Treatment with Human Mesenchymal Stem Cells (Remestemcel-L) Is Effective in Pediatric Patients with Refractory Acute Graft Versus Host Disease

Severe steroid-refractory acute graft-versus-host disease (aGVHD) causes significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Early clinical trials of therapy with human mesenchymal stem cells (hMSCs) in pediatric patients with severe aGVHD, resistant to multiple immunosuppressive agents, showed promising results. In this study, we evaluated the risk/benefit profile of remestemcel-L, an off-the-shelf source of culture expanded human mesenchymal stem cells, provided by Mesoblast, Inc. under an expanded access program, as a rescue agent for treatment-resistant aGVHD in pediatric patients. Children with grade B-D aGVHD failing steroids and, in most cases, other immunosuppressive agents were eligible for enrollment. Patients received 8 bi-weekly i.v. infusions of 2 × 10⁶ hMSCs/kg for 4 weeks, with an additional 4 weekly infusions after day +28 for patients who achieved either a partial or mixed response. The enrolled patients compose a very challenging population with severe disease that was nonresponsive to standard of care. One hundred sixty patients (median age, 10 years; 60% male; and 61% Caucasian) were treated in this study. One hundred thirty five patients (84%) received unrelated donor transplant. Graft source was bone marrow in 65 (41%), PBSC in 34 (21%), cord blood in 54 (34%) and donor leukocyte infusion in 5(3%).  At baseline, the distribution of aGVHD grades B, C, and D was 19%, 28%, and 53%, respectively; 81% of the patients had severe aGVHD (grade C or D). Median duration of aGVHD before enrollment was 28 d (range, 1 to 237), and patients had failed a median of 3 immunosuppressive agents. Organ involvement at baseline was 89% gastrointestinal (GI), 50% skin, and 29% liver. Sixty-six patients (41%) had 2 organs involved, and 24 patients (15%) had all 3 organs involved. The rate of overall response (complete and partial response) at day +28 was 74% for aGVHD grade B, 66% for grade C, and 59% for grade D. Overall response for individual organs at day +28 was 62% for GI, 77% for skin, and 53% for liver. Collectively, overall response at day +28 for patients treated for severe refractory aGVHD was 64%, and this response was correlated with statistically significant improved survival at day +100 after hMSC infusion. Patients who responded to therapy by day +28 had a higher Kaplan-Meier estimated probability of 100-d survival compared with patients who did not respond (79% vs. 21%; P < .0001).  Substantial numbers of patients benefited from additional therapy beyond the initial 4 weeks of treatment.  Ninety one patients (57%) received more than 8 infusions, with 48% of those patients experiencing additional improvement by day +100.  Remestemcel-L infusions were generally well tolerated, without excessive infusional toxicities or ectopic tissue formation.   The results of this study support the use of remestemcel-L for pediatric patients with refractory aGVHD.