Allogeneic hematopoietic stem cell transplantation is an important potentially curative treatment for hematologic diseases. However, chronic graft-versus-host disease (GVHD), a common post-transplant complication, continues to have a substantial long-term impact on patients' quality of life. In China, significant clinical challenges remain in understanding the underlying mechanisms of the disease, achieving accurate diagnosis, implementing risk-stratified treatment, and providing long-term management.Oncology Frontier – Hematology Frontier invited Professor Xi Zhang of the Second Affiliated Hospital of Army Medical University (Xinqiao Hospital) to review the major unmet clinical needs in chronic GVHD and propose practical strategies across three key areas: guideline implementation, translational research, and chronic disease follow-up. His insights offer valuable perspectives on establishing a standardized chronic GVHD diagnosis and treatment system in China and improving the long-term outcomes of transplant recipients.
Oncology Frontier – Hematology Frontier: Chronic GVHD remains a major challenge affecting patients’ long-term quality of life after transplantation. Considering the current clinical landscape in China, what are the most prominent unmet needs in the diagnosis and treatment of chronic GVHD?
Professor Xi Zhang: Chronic graft-versus-host disease (GVHD) is one of the major complications following allogeneic hematopoietic stem cell transplantation, with an incidence of approximately 50%–70%. It is also a key factor affecting patients’ quality of life after transplantation. At present, substantial unmet clinical needs remain in several areas of chronic GVHD, including its underlying mechanisms, diagnosis, prevention, treatment, and long-term management.
01. The Pathogenesis Remains Incompletely Understood
Although previous research has made some progress, the mechanisms underlying chronic GVHD and its organ-specific damage have not yet been fully elucidated. Clinically, phenomena such as different treatment responses among patients with the same disease, and variations in disease progression and treatment response over time, also lack a sufficiently detailed mechanistic explanation. Therefore, further treatment advances will require deeper investigation into the mechanisms of chronic rejection, as well as the identification of new therapeutic targets and pathways.
02. Diagnostic Precision Remains Insufficient
Currently, the diagnosis of chronic GVHD relies primarily on clinical symptoms, with tissue biopsy used to confirm the diagnosis in some cases. A precision diagnostic system centered on biomarkers has yet to be established.
Although tests involving cytokine profiles, chemokines, autoantibodies, and immune cell subsets are being explored and increasingly introduced into clinical practice, large-scale supporting data remain limited. In addition, artificial intelligence models have not yet been adequately incorporated into diagnostic workflows, making it difficult to further improve diagnostic performance.
03. Stronger Evidence Is Needed to Support Preventive Strategies
Existing preventive measures are primarily designed to address GVHD in general, and prospective studies specifically targeting chronic GVHD remain limited.
Meanwhile, immunosuppressive agents have a double-edged effect. Long-term use may lead to impaired immune function, infections, organ damage, and even an increased risk of disease relapse. Therefore, new approaches—including more effective and less toxic immunosuppressive agents and cell therapies—need to be explored to reduce the incidence of chronic GVHD.
04. First-Line Treatment Requires Further Optimization
Corticosteroids remain the cornerstone of first-line treatment for chronic GVHD, but their efficacy rate is only approximately 50%. A recent large-scale domestic survey in China similarly indicated that the overall response rate to corticosteroid treatment was below 50%.
Various emerging therapies, including small-molecule targeted agents, may offer alternatives to corticosteroids. However, high-quality clinical studies are still needed to provide the evidence required to support their adoption as first-line treatments.
05. Precision-Based Treatment Selection in the Second-Line Setting Remains a Challenge
Currently, second-line treatment selection relies largely on clinical experience, and preferences vary among medical centers. Available options include belumosudil, ruxolitinib, and mTOR inhibitors.
For patients with different affected organs and varying degrees of disease severity, there is still no clear evidence-based guidance on how to select individualized treatments or when to initiate combination therapy. These are important clinical questions that urgently need to be addressed.
06. A Chronic Disease Management Approach and Multidisciplinary Teams Are Needed
Once chronic GVHD is diagnosed, patients often require systemic treatment, with the total treatment duration potentially reaching one to three years. Establishing comprehensive long-term follow-up mechanisms, enabling dynamic monitoring, and adjusting treatment promptly are essential to improving long-term patient outcomes.
Oncology Frontier – Hematology Frontier: To address these unmet clinical needs, what practical strategies do you believe can be implemented in terms of promoting expert consensus and guidelines, exploring new therapies, and strengthening long-term follow-up and management to improve patient outcomes?
