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

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC (Other)

Overall Status

Unknown status

CT.gov ID

NCT00002701

Collaborator

Gruppo Italiano Malattie EMatologiche dell'Adulto (Other)

750

Enrollment

Locations

10.6

Patients Per Site

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: busulfan Drug: cyclophosphamide Drug: cytarabine Drug: etoposide Drug: idarubicin Drug: mercaptopurine Drug: methotrexate Drug: mitoxantrone hydrochloride Drug: thioguanine Drug: tretinoin Procedure: allogeneic bone marrow transplantation Procedure: autologous bone marrow transplantation Radiation: radiation therapy	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

750 participants

Allocation:

Randomized

Primary Purpose:

Treatment

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 Start Date :

Oct 1, 1995

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years to 74 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Innsbruck Universitaetsklinik	Innsbruck	Austria	A-6020
2	Algemeen Ziekenhuis Middelheim	Antwerp	Belgium	2020
3	A.Z. St. Jan	Brugge	Belgium	8000
4	C.H.U. Saint-Pierre	Brussels (Bruxelles)	Belgium	1000
5	Institut Jules Bordet	Brussels (Bruxelles)	Belgium	1000
6	Hopital Universitaire Erasme	Brussels	Belgium	1070
7	Universitair Ziekenhuis Antwerpen	Edegem	Belgium	B-2650
8	U.Z. Gasthuisberg	Leuven	Belgium	B-3000
9	CHU Sart-Tilman	Liege	Belgium	B-4000
10	Centre Hospitalier Peltzer-La Tourelle	Verviers	Belgium	B-4800
11	Medical School/University of Zagreb	Zagreb (Agram)	Croatia	41000
12	University Hospital Rebro	Zagreb	Croatia	41000
13	Onkologicka Klinka A Onkologicka Lab	Prague	Czech Republic	128 08
14	Centre Hospitalier Regional de Lille	Lille	France	59037
15	Hopital Edouard Herriot	Lyon	France	69437
16	Centre Antoine Lacassagne	Nice	France	06189
17	Hotel Dieu de Paris	Paris	France	75181
18	Hopital Necker	Paris	France	75743
19	Centre Medico-Chirurgical Foch	Suresnes	France	92151
20	Institut Gustave Roussy	Villejuif	France	F-94805
21	Klinikum Duisburg	Duisburg	Germany	D-47055
22	Klinikum Grosshadern	Munich (Muenchen)	Germany	D-81377
23	Ospedale Civile Alessandria	Alessandria	Italy	I-15100
24	Ospedale Torrette University Ancona	Ancona	Italy	60020
25	Ospedale Civile Avellino	Avellino	Italy
26	Universita Degli Studi di Bari Policlinico	Bari	Italy	70124
27	Ospedale Regionale A. Di Summa	Brindisi	Italy	I-72100
28	Ospedale Oncologico A. Businco	Cagliari	Italy	09124
29	Ospedale Ferrarotto	Catania	Italy	95124
30	Ospedale Regionale A. Pugliese	Catanzaro	Italy	88100
31	Centro Trapianti di Midollo Osseo	Cremona	Italy	26100
32	Ospedale Santa Croce	Cuneo	Italy	12100
33	Policlinico di Careggi	Firenze (Florence)	Italy	50134
34	Ospedali Riuniti Foggia	Foggia	Italy	71100
35	Ospedale S. Antonio Abate	Gallarate Varese	Italy	21013
36	Ospedale San Martino/Cliniche Universitarie Convenzionate	Genoa (Genova)	Italy	16132
37	Ospedale Gen. Provinciale Santa Maria Goretti	Latina	Italy	04100
38	Ospedale Maggiore Lodi	Lodi	Italy	I-20075
39	Ospedale Maggiore Ca Granda	Milano (Milan)	Italy	20162
40	Istituto Scientifico H.S. Raffaele	Milano	Italy	20132
41	Ospedale Di Montefiascone	Montefiascone	Italy	I-01027
42	Azienda Ospedaliera "A. Cardarelli"	Naples (Napoli)	Italy	80127
43	Federico II University Medical School	Naples (Napoli)	Italy	80131
44	Ospedale S. Gennora USL 42	Naples (Napoli)	Italy	80136
45	Ospedale Nuovo Pellegrini	Naples (Napoli)	Italy	80144
46	Ospedale San Francesco	Nuoro	Italy	08100
47	Azienda Ospedaliera di Padova	Padova (Padua)	Italy	35128
48	Policlinico - Cattedra di Ematologia	Palermo	Italy	90100
49	Ospedale Cervello	Palermo	Italy	90146
50	Azienda Ospedaliera Di Parma	Parma	Italy	43100
51	I.R.C.C.S. Policlinico San Matteo	Pavia	Italy	27100
52	Policlinico Monteluce	Perugia	Italy	06122
53	Ospedale San Salvatore	Pesaro	Italy	I-61100
54	Ospedale Civile Pescara	Pescara	Italy	65100
55	Ospedale San Carlo	Potenza	Italy	85100
56	Ospedale San Eugenio	Rome	Italy	00144
57	Azienda Policlinico Umberto Primo	Rome	Italy	00161
58	Policlinico A. Gemelli - Universita Cattolica del Sacro Cuore	Rome	Italy	00168
59	Ospedale Casa Sollievo della Sofferenza	San Giovanni - Rotondo	Italy	71013
60	Istituto di Ematologia Universita - University di Sassari	Sassari	Italy	07100
61	Ospedal SS Annunziata	Taranto	Italy	74100
62	Cattedra di Immunologia Clinica	Turin (TO)	Italy	10128
63	Ospedale Molinette	Turin (Torino)	Italy	10126
64	Leyenburg Ziekenhuis	's-Gravenhage (Den Haag, The Hague)	Netherlands	2545 CH
65	Groot Ziekengasthuis 's-Hertogenbosch	's-Hertogenbosch	Netherlands	5211 NL
66	Academisch Medisch Centrum	Amsterdam	Netherlands	1105 AZ
67	Academisch Ziekenhuis Groningen	Groningen	Netherlands	9713 EZ
68	Leiden University Medical Center	Leiden	Netherlands	2300 CA
69	University Medical Center Nijmegen	Nijmegen	Netherlands	NL-6500 HB
70	University Hospital - Rotterdam Dijkzigt	Rotterdam	Netherlands	3000 CA
71	Ibn-i Sina Hospital, Ankara University	Ankara	Turkey	06100

Sponsors and Collaborators

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

Investigators

Study Chair: Petra Muus, MD, PhD, Universitair Medisch Centrum St. Radboud - Nijmegen
Study Chair: Franco Mandelli, MD, Azienda Policlinico Umberto Primo