Clinical trial NCT00002701: Combination Chemotherapy With or Without Bone Marrow Transplantation in Treating Patients With Acute 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 type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Leukemia
Keywords: untreated adult acute myeloid leukemia
adult acute promyelocytic leukemia (M3)
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: Gruppo Italiano Malattie EMatologiche dell'Adulto
First posted: 2003-04-11
Enrollment: 750
Sex: ALL
Minimum age (years): 16
Maximum age (years): 74
Standard ages: CHILD
ADULT
OLDER_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. 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.

Eligibility 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

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Innsbruck Universitaetsklinik
city: Antwerp
country: Belgium
facility: Algemeen Ziekenhuis Middelheim
city: Brugge
country: Belgium
facility: A.Z. St. Jan
city: Brussels (Bruxelles)
country: Belgium
facility: C.H.U. Saint-Pierre
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: Leuven
country: Belgium
facility: U.Z. Gasthuisberg
city: Liege
country: Belgium
facility: CHU Sart-Tilman
city: Verviers
country: Belgium
facility: Centre Hospitalier Peltzer-La Tourelle
city: Zagreb (Agram)
country: Croatia
facility: Medical School/University of Zagreb
city: Zagreb
country: Croatia
facility: University Hospital Rebro
city: Prague
country: Czech Republic
facility: Onkologicka Klinka A Onkologicka Lab
city: Lille
country: France
facility: Centre Hospitalier Regional de Lille
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 Necker
city: Suresnes
country: France
facility: Centre Medico-Chirurgical Foch
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Duisburg
country: Germany
facility: Klinikum Duisburg
city: Munich (Muenchen)
country: Germany
facility: Klinikum Grosshadern
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: Policlinico 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 Convenzionate
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: Ospedale Maggiore Ca Granda
city: Milano
country: Italy
facility: Istituto Scientifico H.S. Raffaele
city: Montefiascone
country: Italy
facility: Ospedale Di Montefiascone
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: Nuoro
country: Italy
facility: Ospedale San Francesco
city: Padova (Padua)
country: Italy
facility: Azienda Ospedaliera di Padova
city: Palermo
country: Italy
facility: Policlinico - Cattedra di Ematologia
city: Palermo
country: Italy
facility: Ospedale Cervello
city: Parma
country: Italy
facility: Azienda Ospedaliera Di Parma
city: Pavia
country: Italy
facility: 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: 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: Taranto
country: Italy
facility: Ospedal SS Annunziata
city: Turin (TO)
country: Italy
facility: Cattedra di Immunologia Clinica
city: Turin (Torino)
country: Italy
facility: Ospedale Molinette
city: 's-Gravenhage (Den Haag, The Hague)
country: Netherlands
facility: Leyenburg Ziekenhuis
city: 's-Hertogenbosch
country: Netherlands
facility: Groot Ziekengasthuis 's-Hertogenbosch
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum
city: Groningen
country: Netherlands
facility: Academisch Ziekenhuis Groningen
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Nijmegen
country: Netherlands
facility: University Medical Center Nijmegen
city: Rotterdam
country: Netherlands
facility: University Hospital - Rotterdam Dijkzigt
city: Ankara
country: Turkey
facility: Ibn-i Sina Hospital, Ankara University
Study officials:
affiliation: Universitair Medisch Centrum St. Radboud - Nijmegen
name: Petra Muus, MD, PhD
role: STUDY_CHAIR
affiliation: Azienda Policlinico Umberto Primo
name: Franco Mandelli, MD
role: STUDY_CHAIR
References: