RARE DISEASE
Rare acquired aplastic anemia
Rare acquired aplastic anemia
Rare acquired aplastic anemia
Drug discovery
1
drug
With orphan designation
Overview
Rare acquired aplastic anemia (aAA) is a life-threatening bone marrow failure syndrome characterized by pancytopenia and hypocellular bone marrow due to immune-mediated destruction of hematopoietic stem cells [1][6][11]. Triggered by dysregulated T-cell responses, viral infections, or environmental exposures, it leads to insufficient blood cell production [1][6][17]. Diagnosis requires bone marrow biopsy and exclusion of inherited syndromes [6][11]. First-line treatment includes immunosuppressive therapy (IST) or allogeneic hematopoietic stem cell transplantation (HSCT) [3][8][13].
Therapies
Categories: rare hematological diseases, rare transplant-related disorders
Research Papers
275 drug discovery papers about Rare acquired aplastic anemia, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
275 drug discovery papers about Rare acquired aplastic anemia, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-13 | Real-world retrospective analysis of clinical outcomes in pediatric acquired aplastic anemia: a single-center 10-year cohort study
Introduction Pediatric aplastic anemia (AA), a rare and potentially fatal disease, demonstrates significant heterogeneity in pathogenesis, disease severity, therapeutic regimens, and clinical outcomes. Methods In this study, clinical features and outcomes of 70 children with AA, including severe AA (SAA, n = 30), very severe AA (vSAA, n = 21) and nonsevere AA (nSAA, n = 19), were retrospectively analyzed, with a median follow-up of 60.7 months (range, 0.4-136.5 months). Results Patients with nSAA were mainly treated with cyclosporine A, whereas SAA/vSAA patients primarily received allogeneic hematopoietic stem cell transplantation (HSCT) followed by standard immunosuppressive therapy (IST). Ultimate therapy regimens differed significantly between patients with SAA/vSAA and nSAA ( p = 0.001). SAA/vSAA group exhibited a higher overall response rate at the 2-year follow-up (85.5% vs. 55.6%, p = 0.019). The 2-year overall survival (OS) and event-free survival (EFS) for the entire cohort were 97.1% and 48.5%, respectively. In patients with SAA/vSAA, HSCT was associated with higher and faster cumulative complete response (CR) rate ( p < 0.0001) and superior EFS ( p = 0.0297) compared with IST. Two IST-resistant patients were observed to achieved CR with eltrombopag (EPAG) salvage therapy. Discussion pediatric AA carries excellent OS but suboptimal EFS. HSCT tends to yield more favorable EFS compared with IST in SAA/vSAA patients, and EPAG may act as an effective salvage option for appropriately selected IST-resistant individuals. Further multicenter prospective research is warranted prior to implementing these findings in routine clinical practice.
2026-04-01 | American Society of Hematology 2026 Guidelines for the Diagnosis and Management of Severe Acquired Aplastic Anemia.
Aplastic anemia is a rare, life-threatening condition marked by pancytopenia and bone marrow hypocellularity. Despite therapeutic advances, clinical practice remains variable, and uncertainties persist regarding diagnosis and optimal management. To address these gaps, the American Society of Hematology (ASH) developed evidence-based guidelines to provide standardized, patient-centered recommendations. The recommendations are intended to support patients, clinicians and other health care professionals in their decisions about the management and diagnosis of severe and very severe immune acquired aplastic anemia. ASH formed a multidisciplinary guideline panel of content experts, methodologists and a patient representative. An evidence synthesis team supported the guideline development process by conducting systematic evidence reviews. The panel prioritized clinical questions and used the GRADE approach, including the Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. The panel agreed on 33 recommendations and 4 good practice statements addressing the use of diagnostic tests, treatment strategies and supportive care. Additional recommendations covered the incorporation of eltrombopag into immunosuppressive regimens and the use of antimicrobial prophylaxis in high-risk patients. For most clinical questions, the certainty of the evidence was rated as low or very low, largely due to the reliance on small, non-randomized studies. Recommendations emphasize prioritizing hematopoietic cell transplantation for younger individuals with an available matched sibling or unrelated donor and as a second-line option following failure of immunosuppressive therapy. The panel also recommended adding eltrombopag to immunosuppressive regimens and using antibiotic and antifungal prophylaxis in neutropenic patients.
2026-03-13 | Successful Treatment of Aplastic Anemia With Eltrombopag During Pregnancy: A Short Report.
Aplastic anemia (AA) is a rare bone marrow failure syndrome with pancytopenia, mainly due to immune-mediated stem cell destruction. First-line therapy for acquired severe AA ≥ 50 years/non-severe AA (NSAA) requiring treatment is immunosuppressive therapy with horse anti-thymocyte globulin, cyclosporine A (CSA), and eltrombopag (EPAG). In pregnancy, cytopenia may worsen, while therapeutic options are limited. We report the first case of a pregnant patient with NSAA/PNH receiving full-dose EPAG (150 mg/d). Counts remained stable, delivery was uneventful, and the child was healthy. Postpartum, EPAG was discontinued, CSA tapered, and transfusion independence achieved. EPAG may represent a feasible option in selected pregnancies.
2026-01-05 | Efficacy and safety of avatrombopag in aplastic anemia: a comprehensive review of clinical evidence.
