从机制到临床：慢性移植物抗宿主病的诊疗进展与挑战

From mechanism to clinical practice: advances and challenges in the diagnosis and treatment of chronic graft-versus-host disease

摘要

慢性移植物抗宿主病（cGVHD）是异基因造血干细胞移植后最常见的晚期并发症，发生率为30%~70%，严重影响患者长期生存。该病临床表现异质性强，可累及皮肤、口腔、眼、肺、肝等多器官，其核心机制涉及慢性炎症、免疫耐受破坏及T、B细胞失调，最终导致组织纤维化。近年来，随着发生机制研究的深化，cGVHD治疗已从传统糖皮质激素，发展为针对JAK、ROCK2、BTK等关键信号通路的靶向药物、耗竭致病免疫细胞的生物制剂，以及重建免疫耐受的细胞疗法，形成多元化、精准化治疗新格局。本文综述了cGVHD在流行病学、发生机制、诊断评估与治疗策略方面的进展。现有证据提示，针对纤维化与免疫耐受的联合及序贯治疗，是突破当前cGVHD治疗瓶颈的关键方向。

Abstract

Chronic graft-versus-host disease (cGVHD) is the most common late complication after allogeneic hematopoietic stem cell transplantation, with an incidence rate of 30% to 70%. It significantly affects the long-term survival of patients. The clinical manifestations of this disease are highly heterogeneous and can involve multiple organs such as the skin, mouth, eyes, lungs and liver. Its core mechanism involves chronic inflammation, disruption of immune tolerance and dysregulation of T and B cells, ultimately leading to tissue fibrosis. In recent years, with the deepening of research on the pathogenesis, the treatment of cGVHD has evolved from traditional glucocorticoids to targeted drugs targeting key signaling pathways such as JAK, ROCK2 and BTK, biological agents that deplete pathogenic immune cells, and cell therapies for reestablishing immune tolerance, forming a diversified and precise treatment landscape. This article reviews the progress in the epidemiology, pathogenesis, diagnostic assessment and treatment strategies of cGVHD. Current evidence suggests that combined and sequential treatment targeting fibrosis and immune tolerance is a key direction for breaking through the current treatment bottleneck of cGVHD.

关键词

慢性移植物抗宿主病 / 异基因造血干细胞移植 / 晚期并发症 / 靶向治疗 / 治疗策略 / 组织损伤 / 免疫失调 / 纤维化

Key words

Chronic graft-versus-host disease / Allogeneic hematopoietic stem cell transplantation / Late complication / Targeted therapy / Treatment strategy / Tissue damage / Immune dysregulation / Fibrosis

参考文献

[1] 陈星驰, 朱小玉. 异基因造血干细胞移植后的免疫相关研究进展[J]. 实用医学杂志, 2025, 41(5): 641-647. DOI: 10.3969/j.issn.1006-5725.2025.05.004.

[2] CHEN X C, ZHU X Y . Advances in immunological research on hematopoietic stem cell transplantation[J]. J Pract Med, 2025, 41(5): 641-647. DOI: 10.3969/j.issn.1006-5725.2025.05.004.

[3] 中华医学会血液学分会干细胞应用学组. 慢性移植物抗宿主病诊断与治疗中国专家共识（2024年版）[J]. 中华血液学杂志, 2024, 45(8): 713-726. DOI: 10.3760/cma.j.cn121090-20240611-00217.

[4] Hematopoietic Stem Cell Application Group of Chinese Society of Hematology of Chinese Medical Association. Chinese expert consensus on the diagnosis and treatment of chronic graft-versus-host disease (2024)[J]. Chin J Hematol, 2024, 45(8): 713-726. DOI: 10.3760/cma.j.cn121090-20240611-00217.

[5] VADAKKEL G, ENG S, PROLI A, et al. Updates in chronic graft-versus-host disease: novel treatments and best practices in the current era[J]. Bone Marrow Transplant, 2024, 59(10): 1360-1368. DOI: 10.1038/s41409-024-02370-8.

[6] BAUMRIN E, LOREN A W, FALK S J, et al. Chronic graft-versus-host disease. part I: epidemiology, pathogenesis, and clinical manifestations[J]. J Am Acad Dermatol, 2024, 90(1): 1-16. DOI: 10.1016/j.jaad.2022.12.024.

