Korean Consensus Framework Adapts Severe Aplastic Anemia Regimens to Local Constraints

A multidisciplinary panel of Korean hematology experts has published a comprehensive clinical consensus statement establishing tailored therapeutic algorithms for severe aplastic anemia, addressing the unique regulatory, pharmacokinetic, and therapeutic constraints present within South Korea. Severe aplastic anemia is a serious bone marrow failure disorder marked by profound bone marrow hypocellularity and peripheral pancytopenia. In adult patients, the majority of presentations are acquired disorders driven by an aberrant immune-mediated destruction of hematopoietic stem and progenitor cells. Activated CD8-positive cytotoxic T lymphocytes and type 1 helper T cells induce apoptosis among early progenitor populations through the perforin-granzyme and Fas-Fas ligand biochemical pathways. Concurrently, elevated concentrations of proinflammatory cytokines, including interferon-gamma and tumor necrosis factor-alpha, further suppress hematopoiesis, ultimately leading to persistent and life-threatening bone marrow failure. The newly formulated consensus establishes updated strategies to integrate thrombopoietin receptor agonists into standard immunosuppressive therapy regimens, specifically reconciling international evidence with South Korea’s exclusive therapeutic dependence on rabbit antithymocyte globulin and restrictive national insurance coverage policies.

For decades, conventional medical intervention for severe aplastic anemia has centered upon combination immunosuppressive therapy using antithymocyte globulin paired with cyclosporine, alongside allogeneic hematopoietic stem cell transplantation for patients presenting with suitable matched sibling donors. While these historical strategies substantially enhanced long-term patient survival, clinical practice continues to encounter critical limitations. These persistent hurdles include incomplete hematologic responses, disease relapse, and the eventual development of clonal evolution during extended post-treatment follow-up. Furthermore, allogeneic hematopoietic stem cell transplantation remains completely unfeasible for significant patient subpopulations owing to advanced patient age, severe concurrent medical comorbidities, or the lack of an available human leukocyte antigen-matched donor. Over the last decade, the therapeutic paradigm has shifted dramatically following the introduction of thrombopoietin receptor agonists, which were initially utilized as salvage options to stimulate hematopoietic recovery in patients refractory to or relapsing after conventional immunosuppression, and subsequently established as critical components of upfront regimens to accelerate the speed and depth of hematologic recovery.

Despite compelling international clinical trial results supporting thrombopoietin receptor agonist combinations, the Korean working group underscored that direct extrapolation of global guidelines is fundamentally impeded by domestic therapeutic realities. In pivotal international trials that established contemporary frontline standards, horse antithymocyte globulin served as the primary immunosuppressive backbone. However, horse antithymocyte globulin is entirely unavailable in South Korea, leaving clinicians to administer immunosuppressive therapy exclusively utilizing rabbit antithymocyte globulin. Furthermore, national insurance reimbursement policies impose rigid barriers across domestic clinical practices. While both eltrombopag and romiplostim hold regulatory approval for aplastic anemia, reimbursement for their upfront combination with immunosuppressive therapy is not permitted, leaving frontline agonist use completely non-reimbursed. Additionally, in the relapsed or refractory settings where monotherapy reimbursement is authorized, domestic regulations strictly cap treatment duration at a maximum of six continuous months, requiring therapy discontinuation regardless of ongoing clinical benefit unless a patient subsequently experiences frank relapse meeting diagnostic criteria for severe aplastic anemia.

