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

16 september 2013 bijgewerkt door: 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.

Studie Overzicht

Toestand

Onbekend

Conditie

Niet-neoplastische aandoening

Interventie / Behandeling

Gedetailleerde beschrijving

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

Ingrijpend

Inschrijving (Verwacht)

288

Fase

Fase 3

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studie Locaties

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

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

Niet ouder dan 17 jaar (Kind)

Accepteert gezonde vrijwilligers

Nee

Geslachten die in aanmerking komen voor studie

Allemaal

Beschrijving

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

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

Primair doel: Behandeling
Masker: Geen (open label)

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Overleving

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

Children's Cancer and Leukaemia Group

Onderzoekers

Studie stoel: Vasanta Nanduri, MD, Watford General Hospital

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start

1 maart 2006

Primaire voltooiing (Verwacht)

1 november 2010

Studieregistratiedata

Eerst ingediend

7 juni 2006

Eerst ingediend dat voldeed aan de QC-criteria