Bone marrow stromal cells (BMSCs) have been used to treat acute graft-versus-host disease (GVHD) and other complications following allogeneic hematopoietic stem cell transplantation (SCT). We conducted a phase I trial using third party, early passage BMSCs for patients with steroid-refractory GVHD, tissue injury or marrow failure following SCT to investigate safety and efficacy. To identify mechanisms of BMSC immunomodulation and tissue repair, patients were serially monitored for plasma GVHD biomarkers, cytokines and lymphocyte phenotype. Ten subjects were infused a fixed dose of 2 × 106 BMSCs/kg intravenously weekly for 3 doses. There was no treatment related toxicity (primary endpoint). Eight subjects were evaluable for response at 4 weeks after the last infusion. Five of the seven patients with steroid-refractory acute GVHD achieved a complete response (CR), two of two patients with tissue injury (pneumomediastinum/pneumothorax) achieved resolution but there was no response in two subjects with delayed marrow failure. Rapid reductions in inflammatory cytokines were observed. Clinical responses correlated with a fall in biomarkers (Reg 3α, CK18, and Elafin) relevant for the site of GVHD or tissue injury. The GVHD complete responders survived significantly longer, had higher baseline absolute lymphocyte and central memory CD4 and CD8 counts. Cytokine changes also segregated with survival. These results confirm that BMSCs are associated with rapid clinical and biomarker responses in GVHD and tissue injury. However BMSCs were ineffective in patients with prolonged GVHD with lower lymphocyte counts, which suggest that effective GVHD control by BMSCs requires a relatively intact immune system.

Long term survivors of allo-SCT have increased risk of cardiovascular disease. We retrospectively studied cardiovascular risk factors (CVRF) in 109 SCT survivors (62 males, 47 females; median age 34 years) ≥5 years after bone-marrow (15) or T-cell-depleted peripheral blood (94) SCT for CML (56), acute leukemia (29), MDS (13), and others (11). One death and 2 cardiovascular events were reported. At 5 and 10 years post-SCT respectively, 44% and 52% had abnormal lipid profiles. 23% of 5-year survivors met the Adult Treatment Panel III threshold for dyslipidemia treatment, which is substantially higher than the age-matched general population. There were significant increases in prevalence of hypertension (p<0.001), diabetes (p=0.018) and body mass index (p=0.044) post-SCT compared to baseline. The Framingham general cardiovascular risk score (FGCRS) in males at 5 years post-SCT projected a doubling (median 10.4% vs. 5.4%) in the 10-year risk of cardiovascular events. Females received HRT post-SCT and none had increased FGCRS. Chronic GVHD and C-reactive protein were not associated with CVRF at any time point. All CVRF stabilized between 5 and 10 years post-SCT. Thus, SCT survivors have sustained elevations in CVRF. Males have a significantly increased risk of cardiovascular events in their second and third decade post-SCT.

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