[7] LEE S J, ZEISER R. FDA-approved therapies for chronic GVHD[J]. Blood, 2025, 145(8): 795-800. DOI: 10.1182/blood.2024026633.

[8] ZEISER R, LEE S J. Three US food and drug administration-approved therapies for chronic GVHD[J]. Blood, 2022, 139(11): 1642-1645. DOI: 10.1182/blood.2021014448.

[9] OLIVIERI A, MANCINI G. Current approaches for the prevention and treatment of acute and chronic GVHD[J]. Cells, 2024, 13(18): 1524. DOI: 10.3390/cells13181524.

[10] PETERSONE L, WALKER L S K. T-cell help in the germinal center: homing in on the role of IL-21[J]. Int Immunol, 2024, 36(3): 89-98. DOI: 10.1093/intimm/dxad056.

[11] JI R, LI Y, HUANG R, et al. Recent advances and research progress in biomarkers for chronic graft versus host disease[J]. Crit Rev Oncol Hematol, 2023, 186: 103993. DOI: 10.1016/j.critrevonc.2023.103993.

[12] TAGAMI N, YUDA J, GOTO Y. Current status of BAFF targeting immunotherapy in B-cell neoplasm[J]. Int J Clin Oncol, 2024, 29(11): 1676-1683. DOI: 10.1007/s10147-024-02611-2.

[13] JAGASIA M H, GREINIX H T, ARORA M, et al. National institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. the 2014 diagnosis and staging working group report[J]. Biol Blood Marrow Transplant, 2015, 21(3): 389-401. e1. DOI: 10.1016/j.bbmt.2014.12.001.

[14] DU J, FLYNN R, PAZ K, et al. Murine chronic graft-versus-host disease proteome profiling discovers CCL15 as a novel biomarker in patients[J]. Blood, 2018, 131(15): 1743-1754. DOI: 10.1182/blood-2017-08-800623.

[15] ALEXOUDI V A, GAVRIILAKI E, CHEVA A, et al. Graft-versus-host disease: can biomarkers assist in differential diagnosis, prognosis, and therapeutic strategy?[J]. Pharmaceuticals, 2024, 17(3): 298. DOI: 10.3390/ph17030298.

[16] SARANTOPOULOS S, STEVENSON K E, KIM H T, et al. Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease[J]. Blood, 2009, 113(16): 3865-3874. DOI: 10.1182/blood-2008-09-177840.

[17] SALIBA R M, SARANTOPOULOS S, KITKO C L, et al. B-cell activating factor (BAFF) plasma level at the time of chronic GVHD diagnosis is a potential predictor of non-relapse mortality[J]. Bone Marrow Transplant, 2017, 52(7): 1010-1015. DOI: 10.1038/bmt.2017.73.

[18] PACINI C P, SOARES M V D, LACERDA J F. The impact of regulatory T cells on the graft-versus-leukemia effect[J]. Front Immunol, 2024, 15: 1339318. DOI: 10.3389/fimmu.2024.1339318.

[19] HARTIGAN C R, MCDONALD-HYMAN C, PAVLETIC S Z, et al. Chronic graft-versus-host disease, part 1: how preclinical models shape our understanding of biology and pave the way for future therapeutic interventions[J]. Transplantation, 2025, 109(11): 1723-1731. DOI: 10.1097/TP.0000000000005444.

[20] SCHULZ E, PIRSL F, HOLTZMAN N G, et al. Red cell distribution width as a new prognostic biomarker in refractory chronic graft-versus-host disease[J]. Haematologica, 2024, 109(1): 298-302. DOI: 10.3324/haematol.2023.283646.

[21] BOS S, MURRAY J, MARCHETTI M, et al. ERS/EBMT clinical practice guidelines on treatment of pulmonary chronic graft-versus-host disease in adults[J]. Eur Respir J, 2024, 63(3): 2301727. DOI: 10.1183/13993003.01727-2023.

[22] BOLAÑOS-MEADE J, HAMADANI M, WU J, et al. Post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis[J]. N Engl J Med, 2023, 388(25): 2338-2348. DOI: 10.1056/NEJMoa2215943.

