Infliximab and Basiliximab for Treatment of Steroid Refractory Acute Graft Versus Host Disease

Corticosteroids are the standard initial therapy for Acute GvHD (aGVHD) after HSCT
(hematopoietic stem cell transplant aka BMT) and 25-41% patients will respond to prednisone
(or methylprednisolone) at a dose of 2mg/kg/day. Complete response of aGvHD is an important
predictor of survival; in patients who respond to steroids, survival is around 50%, while it
is as low as 11% for non-responders. Patients who do not develop aGvHD are normally
discharged by 4-5 weeks after HSCT. However patients with aGvHD may need to be admitted and
require prolonged hospitalization. Patients, who do not respond to treatment, usually have
worsening skin symptoms, the protracted diarrhea and vomiting leading to severe life
threatening dehydration. Secondary bacterial, fungal and/or viral infections are common and
they may eventually die of multiorgan failure.

There is no consensus to the definition of steroid refractory (SR) aGvHD, but generally aGvHD
is considered to be SR, when there is progression of GvHD after 3 days or no response after 7
days of treatment with 2mg/kg/day of methyl prednisolone. There is no standard of care for
such patients and treatment varies from institution to institution. Salvage regimens for SR
GvHD have included high dose steroids, antithymocyte globulin (ATG), monoclonal antibodies
(infliximab, daclizumab, basiliximab etc.),pentostatin, mesenchymal stem cells and
immunotoxins. Generally if the manifestations of aGvHD worsen over 3 days after starting
steroids, or if there is no improvement within 5 days, then it is unlikely that a response
will be achieved and secondary therapy should be initiated.

High dose steroids have not been associated with any improvement in response rates for SR
aGvHD. In a prospective trial comparing 2mg/kg/day with 10mg/kg/day of methylprednisolone in
94 patients with grade II-IV aGvHD, response rates, progression to grade III-IV disease, non-
relapse mortality (NRM) and overall survival were similar in both treatment groups. In
addition high dose steroids are associated with many acute and long term complications.
Hyperglycemia, hypertension, infections, aseptic necrosis and neurological complications are
commonly seen.

Outcome of patients with SR aGvHD is poor. Only 7/57 (12%) patients achieved CR (complete
Response)after secondary therapy for aGvHD as reported by Weisdorf et al and only 4/45 (9 %)
patients who received high dose methylprednisolone as secondary therapy responded. ATG has
been extensively used for treatment of SR GvHD and CR rates of 14-20 % have been reported.

Rationale for using Infliximab and Basiliximab:

The pathophysiology of GvHD is triphasic involving tissue damage from the conditioning
regimen, followed by donor T cell activation leading to the effector phase of cytokine
dysregulation. The cytokines interleukin (IL) 2 and tumor necrosis factor-α (TNF-α) play a
central role in mediating tissue damage and causing proliferation of the activated
alloreactive T cells. Over the last few years monoclonal antibodies have been used to treat
such patients as monotherapy and recently as combination therapy with more promising results.
The anti-CD25 MoAb - daclizumab provides competitive inhibition of binding of IL-2 to the
high affinity α subunit IL2 receptor. It has been used as monotherapy for steroid refractory
aGvHD with promising results. TNF is another cytokine involved in GvHD and early studies with
anti-TNF-α administration have shown encouraging results. Antibodies to TNF (infliximab) or
to TNF receptor (etanercept) have been developed. Infliximab blocks the interaction between
TNF-and its receptors and causes lysis of the cells that produce TNF- . Srinivasan et al used
infliximab and daclizumab in combination therapy for patients who developed SR GvHD after non
myeloablative HSCT in adult patients. All 12 patients treated with the combination therapy
had complete resolution of GvHD in all involved organs. The Kaplan-Meier probability of
survival was 100% at 100 days and 73% at 200 days after transplantation. Rao et al in their
study used the same regimen (infliximab and daclizumab) in pediatric population who underwent
HSCT for immunodeficiency. In their study 86% (19/22) patients responded with a median
response time of 15 days after start of monoclonal antibody therapy. 12/22 (54%) had CR, and
7/22 (32%) had a PR while 3 patients had no response to treatment. At a median follow-up of
31 months 68% of the patients were alive.

As of Jan 2010 Daclizumab is not available due to manufacturer related issues. Basiliximab is
another chimeric murine-human IL-2 receptor antagonist, with a half-life of around 7 days.
It's mechanism of action is similar to daclizumab and it has been used in SR GVHD as
monotherapy. Massenkeil et al in their study of 17 patients with steroid refractory GvHD
showed the 53% of patients had a complete response, 18% had a partial response and 29% had no
response. Recently Funke et al in their study of 34 patients with SR GvHD, showed a CR rate
of 84% for skin, 48% of gut and 26% of patients with liver GvHD. However it is difficult to
compare one study with another due to lack of uniformity in response definitions, dosing
schedules and the number of doses used.

The higher CR rates and survival in the studies by Srinivasan and Rao et al were possibly due
to the following factors:

1. Use of combination therapy of monoclonal antibodies, selectively inhibiting alloreactive
T cells by targeting 2 different cytokines involved in the pathophysiology of GvHD;

2. Rapid taper of steroids, thereby decreasing the steroid induced side effects like
infections;

3. Prophylactic use of antimicrobials (antibiotics and antifungals) and close monitoring
for viral reactivation.

These factors led to decrease in infection related morbidity and mortality in this population
of heavily immunosuppressed patients; thus contributing to the improved survival in these
studies.

Overall CR rates for SR GvHD have ranged from 9% to 54% with a median of 26%. Mostly these
results are based on single center experience, with small sample sizes, and these studies are
not comparable. There is no standard of care; however infliximab may be used as monotherapy
if a diagnosis of SR GvHD has been made. The only promising treatment with infliximab and
daclizumab is not possible to give now due to unavailability of daclizumab from January 2010.
Basiliximab has not been used in combination therapy with other monoclonal antibodies.
Combination therapy with infliximab and basiliximab will target two different points in the
cytokine cascade and selectively control proliferation of activated T cells. As this
combination has not been used before it is difficult to predict the safety and efficacy
profile.

Inclusion Criteria:

- Any patient with either progressive aGvHD or Steroid Refractory aGvHD after Bone
marrow transplant

- Prophylactic GvHD therapy with cyclosporine, tacrolimus, MMF, or sirolimus can be
continued.

- Patients with late onset acute GvHD will be eligible

- Patients should have an absolute neutrophil count (ANC) of >500µL

- Patients with renal dysfunction or veno-occlusive disease are eligible

Exclusion Criteria:

- Patient should not be getting any other experimental therapy for aGvHD

- Patients with active uncontrolled life threatening infection (s) from viral,
bacterial, fungal or other organisms will be excluded. Patients with HIV infection
will be excluded

- Patients who are pregnant, breast feeding, or if sexually active and unwilling to use
effective birth control for the duration of this study will be excluded

- Patients with NYHA Class III or IV heart failure will be excluded