Hybrid Immunotherapy for Hemophagocytic LymphoHistiocytosis

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).

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