[23] HUANG R, CHEN T, WANG S, et al. Mesenchymal stem cells for prophylaxis of chronic graft-vs-host disease after haploidentical hematopoietic stem cell transplant: an open-label randomized clinical trial[J]. JAMA Oncol, 2024, 10(2): 220-226. DOI: 10.1001/jamaoncol.2023.5757.

[24] YAO H, HUANG R, FU H, et al. Sequential infusion of mesenchymal stem cell for graft-versus-host disease prevention in haploidentical hematopoietic stem cell transplantation: an open-label, multicenter, randomized controlled clinical trial[J]. J Clin Oncol, 2025, 43(17): 1997-2006. DOI: 10.1200/JCO-24-02119.

[25] DEFILIPP Z, KIM H T, KNIGHT L W, et al. Low rates of chronic graft-versus-host disease with ruxolitinib maintenance following allogeneic HCT[J]. Blood, 2025, 145(20): 2312-2316. DOI: 10.1182/blood.2024028005.

[26] WOLFF D, CUTLER C, MERCEP I, et al. Toward better and more effective clinical trials for chronic graft-versus-host disease[J]. Transplant Cell Ther, 2026, 32(4): 388-397. DOI: 10.1016/j.jtct.2025.11.008.

[27] ZEISER R, RUSSO D, RAM R, et al. Ruxolitinib in patients with corticosteroid-refractory or corticosteroid-dependent chronic graft-versus-host disease: 3-year final analysis of the phase III REACH3 study[J]. J Clin Oncol, 2025, 43(23): 2566-2571. DOI: 10.1200/JCO-24-02477.

[28] BHATT V R, SHOSTROM V K, CHOE H K, et al. A multicenter phase II trial of ruxolitinib for treatment of corticosteroid refractory sclerotic chronic graft-versus-host disease[J]. J Clin Oncol, 2024, 42(33): 3977-3985. DOI: 10.1200/JCO.24.00205.

[29] MIKLOS D, CUTLER C S, ARORA M, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy[J]. Blood, 2017, 130(21): 2243-2250. DOI: 10.1182/blood-2017-07-793786.

[30] MIKLOS D B, ABU ZAID M, COONEY J P, et al. Ibrutinib for first-line treatment of chronic graft-versus-host disease: results from the randomized phase III iNTEGRATE study[J]. J Clin Oncol, 2023, 41(10): 1876-1887. DOI: 10.1200/JCO.22.00509.

[31] WANG X, LIU Y, CHEN T, et al. ROCK 2 inhibition with belumosudil for the treatment of chronic graft-versus-host disease: a narrative review[J]. Ther Adv Hematol, 2025, 16: 20406207251367462. DOI: 10.1177/20406207251367462.

[32] CUTLER C, LEE S J, ARAI S, et al. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar study[J]. Blood, 2021, 138(22): 2278-2289. DOI: 10.1182/blood.2021012021.

[33] KITKO C L, ARORA M, DEFILIPP Z, et al. Axatilimab for chronic graft-versus-host disease after failure of at least two prior systemic therapies: results of a phase I/II study[J]. J Clin Oncol, 2023, 41(10): 1864-1875. DOI: 10.1200/JCO.22.00958.

[34] FATOUM H, ZEISER R, HASHMI S K. A personalized, organ-based approach to the treatment of chronic steroid-refractory graft-versus-host disease[J]. Blood Rev, 2024, 63: 101142. DOI: 10.1016/j.blre.2023.101142.

[35] KRAAIJEVELD R, HESSELINK D A, DIETERICH M, et al. Small molecule BCL6-inhibition suppresses follicular T helper cell differentiation and plasma blast formation[J]. Hum Immunol, 2025, 86(2): 111242. DOI: 10.1016/j.humimm.2025.111242.

[36] KOSHY A G, KIM H T, LIEGEL J, et al. Phase 2 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease[J]. Blood, 2023, 141(24): 2932-2943. DOI: 10.1182/blood.2022019107.

[37] HOLTZMAN N G, CURTIS L M, SALIT R B, et al. High-dose alemtuzumab and cyclosporine vs tacrolimus, methotrexate, and sirolimus for chronic graft-versus-host disease prevention[J]. Blood Adv, 2024, 8(16): 4294-4310. DOI: 10.1182/bloodadvances.2023010973.

