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Mammalian target of rapamycin inhibitors as the treatment for steroid‑refractory acute graft‑vs.‑host disease after allogeneic hematopoietic stem cell transplantation: A systematic review and individual patient data meta‑analysis

  • Authors:
    • Yanru Guo
    • Zhi Li
    • Yiqun Zhang
    • Zhijuan Pan
    • Jiajia Sun
    • Ying Zhang
    • Shuting Chang
    • Zhiping Guo
  • View Affiliations / Copyright

    Affiliations: Department of Hematology, Peking University First Hospital Taiyuan Branch (Taiyuan Central Hospital), The Ninth Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi 030009, P.R. China, School of Sport And Physical Education, North University of China, Taiyuan, Shanxi 030000, P.R. China
    Copyright: © Guo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 36
    |
    Published online on: December 1, 2025
       https://doi.org/10.3892/etm.2025.13031
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Abstract

The prognosis of patients with steroid‑refractory acute graft‑vs.‑host disease (SR‑aGVHD) following allogeneic hematopoietic stem cell transplantation (allo‑HSCT) remains poor. Furthermore, the recommendations for second‑ and third‑line therapeutic approaches are controversial. The present study aimed to analyze the efficacy and safety of mammalian target of rapamycin (mTOR) inhibitors in SR‑aGVHD after allo‑HSCT. The present study searched the PubMed and Embase databases for relevant publications from December 2001 to September 2024. The primary endpoints were overall response rate (ORR), complete response rate (CRR), chronic GVHD, overall survival (OS) and infection‑related complications at any time after mTOR inhibitor therapy. The response rate at 1 month after mTOR inhibitor therapy was also assessed. The present meta‑analysis included 5 studies involving 134 patients. The ORR and CRR at any time were 65% (95% CI, 44‑81%) and 46% (95% CI, 22‑72%) after mTOR inhibitor‑based therapy for SR‑aGVHD, respectively, with 1‑ to 3‑year OS rate ranging from 36% (95% CI, 27‑46%) to 30% (95% CI, 20‑42%) The ORR and CRR after a 1‑month treatment with mTOR inhibitors were 57% (95% CI, 34‑78%) and 58% (95% CI, 13‑93%), respectively. Transplant‑associated thrombotic microangiopathy (TA‑TMA) and cytopenia occurred in 36% (95% CI, 22‑52%) and 43% (95% CI, 18‑72%) of patients with SR‑aGVHD, leading to treatment interruption with mTOR inhibitors in 10% (95% CI, 5‑22%) and in 6% (95% CI, 2‑13%) of patients, respectively. The highest CRR (78%) was observed in steroid‑refractory patients treated with mTOR inhibitors combined with IL‑2R antagonists, with an mTOR inhibitor serum trough level of 7‑13 ng/ml, although a minimum therapeutic level was 4 ng/ml. Prolonged therapy was more likely to be effective. In conclusion, mTOR inhibitors exhibit potent activity against SR‑aGVHD. However, their use may be associated with complications such as TA‑TMA and cytopenia.
View Figures

Figure 1

Risk of bias assessment of the
included studies.

Figure 2

Flowchart for study selection. GVHD,
graft-vs.-host disease; cGVHD, chronic GVHD; SR-aGVHD,
steroid-refractory acute GVHD; mTOR, mammalian target of
rapamycin.

Figure 3

Response to mTOR inhibitor treatment
in patients with steroid-refractory acute graft-vs.-host disease.
Forest plots of (A and B) ORR and (C and D) CRR recorded (A and C)
at any time and (B and D) at 1 month post-treatment. ORR, overall
response rate; CRR, complete response rate; 1M, 1 month; mTOR,
mammalian target of rapamycin.

Figure 4

Adverse events following mTOR
inhibitor therapy in patients with steroid-refractory acute
graft-vs.-host disease. Forest plots of incidence of (A) TA-TMA,
(B) interruption due to TA-TMA, (C) cytopenias, (D) interruption
due to cytopenias and (E) hyperlipidemia. mTOR, mammalian target of
rapamycin; TA-TMA, transplant-associated thrombotic
microangiopathy; T, TA-TMA; C, cytopenias.