Professor Xi Zhang: Clinical management of chronic GVHD can be advanced through three key approaches:
01. Emphasize Standardized Diagnosis and Treatment
Standardized diagnosis and treatment form the foundation of GVHD management. The Hematopoietic Stem Cell Application Group of the Hematology Branch of the Chinese Medical Association has published two editions of the Chinese Expert Consensus on Chronic GVHD. The latest edition was released in 2024, and a third edition of the guidelines is planned for publication next year.
In clinical practice, the diagnosis and treatment of chronic GVHD should prioritize adherence to established expert consensus and guidelines.
02. Advance Mechanistic and Translational Research to Address Clinical Challenges Not Covered by Existing Guidelines
Efforts should focus on elucidating novel mechanisms, identifying new therapeutic targets, and developing new drugs. At the same time, innovative cell therapy approaches, including mesenchymal stem cell therapy and in vivo cell therapy, should be explored.
High-quality evidence-based research is essential to providing new treatment strategies for patients with refractory disease.
03. Prioritize Long-Term Chronic Disease Management
Chronic GVHD often has a prolonged disease course and can affect multiple organs. Patients therefore need to maintain regular outpatient follow-up and ongoing communication with their physicians to ensure that disease manifestations are identified and treated early, thereby minimizing the risk of irreversible organ damage.
Expert Profile
Professor Xi Zhang
Second Affiliated Hospital of Army Medical University (Xinqiao Hospital)
Director, Chinese People’s Liberation Army Hematology Center (Military Clinical Key Specialty)
Director, Hematology Medical Center, Second Affiliated Hospital of Army Medical University
Director, Hematopoietic Ecology and Intelligent Cell Innovation Center, Xinqiao Hospital, Army Medical University
Director, Cell Therapy Center, Xinqiao Hospital, Army Medical University
Chief Physician and Professor; Doctoral and Postdoctoral Supervisor; Distinguished Professor under the Chang Jiang Scholars Program
Professor Xi Zhang’s research primarily focuses on the clinical and basic research of hematopoietic stem cell transplantation. He has led 52 research projects, including projects under the National Key R&D Program for Stem Cell Research, key projects funded by the National Natural Science Foundation of China, major military research projects, Chongqing municipal priority projects, and other major research initiatives.
He has published 183 SCI-indexed papers in journals including Journal of Clinical Oncology (JCO), Journal of Hematology & Oncology (JHO), JAMA Oncology, Blood, The Lancet Haematology, Journal of Clinical Investigation (JCI), and Leukemia. He has served as editor-in-chief or deputy editor-in-chief of eight academic books, drafted 12 professional guidelines, and contributed to another 50.
As the principal award recipient, he has received one Second Prize of the National Science and Technology Progress Award, one First Prize of the Chinese Medical Science and Technology Award, three First Prizes and one Second Prize of the Chongqing Science and Technology Progress Award, three Second Prizes for Military Medical or Scientific and Technological Achievements, one Third Prize of the China Anti-Cancer Association Science and Technology Award, and one Third Prize for Outstanding Educational and Scientific Research Achievements of Chongqing Higher Education Institutions. He has also received the State Council Special Allowance and holds 68 granted national invention patents.
Professor Zhang currently serves in numerous academic leadership positions, including:
Vice Chairman, Hematology Branch of the Chinese Medical Association
Vice President, Hematology Physicians Branch of the Chinese Medical Doctor Association
Vice Chairman, Hematologic Oncology Committee of the Chinese Anti-Cancer Association
Vice Chairman, CSCO Leukemia Expert Committee
Vice Chairman, China Hematology Specialty Alliance
Standing Committee Member, Experimental Hematology Committee of the Chinese Society of Pathophysiology
Vice Chairman, Expert Committee of the China Marrow Donor Program
Chair, Critical Care Hematology Group, Hematology Branch of the Chinese Medical Association
Deputy Chair, Hematopoietic Stem Cell Application Group, Hematology Branch of the Chinese Medical Association
He also serves as Editor-in-Chief of Recent Patents on Anti-Cancer Drug Discovery and Blood & Genomics, and is an editorial board member and reviewer for journals including The Lancet, JCO, Blood, JHO, Leukemia, The Lancet Haematology, Science Bulletin, and Chinese Medical Journal (CMJ).
