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Combination Chemotherapy Followed By Donor Stem Cell Transplant in Treating Patients With Hemophagocytic Lymphohistiocytosis

16 de setembro de 2013 atualizado por: Children's Cancer and Leukaemia Group

Hemophagocytic Lymphohistiocytosis

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of hemophagocytic lymphohistiocytosis cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more hemophagocytic lymphohistiocytosis cells. A donor stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Cyclosporine and methotrexate may stop this from happening.

PURPOSE: This phase III trial is studying how well combination chemotherapy followed by a donor stem cell transplant works in treating patients with hemophagocytic lymphohistiocytosis.

Visão geral do estudo

Status

Desconhecido

Condições

Condição não neoplásica

Intervenção / Tratamento

Descrição detalhada

OBJECTIVES:

Primary

Provide and evaluate revised induction and maintenance therapy comprising etoposide, dexamethasone, and cyclosporine, in terms of achieving and maintaining an acceptable clinical condition in order to perform a curative allogeneic hematopoietic stem cell transplantation (AHSCT), in patients with primary inherited or severe and persistent secondary hemophagocytic lymphohistiocytosis (HLH).
Evaluate and improve the outcome of AHSCT with various types of donors.
Determine the prognostic importance of the state of remission at the time of AHSCT.
Evaluate the neurological complications, in terms of early neurological alterations and cerebrospinal fluid (CSF) findings, in patients treated with this regimen.

Secondary

Improve the understanding of the pathophysiology of HLH by conducting biological studies of genetics and cytotoxicity in these patients, including genotype-phenotype studies and the prognostic value of natural killer (NK) cell activity subtyping.

OUTLINE: This is a multicenter study.

Induction therapy (weeks 1-8): Patients receive etoposide IV over 1-3 hours twice weekly in weeks 1 and 2 and then once weekly in weeks 3-8. Patients also receive dexamethasone IV or orally once daily and cyclosporine IV or orally twice daily in weeks 1-8. Patients with clinically evident, progressive neurological symptoms or an abnormal cerebrospinal fluid (CSF) (cell count and protein) that has not improved after 2 weeks of induction therapy undergo intrathecal therapy comprising methotrexate and hydrocortisone once weekly in weeks 3-6.

Patients are evaluated after 8 weeks of induction therapy. Patients with primary (i.e., familial) hemophagocytic lymphohistiocytosis (HLH) or genetic evidence of HLH proceed to maintenance therapy. Patients with severe and persistent secondary (i.e., nonfamilial) HLH and no genetic evidence of HLH proceed to maintenance therapy only if their disease is still active after induction therapy. Patients with nonfamilial HLH and no genetic evidence of HLH who have achieved complete remission (CR) discontinue treatment. If their disease reactivates, they may then proceed to allogeneic hematopoietic stem cell transplantation (AHSCT).

Maintenance therapy (weeks 9-40): Patients receive dexamethasone IV on days 1-3 in weeks 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, and 40; etoposide IV over 1-3 hours once in weeks 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, and 39; and cyclosporine IV or orally twice daily in weeks 9-40.

After completion of maintenance therapy, patients with primary (i.e., familial) HLH, severe and persistent secondary (i.e., nonfamilial) HLH, or reactivating disease proceed to AHSCT. Patients with nonfamilial HLH who have completed maintenance therapy, but do not go on to receive AHSCT, may be recommended for additional maintenance therapy at the discretion of the treating physician.

AHSCT:
- Preparative regimen: Patients receive a preparative regimen comprising busulfan orally or IV four times daily on days -8 to -5, etoposide IV over 6 hours on day -4, and cyclophosphamide IV over 1 hour on days -3 and -2. Patients who are undergoing unrelated AHSCT, also receive antithymocyte globulin (ATG) IV over 12 hours on days -3 to -1.
- Transplantation: Patients undergo AHSCT on day 0.
- Graft-versus-host disease prophylaxis: Beginning on day -1, patients receive cyclosporine IV continuously and then orally, when tolerated, once daily for 6-12 months. Patients also receive methotrexate* IV on days 1, 3, and 6.

NOTE: *As a substitute for methotrexate, patients may receive oral mycophenolate mofetil twice daily on days 0-40, followed by a taper and discontinuation.

Patients undergo periodic blood collection and bone marrow biopsies for biological studies.

After completion of study treatment, patients are followed periodically for up to 5 years.

PROJECTED ACCRUAL: A total of 288 patients will be accrued for this study.

