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

Sponsor

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

Overall Status

Completed

CT.gov ID

NCT00002700

Collaborator

Acute Leukemia French Association (Other)

392

Enrollment

Locations

8.9

Patients Per Site

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with radiation therapy may kill more tumor cells. Bone marrow transplantation can replace immune cells that were destroyed by chemotherapy.

PURPOSE: Randomized phase III trial to study the effectiveness of chemotherapy compared with or without bone marrow transplantation in treating patients with acute lymphoblastic leukemia.

Condition or Disease	Intervention/Treatment	Phase
Leukemia Lymphoma	Drug: asparaginase Drug: cyclophosphamide Drug: cytarabine Drug: daunorubicin hydrochloride Drug: dexamethasone Drug: doxorubicin hydrochloride Drug: leucovorin calcium Drug: mercaptopurine Drug: methotrexate Drug: mitoxantrone hydrochloride Drug: prednisolone Drug: prednisone Drug: therapeutic hydrocortisone Drug: vincristine sulfate Procedure: allogeneic bone marrow transplantation Procedure: autologous bone marrow transplantation Radiation: radiation therapy	Phase 3

Detailed Description

OBJECTIVES:

Compare the remission induction, toxicity, and duration of remission in patients with newly diagnosed acute lymphoblastic leukemia or lymphoblastic lymphoma treated with prednisone vs dexamethasone plus cyclophosphamide, daunorubicin, and vincristine as induction.
Compare the survival and disease-free survival of patients treated with autologous bone marrow transplantation (BMT) followed by low- or high-intensity maintenance chemotherapy with cranial irradiation after consolidation.
Determine the relative and disease-free survival of patients treated with autologous or allogeneic BMT after identical induction, consolidation, and conditioning regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to center and risk group (high vs standard).

Induction

Patients are randomized to 1 of 2 treatment arms.
Arm I:Patients receive daunorubicin IV on days 1-3 and 15 and 16; cyclophosphamide (CTX) IV on days 1 and 8; vincristine (VCR) IV on days 1, 8, 15, and 22; and prednisone IV or orally every 8 hours on days 1-7 and 15-21.
Arm II: Patients receive daunorubicin, CTX, and VCR as in arm I and dexamethasone IV or orally on days 1-8 and 15-22.
Patients on both arms without CNS disease at presentation receive CNS prophylaxis comprising methotrexate (MTX) intrathecally (IT) on days 1, 8, 15, and 22. Patients on both arms with CNS disease at presentation receive CNS therapy comprising hydrocortisone (HC) IT and MTX IT alternating with cytarabine (ARA-C) IT twice a week until CSF clears. After induction, patients on both arms proceed to consolidation, regardless of response.

Consolidation

Patients receive ARA-C IV over 2 hours every 12 hours on days 29-34 and mitoxantrone IV on days 33-35. Patients without CNS disease at presentation receive CNS prophylaxis comprising MTX IT on day 29. Patients with CNS disease at presentation receive CNS therapy comprising HC IT and MTX IT alternating with ARA-C weekly for 6 weeks. Patients who achieve complete response (CR) at day 55-60 receive MTX IV on days 64 and 79, leucovorin calcium IV or orally every 6 hours on days 65-67 and 80-82, and asparaginase IV over 1 hour or intramuscularly on days 65 and 80.
Standard-risk patients who are under age 20 and achieve CR after day 80 are assigned to arm IV of group A. Patients who achieve CR after day 80 and have a genotypically or phenotypically HLA-matched family donor, a family donor mismatched at only 1 locus (A, B, or DR), or an HLA-matched unrelated donor proceed to group B. Patients who achieve CR after day 80 and are eligible for autologous bone marrow transplantation (BMT) proceed to group A. Patients found to be at extremely high risk are taken off study.

Group A

Patients are randomized to 1 of 2 treatment arms.
Arm III: Autologous bone marrow is harvested. Patients receive bone marrow ablation comprising CTX IV over 1 hour on days -4 and -3 and total body irradiation on day -1. Autologous bone marrow is reinfused on day 0. Beginning at month 8 (4 months after BMT), patients receive first maintenance comprising VCR IV, doxorubicin IV, and dexamethasone IV (VAD) or VCR IV, doxorubicin IV, and prednisolone IV (VAP) on days 1-4 and 29-32. Patients receive second maintenance comprising oral mercaptopurine daily and oral MTX daily beginning at month 10 and continuing through year 3. Patients without CNS disease at presentation receive CNS prophylaxis comprising MTX IT on days 1 and 29. Patients with CNS disease at presentation receive CNS therapy comprising ARA-C IT, MTX IT, and HC IT beginning at 1 month after BMT and continuing monthly for 1 year and then every 3 months through year 3.
Arm IV: Patients receive CTX IV and ARA-C IV continuously on day 1, oral mercaptopurine on days 8-28, and oral MTX on days 8, 15, and 22 during months 4, 7, 11, 13, 17, 21, 25, and 29. Patients receive MTX IV over 30 minutes on day 1, leucovorin calcium IV or orally every 6 hours on days 2-4, asparaginase IV over 1 hour or intramuscularly on day 2, oral mercaptopurine on days 8-28, and oral MTX on days 8, 15, and 22 during months 6, 10, 12, 15, 19, 23, and 27. Patients receive VAD or VAP as in arm III beginning at month 8. Patients without CNS disease at presentation receive CNS prophylaxis comprising whole brain radiotherapy and MTX IT on day 1 of radiotherapy during month 5. Patients with CNS disease at presentation receive CNS therapy as in arm III.

