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

Phase 2
6 Months
75 Years
Open (Enrolling)
Graft Versus Host Disease, Steroid Refractory GVHD, Acute GVH Disease

Thank you

Trial Information

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

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

- 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

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:


Outcome Description:

To estimate the complete response rate by 28 days after starting study drugs, without additional therapy for patients with steroid refractory aGvHD.

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Rajinder S Bajwa, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Nationwide Children's Hospital


United States: Institutional Review Board

Study ID:




Start Date:

December 2011

Completion Date:

December 2014

Related Keywords:

  • Graft Versus Host Disease
  • Steroid Refractory GVHD
  • Acute GVH Disease
  • aGVHD
  • GVHD
  • Graft versus host disease
  • Acute graft versus host disease
  • Steroid refractory graft versus host disease
  • Bone marrow transplant
  • BMT
  • HSCT
  • infliximab
  • basiliximab
  • Monoclonal antibody treatment
  • Graft vs Host Disease



Nationwide Children's Hospital Columbus, Ohio  43205-2696