Infliximab and Basiliximab for Treatment of Steroid Refractory Acute Graft Versus Host Disease
Infliximab and Basiliximab for Treatment of Steroid Refractory Acute Graft Versus Host Disease
Acute Graft Versus Host Disease (GVHD) is a serious medical condition that is a common
 development after Bone Marrow Transplant (BMT). Acute GVHD happens when the donor cells
 attack and damage your tissues and organs after transplant.

 Acute GVHD often causes: Skin rashes, nausea, vomiting, abdominal pain, diarrhea (may have
 blood), liver damage that can cause inflammation in the liver or jaundice (yellowing of the
 skin or eyes), damage to other organs

 Steroids are the first line of treatment for acute GVHD. About a quarter of the patients that
 develop acute GVHD may not respond to steroid and have steroid refractory GVHD (SR-aGVHD).
 Patients with SR-aGVHD may need other medications. SR-aGVHD, is a potentially life
 threatening condition. There is no standard treatment and it may not respond to treatment.

 The goals of this study are to find out if Infliximab and basiliximab can treat SR-aGVHD.

 Participants in this study will receive combination therapy (2 drugs: infliximab and
 basiliximab) once a week for four weeks.
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