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

Primary Purpose

Nonneoplastic Condition

Status
Unknown status
Phase
Phase 3
Locations
United Kingdom
Study Type
Interventional
Intervention
anti-thymocyte globulin
busulfan
cyclophosphamide
cyclosporine
dexamethasone
etoposide
methotrexate
mycophenolate mofetil
therapeutic hydrocortisone
laboratory biomarker analysis
allogeneic hematopoietic stem cell transplantation
biopsy
Sponsored by
Children's Cancer and Leukaemia Group
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Nonneoplastic Condition focused on measuring hemophagocytic lymphohistiocytosis

Eligibility Criteria

undefined - 17 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Birmingham Children's Hospital
  • Institute of Child Health at University of Bristol
  • Addenbrooke's Hospital
  • Watford General Hospital
  • Leeds Cancer Centre at St. James's University Hospital
  • Royal Liverpool Children's Hospital, Alder Hey
  • Great Ormond Street Hospital for Children
  • Royal Manchester Children's Hospital
  • Children's Hospital - Sheffield
  • Southampton General Hospital
  • Royal Aberdeen Children's Hospital
  • Royal Hospital for Sick Children
  • Royal Hospital for Sick Children

Outcomes

Primary Outcome Measures

Survival

Secondary Outcome Measures

Full Information

First Posted
June 7, 2006
Last Updated
September 16, 2013
Sponsor
Children's Cancer and Leukaemia Group
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1. Study Identification

Unique Protocol Identification Number
NCT00334672
Brief Title
Combination Chemotherapy Followed By Donor Stem Cell Transplant in Treating Patients With Hemophagocytic Lymphohistiocytosis
Official Title
Hemophagocytic Lymphohistiocytosis
Study Type
Interventional

2. Study Status

Record Verification Date
June 2009
Overall Recruitment Status
Unknown status
Study Start Date
March 2006 (undefined)
Primary Completion Date
November 2010 (Anticipated)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Name of the Sponsor
Children's Cancer and Leukaemia Group

4. Oversight

5. 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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Nonneoplastic Condition
Keywords
hemophagocytic lymphohistiocytosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Masking
None (Open Label)
Enrollment
288 (Anticipated)

8. Arms, Groups, and Interventions

Intervention Type
Biological
Intervention Name(s)
anti-thymocyte globulin
Intervention Type
Drug
Intervention Name(s)
busulfan
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Intervention Type
Drug
Intervention Name(s)
cyclosporine
Intervention Type
Drug
Intervention Name(s)
dexamethasone
Intervention Type
Drug
Intervention Name(s)
etoposide
Intervention Type
Drug
Intervention Name(s)
methotrexate
Intervention Type
Drug
Intervention Name(s)
mycophenolate mofetil
Intervention Type
Drug
Intervention Name(s)
therapeutic hydrocortisone
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Type
Procedure
Intervention Name(s)
allogeneic hematopoietic stem cell transplantation
Intervention Type
Procedure
Intervention Name(s)
biopsy
Primary Outcome Measure Information:
Title
Survival

10. Eligibility

Sex
All
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility 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/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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Vasanta Nanduri, MD
Organizational Affiliation
Watford General Hospital
Official's Role
Study Chair
Facility Information:
Facility Name
Birmingham Children's Hospital
City
Birmingham
State/Province
England
ZIP/Postal Code
B4 6NH
Country
United Kingdom
Facility Name
Institute of Child Health at University of Bristol
City
Bristol
State/Province
England
ZIP/Postal Code
BS2 8AE
Country
United Kingdom
Facility Name
Addenbrooke's Hospital
City
Cambridge
State/Province
England
ZIP/Postal Code
CB2 2QQ
Country
United Kingdom
Facility Name
Watford General Hospital
City
Herts
State/Province
England
ZIP/Postal Code
WD18 0HB
Country
United Kingdom
Facility Name
Leeds Cancer Centre at St. James's University Hospital
City
Leeds
State/Province
England
ZIP/Postal Code
LS9 7TF
Country
United Kingdom
Facility Name
Royal Liverpool Children's Hospital, Alder Hey
City
Liverpool
State/Province
England
ZIP/Postal Code
L12 2AP
Country
United Kingdom
Facility Name
Great Ormond Street Hospital for Children
City
London
State/Province
England
ZIP/Postal Code
WC1N 3JH
Country
United Kingdom
Facility Name
Royal Manchester Children's Hospital
City
Manchester
State/Province
England
ZIP/Postal Code
M27 4HA
Country
United Kingdom
Facility Name
Children's Hospital - Sheffield
City
Sheffield
State/Province
England
ZIP/Postal Code
S10 2TH
Country
United Kingdom
Facility Name
Southampton General Hospital
City
Southampton
State/Province
England
ZIP/Postal Code
SO16 6YD
Country
United Kingdom
Facility Name
Royal Aberdeen Children's Hospital
City
Aberdeen
State/Province
Scotland
ZIP/Postal Code
AB25 2ZG
Country
United Kingdom
Facility Name
Royal Hospital for Sick Children
City
Edinburgh
State/Province
Scotland
ZIP/Postal Code
EH9 1LF
Country
United Kingdom
Facility Name
Royal Hospital for Sick Children
City
Glasgow
State/Province
Scotland
ZIP/Postal Code
G3 8SJ
Country
United Kingdom

12. IPD Sharing Statement

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

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