Figure 5

Incidence of infections after
treatment with mTOR inhibitors in patients with steroid-refractory
acute graft-vs.-host disease. Forest plots of incidence of (A)
bacterial, (B) viral and (C) fungal infection and (D) CMV
reactivation rate. mTOR, mammalian target of rapamycin; CMV,
cytomegalovirus.

Figure 6

Forest plots of incidence of (A)
cGVHD, (B) 1-year OS rate and (C) 3-year OS rate after treatment
with mTOR inhibitors in patients with SR-aGVHD. mTOR, mammalian
target of rapamycin; OS, overall survival; GVHD, graft-vs.-host
disease; SR-aGVHD, steroid-refractory aGVHD; cGVHD, chronic GVHD;
Y, year.
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Copy and paste a formatted citation
Spandidos Publications style
Guo Y, Li Z, Zhang Y, Pan Z, Sun J, Zhang Y, Chang S and Guo Z: Mammalian target of rapamycin inhibitors as the treatment for steroid‑refractory acute graft‑vs.‑host disease after allogeneic hematopoietic stem cell transplantation: A systematic review and individual patient data meta‑analysis. Exp Ther Med 31: 36, 2026.
APA
Guo, Y., Li, Z., Zhang, Y., Pan, Z., Sun, J., Zhang, Y. ... Guo, Z. (2026). Mammalian target of rapamycin inhibitors as the treatment for steroid‑refractory acute graft‑vs.‑host disease after allogeneic hematopoietic stem cell transplantation: A systematic review and individual patient data meta‑analysis. Experimental and Therapeutic Medicine, 31, 36. https://doi.org/10.3892/etm.2025.13031
MLA
Guo, Y., Li, Z., Zhang, Y., Pan, Z., Sun, J., Zhang, Y., Chang, S., Guo, Z."Mammalian target of rapamycin inhibitors as the treatment for steroid‑refractory acute graft‑vs.‑host disease after allogeneic hematopoietic stem cell transplantation: A systematic review and individual patient data meta‑analysis". Experimental and Therapeutic Medicine 31.2 (2026): 36.
Chicago
Guo, Y., Li, Z., Zhang, Y., Pan, Z., Sun, J., Zhang, Y., Chang, S., Guo, Z."Mammalian target of rapamycin inhibitors as the treatment for steroid‑refractory acute graft‑vs.‑host disease after allogeneic hematopoietic stem cell transplantation: A systematic review and individual patient data meta‑analysis". Experimental and Therapeutic Medicine 31, no. 2 (2026): 36. https://doi.org/10.3892/etm.2025.13031
Copy and paste a formatted citation
x
Spandidos Publications style
Guo Y, Li Z, Zhang Y, Pan Z, Sun J, Zhang Y, Chang S and Guo Z: Mammalian target of rapamycin inhibitors as the treatment for steroid‑refractory acute graft‑vs.‑host disease after allogeneic hematopoietic stem cell transplantation: A systematic review and individual patient data meta‑analysis. Exp Ther Med 31: 36, 2026.
APA
Guo, Y., Li, Z., Zhang, Y., Pan, Z., Sun, J., Zhang, Y. ... Guo, Z. (2026). Mammalian target of rapamycin inhibitors as the treatment for steroid‑refractory acute graft‑vs.‑host disease after allogeneic hematopoietic stem cell transplantation: A systematic review and individual patient data meta‑analysis. Experimental and Therapeutic Medicine, 31, 36. https://doi.org/10.3892/etm.2025.13031
MLA
Guo, Y., Li, Z., Zhang, Y., Pan, Z., Sun, J., Zhang, Y., Chang, S., Guo, Z."Mammalian target of rapamycin inhibitors as the treatment for steroid‑refractory acute graft‑vs.‑host disease after allogeneic hematopoietic stem cell transplantation: A systematic review and individual patient data meta‑analysis". Experimental and Therapeutic Medicine 31.2 (2026): 36.
Chicago
Guo, Y., Li, Z., Zhang, Y., Pan, Z., Sun, J., Zhang, Y., Chang, S., Guo, Z."Mammalian target of rapamycin inhibitors as the treatment for steroid‑refractory acute graft‑vs.‑host disease after allogeneic hematopoietic stem cell transplantation: A systematic review and individual patient data meta‑analysis". Experimental and Therapeutic Medicine 31, no. 2 (2026): 36. https://doi.org/10.3892/etm.2025.13031
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