Tipo de estudo

Intervencional

Inscrição (Antecipado)

288

Estágio

Fase 3

Contactos e Locais

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Locais de estudo

Reino Unido
- England
  - Birmingham, England, Reino Unido, B4 6NH
    - Birmingham Children's Hospital
  - Bristol, England, Reino Unido, BS2 8AE
    - Institute of Child Health at University of Bristol
  - Cambridge, England, Reino Unido, CB2 2QQ
    - Addenbrooke's Hospital
  - Herts, England, Reino Unido, WD18 0HB
    - Watford General Hospital
  - Leeds, England, Reino Unido, LS9 7TF
    - Leeds Cancer Centre at St. James's University Hospital
  - Liverpool, England, Reino Unido, L12 2AP
    - Royal Liverpool Children's Hospital, Alder Hey
  - London, England, Reino Unido, WC1N 3JH
    - Great Ormond Street Hospital for Children
  - Manchester, England, Reino Unido, M27 4HA
    - Royal Manchester Children's Hospital
  - Sheffield, England, Reino Unido, S10 2TH
    - Children's Hospital - Sheffield
  - Southampton, England, Reino Unido, SO16 6YD
    - Southampton General Hospital
- Scotland
  - Aberdeen, Scotland, Reino Unido, AB25 2ZG
    - Royal Aberdeen Children's Hospital
  - Edinburgh, Scotland, Reino Unido, EH9 1LF
    - Royal Hospital for Sick Children
  - Glasgow, Scotland, Reino Unido, G3 8SJ
    - Royal Hospital for Sick Children

Critérios de participação

Os pesquisadores procuram pessoas que se encaixem em uma determinada descrição, chamada de critérios de elegibilidade. Alguns exemplos desses critérios são a condição geral de saúde de uma pessoa ou tratamentos anteriores.

Critérios de elegibilidade

Idades elegíveis para estudo

Não mais velho que 17 anos (Filho)

Aceita Voluntários Saudáveis

Não

Gêneros Elegíveis para o Estudo

Tudo

Descrição

DISEASE CHARACTERISTICS:

Newly diagnosed hemophagocytic lymphohistiocytosis (HLH) meeting 1 of the following criteria*:
- Diagnosis by molecular/genetic methods
- Diagnosis by meeting 5 out of 8 of the following criteria:
  - Clinical criteria:
    - Fever
    - Splenomegaly
  - Laboratory criteria:
    - Cytopenias affecting ≥ 2 of 3 lineages in the peripheral blood, including the following:
      - Hemoglobin < 9.0 g/dL (< 10.0 g/dL in infants < 4 weeks of age)
      - Platelet count < 100,000/mm^3
      - Neutrophil count < 1,000/mm^3
    - Hypertriglyceridemia and/or hypofibrinogenemia:
      - Fasting triglycerides ≥ 3.0 mmol/L (i.e., ≥ 265 mg/dL)
      - Fibrinogen ≤ 1.5 g/L
  - Histopathologic criteria:
    - Hemophagocytosis in bone marrow, spleen, or lymph nodes
      - No evidence of malignancy
  - New diagnostic criteria:
    - Low or absent natural killer (NK) cell activity
    - Ferritin ≥ 500 mcg/L
    - Soluble CD25 (i.e., soluble interleukin-2 receptor) ≥ 2,400 U/mL NOTE: *Patients who do not meet the diagnostic criteria for HLH but who have a strong clinical suspicion of HLH may be eligible at the discretion of the investigator
Primary HLH (i.e., familial hemophagocytic lymphohistiocytosis [FLH]) OR secondary HLH (i.e., severe acquired form of HLH)
Acceptable donor meeting 1 of the following criteria:
- HLA-identical related donor
- Matched unrelated donor
- Mismatched unrelated donor
- Familial haploidentical donor

PATIENT CHARACTERISTICS:

Not specified

PRIOR CONCURRENT THERAPY:

No prior cytotoxic treatment for HLH
No prior cyclosporine treatment for HLH

Plano de estudo

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Como o estudo é projetado?

Detalhes do projeto

Finalidade Principal: Tratamento
Mascaramento: Nenhum (rótulo aberto)

O que o estudo está medindo?

Medidas de resultados primários

Medida de resultado
Sobrevivência

Colaboradores e Investigadores

É aqui que você encontrará pessoas e organizações envolvidas com este estudo.

Patrocinador

Children's Cancer and Leukaemia Group

Investigadores

Cadeira de estudo: Vasanta Nanduri, MD, Watford General Hospital

Datas de registro do estudo

Essas datas acompanham o progresso do registro do estudo e os envios de resumo dos resultados para ClinicalTrials.gov. Os registros do estudo e os resultados relatados são revisados pela National Library of Medicine (NLM) para garantir que atendam aos padrões específicos de controle de qualidade antes de serem publicados no site público.

Datas Principais do Estudo

Início do estudo

1 de março de 2006

Conclusão Primária (Antecipado)

1 de novembro de 2010

Datas de inscrição no estudo

Enviado pela primeira vez

7 de junho de 2006

Enviado pela primeira vez que atendeu aos critérios de CQ