Treatment Protocol for Hemophagocytic Lymphohistiocytosis 2004

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Azienda Ospedaliero, Universitaria Meyer
Leiden University Medical Center
Children's Hospital Medical Center, Cincinnati
Ehime University Graduate School of Medicine
Universitätsklinikum Hamburg-Eppendorf
Texas Children's Hospital
Great Ormond Street Hospital for Children NHS Foundation Trust
St. Anna Kinderkrebsforschung
Hospital de Cruces
Hospital JP Garrahan
Information provided by (Responsible Party):
Jan-Inge Henter, Karolinska University Hospital
ClinicalTrials.gov Identifier:
NCT00426101
First received: January 23, 2007
Last updated: November 22, 2012
Last verified: November 2012
  Purpose

Without therapy HLH is often fatal, and often rapidly fatal. The treatment protocol HLH-94 has improved survival markedly as compared to the survival earlier. We now aim to improve survival further.


Condition Intervention Phase
Hemophagocytic Lymphohistiocytosis
Drug: Dexamethasone
Drug: Etoposide
Drug: Cyclosporin
Procedure: Intrathecal therapy
Procedure: Stem cell transplant
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: HLH-2004 Treatment Protocol

Resource links provided by NLM:


Further study details as provided by Karolinska University Hospital:

Primary Outcome Measures:
  • Survival [ Time Frame: 1-year after diagnosis ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Late effects [ Time Frame: At last follow-up report ] [ Designated as safety issue: No ]

Estimated Enrollment: 300
Study Start Date: January 2004
Estimated Study Completion Date: December 2016
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Dexamethasone
    • Dexamethasone 10 mg/m2 daily, for the first 2 weeks (week 1-2).
    • Dexamethasone 5 mg/m2 daily, for another 2 weeks (week 3-4).
    • Dexamethasone 2.5 mg/m2 daily, for another 2 weeks (week 5-6)
    • Dexamethasone 1.25 mg/m2 daily, for another week (week 7). Steroids are tapered and discontinued during week 8.

    If continuation therapy is provided, then:

    - Dexamethasone pulses every second week, 10 mg/m2 for 3 days.

    Drug: Etoposide
    • 150 mg/m2 iv twice weekly (week 1-2).
    • 150 mg/m2 iv once weekly (week 3-8).

    If continuation therapy is provided, then:

    - 150 mg/m2 iv, every second week.

    Drug: Cyclosporin

    WEEK 1-8:

    - The blood levels determine the dosages, aim at levels around 200 microgram/L (trough value) (monoclonal antibody assay of whole blood). Start with 6 mg/kg daily (divided in 2 daily doses) already week 1, if kidney function is normal.

    If continuation therapy is provided, then:

    - Aim for blood levels around 200 microgram/L, as above. Monitor GFR.

    Procedure: Intrathecal therapy

    The CSF is evaluated at diagnosis and after 2 weeks. If after 2 weeks there is clinical evidence of progressive neurological symptoms or if an abnormal CSF (cell count and protein) has not improved, additional CNS-therapy is initiated with 4 weekly intrathecal injections. Be aware that some patients may have increased intracranial pressure.

    • Methotrexate: <1 yr 6 mg, 1-2 yrs 8 mg, 2-3 yrs 10 mg, >3 yrs 12 mg.
    • Prednisolone: <1 yr 4 mg, 1-2 yrs 6 mg, 2-3 yrs 8 mg, >3 yrs 10 mg.
    Procedure: Stem cell transplant

    Suggested regimen:

    Preparative Regimen

    • Day -8,-7,-6,-5 Busulfan 2mg/kg po, or eq iv (as 1.6mg/kg), twice daily.
    • Day -4 Etoposide 30 mg/kg iv (6 hr inf) (maximum 1800 mg)
    • Day -3, -2 Cyclophosphamide 60 mg/kg iv (1 hr inf)
    • Day 0 Marrow infusion (preferably ³3 x 108 nucleated cells/kg, non T-cell-depleted).

    GVHD Prophylaxis:

    1. CSA continuous infusion starting day -1 pre-transplant with 3 mg/kg until oral nutrition re-established, thereafter 12.5 mg/kg orally daily. Monitoring of CSA through concentration levels. The immunosuppression is discontinued after 6-12 months, if possible.
    2. Short course methotrexate:

      • Day +1 15 mg/m2 iv
      • Day +3 10 mg/m2 iv
      • Day +6 10 mg/m2 iv Methotrexate may be substituted by mycophenolate mofetil (MMF).

    Additional Treatment for URD

    • ATG (12 hr inf iv) on days -3, -2 and -1 (according to manufacturers rec).
    • Metronidazole 22 mg/kg daily (po or iv) from day -8 until discharge.
Detailed Description:

The most dangerous period after HLH diagnosis is the first 2 months. In HLH-2004 we provide additional therapy during this period as compared to in HLH-94.

  Eligibility

Ages Eligible for Study:   up to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients who fulfil the diagnostic criteria of HLH.

Exclusion Criteria:

  • Prior cytotoxic or cyclosporin treatment for HLH.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00426101

Locations
Sweden
Childhood Cancer Research Unit, Karolinska Hospital
Stockholm, Sweden, S-171 76
Sponsors and Collaborators
Karolinska University Hospital
Azienda Ospedaliero, Universitaria Meyer
Leiden University Medical Center
Children's Hospital Medical Center, Cincinnati
Ehime University Graduate School of Medicine
Universitätsklinikum Hamburg-Eppendorf
Texas Children's Hospital
Great Ormond Street Hospital for Children NHS Foundation Trust
St. Anna Kinderkrebsforschung
Hospital de Cruces
Hospital JP Garrahan
Investigators
Principal Investigator: Jan-Inge Henter, MD, PhD Karolinska Institutet
  More Information

Publications:
Responsible Party: Jan-Inge Henter, Professor, Karolinska University Hospital
ClinicalTrials.gov Identifier: NCT00426101     History of Changes
Other Study ID Numbers: HLH-2004
Study First Received: January 23, 2007
Last Updated: November 22, 2012
Health Authority: Sweden: Regional Ethical Review Board

Keywords provided by Karolinska University Hospital:
Hemophagocytic lymphohistiocytosis

Additional relevant MeSH terms:
Lymphohistiocytosis, Hemophagocytic
Histiocytosis, Non-Langerhans-Cell
Histiocytosis
Lymphatic Diseases
Cyclosporins
Cyclosporine
BB 1101
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
Etoposide phosphate
Etoposide
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Gastrointestinal Agents
Glucocorticoids

ClinicalTrials.gov processed this record on April 14, 2014