Hybrid Immunotherapy for Hemophagocytic LymphoHistiocytosis

• Time to Response [ Time Frame: 8 Weeks ] [ Designated as safety issue: Yes ]
  To determine the median time to complete response
• Overall Survival [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
  To determine overall survival prior to the initiation of BMT (bone marrow transplant) preparative regimen (or day 180, if BMT preparative regimen not yet begun)
• Incidence of Infection [ Time Frame: 8 Weeks or day 180 ] [ Designated as safety issue: Yes ]
  To determine the incidence of serious infection and other adverse events by week 8 and prior to initiation of BMT preparative regimen (or day 180, if BMT preparative regimen not yet begun)
• Incidence and Time to Relapse [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
  To determine the incidence and median time to relapse prior to initiation of BMT preparative regimen (or day 180, if BMT preparative regimen not yet begun)
• Overall Survival to day +100 [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
  To determine overall survival to day +100 after BMT, for patients who have undergone BMT within 6 months of study entry
• Gather Biologic Samples [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  To gather biologic samples from patients with HLH to facilitate future basic and translational studies

• Time to Response [ Time Frame: 8 Weeks ] [ Designated as safety issue: No ]
  To determine the median time to complete response
• Overall Survival [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  To determine overall survival prior to the initiation of BMT preparative regimen (or day 180, if BMT preparative regimen not yet begun)
• Incidence of Infection [ Time Frame: 8 Weeks or day 180 ] [ Designated as safety issue: Yes ]
  To determine the incidence of serious infection and other adverse events by week 8 and prior to initiation of BMT preparative regimen (or day 180, if BMT preparative regimen not yet begun)
• Incidence and Time to Relapse [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
  To determine the incidence and median time to relapse prior to initiation of BMT preparative regimen (or day 180, if BMT preparative regimen not yet begun)
• Overall Survival to day +100 [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
  To determine overall survival to day +100 after BMT, for patients who have undergone BMT within 6 months of study entry
• Gather Biologic Samples [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  To gather biologic samples from patients with HLH to facilitate future basic and translational studies

Despite good progress during the last decade, hemophagocytic lymphohistiocytosis (HLH) remains difficult to treat. Two different treatment regimens have been used successfully. The first one, a treatment regimen based on two drugs called etoposide and dexamethasone, has been used worldwide. The second regimen, based on two drugs called Anti-thymocyte globulin (ATG) and prednisone, has been used mostly at one hospital in Paris, for over 15 years. With either regimen, about three quarters of treated children survive the most difficult time, the first two months after diagnosis. These two different regimens appear to work somewhat differently, and we suspect that combining them may give better results than either regimen alone. We are conducting this clinical trial to test the combination of ATG, dexamethasone, and etoposide for the treatment of HLH.

The purpose of this research study is to find out what effects (good and bad) this drug combination has on you and your HLH.

Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological disorder first recognized almost 70 years ago.(1) Genetic and animal studies have indicated that the familial form of HLH is clearly due to a deficiency of cytotoxic killing. Patients with HLH present with a potentially fatal syndrome of 'hyperimmunity.' These patients have severe inflammation, associated with cytopenias and variably severe bone marrow, liver, or CNS damage. Tissue damage and mortality appear to be due to hypercytokinemia related to persistent immune hyperactivation. An animal model of HLH and correlative human studies all suggest that excessive and abnormal activation of T cells drives the pathophysiology of this disorder, and that suppressing this excessive activation is critical for successful therapy of HLH. It is believed a combination of the two proven induction regimens for hemophagocytic lymphohistiocytosis (HLH) (anti-thymocyte globulin (ATG)- and etoposide-based) will result in response rates and overall survival rates at eight weeks which are comparable or better than the current standard of care (induction therapy per the HLH-94 protocol).

• Drug: ATG, rabbit
  ATG, rabbit (Thymoglobulin, Genzyme) will be dosed at 5 mg/kg/dose, given IV on 5 consecutive days (titrated over 4 to 8 hours).
  Other Name: Thymoglobulin
• Drug: Etoposide
  Etoposide will be dosed at 150mg/m2, given IV. The first dose will be given 7 days (+/- 2 days) after the first dose of ATG, and be given weekly for a total of 7 doses.
  Other Names:

  • Etopophos
  • Toposar
  • VePesid
• Drug: Intrathecal Methotrexate
  Intrathecal Methotrexate and hydrocortisone will be administered to CNS+ patients (CNS+ patients are those patients which have any of the following: elevated CSF (cerebral spinal fluid) protein or white count, seizures, focal or global neurologic deficit, MRI abnormalities consistent with CNS involvement by HLH.) in the following doses: age< 1 yr: 6/8mg (MTX/HC), 1-2 yrs: 8/10mg, 2-3 yrs: 10/12mg, >3 yrs: 12/15 mg. It will be administered (+/- 3 days) on day 7, 14, 21 and 42.
• Drug: hydrocortisone
  Intrathecal Methotrexate and hydrocortisone will be administered to CNS+ patients (CNS+ patients are those patients which have any of the following: elevated CSF (cerebral spinal fluid) protein or white count, seizures, focal or global neurologic deficit, MRI abnormalities consistent with CNS involvement by HLH.) in the following doses: age< 1 yr: 6/8mg (MTX/HC), 1-2 yrs: 8/10mg, 2-3 yrs: 10/12mg, >3 yrs: 12/15 mg. It will be administered (+/- 3 days) on day 7, 14, 21 and 42.

Inclusion Criteria:

• diagnosis of hemophagocytic lymphohistiocytosis
• Patients <18 years of age
• The patient must have active disease at the time of enrollment
• Patient's legal guardians must sign an Institutional Review Board approved consent form indicating their awareness of the investigational nature and the risks of this study.
• Eligible subjects must be enrolled with the protocol coordinating center

Exclusion Criteria:

• Recent treatment, within 3 months, with another therapeutic regimen for HLH
• Known active malignancy
• Known rheumatologic diagnosis which may be the underlying cause of HLH
• Pregnancy (as determined by serum or urine test) or active breast feeding
• Failure to provide signed informed consent