A Phase 3 Randomized Study of Remestemcel-L versus Placebo Added to Second-Line Therapy in Patients with Steroid-Refractory Acute Graft-versus-Host Disease

Abstract

Uncontrolled studies have suggested that bone marrow-derived mesenchymal stem cells (MSCs) may be effective against acute graft-versus-host disease (aGVHD). We conducted a multicenter, randomized study to assess the efficacy of using ex vivo cultured adult human MSC (remestemcel-L) in addition to second-line therapy to treat steroid-refractory aGVHD (NCT00366145). In total, 260 patients, 6 months to 70 years of age, were enrolled from August 2006 to May 2009 and were randomized 2:1 to receive 8 intravenous infusions of remestemcel-L or placebo, given over 4 weeks, in addition to second-line therapy according to institutional standards. Four additional infusions over 4 weeks were indicated for patients with incomplete response at day 28. Randomization was stratified by aGVHD grade. Efficacy and safety were assessed through 180 days of follow-up, with the primary endpoint being durable complete response (DCR), defined as complete resolution of aGVHD symptoms for any period of at least 28 days after beginning treatment. Remestemcel-L did not meet the primary endpoint of greater DCR in the intent-to-treat population (35% versus 30%; P = 0.42). In post hoc analyses, patients with liver involvement who received at least 1 infusion of remestemcel-L had a higher DCR, and higher overall complete or partial response rate (OR) than those who received placebo (29% versus 5%; P = .047). Among high-risk patients (aGVHD grades C and D), remestemcel-L demonstrated significantly higher OR at day 28 than placebo (58% versus 37%; P = 0.03). Furthermore, pediatric patients had a higher OR with MSCs compared with placebo (64% versus 23%; P = .05). Similar rates of adverse events were observed between treatment groups. Remestemcel-L was safe and well tolerated. Results of this study did not demonstrate superior DCR compared with placebo when added to standard of care. The favorable clinical responses seen in some patient subsets may warrant further investigation.

Keywords: Acute graft-versus-host disease; Allogeneic; Hematopoietic cell transplantation; Mesenchymal stem cells; Steroid.

Figure 1.

Trial profile. A total of 38 patients (28 remestemcel-L, 10 placebo) did not meet inclusion or exclusion criteria, and 32 of these patients were granted a waiver to protocol eligibility criteria by the sponsor’s medical monitor. Thirty-five of these patients are included in the safety and mITT populations (26 remestemcel-L, 9 placebo), having received at least 1 infusion. Entry criteria that were waived include patient age outside of range specified in the protocol (8 remestemcel-L, 3 placebo); patient not considered to have failed to respond to steroid treatment (3 remestemcel-L, 1 placebo); patient not able to be treated with 4 days of randomization (4 remestemcel-L, 1 placebo); patient started second-line therapy before randomization (6 remestemcel-L); patient received experimental therapy not approved by the Food and Drug Administration within 30 days of randomization (2 remestemcel-L); pregnancy, breastfeeding, or contraceptive requirements (1 remestemcel-L, 1 placebo); and patient received primary therapy other than steroids (1 remestemcel-L).

Figure 2.

DCR ≥ 28 days (left)/OR at day 28 (right): mITT population. Figure display of odds ratios and 95% confidence intervals, overall and for prespecified and post hoc subgroups, for DCR ≥ 28 days on the left and OR at day 28 on the right. Prespecified subgroups are GVHD grade at baseline, organ involvement, age category, sex, donor status, duration of steroid use, and use of second-line therapies. Categorization of risk and single- versus multiorgan involvement are post hoc subgroups. Risk scoring classifies patients as standard or high risk based on organ staging at baseline using methods reported in Macmillan et al. [6,27]. Minnesota risk scoring defines high-risk as stage 4 skin, stage 3 to 4 lower GI, stage 3 to 4 liver, or skin stage 3 to 4 + stage 3 to 4 liver or lower GI, with all other patients classified as standard risk. Second-line therapies are included if at least 10% of the study population in a treatment arm or overall received them.

Figure 3.

Survival of standard- and high-risk patients: mITT population.