The pharmacological discrepancies between antithymocyte globulin preparations represent a central pillar of the expert panel’s recommendations. Prospective randomized investigations conducted by the United States National Institutes of Health, alongside meta-analyses from the European Society for Blood and Marrow Transplantation, demonstrated that horse antithymocyte globulin generated significantly superior survival outcomes and higher hematologic response rates at three and six months compared to rabbit-derived formulations. Conversely, retrospective single-center data from South Korea demonstrated comparable long-term overall survival and equivalent hematologic response rates at twelve and eighteen months between the two formulations. However, patients treated with rabbit antithymocyte globulin required a significantly longer time to achieve complete response compared to those receiving horse-derived formulations. This latency reflects the biological properties of rabbit antithymocyte globulin, which exhibits an extended circulation half-life of roughly 29.8 days compared to 5.7 days for horse antithymocyte globulin, resulting in deeper, more persistent absolute lymphocyte depletion, prolonged CD4-positive T-cell clearance, and heightened susceptibility to serious opportunistic infectious complications.

Distinct pharmacokinetic characteristics among East Asian populations further dictate the panel’s practical recommendations regarding oral eltrombopag administration. Pharmacokinetic investigations demonstrate that eltrombopag clearance is approximately thirty-three percent lower in East Asian individuals, including Korean, Chinese, Japanese, and Taiwanese cohorts, relative to Western populations. Controlled healthy volunteer trials in Japan demonstrated that systemic drug exposure, measured by the area under the concentration-time curve, reached approximately twice the exposure levels recorded in non-Japanese subjects. Consequently, major international studies protocolized a fifty percent initial dose reduction for Asian participants, and South Korean regulatory approval explicitly restricted the maximum permissible dose of eltrombopag to 75 milligrams daily in the frontline setting and 100 milligrams daily in second-line therapy, whereas global pivotal trials evaluated doses reaching 150 milligrams daily. Because comparative trials evaluating whether this restricted dosing influences long-term hematologic recovery are lacking, the panel emphasized that eltrombopag’s clinical efficacy cannot be assumed to match horse-antithymocyte-globulin-based international trials.

In contrast to eltrombopag, the consensus panel highlighted romiplostim as an exceptionally suitable therapeutic option within the Korean clinical landscape. The pivotal clinical trials evaluating romiplostim were conducted predominantly within East Asian cohorts, specifically enrolling patients across South Korea and Japan, and directly combined the agent with a rabbit antithymocyte globulin backbone. In a prospective phase 2/3 first-line trial assessing weekly romiplostim at doses between 10 and 20 micrograms per kilogram alongside rabbit antithymocyte globulin and cyclosporine, the overall hematologic response rate reached 76.5 percent at week 27, accompanied by a 35.3 percent complete response rate. These outcomes significantly exceeded historical response rates associated with rabbit antithymocyte globulin and cyclosporine monotherapy, which traditionally range between 33 and 57 percent at six months. Moreover, 41 percent of patients achieved documented hematologic responses within fourteen weeks of initiation, demonstrating rapid therapeutic onset, while the maximum trial dosage of 20 micrograms per kilogram aligns precisely with approved domestic dosing parameters.

The consensus statement establishes a practical treatment algorithm structured around chronological age brackets, donor availability, and domestic regulatory frameworks. For young patients, generally defined as individuals younger than 40 years of age, allogeneic hematopoietic stem cell transplantation remains the undisputed preferred first-line therapy whenever an human leukocyte antigen-matched sibling donor is identified. In the absence of an available sibling donor, frontline therapy consists of immunosuppressive therapy combining rabbit antithymocyte globulin and cyclosporine, with active panel recommendations to incorporate a thrombopoietin receptor agonist despite existing reimbursement hurdles. Formal therapeutic response must be assessed at six months post-treatment initiation, reflecting the recognized delayed response kinetics of rabbit antithymocyte globulin. For patients failing to respond or experiencing secondary treatment failure, clinicians are advised to consider initiating agonist therapy, switching between agents—specifically transitioning from eltrombopag to romiplostim due to eltrombopag dosing ceilings—or pursuing alternative-donor hematopoietic stem cell transplantation utilizing matched unrelated or haploidentical donors.

