Trial Information

Hemophagocytic Lymphohistiocytosis

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.