Phase III Study of Induction and Maintenance Therapy Comprising Etoposide, Dexamethasone, and Cyclosporine Followed by Allogeneic Hematopoietic Stem Cell Transplantation in Patients With Primary Inherited or Severe and Persistent Secondary Hemophagocytic Lymphohistiocytosis
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 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
This phase III trial is studying how well combination
chemotherapy followed by a donor stem cell transplant works in treating
patients with hemophagocytic lymphohistiocytosis.
- 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
- 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 Outcome: 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 cell activity subtyping.
This is a multicenter study. 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 CSF 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 HLH or genetic evidence of HLH proceed to
maintenance therapy. Patients with severe and persistent secondary 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 discontinue
treatment. If their disease reactivates, they may then proceed
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 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
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 IV over 12 hours on days -3 to -1.
- Transplantation: Patients undergo AHSCT on day 0.
- 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.
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.
View this trial on ClinicalTrials.gov