For middle-aged patients, defined by the panel as individuals aged 40 to 55 years, the consensus recommends abandoning rigid chronological cutoffs in favor of individualized, multidisciplinary clinical evaluations. Historical Korean management guidelines established a strict threshold at 50 years of age, universally recommending matched sibling donor transplantation for younger individuals while relegating patients aged 50 and older to immunosuppressive therapy alone. In light of substantial outcome improvements achieved with modern thrombopoietin receptor agonist combinations, alongside concurrent advancements in transplantation safety, the panel concluded that middle-aged patients presenting with matched sibling donors should be evaluated individually for either upfront transplantation or rabbit antithymocyte globulin-based immunosuppression paired with a thrombopoietin receptor agonist. This tailored selection must balance baseline performance status, specific medical comorbidities, individual response probabilities, and patient preference. For middle-aged patients lacking matched donors, combination therapy with rabbit antithymocyte globulin, cyclosporine, and a receptor agonist is strongly recommended, followed by standard six-month response evaluations.

In older patients, typically comprising individuals aged 55 to 60 years or older, pharmacologic medical management is broadly prioritized over upfront transplantation. For this cohort, first-line intervention centers upon rabbit antithymocyte globulin and cyclosporine combined with a thrombopoietin receptor agonist, coupled with aggressive clinical vigilance for infectious complications. Although large retrospective analyses from the United States National Institutes of Health indicated that older patients aged 60 to 82 years experienced safety endpoints comparable to younger cohorts under immunosuppression, the prolonged biological persistence and profound CD4-positive T-cell depletion unique to rabbit antithymocyte globulin necessitate heightened surveillance in older Korean patients. The algorithm advises against universally excluding older individuals from transplantation solely due to age, instead advocating for cautious, stepwise evaluations of physiological fitness and organ comorbidities. Six months following initiation, non-responding or relapsing older patients should be considered for agonist initiation, dose optimization, or retreatment pathways according to standardized refractory guidelines.

A critical consideration emphasized throughout the expert consensus is the rigorous monitoring of clonal evolution, a recognized natural phenomenon occurring in approximately 10 to 15 percent of aplastic anemia cases over time. Clinical trials evaluating eltrombopag reported clonal evolution rates between 8 and 19 percent, frequently involving chromosome 7 abnormalities and progression toward myelodysplastic syndrome, whereas studies evaluating romiplostim observed lower rates ranging from 0 to 12.5 percent. However, comprehensive analyses demonstrate that the overall incidence of secondary clonal evolution and hematologic malignancies among patients receiving thrombopoietin receptor agonists alongside immunosuppressive therapy does not exceed rates observed with immunosuppressive monotherapy alone. Consequently, the panel advises that any insufficient response or emergence of new hematologic cytopenias warrants prompt bone marrow examination and cytogenetic testing, regardless of the specific agent administered. The panel concluded by calling for future policy refinements to eliminate the six-month second-line reimbursement restriction and expand coverage for upfront combinations, thereby aligning domestic healthcare practice with modern clinical evidence.

Subject of Research: Clinical management and treatment algorithms for severe aplastic anemia incorporating thrombopoietin receptor agonists under Korean regulatory and pharmacological constraints

Article Title: 2026 Korean expert recommendations for the use of thrombopoietin receptor agonists in severe aplastic anemia

Article References: Park, S., Jang, J. H., Song, I.-C., Ahn, S.-Y., Shin, D.-Y., Park, Y., & Mun, Y.-C. (2026). 2026 Korean expert recommendations for the use of thrombopoietin receptor agonists in severe aplastic anemia. Blood Research, 61(1), Article 39. https://doi.org/10.1007/s44313-026-00152-3

Image Credits: AI Generated

DOI: 10.1007/s44313-026-00152-3

Keywords: severe aplastic anemia, thrombopoietin receptor agonists, immunosuppressive therapy, rabbit antithymocyte globulin, eltrombopag, romiplostim, hematology, stem cell transplantation, Korean, expert, recommendations, thrombopoietin