[38] HUANG S, CHENG X, YANG G, et al. Recent advances and research progress regarding monoclonal antibodies for chronic graft-versus-host disease[J]. Heliyon, 2024, 10(19): e38460. DOI: 10.1016/j.heliyon.2024.e38460.

[39] KATTNER A S, HOLLER E, HOLLER B, et al. IL6-receptor antibody tocilizumab as salvage therapy in severe chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: a retrospective analysis[J]. Ann Hematol, 2020, 99(4): 847-853. DOI: 10.1007/s00277-020-03968-w.

[40] MAHAT U, PRZEPIORKA D, FASHOYIN-AJE L A. Remestemcel-L-rknd for steroid-refractory acute graft-vs-host disease in pediatric patients[J]. JAMA, 2025, 334(1): 81-82. DOI: 10.1001/jama.2025.6179.

[41] WENG J Y, DU X, GENG S X, et al. Mesenchymal stem cell as salvage treatment for refractory chronic GVHD[J]. Bone Marrow Transplant, 2010, 45(12): 1732-1740. DOI: 10.1038/bmt.2010.195.

[42] BOBERG E, VON BAHR L, AFRAM G, et al. Treatment of chronic GvHD with mesenchymal stromal cells induces durable responses: a phase II study[J]. Stem Cells Transl Med, 2020, 9(10): 1190-1202. DOI: 10.1002/sctm.20-0099.

[43] BAO Y, LIU J, LI Z, et al. Ex vivo-generated human CD1c(+) regulatory B cells by a chemically defined system suppress immune responses and alleviate graft-versus-host disease[J]. Mol Ther, 2024, 32(12): 4372-4382. DOI: 10.1016/j.ymthe.2024.10.026.

[44] DONATO V, KIM H T, STOWE P, et al. Durability of clinical and immunologic responses to extended low-dose interleukin-2 therapy in patients with refractory chronic graft-versus-host disease[J]. Front Immunol, 2022, 13: 954966. DOI: 10.3389/fimmu.2022.954966.

[45] KREITMEIER K G, ALBRECHT C, KOLODOVA K, et al. Treatment of SR/SD chronic GVHD with in vitro expanded donor regulatory T cells[J]. Transplant Cell Ther, 2025, 31(2): S32. DOI: 10.1016/j.jtct.2025.01.055.

[46] ROTOLO A, MASON N J, EXLEY M A. Innate iNKT cells: from biological insight to clinical impact[J]. Front Immunol, 2025, 16: 1653183. DOI: 10.3389/fimmu.2025.1653183.

[47] DEFILIPP Z, FOX L, HOLDERRIED T A W, et al. Systematic review and meta-analysis of extracorporeal photopheresis for the treatment of steroid-refractory chronic graft-versus-host disease[J]. Transplant Cell Ther, 2025, 31(2): 76. e1-76. e13. DOI: 10.1016/j.jtct.2024.11.004.

[48] DU J, PAZ K, FLYNN R, et al. Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-β production[J]. Blood, 2017, 129(18): 2570-2580. DOI: 10.1182/blood-2017-01-758854.

[49] HONG X, XIAO Y, XU L, et al. Combination therapies of porcupine inhibition with ruxolitinib, ibrutinib, or belumosudil in murine sclerodermatous GVHD[J]. Blood Adv, 2025, 9(6): 1261-1266. DOI: 10.1182/bloodadvances.2024014387.

[50] CARPENTER P A, KANG H J, YOO K H, et al. Ibrutinib treatment of pediatric chronic graft-versus-host disease: primary results from the phase 1/2 iMAGINE study[J]. Transplant Cell Ther, 2022, 28(11): 771. e1-771. e10. DOI: 10.1016/j.jtct.2022.08.021.

[51] ZEISER R, POLVERELLI N, RAM R, et al. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease[J]. N Engl J Med, 2021, 385(3): 228-238. DOI: 10.1056/NEJMoa2033122.

[52] WOLFF D, CUTLER C, LEE S J, et al. Axatilimab in recurrent or refractory chronic graft-versus-host disease[J]. N Engl J Med, 2024, 391(11): 1002-1014. DOI: 10.1056/NEJMoa2401537.

基金资助

国家自然科学基金(81873444)

国家自然科学基金(82070213)

国家自然科学基金(82370196)