSIVE CONSOLIDATION FOLLOWED BY BONE MARROW TRANSPLANTATION OR A RANDOMIZED MAINTENANCE TREATMENT DEPENDING UPON THE AMOUNT OF MINIMAL RESIDUAL DISEASE IN ACUTE PROMYELOCYTIC LEUKEMIA

Study design: Treatment, Randomized, Active Control

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.

Minimum age: 16 Years. Maximum age: 74 Years. Gender(s): Both.

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

Innsbruck Universitaetsklinik, Innsbruck A-6020, Austria

A.Z. St. Jan, Brugge 8000, Belgium

Algemeen Ziekenhuis Middelheim, Antwerp 2020, Belgium

C.H.U. Saint-Pierre, Brussels (Bruxelles) 1000, Belgium

Centre Hospitalier Peltzer-La Tourelle, Verviers B-4800, Belgium

CHU Sart-Tilman, Liege B-4000, Belgium

Hopital Universitaire Erasme, Brussels 1070, Belgium

Institut Jules Bordet, Brussels (Bruxelles) 1000, Belgium

U.Z. Gasthuisberg, Leuven B-3000, Belgium

Universitair Ziekenhuis Antwerpen, Edegem B-2650, Belgium

Medical School/University of Zagreb, Zagreb (Agram) 41000, Croatia

University Hospital Rebro, Zagreb 41000, Croatia

Onkologicka Klinka A Onkologicka Lab, Prague 128 08, Czech Republic

Centre Antoine Lacassagne, Nice 06189, France

Centre Hospitalier Regional de Lille, Lille 59037, France

Centre Medico-Chirurgical Foch, Suresnes 92151, France

Hopital Edouard Herriot, Lyon 69437, France

Hopital Necker, Paris 75743, France

Hotel Dieu de Paris, Paris 75181, France

Institut Gustave Roussy, Villejuif F-94805, France

Klinikum Duisburg, Duisburg D-47055, Germany

Klinikum Grosshadern, Munich (Muenchen) D-81377, Germany

Azienda Ospedaliera "A. Cardarelli", Naples (Napoli) 80127, Italy

Azienda Ospedaliera di Padova, Padova (Padua) 35128, Italy

Azienda Ospedaliera Di Parma, Parma 43100, Italy

Azienda Policlinico Umberto Primo, Rome 00161, Italy

Cattedra di Immunologia Clinica, Turin (TO) 10128, Italy

Centro Trapianti di Midollo Osseo, Cremona 26100, Italy

Federico II University Medical School, Naples (Napoli) 80131, Italy

I.R.C.C.S. Policlinico San Matteo, Pavia 27100, Italy

Istituto di Ematologia Universita - University di Sassari, Sassari 07100, Italy

Istituto Scientifico H.S. Raffaele, Milano 20132, Italy

Ospedal SS Annunziata, Taranto 74100, Italy

Ospedale Casa Sollievo della Sofferenza, San Giovanni - Rotondo 71013, Italy

Ospedale Cervello, Palermo 90146, Italy

Ospedale Civile Alessandria, Alessandria I-15100, Italy

Ospedale Civile Avellino, Avellino, Italy

Ospedale Civile Pescara, Pescara 65100, Italy

Ospedale Di Montefiascone, Montefiascone I-01027, Italy

Ospedale Ferrarotto, Catania 95124, Italy

Ospedale Gen. Provinciale Santa Maria Goretti, Latina 04100, Italy

Ospedale Maggiore Ca Granda, Milano (Milan) 20162, Italy

Ospedale Maggiore Lodi, Lodi I-20075, Italy

Ospedale Molinette, Turin (Torino) 10126, Italy

Ospedale Nuovo Pellegrini, Naples (Napoli) 80144, Italy

Ospedale Oncologico A. Businco, Cagliari 09124, Italy

Ospedale Regionale A. Di Summa, Brindisi I-72100, Italy

Ospedale Regionale A. Pugliese, Catanzaro 88100, Italy

Ospedale S. Antonio Abate, Gallarate Varese 21013, Italy

Ospedale S. Gennora USL 42, Naples (Napoli) 80136, Italy

Ospedale San Carlo, Potenza 85100, Italy

Ospedale San Eugenio, Rome 00144, Italy

Ospedale San Francesco, Nuoro 08100, Italy

Ospedale San Martino/Cliniche Universitarie Convenzionate, Genoa (Genova) 16132, Italy

Ospedale San Salvatore, Pesaro I-61100, Italy

Ospedale Santa Croce, Cuneo 12100, Italy

Ospedale Torrette University Ancona, Ancona 60020, Italy

Ospedali Riuniti Foggia, Foggia 71100, Italy

Policlinico - Cattedra di Ematologia, Palermo 90100, Italy

Policlinico A. Gemelli - Universita Cattolica del Sacro Cuore, Rome 00168, Italy

Policlinico di Careggi, Firenze (Florence) 50134, Italy

Policlinico Monteluce, Perugia 06122, Italy

Universita Degli Studi di Bari Policlinico, Bari 70124, Italy

Academisch Medisch Centrum, Amsterdam 1105 AZ, Netherlands

Academisch Ziekenhuis Groningen, Groningen 9713 EZ, Netherlands

Groot Ziekengasthuis 's-Hertogenbosch, 's-Hertogenbosch 5211 NL, Netherlands

Leiden University Medical Center, Leiden 2300 CA, Netherlands

Leyenburg Ziekenhuis, 's-Gravenhage (Den Haag, The Hague) 2545 CH, Netherlands

University Hospital - Rotterdam Dijkzigt, Rotterdam 3000 CA, Netherlands

University Medical Center Nijmegen, Nijmegen NL-6500 HB, Netherlands

Ibn-i Sina Hospital, Ankara University, Ankara 06100, Turkey

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: October 1995
Last updated: May 23, 2008