Severe aplastic anemia (AA) remains a significant therapeutic challenge despite progress in its diagnosis and treatment. Issues such as difficulty in donor matching, side effects of immunosuppressive therapy (IST), and suboptimal hematologic responses demand continued exploration of innovative solutions. Prof. Fengkui Zhang of the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences delivered a compelling presentation on treating severe aplastic anemia. In an interview with Hematology Frontier, Prof. Zhang shared insights into managing refractory aplastic anemia and the latest treatment advancements.Definition and Treatment of Refractory Aplastic Anemia
Hematology Frontier: Patients with AA or very severe aplastic anemia who fail to achieve hematologic response six months post-IST are classified as refractory aplastic anemia. What is your recommended approach for second-line treatment strategies for these patients?
Prof. Fengkui Zhang: Approximately 20% of AA patients do not respond to standard IST within six months, which defines them as refractory cases. The primary strategy for such patients is to identify a suitable donor for hematopoietic stem cell transplantation (HSCT). For those unable to undergo transplantation due to health limitations or donor unavailability, a second round of IST is an alternative.
For second-line IST, it is crucial to select an anti-thymocyte globulin (ATG) formulation different from the one used initially, such as switching from horse ATG to rabbit ATG. This reduces the likelihood of immune resistance. However, the effectiveness of second-line IST remains limited, with response rates around 30%, as reported in studies from the U.S. and Japan. This underscores the importance of pursuing HSCT, even with alternative donors, as it provides the best opportunity for improved outcomes.
In recent years, thrombopoietin receptor agonists (TPO-RAs) have emerged as a promising option for patients who are ineligible for HSCT or IST. While supportive care remains essential, it alone cannot address hematopoietic failure and should be used alongside other therapeutic modalities or as a palliative measure to improve patient quality of life.
Clinical Implementation of HSCT
Hematology Frontier: HSCT is the preferred second-line treatment for refractory aplastic anemia. How do you approach HSCT in clinical practice for these patients?
Prof. Fengkui Zhang: For refractory aplastic anemia patients under 40 years old, when matched sibling donors are unavailable, alternatives include fully matched unrelated donors, partially matched unrelated donors, or haploidentical transplantation, which has been extensively validated in China with favorable outcomes. Cord blood transplantation is also an option for pediatric patients with low body weight.
The choice of transplantation strategy should prioritize optimal efficacy and minimal adverse effects, tailored to the patient’s condition and stem cell source. This ensures the best possible treatment outcome for each individual.
Optimization of Second-Line IST
Hematology Frontier: Should second-line IST replicate the original regimen or adopt enhanced and modified approaches?
Prof. Fengkui Zhang: Repeating an ineffective initial IST regimen is unlikely to yield success. Second-line IST should involve either an intensified treatment approach or a change in ATG formulation, as these measures have shown higher efficacy in achieving hematologic responses. Switching ATG formulations not only enhances treatment effectiveness but also minimizes severe adverse effects, ensuring both therapeutic success and patient safety.
Advances Beyond IST and HSCT
Hematology Frontier: Apart from second-line IST and HSCT, what other notable advances are there in treating refractory aplastic anemia?
Prof. Fengkui Zhang: The most significant recent advancement is the application of TPO-RAs. These agents achieve response rates of approximately 40% in refractory aplastic anemia patients, offering new hope for those who cannot undergo transplantation or IST. However, the quality of hematologic responses with TPO-RAs still leaves room for improvement, driving further research into more effective treatments.
Current research focuses on improving the hematopoietic microenvironment. Strategies include modulating T lymphocyte function and controlling inflammatory cytokines within the microenvironment to suppress abnormal immune responses and promote residual hematopoietic stem and progenitor cell proliferation. This direction holds great promise for revolutionizing aplastic anemia treatment.
Prof. Fengkui Zhang Chief Specialist, Chinese Academy of Medical Sciences Institute of Hematology
Prof. Zhang is a leading expert in red blood cell disorders and aplastic anemia, known for groundbreaking research in large granular lymphocyte leukemia, congenital dyserythropoietic anemia, and genetic instability in aplastic anemia. He has pioneered the use of ATG combined with cyclosporine and high-dose cyclophosphamide in treating aplastic anemia.
As Deputy Editor of Chinese Journal of Hematology and a member of numerous editorial boards, Prof. Zhang has contributed significantly to hematology research, with over 90 publications. His accolades include recognition as an outstanding teacher, advanced worker, and recipient of the Tianjin “May 1st” Labor Medal.
