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

June 11, 2013 updated by: European Organisation for Research and Treatment of Cancer - EORTC

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)

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Anticipated)

392

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

15 years to 60 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC

Collaborators

Acute Leukemia French Association

Investigators

  • Study Chair: Roel Willemze, MD, PhD, Leiden University Medical Center
  • Study Chair: Denis Fiere, MD, Acute Leukemia French Association

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 1995

Primary Completion (Actual)

March 1, 2004

Study Registration Dates

First Submitted

November 1, 1999

First Submitted That Met QC Criteria

January 26, 2003

First Posted (Estimate)

January 27, 2003

Study Record Updates

Last Update Posted (Estimate)

June 12, 2013

Last Update Submitted That Met QC Criteria

June 11, 2013

Last Verified

June 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EORTC-06951
  • FRE-LALA-94

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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