- ICH GCP
- Registro de ensaios clínicos dos EUA
- Ensaio Clínico NCT00002700
Chemotherapy With or Without Bone Marrow Transplantation in Treating Patients With Acute Lymphoblastic Leukemia
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.
Visão geral do estudo
Status
Intervenção / Tratamento
- Medicamento: ciclofosfamida
- Medicamento: leucovorina cálcica
- Radiação: radioterapia
- Medicamento: cloridrato de mitoxantrona
- Medicamento: prednisona
- Medicamento: asparaginase
- Medicamento: citarabina
- Medicamento: cloridrato de daunorrubicina
- Medicamento: dexametasona
- Medicamento: metotrexato
- Medicamento: hidrocortisona terapêutica
- Medicamento: sulfato de vincristina
- Procedimento: Transplante de Medula Óssea Alogênico
- Medicamento: mercaptopurina
- Medicamento: cloridrato de doxorrubicina
- Procedimento: transplante autólogo de medula óssea
- Medicamento: prednisolona
Descrição detalhada
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.
Tipo de estudo
Inscrição (Antecipado)
Estágio
- Fase 3
Contactos e Locais
Locais de estudo
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Meissen, Alemanha, D-01662
- Kreiskrankenhaus Meissen
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Antwerpen, Bélgica, B-2020
- Algemeen Ziekenhuis Middelheim
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Brugge, Bélgica, 8000
- A.Z. St. Jan
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Brussels, Bélgica, 1070
- Hopital Universitaire Erasme
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Brussels, Bélgica, 1000
- C.H.U. Saint-Pierre
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Edegem, Bélgica, B-2650
- Universitair Ziekenhuis Antwerpen
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Liege, Bélgica, B-4000
- CHU Sart-Tilman
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Verviers, Bélgica, B-4800
- Centre Hospitalier Peltzer-La Tourelle
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Zagreb, Croácia, 10000
- University Hospital Rebro
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Zagreb (Agram), Croácia, 10000
- Medical School/University of Zagreb
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Bratislava, Eslováquia, 85107
- Institute of Hematology & Transfusiology, University Hospital
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Lyon, França, 69437
- Hôpital Edouard Herriot
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Paris, França, 75743
- Hopital Necker
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Paris, França, 75181
- Hotel Dieu de Paris
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Suresnes, França, 92151
- Centre Médico-Chirurgical Foch
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's-Hertogenbosch, Holanda, 5211 NL
- Groot Ziekengasthuis 's-Hertogenbosch
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Amsterdam, Holanda, 1091 HA
- Onze Lieve Vrouwe Gasthuis
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Eindhoven, Holanda, 5631 BM
- Maxima Medisch Centrum - locatie Eindhoven
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Leiden, Holanda, 2300 CA
- Leiden University Medical Center
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Nijmegen, Holanda, NL-6500 HB
- University Medical Center Nijmegen
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Alessandria, Itália, I-15100
- Ospedale Civile Alessandria
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Avellino, Itália
- Ospedale Civile Avellino
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Bari, Itália, 70124
- Universita Degli Studi di Bari Policlinico
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Brindisi, Itália, 72100
- A. Perrino Hospital
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Catania, Itália, 95124
- Ospedale Ferrarotto
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Catanzaro, Itália, 88100
- Ospedale Regionale A. Pugliese
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Cuneo, Itália, 12100
- Ospedale Santa Croce
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Firenze (Florence), Itália, 50134
- Policlinico di Careggi
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Foggia, Itália, 71100
- Ospedali Riuniti Foggia
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Gallarate Varese, Itália, 21013
- Ospedale S. Antonio Abate
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Latina, Itália, 04100
- Ospedale Gen. Provinciale Santa Maria Goretti
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Lodi, Itália, I-20075
- Ospedale Maggiore Lodi
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Montefiascone, Itália, I-01027
- Ospedale Di Montefiascone
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Naples (Napoli), Itália, 80136
- Ospedale S. Gennaro ASL NA1
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Palermo, Itália, 90100
- Policlinico - Cattedra di Ematologia
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Perugia, Itália, 06122
- Policlinico Monteluce
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Potenza, Itália, 85100
- Ospedale San Carlo
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San Giovanni - Rotondo, Itália, 71013
- Ospedale Casa Sollievo della Sofferenza
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Sassari, Itália, 07100
- Istituto di Ematologia Universita - University di Sassari
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Taranto, Itália, 74100
- Ospedal SS Annunziata
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Turin (Torino), Itália, 10126
- Ospedale Molinette
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Ankara, Peru, 06100
- Ibn-i Sina Hospital
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Porto, Portugal, 4200
- Hospital Escolar San Joao
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Olomouc, República Checa, 775 20
- University Hospital - Olomouc
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Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
Aceita Voluntários Saudáveis
Gêneros Elegíveis para o Estudo
Descrição
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
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Tratamento
- Alocação: Randomizado
Colaboradores e Investigadores
Colaboradores
Investigadores
- Cadeira de estudo: Roel Willemze, MD, PhD, Leiden University Medical Center
- Cadeira de estudo: Denis Fiere, MD, Acute Leukemia French Association
Publicações e links úteis
Publicações Gerais
- Boissel N, Auclerc MF, Lheritier 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, Fiere 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. doi: 10.1200/JCO.2003.02.053. Epub 2003 Mar 1.
- Reman O, Pigneux A, Huguet F, Vey N, Delannoy A, Fegueux N, de Botton S, Stamatoullas A, Tournilhac O, Buzyn A, Charrin C, Boucheix C, Gabert J, Lheritier V, Vernant JP, Fiere D, Dombret H, Thomas X; GET-LALA group. Central nervous system involvement in adult acute lymphoblastic leukemia at diagnosis and/or at first relapse: results from the GET-LALA group. Leuk Res. 2008 Nov;32(11):1741-50. doi: 10.1016/j.leukres.2008.04.011. Epub 2008 May 27.
