Combination Chemotherapy Followed By Donor Stem Cell Transplant in Treating Patients With Hemophagocytic Lymphohistiocytosis
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.
Přehled studie
Postavení
Podmínky
Intervence / Léčba
- Lék: cyklofosfamid
- Jiný: laboratorní analýza biomarkerů
- Lék: dexamethason
- Lék: etoposid
- Lék: methotrexát
- Lék: terapeutický hydrokortison
- Biologický: anti-thymocytární globulin
- Postup: alogenní transplantace hematopoetických kmenových buněk
- Postup: biopsie
- Lék: busulfan
- Lék: cyklosporin
- Lék: mykofenolát mofetil
Detailní popis
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.
Typ studie
Zápis (Očekávaný)
Fáze
- Fáze 3
Kontakty a umístění
Studijní místa
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England
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Birmingham, England, Spojené království, B4 6NH
- Birmingham Children's Hospital
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Bristol, England, Spojené království, BS2 8AE
- Institute of Child Health at University of Bristol
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Cambridge, England, Spojené království, CB2 2QQ
- Addenbrooke's Hospital
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Herts, England, Spojené království, WD18 0HB
- Watford General Hospital
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Leeds, England, Spojené království, LS9 7TF
- Leeds Cancer Centre at St. James's University Hospital
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Liverpool, England, Spojené království, L12 2AP
- Royal Liverpool Children's Hospital, Alder Hey
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London, England, Spojené království, WC1N 3JH
- Great Ormond Street Hospital for Children
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Manchester, England, Spojené království, M27 4HA
- Royal Manchester Children's Hospital
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Sheffield, England, Spojené království, S10 2TH
- Children's Hospital - Sheffield
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Southampton, England, Spojené království, SO16 6YD
- Southampton General Hospital
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Scotland
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Aberdeen, Scotland, Spojené království, AB25 2ZG
- Royal Aberdeen Children's Hospital
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Edinburgh, Scotland, Spojené království, EH9 1LF
- Royal Hospital for Sick Children
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Glasgow, Scotland, Spojené království, G3 8SJ
- Royal Hospital for Sick Children
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Kritéria účasti
Kritéria způsobilosti
Věk způsobilý ke studiu
Přijímá zdravé dobrovolníky
Pohlaví způsobilá ke studiu
Popis
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
Studijní plán
Jak je studie koncipována?
Detaily designu
- Primární účel: Léčba
- Maskování: Žádné (otevřený štítek)
Co je měření studie?
Primární výstupní opatření
Měření výsledku |
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Přežití
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Spolupracovníci a vyšetřovatelé
Vyšetřovatelé
- Studijní židle: Vasanta Nanduri, MD, Watford General Hospital
Termíny studijních záznamů
Hlavní termíny studia
Začátek studia
Primární dokončení (Očekávaný)
Termíny zápisu do studia
První předloženo
První předloženo, které splnilo kritéria kontroly kvality
První zveřejněno (Odhad)
Aktualizace studijních záznamů
Poslední zveřejněná aktualizace (Odhad)
Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality
Naposledy ověřeno
Více informací
Termíny související s touto studií
Klíčová slova
Další relevantní podmínky MeSH
- Lymfatická onemocnění
- Histiocytóza, non-Langerhansovy buňky
- Histiocytóza
- Lymfohistiocytóza, hemofagocytární
- Fyziologické účinky léků
- Molekulární mechanismy farmakologického působení
- Antiinfekční látky
- Autonomní agenti
- Agenti periferního nervového systému
- Inhibitory syntézy nukleových kyselin
- Inhibitory enzymů
- Protizánětlivé látky
- Antirevmatika
- Antimetabolity, Antineoplastika
- Antimetabolity
- Antineoplastická činidla
- Imunosupresivní látky
- Imunologické faktory
- Antiemetika
- Gastrointestinální látky
- Glukokortikoidy
- Hormony
- Hormony, hormonální náhražky a antagonisté hormonů
- Antineoplastická činidla, Hormonální
- Antineoplastická činidla, Alkylační
- Alkylační činidla
- Myeloablativní agonisté
- Antineoplastické látky, fytogenní
- Inhibitory topoizomerázy II
- Inhibitory topoizomerázy
- Dermatologická činidla
- Antibakteriální látky
- Antibiotika, antineoplastika
- Antifungální látky
- Činidla pro kontrolu reprodukce
- Antituberkulární látky
- Abortivní látky, nesteroidní
- Abortivní látky
- Antagonisté kyseliny listové
- Antibiotika, antituberkulo
- Inhibitory kalcineurinu
- Dexamethason
- Cyklofosfamid
- Etoposid
- Methotrexát
- Kyselina mykofenolová
- Busulfan
- Hydrokortison
- Hydrokortison 17-butyrát 21-propionát
- Hydrokortison acetát
- Hydrokortison hemisukcinát
- Antilymfocytární sérum
- Cyklosporin
- Cyklosporiny
Další identifikační čísla studie
- CDR0000481605
- CCLG-LCH-2006-02
- EU-20619
- UKCCSG-HLH-2004
- EUDRACT-2005-002187-28
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