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

NCT ID: NCT00002700

Last Updated: 2013-06-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 392 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 1995-08-31

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.

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.

Conditions

Leukemia; Lymphoma

Study Design

• Allocation Method: RANDOMIZED
• Primary Study Purpose: TREATMENT

Interventions

asparaginase

Intervention Type: DRUG

cyclophosphamide

Intervention Type: DRUG

cytarabine

Intervention Type: DRUG

daunorubicin hydrochloride

Intervention Type: DRUG

dexamethasone

Intervention Type: DRUG

doxorubicin hydrochloride

Intervention Type: DRUG

leucovorin calcium

Intervention Type: DRUG

mercaptopurine

Intervention Type: DRUG

methotrexate

Intervention Type: DRUG

mitoxantrone hydrochloride

Intervention Type: DRUG

prednisolone

Intervention Type: DRUG

prednisone

Intervention Type: DRUG

therapeutic hydrocortisone

Intervention Type: DRUG

vincristine sulfate

Intervention Type: DRUG

allogeneic bone marrow transplantation

Intervention Type: PROCEDURE

autologous bone marrow transplantation

Intervention Type: PROCEDURE

radiation therapy

Intervention Type: RADIATION

Eligibility Criteria

Inclusion Criteria

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

• Minimum Eligible Age: 15 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Acute Leukemia French Association

OTHER

Sponsor Role: collaborator

European Organisation for Research and Treatment of Cancer - EORTC

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Roel Willemze, MD, PhD

Role: STUDY_CHAIR

Leiden University Medical Center

Denis Fiere, MD

Role: STUDY_CHAIR

Acute Leukemia French Association

Locations

Algemeen Ziekenhuis Middelheim

Antwerp, , Belgium

A.Z. St. Jan

Bruges, , Belgium

C.H.U. Saint-Pierre

Brussels, , Belgium

Hopital Universitaire Erasme

Brussels, , Belgium

Universitair Ziekenhuis Antwerpen

Edegem, , Belgium

CHU Sart-Tilman

Liège, , Belgium

Centre Hospitalier Peltzer-La Tourelle

Verviers, , Belgium

University Hospital Rebro

Zagreb, , Croatia

Medical School/University of Zagreb

Zagreb (Agram), , Croatia

University Hospital - Olomouc

Olomouc, , Czechia

Hopital Edouard Herriot

Lyon, , France

Hotel Dieu de Paris

Paris, , France

Hopital Necker

Paris, , France

Centre Medico-Chirurgical Foch

Suresnes, , France

Kreiskrankenhaus Meissen

Meissen, , Germany

Ospedale Civile Alessandria

Alessandria, , Italy

Ospedale Civile Avellino

Avellino, , Italy

Universita Degli Studi di Bari Policlinico

Bari, , Italy

A. Perrino Hospital

Brindisi, , Italy

Ospedale Ferrarotto

Catania, , Italy

Ospedale Regionale A. Pugliese

Catanzaro, , 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 Gen. Provinciale Santa Maria Goretti

Latina, , Italy

Ospedale Maggiore Lodi

Lodi, , Italy

Ospedale Di Montefiascone

Montefiascone, , Italy

Ospedale S. Gennaro ASL NA1

Naples (Napoli), , Italy

Policlinico - Cattedra di Ematologia

Palermo, , Italy

Policlinico Monteluce

Perugia, , Italy

Ospedale San Carlo

Potenza, , Italy

Ospedale Casa Sollievo della Sofferenza

San Giovanni Rotondo, , Italy

Istituto di Ematologia Universita - University di Sassari

Sassari, , Italy

Ospedal SS Annunziata

Taranto, , Italy

Ospedale Molinette

Turin (Torino), , Italy

Groot Ziekengasthuis 's-Hertogenbosch

's-Hertogenbosch, , Netherlands

Onze Lieve Vrouwe Gasthuis

Amsterdam, , Netherlands

Maxima Medisch Centrum - locatie Eindhoven

Eindhoven, , Netherlands

Leiden University Medical Center

Leiden, , Netherlands

University Medical Center Nijmegen

Nijmegen, , Netherlands

Hospital Escolar San Joao

Porto, , Portugal

Institute of Hematology & Transfusiology, University Hospital

Bratislava, , Slovakia

Ibn-i Sina Hospital

Ankara, , Turkey (Türkiye)

Countries

Belgium; Croatia; Czechia; France; Germany; Italy; Netherlands; Portugal; Slovakia; Turkey (Türkiye)

References

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Other Identifiers

EORTC-06951

Identifier Type: -

Identifier Source: secondary_id

FRE-LALA-94

Identifier Type: -

Identifier Source: secondary_id

EORTC-06951

Identifier Type: -

Identifier Source: org_study_id