- Tavernier E, Le QH, de Botton S, Dhedin N, Bulabois CE, Reman O, Vey N, Lheritier 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. doi: 10.1002/cncr.23097.
- Dhedin N, Dombret H, Thomas X, Lheritier 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, Fiere 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. doi: 10.1038/sj.leu.2404065.
- 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, Lheritier V, Thomas X, Charrin C, Boucheix C, Dombret H, Macintyre E, Fiere 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. doi: 10.1038/sj.leu.2404408. Epub 2006 Oct 12. No abstract available.
- Charrin C, Thomas X, Ffrench M, Le QH, Andrieux J, Mozziconacci MJ, Lai JL, Bilhou-Nabera C, Michaux L, Bernheim A, Bastard C, Mossafa H, Perot C, Maarek O, Boucheix C, Lheritier V, Delannoy A, Fiere 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. doi: 10.1182/blood-2003-04-1299. Epub 2004 Mar 23.
- 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 adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group. Haematologica. 2010 Sep;95(9):1489-95. doi: 10.3324/haematol.2009.018580. Epub 2010 Apr 7.
- Le QH, Thomas X, Ecochard R, Iwaz J, Lheritier 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 leukemia-94 trial. Cancer. 2007 May 15;109(10):2058-67. doi: 10.1002/cncr.22632.
- 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, Lheritier V, Vernant JP, Dombret H, Thomas X; GET-LALA Group; Swiss Group for Clinical Cancer Research SAKK; Australasian Leukaemia and Lymphoma Group. Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial. Leukemia. 2007 Sep;21(9):1907-14. doi: 10.1038/sj.leu.2404824. Epub 2007 Jul 5.
- 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 Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. doi: 10.1038/sj.leu.2404420. Epub 2006 Oct 12.
- 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 Apr 15;105(8):3072-8. doi: 10.1182/blood-2004-09-3666. Epub 2005 Jan 6.
- 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, Lheritier V, Fiere D. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. doi: 10.1200/JCO.2004.10.050. Epub 2004 Sep 7.
- 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.
- 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, Lheritier V, Esperou H, MacIntyre E, Vernant JP, Fiere D; Groupe d'Etude et de Traitement de la Leucemie Aigue Lymphoblastique de l'Adulte (GET-LALA Group). Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia--results of the prospective multicenter LALA-94 trial. Blood. 2002 Oct 1;100(7):2357-66. doi: 10.1182/blood-2002-03-0704.
Datas de registro do estudo
Datas Principais do Estudo
Início do estudo
Conclusão Primária (Real)
Datas de inscrição no estudo
Enviado pela primeira vez
Enviado pela primeira vez que atendeu aos critérios de CQ
Primeira postagem (Estimativa)
Atualizações de registro de estudo
Última Atualização Postada (Estimativa)
Última atualização enviada que atendeu aos critérios de controle de qualidade
Última verificação
Mais Informações
Termos relacionados a este estudo
Palavras-chave
Termos MeSH relevantes adicionais
- Doenças do sistema imunológico
- Neoplasias por Tipo Histológico
- Neoplasias
- Distúrbios Linfoproliferativos
- Doenças Linfáticas
- Distúrbios imunoproliferativos
- Linfoma
- Leucemia
- Leucemia-Linfoma Linfoblástico de Células Precursoras
- Leucemia Linfóide
- Efeitos Fisiológicos das Drogas
- Mecanismos Moleculares de Ação Farmacológica
- Agentes Anti-Infecciosos
- Agentes Autônomos
- Agentes do Sistema Nervoso Periférico
- Antivirais
- Inibidores da Síntese de Ácido Nucleico
- Inibidores Enzimáticos
- Analgésicos
- Agentes do Sistema Sensorial
- Antiinflamatórios
- Agentes Antirreumáticos
- Antimetabólitos, Antineoplásicos
- Antimetabólitos
- Agentes Antineoplásicos
- Agentes imunossupressores
- Fatores imunológicos
- Moduladores de Tubulina
- Agentes Antimitóticos
- Moduladores de Mitose
- Antieméticos
- Agentes gastrointestinais
- Glicocorticóides
- Hormônios
- Hormônios, Substitutos Hormonais e Antagonistas Hormonais
- Agentes Antineoplásicos Hormonais
- Agentes de proteção
- Agentes Antineoplásicos Alquilantes
- Agentes Alquilantes
- Agonistas Mieloablativos
- Agentes Antineoplásicos Fitogênicos
- Inibidores da Topoisomerase II
- Inibidores da Topoisomerase
- Agentes dermatológicos
- Micronutrientes
- Antibióticos, Antineoplásicos
- Vitaminas
- Agentes de Controle Reprodutivo
- Antídotos
- Complexo de Vitamina B
- Agentes abortivos, não esteróides
- Agentes abortivos
- Antagonistas do ácido fólico
- Dexametasona
- Prednisolona
- Ciclofosfamida
- Leucovorina
- Levoleucovorina
- Prednisona
- Doxorrubicina
- Doxorrubicina lipossomal
- Citarabina
- Metotrexato
- Vincristina
- Daunorrubicina
- Asparaginase
- Mitoxantrona
- Mercaptopurina
- Hidrocortisona
- Hidrocortisona 17-butirato 21-propionato
- Acetato de hidrocortisona
- Hemisuccinato de hidrocortisona
Outros números de identificação do estudo
- EORTC-06951
- FRE-LALA-94
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