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

16. september 2013 oppdatert av: 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.

Studieoversikt

Status

Ukjent

Forhold

Ikke-neoplastisk tilstand

Intervensjon / Behandling

Detaljert 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.

Studietype

Intervensjonell

Registrering (Forventet)

288

Fase

Fase 3

Kontakter og plasseringer

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Studiesteder

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

Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

Ikke eldre enn 17 år (Barn)

Tar imot friske frivillige

Nei

Kjønn som er kvalifisert for studier

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

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

Primært formål: Behandling
Masking: Ingen (Open Label)

Hva måler studien?

Primære resultatmål

Resultatmål
Overlevelse

Samarbeidspartnere og etterforskere

Det er her du vil finne personer og organisasjoner som er involvert i denne studien.

Sponsor

Children's Cancer and Leukaemia Group

Etterforskere

Studiestol: Vasanta Nanduri, MD, Watford General Hospital

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart

1. mars 2006

Primær fullføring (Forventet)

1. november 2010

Datoer for studieregistrering

Først innsendt

7. juni 2006

Først innsendt som oppfylte QC-kriteriene