A Pilot Study of Ruxolitinib in Secondary Hemophagocytic Syndrome

Hemophagocytic Syndrome (HPS) is a disorder characterized by pathological activation of the
immune system resulting in a systemic disorder characterized by excessive cytokine production
and macrophage activation, culminating in cytopenias and evidence of hemophagocytosis on
tissue specimens. The disorder can be sporadic or familial due to one of several mutations
and is primarily seen in the pediatric population, with a reported incidence of 1 case per
3000 admissions. The actual incidence in adults is unknown and can be rarely sporadic, or
secondary to viral infections, malignancy, or autoimmune disease.

HPS is a universally fatal disease if untreated. In adults, the median survival has been
reported to be less than 2 months if diagnosis and treatment is delayed. Adult patients are
treated with pediatric protocols with early institution of etoposide and steroids and
consolidation with allogeneic stem cell transplant in appropriately selected patients if a
familial form is identified. Other treatment strategies have been attempted, including
rituximab, infliximab, entaracept, tocilizumab, and alemtuzumab. These anecdotal reports
highlight the therapeutic potential of cytokine-targeted therapies in this disorder.

This is a pilot study to determine the efficacy of Ruxolitinib in secondary hemophagocytic
syndrome. The primary objective is to assess the efficacy of ruxolitinib 15 mg PO twice daily
in patients with HPS. The primary endpoint is overall survival at two months.

Patients will receive Ruxolitinib at 15 mg twice daily orally either on an empty stomach or
with food for 4 weeks (28 days) in a 4 week (28 day) cycle. Ruxolitinib will be administered
in continuous 28-day cycles.

In the absence of treatment delays or cessation due to adverse events, treatment may continue
indefinitely or until one of the following criteria applies:

- Disease progression.

- Intercurrent illness that prevents further administration of treatment.

- The investigator considers it, for safety reasons, to be in the best interest of the
patient.

- Unacceptable adverse events such as any toxicity or other issue that causes a delay of
study drug administration by more than 4 weeks.

- General or specific changes in the patient's condition render the patient unacceptable
for further treatment in the judgment of the investigator.

- Patient decision to withdraw from treatment (partial consent) or from the study (full
consent.

- Death.

Patients will be followed for toxicity for 30 days after treatment has been discontinued or
until death, whichever occurs first.

Inclusion Criteria:

- Patients, or their legally authorized representative, must voluntarily provide written
IRB-approved informed consent.

- Males and females, 18 years of age or older at the time of enrollment.

- Patients must meet the diagnostic criteria for HPS (at least 5 of the following):
fever, splenomegaly, cytopenia involving ≥2 cell lines (Hemoglobin <9 g/dL; platelets
<100,000/μL; absolute neutrophil count <1000/μL), hypertriglyceridemia or
hypofibrinogenemia, tissue demonstration of hemophagocytosis, low or absent NK
(Natural Killer) cell activity, serum ferritin ≥3000 ug/L, soluble IL-2 receptor
(CD25) >2400 U/mL.

- In the investigator's opinion, the patient has the ability to participate fully in the
study, and comply with all its requirements.

Exclusion Criteria:

- CNS (Central Nervous System) involvement

- Malabsorption

- Known secondary HPS (Hemophagocytic Syndrome) that is otherwise treatable (e.g.
non-Hodgkin's lymphoma).

- Pregnant or lactating female: all females of child-bearing potential must have a
negative serum pregnancy test within 7 days of treatment; lactating females must
discontinue breast feeding.

- Estimated creatinine clearance <15mL/min

- Has received any prior systemic therapy, excluding corticosteroids, within 7 days (or
5 half-lives) of treatment.

- No active malignancy at the time of enrollment, except nonmelanoma skin cancers or
carcinoma in situ. Patients with a prior history of malignancy are eligible if their
malignancy has been definitely treated or is in remission and does not require ongoing
adjuvant or cancer-directed therapies.

- Active hepatitis B or hepatitis C or known HIV infection

- Known (and biopsy-confirmed) liver cirrhosis; or, a reported history of liver
cirrhosis with a Model for End-stage Liver Disease (MELD) score >20.