Hybrid Immunotherapy for Hemophagocytic LymphoHistiocytosis

• Complete Response Rate [ Time Frame: 8 Weeks ] [ Designated as safety issue: Yes ]
  To determine the complete response rate and overall survival at 8 weeks after an ATG/Dexamethasone/Etoposide based induction regimen for patients with 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
  
  

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.

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).