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

Leukemia Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00002701
• Other study ID #: CDR0000064499
• Secondary ID: EORTC-06952ITA-G
• Status: Active, not recruiting
• Phase: Phase 3
• First received: November 1, 1999
• Last updated: September 19, 2013
• Start date: October 1995

Study information

• Verified date: November 2006
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 750
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years to 74 Years

Eligibility

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

Study Design

Allocation: Randomized, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Promyelocytic, Acute

Intervention

Drug:
• busulfan

• cyclophosphamide

• cytarabine

• etoposide

• idarubicin

• mercaptopurine

• methotrexate

• mitoxantrone hydrochloride

• thioguanine

• tretinoin

Procedure:
• allogeneic bone marrow transplantation

• autologous bone marrow transplantation

Radiation:
• radiation therapy

Locations

Country	Name	City	State
Austria	Innsbruck Universitaetsklinik	Innsbruck
Belgium	Algemeen Ziekenhuis Middelheim	Antwerp
Belgium	A.Z. St. Jan	Brugge
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	Liege
Belgium	Centre Hospitalier Peltzer-La Tourelle	Verviers
Croatia	University Hospital Rebro	Zagreb
Croatia	Medical School/University of Zagreb	Zagreb (Agram)
Czech Republic	Onkologicka Klinka A Onkologicka Lab	Prague
France	Centre Hospitalier Regional de Lille	Lille
France	Hopital Edouard Herriot	Lyon
France	Centre Antoine Lacassagne	Nice
France	Hopital Necker	Paris
France	Hotel Dieu de Paris	Paris
France	Centre Medico-Chirurgical Foch	Suresnes
France	Institut Gustave Roussy	Villejuif
Germany	Klinikum Duisburg	Duisburg
Germany	Klinikum Grosshadern	Munich (Muenchen)
Italy	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	Milano
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 Nuovo Pellegrini	Naples (Napoli)
Italy	Ospedale S. Gennora USL 42	Naples (Napoli)
Italy	Ospedale San Francesco	Nuoro
Italy	Azienda Ospedaliera di Padova	Padova (Padua)
Italy	Ospedale Cervello	Palermo
Italy	Policlinico - Cattedra di Ematologia	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	Azienda Policlinico Umberto Primo	Rome
Italy	Ospedale San Eugenio	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)
Netherlands	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
Turkey	Ibn-i Sina Hospital, Ankara University	Ankara

Sponsors (2)

Lead Sponsor	Collaborator
European Organisation for Research and Treatment of Cancer - EORTC	Gruppo Italiano Malattie EMatologiche dell'Adulto

Countries where clinical trial is conducted

Austria,  Belgium,  Croatia,  Czech Republic,  France,  Germany,  Italy,  Netherlands,  Turkey,