Hematopoietic stem cell transplantation (HSCT) remains the only potentially curative therapy for a variety of benign and malignant hematologic disorders. It is often considered a “restart button” for life by many patients. However, post-transplant immune hemolytic disease (IHD) continues to pose a persistent clinical challenge, particularly in pediatric patients.

At the Nanfang Chunfu Institute of Hematology, Professor Chunfu Li and Director Jianyun Liao are leading efforts to explore more precise and safer therapeutic approaches. Their findings have been presented on international academic stages such as the 2025 Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) and the 2025 Korean Society of Hematology (ICKSH) Congress. In this interview, Dr. Jianyun Liao shares cutting-edge therapeutic concepts, clinical practice outcomes, and the humanistic motivations behind these innovations.

1. POST-HSCT IHD remains a clinical concern. Could you describe its typical clinical manifestations?

Dr. Jianyun Liao: POST-HSCT IHD is a serious complication with diverse clinical manifestations, typically associated with the hemolytic process. Patients may present with fatigue, pallor, and exertional palpitations or dyspnea—symptoms directly related to a rapid decline in hemoglobin levels. Specific signs of hemolysis include jaundice (yellowing of the skin and sclera), dark tea-colored urine (indicative of hemoglobinuria), and, in some cases, splenomegaly due to red blood cell fragment deposition. Systemic inflammatory responses—such as fever, back pain, or abdominal pain—may also occur, suggesting hemolysis-induced systemic inflammation.

Key laboratory indicators include:

• Direct evidence of hemolysis: progressive decline in hemoglobin, marked elevation of indirect bilirubin and lactate dehydrogenase (LDH)
• Compensatory hematopoietic response: increased reticulocyte count, although this may be blunted in cases of concurrent bone marrow suppression

Without timely intervention, IHD can lead to severe anemia, multi-organ damage, and potentially progress to multiple organ failure. Early recognition of symptoms and dynamic laboratory monitoring are critical to improving prognosis.

2. What are the underlying mechanisms of IHD? Why does it occur even in ABO-matched transplants?

Dr. Jianyun Liao: The pathogenesis of IHD is indeed complex. It involves newly formed auto- or alloantibodies in conjunction with T cell and cytokine-mediated inflammatory processes. Even with ABO compatibility, disparities in minor blood group antigens—such as Rh, Kell, and Duffy—can trigger the production of alloantibodies. These antibodies mediate red cell destruction through complement activation or monocyte-macrophage phagocytosis.

Another important factor is mixed chimerism. Residual recipient immune cells may continue to produce antibodies targeting donor red blood cells. Additionally, the use of immunosuppressive agents post-transplant may impair graft-versus-leukemia (GVL) effects, allowing residual recipient B cells to persist. Abnormal immune reconstitution (e.g., deficiency in regulatory T cells) can further lead to autoantibody generation against donor-derived red cell antigens. These interacting mechanisms contribute to the unpredictable and multifaceted nature of IHD.

3. In your view, do donor type and blood group incompatibility influence the incidence of POST-HSCT IHD?

Dr. Jianyun Liao: Absolutely. Donor type and blood group incompatibility have a significant impact on the incidence of immune hemolytic disease post-HSCT. Our retrospective analysis revealed that the incidence of hemolysis in patients with fully matched donors was 8.5%, markedly higher than in those with haploidentical donors (2.6%). Patients with mixed chimerism had an even higher incidence of hemolysis at 25.3%, compared to only 2.4% in those with complete donor chimerism. This suggests that the presence of recipient cells is a major contributing factor to IHD.

Additionally, the hemolysis rate in patients with major ABO mismatches (e.g., A→O, B→O, AB→O) was 8.8%, compared to 3.9% in patients with ABO-macthed donors. Particularly, transplants from A-type blood donors (such as A→O or A→B) had higher hemolysis rates. This is attributed to the longer half-life of anti-A isoagglutinins in the recipient and the higher immunogenicity of A antigens, which elicit a stronger host immune response. These findings indicate that antibodies driving hemolysis may predominantly originate from the recipient, underscoring the need to carefully consider donor type and blood group compatibility when planning treatment strategies.

4. Your team has applied strategies such as tapering immunosuppressants and donor lymphocyte infusion (DLI) to manage graft rejection in transfusion-dependent thalassemia patients. What comprehensive benefits do these strategies offer, especially for pediatric and adolescent patients?

Dr. Jianyun Liao: In some post-transplant patients, donor-recipient chimerism can lead to relapse of the primary disease if not addressed promptly. This is mechanistically similar to the management of hemolysis. Therefore, tapering immunosuppressants and administering DLI have brought significant clinical benefits in thalassemia patients.

Firstly, these strategies promote complete donor chimerism, helping to prevent disease relapse and ensuring long-term transplant success. Reducing or discontinuing immunosuppressants minimizes drug-related side effects such as infections, metabolic disturbances, and growth retardation—factors particularly crucial for children and adolescents. This improves both physical development and quality of life.

Secondly, our stratified treatment protocols allow precise control over the timing and dosing of DLI, thereby minimizing the risk of graft-versus-host disease (GVHD). Finally, these approaches help reduce psychological stress, enabling young patients to return to normal life more confidently. The combined physical and mental health benefits represent a holistic gain for pediatric and adolescent populations.

We believe these strategies offer renewed hope, protection, and an improved quality of life for more patients—especially children and adolescents. This, ultimately, is the most heartwarming goal of medical innovation.