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

16. september 2013 opdateret af: 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.

Studieoversigt

Status

Ukendt

Betingelser

Intervention / Behandling

Detaljeret beskrivelse

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.

Undersøgelsestype

Interventionel

Tilmelding (Forventet)

288

Fase

  • Fase 3

Kontakter og lokationer

Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.

Studiesteder

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

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

Ikke ældre end 17 år (Barn)

Tager imod sunde frivillige

Ingen

Køn, der er berettiget til at studere

Alle

Beskrivelse

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

Studieplan

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Primært formål: Behandling
  • Maskning: Ingen (Åben etiket)

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Overlevelse

Samarbejdspartnere og efterforskere

Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.

Sponsor

Children's Cancer and Leukaemia Group

Efterforskere

  • Studiestol: Vasanta Nanduri, MD, Watford General Hospital

Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart

1. marts 2006

Primær færdiggørelse (Forventet)

1. november 2010

Datoer for studieregistrering

Først indsendt

7. juni 2006

Først indsendt, der opfyldte QC-kriterier

7. juni 2006

Først opslået (Skøn)

8. juni 2006

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Skøn)

17. september 2013

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

16. september 2013

Sidst verificeret

1. juni 2009

Mere information

Begreber relateret til denne undersøgelse

Nøgleord

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • CDR0000481605
  • CCLG-LCH-2006-02
  • EU-20619
  • UKCCSG-HLH-2004
  • EUDRACT-2005-002187-28

Disse oplysninger blev hentet direkte fra webstedet clinicaltrials.gov uden ændringer. Hvis du har nogen anmodninger om at ændre, fjerne eller opdatere dine undersøgelsesoplysninger, bedes du kontakte register@clinicaltrials.gov. Så snart en ændring er implementeret på clinicaltrials.gov, vil denne også blive opdateret automatisk på vores hjemmeside .

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