Acute graft-versus-host disease (aGvHD) is the main cause of treatment-related mortality after allogeneic stem cell transplantation (SCT), especially in patients with gastrointestinal involvement. Forty-one per cent of patients fail to respond to first-line high-dose corticosteroids. Ruxolitinib has been validated as the best second-line treatment, with an overall response rate (ORR) of 62% at Day 28, a median failure-free survival (FFS) of 5.0 months and median overall survival (OS) of 11.1 months (Zeiser NEJM 2020). For patients refractory or intolerant to ruxolitinib, there is no standard of care and outcomes are poor, with an ORR to third- and subsequent-line treatment of 36%, median survival of 28 days and OS of 20% at 6 months (Abedin BJH 2021).

MC0518 (Obnitix) is made from mesenchymal stromal cells (MSCs), which provide a therapeutic effect against aGvHD through immunomodulation. They are generated from a pool of bone marrow mononuclear cells from 8 HLA-disparate healthy donors, selected, expanded and cryopreserved until use. Real-world data suggest effectiveness of allogeneic MSCs, with a reported ORR of 49% at Day 28, and OS of 47% at 6 months and 35% at 1 year in patients refractory to steroids and ruxolitinib (Bader ASH 2023).

In this study, we report the outcome of 43 patients with steroid- and ruxolitinib-refractory aGvHD from 21 transplant centers, who received MC0518 between Februray 2019 and November 2024 through a compassionate use programme. Patients received MC0518 infusions of 1-2 million cells/kilogram once a week for 4 weeks, with 2 additional doses if a partial response was achieved by Day 28. To fulfil the criteria for compassionate use, patients had to have steroid- and ruxolitinib-refractory aGvHD classified as grade II or higher, and could not be included in any randomized trial (such as IDUNN or BALDER trials). Data were collected from data managers at transplant centers. The study was approved by the Scientific Committee of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC).

Twenty-six patients (60%) were male. The median age was 56 years (range, 1.9-72.5), with 9 patients (21%) aged under 15 years. Hematopoietic SCT had been performed for haematological malignancies in 35 patients (81%) or for non-malignant hemopathy in 8 patients (19%). Most patients (95%, 41/43) had gastrointestinal aGvHD, 10 (23%) had cutaneous aGvHD and 4 (9%) had hepatic aGvHD. The severity of aGvHD was grade II for 7 patients (16%), grade III for 6 patients (14%) and grade IV for 30 patients (70%). The median time from onset of GvHD to the first MC0518 infusion was 64 days, and the median number of prior lines was 3 (range, 2-9). All patients had received corticosteroids, and 42 (98%) patients had received ruxolitinib.

Patients received a median of 4 doses of MC0518 (range, 1-6). The ORR was 67% (31/43), including 9 patients (21%) with a complete response (CR), 20 patients (47%) with a partial response (PR) and 2 patients (5%) with a mixed response. At Day 28, of 35 patients alive (81%), 4 (11%) had reached a CR and 18 (51%) had a PR, whereas 10 (29%) had a stable or progressive disease. At Day 60, 25 patients (58%) were alive and had not received further treatment. Among them, 6 (24%) had achieved CR and 9 (36%) had achieved PR, whereas 9 (36%) had a stable or progressive disease (data missing for 1 patient). With a median follow-up of 15.1 months after the first MSCs infusion, OS was 51% (95%CI, 37-70) at 6 months and 34% (95%CI, 21-55) at 1 year, and the median OS was 7.1 months. Median FFS was 1.6 months, and FFS was 30% (95%CI, 19-49) at 6 months. The non-relapse mortality was 15% (95%CI, 3-25) at Day 28, 46% (95%CI, 27-60) at 6 months and 65% (95%CI, 43-79) at 1 year. MSCs infusions were safe, with no correlated toxicity. The cumulative incidence of relapse at 6 months and 1 year was 4.9% (95%CI, 0-11).Altogether, 22 patients (51%) were alive with a CR/PR at Day 28, and 15 patients (35%) were alive with CR/PR at Day 60. Although the mortality of patients with severe and advanced refractory gastrointestinal aGvHD remains high, these results are encouraging with high ORR. These findings require confirmation in randomized trials, preferably on third line to limit immunosuppressive toxicity.

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2025
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