Third-Line Therapy Shows Limited Efficacy in Real-World aGVHD Population

Third-line interventions demonstrated limited benefits among patients with acute graft-versus-host-disease and gastrointestinal involvement (GI-aGVHD) who were refractory to ruxolitinib (Jakafi) and steroids, according to findings from the real-world CHRONOS study published in Bone Marrow Transplantation.¹

Among 59 patients who underwent treatment at 16 sites, an all-organ response occurred in 36% (95% CI, 24%-49%) at day 28, and 37% (95% CI, 25%-51%) experienced a GI response. A prespecified sensitivity analysis for the primary end point of the study reflected all-organ response and GI response rates of 39% (95% CI, 25%-54%) and 41% (95% CI, 27%-56%), respectively.

Additional data showed that 29% (95% CI, 11%-49%) of responders at day 28 lost their response within the next 30 days, while 52% (95% CI, 29%-72%) lost their responses within 90 days. After the end of the 12-month follow-up period, the overall survival (OS) rate was 29%, and 41 patients had a real-world progression-free survival (PFS) event. The median real-world PFS and OS were both 86 days (95% CI, 54-128); 1 patient had a relapse of underlying malignancy during the observation period and died.

Among those with a response by day 28, the median OS was 186 days (95% CI, 115-not reached [NR]) compared with 45 days (95% CI, 28-86) in those without a response. In a landmark analysis evaluating patients who were alive and under observation at day 28, the median post-landmark OS was 158 days (78-NR) for responders and 51 days (95% CI, 23-NR) among those without a response.

“CHRONOS provides a contemporary reference point for third-line GI-aGVHD, underscoring both the gravity of this condition and the persistent lack of standardized, effective therapies,” lead study author Johannes Clausen, MD, hematologist in the Hematology Department of Ordensklinikum Linz Elisabethinen in Linz, Austria, stated in a press release about these findings.² “The study highlights the stark limitations of current options and sets a meaningful new benchmark for this challenging clinical setting.”

According to the press release, the CHRONOS study may contextualize data from the phase 3 ARES trial (NCT04769895) assessing MaaT013 (Xervyteg), a microbiome ecosystem therapy, among patients with refractory GI-aGVHD.³ Data presented at the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition showed “durable clinical benefit” with MaaT013 in this GI-aGVHD population. These findings supported the submission of a marketing authorization application for MaaT013 in this patient population; a decision from the European Medicines Agency is anticipated in mid-2026.

“Acute GVHD remains a devastating disease with a profound unmet medical need. There is a clear necessity for evidence-based, standardized strategies in the third-line setting. By providing an updated and credible benchmark, CHRONOS offers critical context to interpret the results of the pivotal ARES trial and the potential clinical benefit observed with MaaT013 in this vulnerable patient population,” CHRONOS study author Florent Malard, MD, PhD, a professor of Hematology at Saint-Antoine Hospital and Sorbonne University, and lead investigator of the ARES trial, stated in the press release.²

In the multicenter, international CHRONOS study, investigators assessed patients who received third-line treatment for GI-aGVHD from May 2019 to September 2024. The primary end points were the all-organ objective response rate (ORR) and the GI-ORR at day 28. Secondary end points included the all-organ ORR and GI-ORR at day 56, cumulative loss of response, real-world PFS, OS, and incidence of chronic GVHD (cGVHD).

All evaluable patients received first-line corticosteroids for a median of 9 days (IQR, 6-16) before initiating second-line ruxolitinib at a median dose of 20 mg per day (range, 5-40). The median time from initial aGVHD diagnosis to the beginning of third-line treatment was 32 days (IQR, 20-53). The most common types of third-line therapy included extracorporeal photopheresis (n = 17), etanercept (Enbrel; n = 14), vedolizumab (Entyvio; n = 10), and infliximab (Remicade; n = 6).

No patients developed cGVHD, although 51% (95% CI, 37%-64%) experienced grade 2 or higher infectious events within 3 months of beginning third-line therapy. Grade 3, 4, and 5 infections occurred in 44% (95% CI, 27%-62%), 12% (95% CI, 3%-27%), and 27% (95% CI, 13%-44%) of those with an infection, respectively. Grade 3/4 thrombocytopenia and neutropenia were reported in 64% (95% CI, 51%-76%) and 32% (95% CI, 21%-46%) of patients. Overall, 32 patients initiated subsequent lines of therapy after exhibiting ongoing refractory or progressive aGVHD after third-line treatment.

References

1. Clausen J, Simón JAP, Carré M, et al. Clinical outcomes of third-line therapy for aGvHD with gastrointestinal involvement after steroids and ruxolitinib failure. Bone Marrow Transplant. Published online March 28, 2026. doi:10.1038/s41409-026-02825-0
2. MaaT Pharma announces publication of retrospective data in third-line acute GvHD from the CHRONOS study in Bone Marrow Transplantation journal. News release. MaaT Pharma. April 1, 2026. Accessed April 1, 2026. https://tinyurl.com/44bm3c3z
3. MaaT Pharma presents pivotal ARES phase 3 results for MaaT013 (Xervyteg®) in acute GvHD at ASH 2025 Annual Congress and announces 54% 1-Year overall survival. News release. MaaT Pharma. December 8, 2025. Accessed April 1, 2026. https://tinyurl.com/mrkfevp3