Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Biomarker/Laboratory analysis, Treatment	Active	Under 18	Other	CCLG-LCH-2006-02 EU-20619, UKCCSG-HLH-2004, EUDRACT-2005-002187-28, NCT00334672

Objectives

Primary

1. 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).
2. Evaluate and improve the outcome of AHSCT with various types of donors.
3. Determine the prognostic importance of the state of remission at the time of AHSCT.
4. Evaluate the neurological complications, in terms of early neurological alterations and cerebrospinal fluid (CSF) findings, in patients treated with this regimen.

Secondary

1. 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.

Entry Criteria

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/mm³
        • Neutrophil count < 1,000/mm³
      • 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

Prior/Concurrent Therapy:

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

Patient Characteristics:

• Not specified

Expected Enrollment

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

Outcomes

Survival

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.

Trial Contact Information

Trial Lead Organizations

Children's Cancer and Leukaemia Group

Vasanta Nanduri, MD, Protocol chair		Ph: 44-192-321-7992

United Kingdom
England
	Birmingham
	Birmingham Children's Hospital
		Martin English, MD	Ph:  44-121-333-8412
			Email: martin.english@bch.nhs.uk
	Bristol
	Institute of Child Health at University of Bristol
		Colin Steward, MD	Ph:  44-117-342-8044
	Cambridge
	Addenbrooke's Hospital
		Mike Gattens, MD	Ph:  44-1223-216-878
	Herts
	Watford General Hospital
		Vasanta Nanduri, MD	Ph:  44-192-321-7992
	Leeds
	Leeds Cancer Centre at St. James's University Hospital
		Mike Richards, MD	Ph:  44-113-206-4984
	Liverpool
	Royal Liverpool Children's Hospital, Alder Hey
		Mark Caswell, MD	Ph:  44-151-293-3679
	London
	Great Ormond Street Hospital for Children
		Nick Goulden, MD	Ph:  44-20-7405-9200
	Manchester
	Royal Manchester Children's Hospital
		Bernadette Brennan, MD	Ph:  44-161-922-2227
			Email: bernadette.brennan@cmmc.nhs.uk
	Sheffield
	Children's Hospital - Sheffield
		Mary Gerrard, MBChB, FRCP, FRCPCH	Ph:  44-114-271-7366
			Email: mary.gerrard@sch.nhs.uk
	Southampton
	Southampton General Hospital
		Mary Morgan, MD	Ph:  44-23-8079-6942
Scotland
	Aberdeen
	Royal Aberdeen Children's Hospital
		Veronica Neefjes	Ph:  44-1224-550-217
	Edinburgh
	Royal Hospital for Sick Children
		Angela Thomas, MD	Ph:  44-131-536-0433
	Glasgow
	Royal Hospital for Sick Children
		Milind Ronghe, MD	Ph:  44-141-201-9309

Registry Information
Official Title		Hemophagocytic Lymphohistiocytosis
Trial Start Date		2006-03-01
Trial Completion Date		2010-11-24 (estimated)
Registered in ClinicalTrials.gov		NCT00334672
Date Submitted to PDQ		2006-04-18
Information Last Verified		2009-06-14

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