Biomarker profiling of steroid-resistant acute GVHD in patients after infusion of mesenchymal stromal cells

Abstract

We performed a prospective phase II study to evaluate clinical safety and outcome in 48 patients with steroid-refractory grade II-IV acute graft-versus-host disease (aGVHD) treated with mesenchymal stromal cells (MSCs). Clinical outcomes were correlated to comprehensive analyses of soluble and cellular biomarkers. Complete resolution (CR) of aGVHD at day 28 (CR-28) occurred in 12 (25%) patients, CR lasting >1 month (CR-B) occurred in 24 (50%) patients. One-year overall survival was significantly improved in CR-28 (75 versus 33%, P=0.020) and CR-B (79 versus 8%, P<0.001) versus non-CR patients. A six soluble biomarker-panel was predictive for mortality (HR 2.924; CI 1.485-5.758) when measured before MSC-administration. Suppression of tumorigenicity 2 (ST2) was only predictive for mortality 2 weeks after but not before MSC-administration (HR 2.389; CI 1.144-4.989). In addition, an increase in immature myeloid dendritic cells associated with decreased mortality (HR 0.554, CI 0.389-0.790). Patients had persisting T-cell responses against defined virus- and leukemia-associated antigens. In conclusion, our data emphasize the need to carefully assess biomarkers in cohorts with homogeneous GVHD treatments. Biomarkers might become an additional valuable component of composite end points for the rapid and efficient testing of novel compounds to decrease lifecycle of clinical testing and improve the success rate of phase II/III trials.

Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey

“…GVHD severity was correlated with CMV reactivation in multiple reported studies 51 . Therefore, better control of GVHD by ruxolitinib could in the long-term also improve CMV control as reported for MSC treatment 52 .…”

Direct Cell–Cell Contact with Chondrocytes Is a Key Mechanism in Multipotent Mesenchymal Stromal Cell-Mediated Chondrogenesis

“…Bone marrow was separated using a density gradient centrifugation (Lymphoprep, Axis Shield, Oslo, Norway). MSCs were isolated by plastic adherence and expanded using the MC3 systems and α-MEM (Minimal Essential medium) with L-glutamine from Macopharma (Tourcoing, France) supplemented with 5% platelet lysate and 3.3 IU/ml Heparin up to passage 3 (16). Characterization of MSCs fit the internationally convened minimal criteria for these cells (17).…”

Combining therapeutic antibodies using basiliximab and etanercept for severe steroid-refractory acute graft-versus-host disease: A multi-center prospective study

“…Severe SR-aGVHD was defined as fulfillment of one of the following criteria: (1) newly diagnosed with grades III-IV aGVHD or overlap syndrome and showed progression after 3 d of steroid therapy, or no improvement after at least 7 d of treatment with 2 mg/kg per day steroids, or inability to taper steroids. 5,38 ; or (2) de novo grades I-II aGVHD but eventually evolved into grades III-IV during treatment with 2 mg/kg per day prednisolone. Biopsy of the organs involved was not required for the diagnosis of aGVHD.…”