Steroid-refractory acute GVHD (SR-GVHD) remains a significant complication of allogeneic hematopoietic cell transplantation (HCT). Prochymal® (Mesenchymal Stem Cells, MSC, derived from unrelated volunteer adult donors) was evaluated in addition to standard of care, including institutionally selected second line treatment, in a randomized (2:1) trial in patients with SR-GVHD (Protocol 280). Patients received 8 infusions of 2 × 106 MSC/kg over 4 weeks (or volume equivalent for placebo), with an additional 4 infusions administered weekly after day 28 in patients who had a partial response, defined as improvement in at least one organ without progression in others. The primary endpoint was durable complete response (DCR) for≥28 days. Additional prospectively defined outcomes included responses in patients by organ involvement. P-values were based on Chi-square tests, unless otherwise specified. 244 patients with SR-GVHD (skin involvement n=144, GI involvement n=179, liver involvement n=61) were enrolled and treated on study: Prochymal (n=163), placebo (n=81). There were no significant differences in age, pre-transplant conditioning, graft source, HLA-matching or second-line therapy between treatment arms. For the Prochymal and placebo arms, respectively, the grades of GVHD at entry were B (22% vs. 26%), C (51% vs. 58%), and D (27% vs. 16%). The respective DCR rates were 35% vs. 30% (p=0.3) in the ITT population and 40% vs. 28% (p=0.08) in the per protocol population. Results for secondary endpoints are shown in the table. Patients with GvHD affecting all 3 organs had overall complete or partial responses rate of 63% vs. 0% (n=22, p<0.05, Fisher's exact test) at day 28. Patients treated with Prochymal had less progression of liver GVHD at weeks 2 and 4 respectively (32% vs 59%, p=0.05; and 37% vs. 65%, p=0.05). The incidence of infections was not different between arms. Incidence rates were 9% vs. 8% for recurrent malignancy, 1.8% vs. 2.5% for infusional toxicity, and 0.6% vs. 4.6% for discontinuation due to an AE in Prochymal versus Placebo, respectively. GVHD with liver or gut involvement is a life-threatening complication of HCT. Our results suggest that the addition of Prochymal produced significant improvement without additive toxicity in patients with SR-GVHD involving visceral organs.Tabled 1Overall Complete or Partial Response Rates in Patients According to Organ InvolvementDay 100 Response RateOrganProchymalPlaceboOdds Ratio95% CIP ValueOverall82%73%1.70.9-3.10.12Skin78%77%1.10.5-2.40.9Liver76%47%3.61.1-11.2<0.05Gut82%68%2.21.1-4.4<0.05 Open table in a new tab
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Martin et al. (2010) studied this question.