Clinical trial NCT00002700: Chemotherapy With or Without Bone Marrow Transplantation in Treating Patients With Acute Lymphoblastic Leukemia
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Leukemia
Lymphoma
Keywords: untreated adult acute lymphoblastic leukemia
stage I adult lymphoblastic lymphoma
stage III adult lymphoblastic lymphoma
stage IV adult lymphoblastic lymphoma
contiguous stage II adult lymphoblastic lymphoma
noncontiguous stage II adult lymphoblastic lymphoma
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
Collaborators: name: Acute Leukemia French Association
First posted: 2003-01-27
Enrollment: 392
Sex: ALL
Minimum age (years): 15
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Antwerpen
country: Belgium
facility: Algemeen Ziekenhuis Middelheim
city: Brugge
country: Belgium
facility: A.Z. St. Jan
city: Brussels
country: Belgium
facility: C.H.U. Saint-Pierre
city: Brussels
country: Belgium
facility: Hopital Universitaire Erasme
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Liege
country: Belgium
facility: CHU Sart-Tilman
city: Verviers
country: Belgium
facility: Centre Hospitalier Peltzer-La Tourelle
city: Zagreb (Agram)
country: Croatia
facility: Medical School/University of Zagreb
city: Zagreb
country: Croatia
facility: University Hospital Rebro
city: Olomouc
country: Czech Republic
facility: University Hospital - Olomouc
city: Lyon
country: France
facility: Hopital Edouard Herriot
city: Paris
country: France
facility: Hotel Dieu de Paris
city: Paris
country: France
facility: Hopital Necker
city: Suresnes
country: France
facility: Centre Medico-Chirurgical Foch
city: Meissen
country: Germany
facility: Kreiskrankenhaus Meissen
city: Alessandria
country: Italy
facility: Ospedale Civile Alessandria
city: Avellino
country: Italy
facility: Ospedale Civile Avellino
city: Bari
country: Italy
facility: Universita Degli Studi di Bari Policlinico
city: Brindisi
country: Italy
facility: A. Perrino Hospital
city: Catania
country: Italy
facility: Ospedale Ferrarotto
city: Catanzaro
country: Italy
facility: Ospedale Regionale A. Pugliese
city: Cuneo
country: Italy
facility: Ospedale Santa Croce
city: Firenze (Florence)
country: Italy
facility: Policlinico di Careggi
city: Foggia
country: Italy
facility: Ospedali Riuniti Foggia
city: Gallarate Varese
country: Italy
facility: Ospedale S. Antonio Abate
city: Latina
country: Italy
facility: Ospedale Gen. Provinciale Santa Maria Goretti
city: Lodi
country: Italy
facility: Ospedale Maggiore Lodi
city: Montefiascone
country: Italy
facility: Ospedale Di Montefiascone
city: Naples (Napoli)
country: Italy
facility: Ospedale S. Gennaro ASL NA1
city: Palermo
country: Italy
facility: Policlinico - Cattedra di Ematologia
city: Perugia
country: Italy
facility: Policlinico Monteluce
city: Potenza
country: Italy
facility: Ospedale San Carlo
city: San Giovanni - Rotondo
country: Italy
facility: Ospedale Casa Sollievo della Sofferenza
city: Sassari
country: Italy
facility: Istituto di Ematologia Universita - University di Sassari
city: Taranto
country: Italy
facility: Ospedal SS Annunziata
city: Turin (Torino)
country: Italy
facility: Ospedale Molinette
city: 's-Hertogenbosch
country: Netherlands
facility: Groot Ziekengasthuis 's-Hertogenbosch
city: Amsterdam
country: Netherlands
facility: Onze Lieve Vrouwe Gasthuis
city: Eindhoven
country: Netherlands
facility: Maxima Medisch Centrum - locatie Eindhoven
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Nijmegen
country: Netherlands
facility: University Medical Center Nijmegen
city: Porto
country: Portugal
facility: Hospital Escolar San Joao
city: Bratislava
country: Slovakia
facility: Institute of Hematology & Transfusiology, University Hospital
city: Ankara
country: Turkey
facility: Ibn-i Sina Hospital
Study officials:
affiliation: Leiden University Medical Center
name: Roel Willemze, MD, PhD
role: STUDY_CHAIR
affiliation: Acute Leukemia French Association
name: Denis Fiere, MD
role: STUDY_CHAIR
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