Tocilizumab and Hemophagocytic Lymphohistiocytosis (HLH)

This study seeks to determine the efficacy of tocilizumab (TCZ) in patients with hemophagocytic lymphohistiocytosis (HLH) and high cytokine levels (proteins involved in inflammation) in an attempt to decrease the damage caused by these proteins; and secondarily to assess its safety and impact on disease activity.

Subjects with hemophagocytic lymphohistiocytosis (HLH) often have life-threatening complications at the time of diagnosis resulting from excessive inflammation. This excessive inflammation is driven by abnormally high levels of cytokines--proteins involved in inflammation. Standard therapy for HLH does not directly target these cytokines. Tocilizumab is a medicine that blocks one of the cytokines that is elevated in patients with HLH.

This is an open-label single-arm uncontrolled trial with biologic endpoint. This study will use tocilizumab in subjects with HLH and high cytokine levels in an attempt to decrease the damage caused by these proteins. All subjects will receive standard therapy, in addition to tocilizumab. We hypothesize the tocilizumab will decrease levels of certain important cytokines. This may make it easier to treat subjects with HLH overall.

TCZ will be administered as a single dose (8mg/kg) intravenously. Eligible subjects will be inpatients at the Children's Hospital of Philadelphia (CHOP) main campus. 10 subjects with HLH will be enrolled. All subjects will be initiated on standard HLH-directed treatment. Cytokine levels \[including serum interferon (IFN-γ) and interleukin (IL-6)\] will be monitored, in addition to other laboratory and clinical markers of HLH disease activity.

Eligibility Criteria:
Inclusion Criteria:

1. Males or females age 3 months to 25 years.
2. Fulfill the clinical diagnostic criteria for HLH, as defined by the Histiocyte Society (see Table 1). Only patients with de novo HLH are eligible.
3. Evidence of cytokine release syndrome (CRS), as defined by EITHER:

   i. Known elevated interferon-γ and interleukin-6 ≥2x ULN, OR ii. If cytokine levels are unknown at the time of study enrollment:

   a. Fever of at least 38.5º celsius at minimum of once every 24 hours for at least 48 hours, AND either i. Respiratory insufficiency requiring oxygen supplementation of at least 2 Liter by nasal cannula for at least 12 hours (also including invasive, noninvasive, continuous positive airway pressure or biphasic airway pressure for the purpose of treating respiratory failure), OR ii. Vasoactive infusion for at least 12 hours, including dopamine ≥5mcg/kg/min, dobutamine≥5mcg/kg/min, or any dose of epinephrine, norepinephrine, milrinone, or vasopressin.
4. Patients must be planned to initiate HLH-directed therapy within 24 hours of study enrollment.
5. Girls \>= 11 years of age must have a negative urine/serum pregnancy test and must use an acceptable method of contraception, including abstinence, a barrier method (diaphragm or condom), Depo-Provera, or an oral contraceptive, for the duration of the study.
6. Parental/guardian permission (informed consent)

Exclusion Criteria:

1. On-going or planned participation in another clinical trial involving HLH-directed treatment
2. Previous administration of any other biologic agent targeted at cytokine blockade within 5 days of enrollment.
3. Renal insufficiency defined by estimated glomerular filtration rate (based on modified Schwartz formula) \<50 ml/min, or need for renal replacement therapy.
4. Hepatic dysfunction as defined by serum alanine aminotransferase (ALT)\>=10x upper limit of normal (ULN). For the purposes of this study, the ULN for ALT is 45 U/L.
5. HLH that is relapsed, refractory, or considered to be therapy-related, as in the case of T cell-activating therapies.
6. Established prior diagnosis of underlying rheumatologic condition, including juvenile idiopathic arthritis.
7. Pregnant or lactating females.
8. Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.
9. Suspected gastrointestinal perforation.
10. Known or suspected demyelinating central nervous system disease.
11. Known history of tuberculosis.
12. Transfusion-refractory thrombocytopenia defined as inability to maintain platelet count over 30,000/ul for at least 6 hours with transfusion support.
13. Known active herpetic infection.
14. Inability to start HLH-directed immunochemotherapy.