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

Lymphoma Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00002700
• Other study ID #: EORTC-06951
• Secondary ID: EORTC-06951FRE-L
• Status: Completed
• Phase: Phase 3
• First received: November 1, 1999
• Last updated: June 11, 2013
• Start date: August 1995

Study information

• Verified date: June 2013
• Source: European Organisation for Research and Treatment of Cancer - EORTC
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 392
• Est. primary completion date: March 2004
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 15 Years to 60 Years

Eligibility

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 Design

Allocation: Randomized, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphoid
• Lymphoma
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• asparaginase

• cyclophosphamide

• cytarabine

• daunorubicin hydrochloride

• dexamethasone

• doxorubicin hydrochloride

• leucovorin calcium

• mercaptopurine

• methotrexate

• mitoxantrone hydrochloride

• prednisolone

• prednisone

• therapeutic hydrocortisone

• vincristine sulfate

Procedure:
• allogeneic bone marrow transplantation

• autologous bone marrow transplantation

Radiation:
• radiation therapy

Locations

Country	Name	City	State
Belgium	Algemeen Ziekenhuis Middelheim	Antwerpen
Belgium	A.Z. St. Jan	Brugge
Belgium	C.H.U. Saint-Pierre	Brussels
Belgium	Hopital Universitaire Erasme	Brussels
Belgium	Universitair Ziekenhuis Antwerpen	Edegem
Belgium	CHU Sart-Tilman	Liege
Belgium	Centre Hospitalier Peltzer-La Tourelle	Verviers
Croatia	University Hospital Rebro	Zagreb
Croatia	Medical School/University of Zagreb	Zagreb (Agram)
Czech Republic	University Hospital - Olomouc	Olomouc
France	Hopital Edouard Herriot	Lyon
France	Hopital Necker	Paris
France	Hotel Dieu de Paris	Paris
France	Centre Medico-Chirurgical Foch	Suresnes
Germany	Kreiskrankenhaus Meissen	Meissen
Italy	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)
Netherlands	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
Portugal	Hospital Escolar San Joao	Porto
Slovakia	Institute of Hematology & Transfusiology, University Hospital	Bratislava
Turkey	Ibn-i Sina Hospital	Ankara

Sponsors (2)

Lead Sponsor	Collaborator
European Organisation for Research and Treatment of Cancer - EORTC	Acute Leukemia French Association

Countries where clinical trial is conducted

Belgium,  Croatia,  Czech Republic,  France,  Germany,  Italy,  Netherlands,  Portugal,  Slovakia,  Turkey, 

References & Publications (14)

Asnafi V, Buzyn A, Thomas X, et al.: Impact of immunophenotype and genotype on outcome in LALA94 T-ALLs: toward risk adapted stratification of adult T-ALL. [Abstract] Blood 102 (11): A-67, 2003.

Asnafi V, Buzyn A, Thomas X, Huguet F, Vey N, Boiron JM, Reman O, Cayuela JM, Lheritier V, Vernant JP, Fiere D, Macintyre E, Dombret H. Impact of TCR status and genotype on outcome in adult T-cell acute lymphoblastic leukemia: a LALA-94 study. Blood. 2005 — View Citation

Boissel N, Auclerc MF, Lhéritier V, Perel Y, Thomas X, Leblanc T, Rousselot P, Cayuela JM, Gabert J, Fegueux N, Piguet C, Huguet-Rigal F, Berthou C, Boiron JM, Pautas C, Michel G, Fière D, Leverger G, Dombret H, Baruchel A. Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol. 2003 Mar 1;21(5):774-80. Epub 2003 Mar 1. — View Citation

Charrin C, Thomas X, Ffrench M, Le QH, Andrieux J, Mozziconacci MJ, Laï JL, Bilhou-Nabera C, Michaux L, Bernheim A, Bastard C, Mossafa H, Perot C, Maarek O, Boucheix C, Lheritier V, Delannoy A, Fière D, Dastugue N. A report from the LALA-94 and LALA-SA groups on hypodiploidy with 30 to 39 chromosomes and near-triploidy: 2 possible expressions of a sole entity conferring poor prognosis in adult acute lymphoblastic leukemia (ALL). Blood. 2004 Oct 15;104(8):2444-51. Epub 2004 Mar 23. — View Citation

Dhédin N, Dombret H, Thomas X, Lhéritier V, Boiron JM, Rigal-Huguet F, Vey N, Kuentz M, Reman O, Witz F, Delannoy A, Kovacsovics T, Bradstock K, Charrin C, Boucheix C, Gabert J, Blaise D, Fière D, Vernant JP. Autologous stem cell transplantation in adults with acute lymphoblastic leukemia in first complete remission: analysis of the LALA-85, -87 and -94 trials. Leukemia. 2006 Feb;20(2):336-44. — View Citation

Dombret H, Gabert J, Boiron JM, Rigal-Huguet F, Blaise D, Thomas X, Delannoy A, Buzyn A, Bilhou-Nabera C, Cayuela JM, Fenaux P, Bourhis JH, Fegueux N, Charrin C, Boucheix C, Lhéritier V, Espérou H, MacIntyre E, Vernant JP, Fière D; Groupe d'Etude et de Tr — View Citation

Labar B, Suciu S, Willemze R, Muus P, Marie JP, Fillet G, Berneman Z, Jaksic B, Feremans W, Bron D, Sinnige H, Mistrik M, Vreugdenhil G, De Bock R, Nemet D, Gilotay C, Amadori S, de Witte T; EORTC Leukemia Group. Dexamethasone compared to prednisolone for — View Citation

Le QH, Thomas X, Ecochard R, Iwaz J, Lhéritier V, Michallet M, Fiere D. Proportion of long-term event-free survivors and lifetime of adult patients not cured after a standard acute lymphoblastic leukemia therapeutic program: adult acute lymphoblastic leuk — View Citation

Picard C, Hayette S, Bilhou-Nabera C, Cayuela JM, Delabesse E, Frenoy N, Preudhomme C, Dupont M, Bastard C, Bories D, Vaerman JL, Davi F, Dastugue N, Raynaud S, Lafage M, Deschaseaux F, Fest T, Gaub MP, Lhéritier V, Thomas X, Charrin C, Boucheix C, Dombret H, Macintyre E, Fière D, Gabert J. Prospective multicentric molecular study for poor prognosis fusion transcripts at diagnosis in adult B-lineage ALL patients: the LALA 94 experience. Leukemia. 2006 Dec;20(12):2178-81. Epub 2006 Oct 12. — View Citation

Reman O, Pigneux A, Huguet F, et al.: Central nervous system involvement in adult acute lymphoblastic leukemia (ALL) at diagnosis and/or at first elapse: results from the GET-LALA group. [Abstract] Blood 110 (11): A-4326, 2007.

Tavernier E, Boiron JM, Huguet F, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Vernant JP, Dombret H, Thomas X; GET-LALA Group; Swiss Grou — View Citation

Tavernier E, Le QH, de Botton S, Dhédin N, Bulabois CE, Reman O, Vey N, Lhéritier V, Dombret H, Thomas X. Secondary or concomitant neoplasms among adults diagnosed with acute lymphoblastic leukemia and treated according to the LALA-87 and LALA-94 trials. Cancer. 2007 Dec 15;110(12):2747-55. — View Citation

Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D. Outcome of treatment in adults — View Citation

Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de — View Citation

* Note: There are 14 references in all — Click here to view all references