Ryoncil (remestemcel-L-rknd): the first approved cellular therapy for steroid-refractory acute GVHD

Abstract

Until recently, the JAK1/2 inhibitor, ruxolitinib (Jakafi), was the only therapy for steroid-refractory acute graft-versus-host disease (SR-aGVHD) approved by the U.S. Food and Drug Administration (FDA) for use in patients older than 12 years. Now the FDA has approved a potent mesenchymal stromal cell product (MSC), remestemcel-L-rknd (Ryoncil), for children 18 and younger, showing 70% response rates and nearly 70% six-month survival. In this Spotlight, we highlight this important advance in the field.

Introduction

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for a range of malignant and non-malignant hematologic disorders. Acute graft-versus-host disease (GVHD), caused by donor T cell–mediated damage to recipient skin, liver, and gastrointestinal (GI) tissue, remains a major barrier to successful outcomes, contributing substantially to early post-transplant morbidity and mortality^1-3. While the field has seen important strides in GVHD prevention, including post-transplant cyclophosphamide (PTCY)-based regimens in adults and αβ T cell receptor–positive cell depletion in children⁴ that decrease the incidence of severe GVHD, clinically significant acute GVHD still occurs in nearly half of both adult and pediatric transplant recipients^1,5-9.

For decades, high-dose corticosteroids have remained the frontline therapy for acute GVHD, achieving initial responses in approximately 50-75% of patients^10,11. For the substantial minority who do not respond, particularly those with lower GI involvement, prognosis is poor¹¹. Steroid-refractory acute GVHD (SR-aGVHD) is associated with high treatment-related mortality, driven by both the disease itself and complications from additional immunosuppressive therapies^12-15. Thus, the recent FDA approval for children with SR-aGVHD of an off-the-shelf mesenchymal stromal cell (MSC) therapy represents a long-awaited and significant advancement. Please note that brand names are used in this Spotlight to avoid confusion, as the generic names for different MSC products are highly similar.

MSC Therapy: Early Promise and Challenges

The concept of MSC therapy for acute GVHD originated in 2004 with a case report of a dramatic resolution of severe SR-aGVHD in a 9-year-old boy following MSC infusions¹⁶. From a logistical standpoint, MSCs can be isolated from donor sources like bone marrow, umbilical cord blood, or Wharton’s Jelly, and expanded in culture at clinical scale^17,18. They can also be cryopreserved and stored as an off-the-shelf product which makes them especially appealing in acute settings such as SR-aGVHD. These observations led to a flurry of research activity; at least 80 clinical trials have since investigated MSCs to treat SR-aGVHD, particularly in children¹⁹.

Studies have consistently shown that MSC infusions are safe, with few infusion-related toxicities. Their efficacy was inconsistent, however, with the response rate at day 28, the conventional primary endpoint for clinical trials in acute GVHD, ranging from 30% to 90%, depending on patient selection, product characteristics, and trial design^20-30.

An early, off-the-shelf commercial, bone marrow derived, MSC product remestemcel-L (Prochymal) was manufactured by Osiris and used in a large randomized, placebo-controlled phase III trial in addition to institutionally selected second-line immunosuppressive therapy for patients with grade II–IV SR-aGVHD ²³ (Table 1). Although the trial confirmed the product’s safety, it failed to demonstrate a statistically significant benefit in either the day 28 response (58% MSC vs. 54% placebo; p=0.59) or 6-month survival (34% vs. 42%; p=0.60). Post-hoc analyses, however, hinted at a possible benefit in two populations: children and those with high-risk acute GVHD per Minnesota criteria.

Table 1:

Clinical trials of Remestemcel-L and Remestemcel-L-rknd

Design	Age (n)	Indication	Product	Additional therapies	Infusion schedule	D28 response	Survival (follow-up )	Reference/comment
Phase III, single arm	children only (54)	2nd line	Remestemcel-L-rknd (Ryoncil)	No additional GVHD therapies allowed	Twice weekly x4, additional infusions permitted for poor response or flare	70%	69% (6m)	Kurtzberg, BBMT, 202024 Supported FDA approval of remestemcel-L-rknd for children with SR-GVHD in US
Expanded access protocol	children only (241)	3rd line or higher	Remestemcel-L-rknd (Ryoncil) or Remestemcel-L (Prochymal)	Additional GVHD therapies permitted	Twice weekly x4, additional infusions permitted for poor response or flare	65%	66% (100d)	Kurtzberg, BBMT, 202020 Expanded access protocol used both products
Phase III, randomized (2:1)	children (27) adults (217)	2nd line	Remestemcel-L (Prochymal)	Additional GVHD therapy required	Twice weekly x4, additional infusions permitted for poor response or flare	58% vs 54%, p=0.59 Children only: 64% vs 23%, p=0.005	34% vs. 42% (6m)	Kebriaei, BBMT, 2020 23 Remestemcel-L not effective in adult patients
Phase I/II, single arm	children (5) adults (20)	2nd line or higher	Remestemcel-L (Temcell) Remestemcel-L product manufactured in Japan under license	No additional GVHD therapies allowed	Twice weekly x4, additional infusions permitted as indicated	60%	48% (1y)	Muroi, Int J Hematol, 201627 Notable as it led to approval for SR-GVHD in Japan, similar results in a real-world analysis of 381 patients26

Subsequent investigations by the manufacturer identified heterogeneity among production lots in potency and viability as potential contributors to these disappointing results. In response, Mesoblast (the company that acquired the remestemcel program) modified production processes to improve consistency, potency, and viability and implemented release criteria based on an in vitro potency assay that measures the suppression of IL-2 receptor alpha (IL-2Rα) expression on T cells and correlates with reduced numbers of activated T cells in vivo. All lots of the new product, remestemcel-L-rknd (Ryoncil) used in subsequent trials met this new potency standard, unlike the earlier product, Prochymal, in which fewer than 70% of lots met potency criteria (remestemcel-L-rknd, Ryoncil biologic licensing application, on file with the FDA).

