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