A Pilot Study of Early Treatment of Acute Graft Versus Host Disease With Bone Marrow- Derived Mesenchymal Stem Cells and Corticosteroids: Correlation of Disease Severity and Response With Biomarkers

This is a pilot study evaluating the addition of bone marrow-derived mesenchymal stem cell (BMSC) infusions to corticosteroids for the early treatment of acute graft versus host disease (GVHD). Acute GVHD is a major complication following allogeneic stem cell transplant. GVHD occurs when T-lymphocytes in the donor graft respond to signals from recipient cells and cause tissue damage. This process can lead to organ injury, increased risk of infection, and graft failure. Corticosteroids have been used as the primary therapy for acute GVHD for decades, and guidelines currently recommend their use as front line treatment. Recent prospective data from the Blood and Marrow Transplant Clinical Trials Network shows that GVHD will be cured in about half of patients with steroids alone. Patients who do not respond to steroids are considered steroid-resistant, and this is associated with much worse survival. It is possible to predict which patients will go on to have steroid-resistant GVHD by measuring the plasma concentration of the molecule called suppression of tumorigenicity 2 (ST2). BMSC infusions have been used to treat steroid-resistant acute GVHD successfully, but despite a track record of safety, little is known about the use of BMSC in the early treatment setting. The main objective of this study is to explore the feasibility of administering BMSC within 5 days of diagnosis of acute GVHD. Our study will for the first time use the ST2 biomarker to more accurately assign acute GVHD to steroid refractory or sensitive, and explore changes in ST2 and other biological markers of BMSC function and their correlation with clinical response. In the process of this study, we will assess the safety and feasibility of early treatment according to our regimen, obtain estimates of efficacy at important GVHD therapy time points, and determine if treatment with BMSC can prevent the progression of GVHD in patients with high risk of GVHD progression as measured by biomarkers.

The Cell Processing Section of the Department of Transfusion Medicine at the Clinical Center NIH has developed a BMSC repository at NIH. The NIH BMSC are a third party, early passage product based on the EU manufacturing approach. The NIH BMSC cellular product was administered safely to transplant recipients with steroid-resistant acute GVHD in a phase I study (protocol 12-H-0010, IND #14596) conducted from March 2012 to October 2012 at NIH. This pilot study is a continuation of the previous study and open to allogeneic stem cell transplantation recipients at NIH (age greater than or equal to 4 yrs) with de novo acute GVHD requiring systemic therapy either directly after allogeneic transplantation or following treatment with donor lymphocyte infusion. Subjects will receive BMSC infusions (target dose of 2 times 10(6) BMSC/kg for up to 12 doses) in addition to standard upfront therapy with corticosteroids. The primary endpoint will be the proportion of patients without a treatment-related severe adverse event (TRSAE) at day +56. Responses will be assessed at day +28 and +56 from the initial diagnosis. Responses will be correlated to changes in GVHD biomarkers including ST2, Reg3a, TNFR1, and IL-6. Subjects will be enrolled at first diagnosis of acute GVHD, and the first BMSC infusion will be given within 120 hours of the first dose of corticosteroids. BMSC infusions will be given twice weekly for the first 4 weeks. Subjects with a complete response at the end of week 4 will not receive further infusions. All other subjects will receive BMSC infusions weekly for four additional weeks. Safety will be monitored continuously with a stopping rule for toxicity based on the treatment-related serious adverse event rate. Research samples will be drawn at regular intervals to explore biological correlates of response and to investigate the mechanism of action of BMSC.