Efficacy of Remestemcel-L Treatment in Steroid Refractory Acute Graft-Versus-Host Disease in Children: An Aggregate Analysis

Introduction: Steroid-refractory acute graft-versus-host dose disease (SR-aGVHD) is a frequent and potentially fatal complication of hematopoietic stem cell transplantation (HSCT). There are no approved therapies specifically indicated for use in children with SR-aGVHD < 12 years old. Treatment with culture-expanded, adult human allogeneic bone marrow (BM)-derived mesenchymal stromal cells (remestemcel-L) has shown excellent safety and efficacy in clinical trials conducted over the past 10 years. Here we describe aggregate results of remestemcel-L treatment of SR-aGVHD in the pediatric population.

Methods: 309 pediatric subjects with SR-aGVHD were treated with remestemcel-L across 3 protocols. Data were derived from a phase 3, single arm study as first line after steroid failure with no other second line aGVHD therapies added through day 28 (NCT02336230, n=54), an expanded access program in subjects with aGVHD that had not responded to multiple other treatments (NCT00759018, n=241) and the pediatric subset of a randomized controlled trial (NCT00366145, n=14) in which remestemcel or placebo were given with a concomitant second line aGVHD therapy. Subjects in each protocol received 8 intravenous infusions of remestemcel-L (2 x 10⁶ cells/kg twice weekly for 4 weeks). Those achieving a partial response could receive an additional 4 doses (once weekly for the subsequent 4 weeks). This analysis included 309 subjects who received at least one remestemcel-L dose. Response was assessed 28 days after the first dose. Survival was evaluated through day 100.

Results: At baseline, mean age was 8.9 years (range 0.3 to 18.2 years) and aGVHD severity by IBMTR grade was C or D in n=252 (82%). Sources of grafts were bone marrow (BM: 46%), mobilized blood (MB: 20%) and cord blood (CB: 31%). Donor grafts were HLA matched related (9%) or unrelated (44%) or HLA-mismatched (46%). Subjects received a mean (standard deviation) of 10.3 (4.2) remestemcel-L infusions for a mean cumulative dose of 660.8 (484.1) x 10⁶ cells. The primary endpoint, overall response (complete + partial response) at day 28 (OR) was observed in 66% of subjects (204/309) and survival at day 100 (OS) was 68% (211/309). Day 28 OR strongly predicted day 100 survival. Among subjects who were alive at day 28 (N=284), 170 of the 204 (83%) responders survived through day 100. In contrast, 41/80 (51%) of non-responders survived through day 100. Day 28 OR frequencies and day 100 OS rates were consistent across baseline aGVHD grades: Grade B OR 70%, OS 77%; Grade C or D OR 65%, OS 66%. Comparable day 28 response frequencies and day 100 survival rates were observed across type of HSCT: OR was achieved in 65%, 64% and 71% of BM, MB and CB, respectively and 67%, 70% and 70% of BM, MB and CB recipients survived through day 100. Comparable OR and OS were observed in HLA compatibility and donor types with OR in 71%, 66% and 66% and day 100 OS in 64%, 66% and 71% of matched related or unrelated and mismatched, respectively. Remestemcel-L was well tolerated with no infusion-related toxicity or other safety concerns. Most treatment-emergent serious adverse events were attributable to aGVHD or the underlying pre-transplant disease.

Conclusions: In this large, diverse sample of pediatric subjects with SR- aGVHD, treatment with remestemcel-L was associated with a high and consistent overall response rate and survival rate through 100 days. Day 28 OR was highly predictive of day 100 survival. Remestemcel-L was well tolerated and effective across transplant types, donor sources, moderate to severe grades of GVHD and prior or concurrent treatment paradigms as defined by the individual protocols in this aggregate analysis. Remestemcel-L is a safe and effective treatment for children with SR- aGVHD addressing an unmet medical need for this highly vulnerable population.