Tocilizumab for Treatment of Steroid Refractory Acute Graft-versus-Host Disease

Patients who underwent an allogeneic hematopoietic stem cell transplantation, with biopsy
proven GVHD, active acute GVHD requiring systemic immune suppressive therapy and that failed
or did not respond to first line of therapy (corticosteroids ± other agent).

Tocilizumab will be administered intravenously at a dose of 8 mg/kg once every three weeks.
Patients with documented responses will continue to receive treatment at 8 mg/kg once every 3
weeks for at least two months (day 56). Patients that have some degree of response but
without complete resolution of signs and symptoms of acute GVHD may continue to receive 8
mg/kg on a 3-week cycle until complete response is achieved or lack of further improvement.
In patients who are beyond day 56 and whose GVHD has resolved, the dose of Tocilizumab will
be reduced to 4 mg/kg every 3 weeks. Subsequent discontinuation of Tocilizumab will occur
once patients are off other immune suppressive medications (including extracorporeal
photopheresis, ECP) or are receiving sub therapeutic levels of immunosuppression (ie. FK
levels <5ng/mL) or prednisone dose <20mg/day (or equivalent) and are free of acute GVHD signs
or symptoms for at least one month.

Patients who fulfill criteria of progression of GVHD not in the setting of immunosuppressive
taper, no response of GVHD or require initiation of other immune suppressive treatment for
GVHD will have Tocilizumab discontinued.

Tocilizumab shall be discontinued and not re-instituted if any one of the following criteria
is met. The patient will be taken off study drug therapy at that point, but still followed
for primary and secondary study endpoints. A response assessment will be made at the time of
therapy discontinuation and at subsequent defined study endpoints. The patient will not be
replaced on study. Follow-up data will be required unless consent for data collection is
withdrawn:

- Additional systemic GVHD therapy is added for disease progression or non-response

- Steroid dose is escalated to ≥ 2.5 mg/kg/day of prednisone (or methylprednisolone
equivalent of 2 mg/kg/day) for GVHD progression or no response

- Development of toxicity that requires withholding of study medication for more then 14
days

Inclusion Criteria:

- Patients age 18 and older who underwent an allogeneic hematopoietic stem cell
transplantation.

- Patients are required to have biopsy proven GVHD.

- Patients must have active acute GVHD requiring systemic immune suppressive therapy and
that failed or did not respond to first line of therapy.

- First line therapy needs to be a minimum of corticosteroids, methylprednisolone
of 1.6mg/kg/day or prednisone of 2mg/kg/day, alone or combined to other agent.

- Failure of GVHD therapy is defined as flare of signs and symptoms of acute GVHD
or progression of GVHD grade after at least 72 hours from starting therapy.

- No response to GVHD treatment (corticosteroids ± other agent) after a minimum of
7 days of treatment.

- Patient must be able to give informed consent.

Exclusion Criteria:

- Intolerance or allergy to Tocilizumab

- Active uncontrolled infection requiring ongoing treatment with antifungals,
antibiotics or anti-viral drugs.

- Relapsed/persistent malignancy requiring rapid immune suppression withdrawal.

- Liver enzymes: ALT and AST > 3x upper limit of normal.

- Patients with severe sinusoidal obstruction syndrome who in the judgment of the
treating physician are not expected to have normalized bilirubin by day 56 after
enrollment.

- Serum bilirubin > 2x upper limit of normal.