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Safety and efficacy of mesenchymal stromal cell therapy for multi-drug-resistant acute and late-acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation

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Abstract

Graft versus host disease (GvHD) remains a significant risk for mortality and morbidity following allogeneic hematopoietic stem cell transplantation (HSCT). A growing literature supports successful applications of mesenchymal stromal cells (MSCs) for the treatment of steroid-refractory acute GvHD (aGvHD). However, there is limited knowledge about the effects of MSC treatment on late-acute GvHD (late aGvHD). In this article, we present our multicenter study on the safety and efficacy of MSC therapy for patients with steroid-refractory late aGvHD in comparison to those with aGvHD. The outcome measures include non-relapse mortality (NRM) and survival probability over a 2-year follow-up. The study includes a total of 76 patients with grades III-IV aGvHD (n = 46) or late aGvHD (n = 30), who had been treated with at least two lines of steroid-containing immunosuppressive therapy. Patients received weekly adipose or umbilical cord-derived MSC infusions at a dose of median 1.55 (ranging from 0.84 to 2.56) × 106/kg in the aGvHD group, and 1.64 (ranging from 0.85 to 2.58) × 106/kg in the late aGvHD group. This was an add-on treatment to ongoing conventional pharmaceutical management. In the aGvHD group, 23 patients received one or two infusions, 20 patients had 3–4, and three had ≥ 5. Likewise, in the late aGvHD group, 20 patients received one or two infusions, nine patients had 3–4, and one had ≥ 5. MSC was safe without acute or late adverse effects in 76 patients receiving over 190 infusions. In aGvHD group, 10.9% of the patients had a complete response (CR), 23.9% had a partial response (PR), and 65.2% had no response (NR). On the other hand, in the late aGvHD group, 23.3% of the patients had CR, 36.7% had PR, and the remaining 40% had NR. These findings were statistically significant (p = 0.031). Also, at the 2-year follow-up, the cumulative incidence of NRM was significantly lower in patients with late aGvHD than in patients with aGvHD at 40% (95% CI, 25–62%) versus 71% (95% CI, 59–86%), respectively (p = 0.032). In addition, the probability of survival at 2 years was significantly higher in patients with late aGvHD than in the aGvHD group at 59% (95% CI, 37–74%) versus 28% (95% CI, 13–40%), respectively (p = 0.002). To our knowledge, our study is the first to compare the safety and efficacy of MSC infusion(s) for the treatment of steroid-resistant late aGVHD and aGVHD. There were no infusion-related adverse effects in either group. The response rate to MSC therapy was significantly higher in the late aGvHD group than in the aGvHD group. In addition, at the 2-year follow-up, the survival and NRM rates were more favorable in patients with late aGVHD than in those with aGVHD. Thus, the results are encouraging and warrant further studies to optimize MSC-based treatment for late aGVHD.

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Data Availability

The datasets analyzed during the current study are available from the corresponding author upon reasonable request.

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Authors and Affiliations

  1. Department of Hematology, Erciyes University, Kayseri, Turkey

    Muzaffer Keklik, Gulsah Akyol, Leylagul Kaynar & Ali Unal

  2. Hematology and Stem Cell Transplantation Unit, Medstar Antalya Hospital, Antalya, Turkey

    Burak Deveci & Mustafa Cetin

  3. Department of Hematology, Kirikkale University, Kirikkale, Turkey

    Serhat Celik

  4. Department of Pathology, Erciyes University, Kayseri, Turkey

    Kemal Deniz

  5. Department of Oral and Maxillofacial Surgery, Faculty of Dentistry and Genome - Stem Cell Center, Erciyes University, Kayseri, Turkey

    Zeynep Burcin Gonen

  6. Department of Biostatistics, Faculty of Medicine, Erciyes University and Turcosa Analytics Solutions Ltd. Co, Erciyes Teknopark, Kayseri, Turkey

    Gokmen Zararsiz

  7. Infectious Disease Unit, Medstar Antalya Hospital, Antalya, Turkey

    Rabin Saba

  8. Department of Medical Genetics, Medical School, Erciyes University, Kayseri, Turkey

    Yusuf Ozkul

  9. Department of Internal Medicine, Division of Hematology, Medipol University, Istanbul, Turkey

    Leylagul Kaynar

  10. Department of Physiology, Kayseri City Hospital, Kayseri, Turkey

    Ertugrul Keklik

  11. Division of Rheumatology, Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Olcay Y. Jones

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Keklik, M., Deveci, B., Celik, S. et al. Safety and efficacy of mesenchymal stromal cell therapy for multi-drug-resistant acute and late-acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. Ann Hematol 102, 1537–1547 (2023). https://doi.org/10.1007/s00277-023-05216-3

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