Editor’s Note: Aplastic Anemia (AA), a type of bone marrow failure syndrome, is challenging to treat. While hematopoietic stem cell transplantation (HSCT) may offer a cure, it is hindered by donor availability and high risk. Medical treatments provide symptom relief but with limited efficacy and potential for relapse. At the recent 18th Annual Chinese Society of Hematology Conference, Dr. Rong Fu from Tianjin Medical University General Hospital presented valuable insights into immunosuppressive therapy (IST) for AA. Following the conference, Hematology Frontier invited Professor Fu to discuss China’s AA prevalence, diagnostic and treatment advancements, current IST options, and future management strategies.

Current Status of AA in China

China reports one of the highest incidences of AA, with a rate of 7.4 per million people, significantly higher than in Western countries and neighboring Asian nations. AA incidence peaks in two age groups: 15-25 and 65-69 years, with a predominance of non-severe AA cases.

Diagnosis of AA remains challenging, requiring exclusion of other conditions. Although most hematologists are adept at distinguishing AA from other acquired and secondary bone marrow failure syndromes, some cases remain difficult to differentiate, particularly:

1. Congenital Bone Marrow Failure Syndromes: Both Chinese and international AA guidelines highlight the need to rule out congenital bone marrow failure syndromes (e.g., Fanconi anemia, GATA-2 deficiency, and other syndromes). Especially in young patients, genetic testing is recommended for those with strong suspicion.
2. Hypocellular Myelodysplastic Syndrome (hMDS): Differentiating AA from hMDS is crucial due to the differences in disease characteristics, treatment, acute myeloid leukemia (AML) transformation rates, and overall survival (OS). Roughly 10-20% of MDS cases are hypocellular, complicating AA diagnosis. The UK guidelines recommend using the hg-score system as a cut-off to assess hMDS. Our research team has included chromosomal testing, MDS-FISH, and MDS next-generation sequencing in routine AA workups and encourages other centers to adopt these measures to avoid misdiagnosing hMDS as AA.

Recent Advancements in AA Understanding

AA is still primarily viewed as an immune-mediated bone marrow failure syndrome. Recent studies suggest that viral antigens might trigger immune responses in AA. German research identified protein segments on hematopoietic stem cells (HSCs) that may mimic Epstein-Barr virus antigens, activating CD8+ T cells. Our research group also observed high expression of human endogenous retroviruses (HERVs) in AA patients, closely linked to CD8+ T cell activation, suggesting that HERV epitopes might drive the T cell response targeting HSCs.

（J Transl Med. 2024 Mar）

Treatment Approaches for Different Types of AA

Treatment strategies for AA vary by type, but they generally converge for transfusion-dependent non-severe AA (TD-NSAA) and severe AA (SAA). HLA-matched sibling donor HSCT (MSD-HSCT) remains the first-line treatment for SAA and TD-NSAA patients who are eligible. In China, age limits for MSD-HSCT have expanded from ≤35 to ≤40 years due to advances in HSCT.

For first-line SAA patients ineligible for MSD-HSCT, guidelines recommend IST (ATG+CsA) combined with a thrombopoietin receptor agonist (TPO-RA) as a foundational treatment, with additional hematopoietic agents as necessary. HLA-matched unrelated donor HSCT (MUD-HSCT) or haploidentical HSCT (Haplo-HSCT) is recommended for young SAA patients unresponsive to IST. For non-transfusion-dependent NSAA (NTD-NSAA), CsA plus TPO-RA and/or other hematopoietic agents are options.

Current IST Options in Clinical Practice

Today, IST has evolved from a dual-agent regimen (CsA±ATG) to a triple-agent approach (CsA±ATG+TPO-RA).

1. Immunosuppressants: Currently, only a limited number of effective IST drugs are available. CsA±ATG remains the primary IST regimen, achieving response rates of 62%-94% when combined with TPO-RA. Studies at our center have shown that sirolimus combined with TPO-RA promotes blood cell recovery in AA models. Institutions like Peking Union Medical College Hospital report approximately 40% efficacy using mTOR inhibitors for relapsed/refractory AA. Tacrolimus, used by hematologists in the U.S., and alemtuzumab, used by the National Institutes of Health, show comparable efficacy to CsA.
2. Hematopoietic Stimulation: Numerous TPO-RAs are now available in China, with eltrombopag and avatrombopag included in AA treatment guidelines. Additional options for specific patients include lusutrombopag and romiplostim. G-CSF, erythropoietin, human thrombopoietin (TPO), and testosterone are also commonly used in clinical practice.

Future Perspectives on AA Treatment and Management

Adding TPO-RA has improved AA treatment outcomes, but further progress could come from developing new immunosuppressive therapies, such as anti-inflammatory agents, small-molecule immunosuppressants, treatments targeting other immune cells, or selective blockage of self-antigens. We hope that more innovative and effective therapies will become available.

For comprehensive AA management, our 2022 AA Diagnosis and Treatment Guidelines recommend assessing AA patients across four dimensions: hematopoietic function, immune markers, clonal evolution, and adverse drug reactions. We encourage AA patients to take an active role in managing their condition to reduce anxiety, build understanding, and ultimately overcome their disease.

References:

1. 《中国再生障碍性贫血指南2022》
2. Guidelines for the diagnosis and management of adult aplastic anaemia: A British Society for Haematology Guideline. Br J Haematol. 2024
3. Leukemia, 2019;33(10):2495–505
4. Blood, April 4, 2024
5. Journal of Translational Medicine, March 2024

About Dr. Rong Fu

Dr. Dr. Rong Fu is a Professor, Chief Physician, and Doctoral Supervisor at Tianjin Medical University General Hospital. She serves as Deputy Director of the hospital and Head of the Hematology Department. Professor Fu holds leadership positions in several hematology societies and is the Deputy Chairperson for the Aplastic Anemia Working Group within the Chinese Medical Association’s Hematology Division. She has led over 20 research projects, including major initiatives funded by the Ministry of Science and Technology and the National Natural Science Foundation, with total funding exceeding RMB 24 million. Professor Fu has authored over 300 core publications, with more than 60 SCI-indexed articles, and has been a PI in numerous international and national clinical trials.