A Breakthrough for Children with SR-aGVHD

A prospective, single-arm phase III trial tested the consistently potent Ryoncil in 54 pediatric patients (ages <1 to 17 years) with grade II–IV SR-aGVHD ²⁴. Importantly, patients received Ryoncil infusions without additional systemic second-line agents. The results were striking: 70% of children achieved a response by day 28, and the 6-month survival rate was 69%. These outcomes were especially notable given that nearly three-quarters of enrolled patients met criteria for Minnesota high risk acute GVHD. Furthermore, more than half of patients discontinued all immunosuppression within six months, and only two developed moderate-to-severe chronic GVHD.

Based on these data, the FDA approved Ryoncil (remestemcel-L-rknd) on December 18, 2024 for pediatric patients aged 2 months to 18 years with SR-aGVHD. Ryoncil became the first cellular therapy approved for GVHD in any population and adds a much-needed option for younger patients, especially those ineligible for ruxolitinib, the only other approved treatment for SR-aGVHD (Figure 1).

Figure 1:

FDA-approved SR-aGVHD therapies for children, adolescents, and adults. Mesenchymal stromal cell (MSC) products have shown positive results in children and a potent product, Ryoncil, is the only FDA-approved therapy for SR-aGVHD in young children. Ruxolitinib has shown positive results for SR-aGVHD across all ages and is FDA-approved for adolescents and adults.

MSC Mechanism(s) of Action: A Work in Progress

A major obstacle to advancing MSC therapy for acute GVHD is our continued poor understanding of their mechanism(s) of action in clinical settings. MSCs are nonhematopoietic, multipotent cells that express surface markers linked to immune regulation and tissue repair along with minimal expression of MHC class I molecules, making them hypoimmunogenic and resistant to rejection.³¹ When exposed to inflammatory cytokines in vitro, MSCs release anti-inflammatory mediators such as prostaglandin E2 (PGE2), transforming growth factor-β (TGF-β), and indoleamine-2,3-dioxygenase (IDO) that may suppress effector T cells and promote regulatory T cell expansion^32-37. Preclinical studies, however, have not detected systemically infused MSCs near damaged acute GVHD target organs. Instead, most are rapidly trapped in the lungs and phagocytosed by immune cells, which may subsequently mediate anti-inflammatory effects^29,35,38-41. In addition, MSCs may contribute to tissue regeneration by secreting trophic factors that accelerate epithelial repair such as hepatocyte growth factor (HGF), TGF-β, and vascular endothelial growth factor (VEGF)⁴². Nonetheless, significant uncertainties remain and further research into their trafficking, biodistribution, and mechanisms of action is needed.

MSC Therapy in an Evolving SR-aGVHD Landscape

Ruxolitinib (Jakafi), a JAK1/2 inhibitor that suppresses downstream inflammatory cytokine production, was approved by the FDA in 2019 as the first treatment for SR-aGVHD in patients 12 years and older^43,44. In a pivotal phase III trial, ruxolitinib significantly improved day 28 (62% vs. 39%; p<0.001) and day 56 response rates (40% vs. 22%; p<0.001) compared with best available therapy (BAT) in adults and adolescents¹². There was no difference in non-relapse mortality or overall survival, however, possibly due in part to a crossover design that allowed patients with no response to BAT to receive ruxolitinib. A separate pediatric phase II trial showed an 85% response rate among children with either treatment-naïve or SR-aGVHD⁴⁵. However, ruxolitinib is not approved for children under 12 and Ryoncil thus fills a critical therapeutic gap for very young patients, and offers an alternative for adolescents.

As additional therapies emerge, a key question is how best to personalize treatment for severe acute GVHD. Not all SR-aGVHD is the same, with wide variations in organ involvement and damage. In this scenario the use of serum biomarkers may help to guide therapy. The MAGIC algorithm probability (MAP), that combines the serum levels of two biomarkers ST2 and REG3α, is a validated measure of acute GVHD severity and predictor of outcome and could serve as one such guide to treatment^46,47. For example, retrospective analyses showed that ruxolitinib was less effective for patients with SR-aGVHD and high MAP scores¹³. In contrast, children with SR-aGVHD and high MAP scores who were treated with Ryoncil had markedly better survival than matched BAT-treated controls (64% vs. 10% at six months)⁴⁸. This result is notable particularly because MSCs appear to be activated by inflammation. Thus, Ryoncil may be a preferable option to ruxolitinib for children with SR-aGVHD when biomarkers are high, although no direct comparisons have been made to date.

After two decades of development, the approval of Ryoncil for pediatric SR-aGVHD provides clinicians with a novel, safe, and effective therapy for a fragile population with limited options. However, many questions remain. Will Ryoncil demonstrate similar efficacy in adults as it has in children? A Blood and Marrow Transplant Clinical Trials Network study under design aims to address this very question although eligibility criteria and endpoints will need to be carefully considered. Moreover, the best cell source, manufacturing, treatment timing, and potential therapeutic partners remains unknown. Can further improvements in production make MSCs yet more efficacious? For example, infusions of MSCs manufactured via co-culture of bone marrow mononuclear cells from multiple donors produced ~80% response rates and ~60% six-month survival in both adults and children³⁰. Should MSC therapy be combined with another agent as suggested by observed synergy with basiliximab⁴⁹? Might early initiation of MSCs for patients identified at high risk by either clinical or biomarker criteria improve outcomes further, especially long-term survival? The answers to such questions will significantly aid our efforts to make allogeneic HCT a safer and more effective therapy for many patients with life-threatening blood disorders.