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

Children's Cancer and Leukaemia Group (Other)
Overall Status
Unknown status ID
Patients Per Site

Study Details

Study Description

Brief Summary

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.

Condition or DiseaseIntervention/TreatmentPhase
Phase 3

Detailed Description



  • 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.


  • 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.

Study Design

Study Type:
Anticipated Enrollment :
288 participants
None (Open Label)
Primary Purpose:
Official Title:
Hemophagocytic Lymphohistiocytosis
Study Start Date :
Mar 1, 2006
Anticipated Primary Completion Date :
Nov 1, 2010

Outcome Measures

Primary Outcome Measures

  1. Survival []

Eligibility Criteria


Ages Eligible for Study:
N/A to 17 Years
Sexes Eligible for Study:
Accepts Healthy Volunteers:
  • 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

  • Not specified
  • No prior cytotoxic treatment for HLH

  • No prior cyclosporine treatment for HLH

Contacts and Locations


SiteCityStateCountryPostal Code
1Birmingham Children's HospitalBirminghamEnglandUnited KingdomB4 6NH
2Institute of Child Health at University of BristolBristolEnglandUnited KingdomBS2 8AE
3Addenbrooke's HospitalCambridgeEnglandUnited KingdomCB2 2QQ
4Watford General HospitalHertsEnglandUnited KingdomWD18 0HB
5Leeds Cancer Centre at St. James's University HospitalLeedsEnglandUnited KingdomLS9 7TF
6Royal Liverpool Children's Hospital, Alder HeyLiverpoolEnglandUnited KingdomL12 2AP
7Great Ormond Street Hospital for ChildrenLondonEnglandUnited KingdomWC1N 3JH
8Royal Manchester Children's HospitalManchesterEnglandUnited KingdomM27 4HA
9Children's Hospital - SheffieldSheffieldEnglandUnited KingdomS10 2TH
10Southampton General HospitalSouthamptonEnglandUnited KingdomSO16 6YD
11Royal Aberdeen Children's HospitalAberdeenScotlandUnited KingdomAB25 2ZG
12Royal Hospital for Sick ChildrenEdinburghScotlandUnited KingdomEH9 1LF
13Royal Hospital for Sick ChildrenGlasgowScotlandUnited KingdomG3 8SJ

Sponsors and Collaborators

  • Children's Cancer and Leukaemia Group


  • Study Chair: Vasanta Nanduri, MD, Watford General Hospital

Study Documents (Full-Text)

None provided.

More Information


None provided.
Responsible Party:
, , Identifier:
Other Study ID Numbers:
  • CDR0000481605
  • CCLG-LCH-2006-02
  • EU-20619
  • UKCCSG-HLH-2004
  • EUDRACT-2005-002187-28
First Posted:
Jun 8, 2006
Last Update Posted:
Sep 17, 2013
Last Verified:
Jun 1, 2009

Study Results

No Results Posted as of Sep 17, 2013