Effect of Human Mesenchymal Stem Cells (Remestemcel-L) on Clinical Response and Survival Confirmed in a Large Cohort of Pediatric Patients with Severe High-Risk Steroid-Refractory Acute Graft Versus Host Disease

Severe steroid-refractory acute graft-versus-host disease (SR aGVHD) causes significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Early clinical trials of therapy with human mesenchymal stem cells (hMSCs) in pediatric patients with aGVHD, resistant to multiple immunosuppressive agents, showed promising results (Kurtzberg et al. BBMT, 2014; 20). We report final results for 241 SR aGVHD pediatric patients treated from 2007-2014 with remestemcel-L, bone marrow-derived and culture expanded hMSCs provided by Mesoblast, Inc. (NCT00759018). Planned treatment was 8 bi-weekly i.v. infusions of 2 × 106 hMSCs/kg for 4 weeks, with 4 additional weekly infusions after day +28 for patients who achieved a partial or mixed response. Median age of patients was 9.6 years; 61% were male; 60% were Caucasian; 85% received an unrelated HSCT; 31% received a cord blood graft. At baseline, the distribution of aGVHD grades B, C, and D was 20%, 30%, and 50%, respectively; organ involvement was 86% gastrointestinal (GI), 47% skin, and 27% liver; 50% of patients had multi-organ involvement (38% 2 organs, 12% 3 organs). Baseline organ staging data were used to retrospectively classify patients as high or standard risk using recently published methods (MacMillan et al. BBMT, 2015; 21), and 79% were found to be high risk. Median time from aGVHD diagnosis to remestemcel-L treatment was 23d (range, 1 to 328); patients had failed a median of 3 immunosuppressive agents; 36 (15%) failed steroids only. Overall response (OR: complete + partial response) at day +28 was 65% for all patients; OR was 73%, 67%, and 61% for aGVHD grades B, C, and D, respectively, and was 64% for high risk and 70% for standard risk patients. OR for individual organs at day +28 was 65% for GI, 68% for skin, and 62% for liver. Among patients refractory to steroids only (n=36), OR at day +28 was 81%. Patients with OR by day +28 had a higher Kaplan-Meier estimated probability of 100-d survival compared with patients without OR (82% vs. 39%; P<0.001). Overall survival at day 100 was 66%. Median duration of treatment was 45 days, with a median of 11 infusions (range, 1 to 24). Remestemcel-L infusions were well tolerated, without evidence of infusion-related toxicities or ectopic tissue formation. The most frequent SAEs by system organ class were infections (24%) and respiratory disorders (16%). These results update and confirm prior reports of remestemcel-L treatment effect on clinical response and survival for pediatric patients with SR aGVHD. Response was consistently high across aGVHD grade and involved organs. Results among patients not treated with other agents demonstrate a high rate of response to remestemcel-L as initial therapy used early in the course of disease. Risk-stratified results show clinical response and associated survival benefit among a pediatric patient population with high risk, severe SR aGVHD.