Group B

Allogeneic bone marrow is harvested. Patients receive bone marrow ablation as in arm III beginning on day 100. Allogeneic bone marrow is infused over 15-30 minutes on day 0.
Patients in groups A and B with CNS disease at presentation undergo radiotherapy to focal infiltration at entry or concurrently with total body irradiation, or whole brain radiotherapy during maintenance (if no prior CNS irradiation). At any time during the study, patients who develop marrow relapse (more than 5% leukemic blasts in bone marrow on 2 occasions), CNS relapse (blasts in CSF, cranial nerve palsy, or CNS mass), or testis or other extramedullary relapse are taken off study.

PROJECTED ACCRUAL: A total of 392 patients will be accrued for this study within approximately 6 years.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

392 participants

Allocation:

Randomized

Primary Purpose:

Treatment

Official Title:

A RANDOMIZED PHASE III TRIAL COMPARING DEXAMETHASONE WITH PREDNISONE IN INDUCTION TREATMENT AND BONE MARROW TRANSPLANTATION WITH INTENSIVE MAINTENANCE TREATMENT IN ADOLESCENT AND ADULT ACUTE LYMPHOBLASTIC LEUKEMIA (ALL-4)

Study Start Date :

Aug 1, 1995

Actual Primary Completion Date :

Mar 1, 2004

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

15 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Newly diagnosed acute lymphoblastic leukemia or lymphoblastic lymphoma with more than 30% blasts in bone marrow

PATIENT CHARACTERISTICS:

Age:

15 to 60

Performance status:

Not specified

Life expectancy:

Not specified

Hematopoietic:

See Disease Characteristics

Hepatic:

Bilirubin less than 2 mg/dL (unless elevation due to leukemic involvement of liver)

Renal:

Creatinine less than 2 mg/dL (unless elevation due to leukemic involvement of kidneys)

Cardiovascular:

No severe cardiac disease

Pulmonary:

No severe pulmonary disease

Other:

No severe neurologic or metabolic disease
HIV negative (if tested)
No other prior malignancy except nonmelanomatous skin cancer, stage I cervical carcinoma, or other curatively treated malignancy

PRIOR CONCURRENT THERAPY:

Biologic therapy:

No prior biologic therapy

Chemotherapy:

No prior chemotherapy

Endocrine therapy:

No prior endocrine therapy

Radiotherapy:

No prior radiotherapy

Surgery:

No prior surgery

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Algemeen Ziekenhuis Middelheim	Antwerpen	Belgium	B-2020
2	A.Z. St. Jan	Brugge	Belgium	8000
3	C.H.U. Saint-Pierre	Brussels	Belgium	1000
4	Hopital Universitaire Erasme	Brussels	Belgium	1070
5	Universitair Ziekenhuis Antwerpen	Edegem	Belgium	B-2650
6	CHU Sart-Tilman	Liege	Belgium	B-4000
7	Centre Hospitalier Peltzer-La Tourelle	Verviers	Belgium	B-4800
8	Medical School/University of Zagreb	Zagreb (Agram)	Croatia	10000
9	University Hospital Rebro	Zagreb	Croatia	10000
10	University Hospital - Olomouc	Olomouc	Czech Republic	775 20
11	Hopital Edouard Herriot	Lyon	France	69437
12	Hotel Dieu de Paris	Paris	France	75181
13	Hopital Necker	Paris	France	75743
14	Centre Medico-Chirurgical Foch	Suresnes	France	92151
15	Kreiskrankenhaus Meissen	Meissen	Germany	D-01662
16	Ospedale Civile Alessandria	Alessandria	Italy	I-15100
17	Ospedale Civile Avellino	Avellino	Italy
18	Universita Degli Studi di Bari Policlinico	Bari	Italy	70124
19	A. Perrino Hospital	Brindisi	Italy	72100
20	Ospedale Ferrarotto	Catania	Italy	95124
21	Ospedale Regionale A. Pugliese	Catanzaro	Italy	88100
22	Ospedale Santa Croce	Cuneo	Italy	12100
23	Policlinico di Careggi	Firenze (Florence)	Italy	50134
24	Ospedali Riuniti Foggia	Foggia	Italy	71100
25	Ospedale S. Antonio Abate	Gallarate Varese	Italy	21013
26	Ospedale Gen. Provinciale Santa Maria Goretti	Latina	Italy	04100
27	Ospedale Maggiore Lodi	Lodi	Italy	I-20075
28	Ospedale Di Montefiascone	Montefiascone	Italy	I-01027
29	Ospedale S. Gennaro ASL NA1	Naples (Napoli)	Italy	80136
30	Policlinico - Cattedra di Ematologia	Palermo	Italy	90100
31	Policlinico Monteluce	Perugia	Italy	06122
32	Ospedale San Carlo	Potenza	Italy	85100
33	Ospedale Casa Sollievo della Sofferenza	San Giovanni - Rotondo	Italy	71013
34	Istituto di Ematologia Universita - University di Sassari	Sassari	Italy	07100
35	Ospedal SS Annunziata	Taranto	Italy	74100
36	Ospedale Molinette	Turin (Torino)	Italy	10126
37	Groot Ziekengasthuis 's-Hertogenbosch	's-Hertogenbosch	Netherlands	5211 NL
38	Onze Lieve Vrouwe Gasthuis	Amsterdam	Netherlands	1091 HA
39	Maxima Medisch Centrum - locatie Eindhoven	Eindhoven	Netherlands	5631 BM
40	Leiden University Medical Center	Leiden	Netherlands	2300 CA
41	University Medical Center Nijmegen	Nijmegen	Netherlands	NL-6500 HB
42	Hospital Escolar San Joao	Porto	Portugal	4200
43	Institute of Hematology & Transfusiology, University Hospital	Bratislava	Slovakia	85107
44	Ibn-i Sina Hospital	Ankara	Turkey	06100