Aplastic anemia is a bone marrow failure disorder marked by cytopenias that impair oxygen delivery, immune defense, and hemostasis. Standard therapy traditionally combines immunosuppression with or without hematopoietic stem cell transplantation, and more recently incorporates thrombopoietin receptor agonists to stimulate residual hematopoiesis. Eltrombopag improved outcomes when added to immunosuppressive therapy, but its association with hepatotoxicity limits its suitability for patients with underlying liver disease or elevated baseline liver enzymes. Avatrombopag is a newer oral thrombopoietin receptor agonist that does not require dietary restrictions and does not undergo significant hepatic metabolism, which offers a potential therapeutic advantage in settings where liver function is compromised. This review evaluated ten clinical studies published from 2023 to October 2025 that investigated avatrombopag in acquired aplastic anemia across varied patient populations, including treatment-naive, relapsed or refractory cases, older adults, and patients with secondary aplastic anemia related to chemoradiation. Across these studies, overall response rates ranged from 55% to 85%, and complete response rates reached up to one-third of treated patients. Response onset typically occurred within 1-2 months, which aligns with clinical decision timelines for assessing therapeutic benefit. Avatrombopag supported reductions in transfusion requirements and sustained hematologic improvement in both severe and non-severe disease. Patients previously intolerant or non-responsive to eltrombopag also demonstrated clinical improvement, which suggests pharmacologic differences translate into meaningful therapeutic effects. Importantly, avatrombopag demonstrated a favorable safety profile in all reviewed settings. Reports did not identify clinically relevant hepatotoxicity, clonal evolution, or treatment-limiting adverse effects. Its tolerability in patients with liver dysfunction distinguishes it from earlier agents in this drug class. Ongoing trials will clarify optimal dosing strategies and define its future role within first-line therapy and salvage treatment pathways for aplastic anemia.
2026-01-01 | Gut Microbiome Alterations in Aplastic Anemia: Mechanistic Insights, Immune-Hematopoietic Crosstalk and Therapeutic Potential
Aplastic anemia (AA) is a rare hematological disorder characterized by peripheral cytopenias and hypocellular bone marrow resulting from failed hematopoiesis. The condition may arise from inherited genetic defects in hematopoietic stem cells (HSCs) or from acquired immune-mediated mechanisms. In acquired AA, immune dysregulation leads to the destruction of hematopoietic stem and progenitor cells (HSPCs), with immunosuppressive therapy remaining the cornerstone of treatment. Emerging evidence highlights the gut microbiome as a critical modulator of immune function and hematopoiesis. Disruptions in gut microbial composition have been linked to autoimmune and inflammatory diseases, yet their specific role in AA pathogenesis is not fully understood. The gut microbiome may influence immune responses, hematopoietic recovery and disease progression. Profiling the gut microbiome could also serve as a non-invasive method for monitoring disease progression, identifying microbial patterns associated with treatment response and assessing individual risk for relapse. Despite these promising insights, clinical trials specifically targeting the gut microbiome in AA remain limited, revealing a significant gap in research. A deeper understanding of the interactions between the gut microbiome, immune system and hematopoiesis is essential for identifying novel biomarkers and therapeutic strategies. These insights could complement existing immunosuppressive therapies and enable more personalized treatment approaches. This review thus synthesizes current evidence on gut microbiome alterations in AA, exploring their potential role in immune regulation, hematopoietic recovery and therapeutic interventions.
cell therapies
2026-01-01 | Management of Acquired Aplastic Anemia in Children
Abstract Acquired aplastic anemia (AA) in children is a rare, life-threatening disorder characterized by pancytopenia and hypocellular bone marrow. Early referral to specialized centers ensures accurate diagnosis and timely treatment. Differential diagnosis must exclude inherited bone marrow failure syndromes and immune-related disorders using comprehensive genetic and immunologic testing. Hematopoietic stem cell transplantation (HSCT) from a matched sibling donor remains the first-line treatment when available, offering high survival rates. In the absence of a suitable donor, immunosuppressive therapy (IST) with horse antithymocyte globulin and cyclosporine is the standard. Upfront matched unrelated donor transplantation is increasingly used due to improved outcomes. Supportive care, including transfusions, infection prophylaxis, and iron chelation, remains critical. Emerging options such as haploidentical transplantation and thrombopoietin receptor agonists provide alternatives for refractory cases. Despite therapeutic advances, long-term follow-up is essential to monitor clonal evolution and late effects. Personalized, risk-adapted strategies are pivotal to optimizing pediatric AA management.
2025-10-31 | Hemophagocytic lymphohistiocytosis in the context of hepatitis-associated severe aplastic anemia: A case report
Rationale: Hemophagocytic lymphohistiocytosis (HLH) is a severe immune dysregulation syndrome. Hepatitis-associated severe aplastic anemia (SAA) is a specific subtype of acquired aplastic anemia characterized by concomitant hepatitis, leading to a challenging diagnosis and poor prognosis. Here, we present a rare case of HLH in the context of hepatitis-associated SAA, emphasizing the need for early recognition and individualized management. Patient concerns: The patient, a 19-year-old male, presented with recurrent fever, jaundice, and cytopenias, indicative of hepatitis. Diagnoses: Bone marrow aspiration and biopsy suggested SAA, while peripheral blood next-generation sequencing detected Candida tropicalis infection on 2 separate occasions. Despite combination antifungal therapy with amphotericin B and posaconazole, the bilirubin level continued to rise. Additional tests revealed an elevated soluble CD25 level of 3659 U/mL, decreased natural killer cell activity of 1.8%, and a serum ferritin level > 2000 μg/L. The final diagnosis was HLH. Interventions: Dexamethasone and ruxolitinib were administered to control the fever. Subsequently, the patient underwent HLA-matched allogeneic bone marrow and peripheral blood hematopoietic stem cell transplantation for SAA. Outcomes: The patient’s symptoms, including fever and fatigue, resolved. Lessons: This case highlights that HLH should be considered in SAA patients with unexplained fever, poor response to anti-infectives, and elevated bilirubin. A treatment strategy addressing both bone marrow failure and hyperinflammation is essential. In this patient, allogeneic hematopoietic stem cell transplantation served as a successful curative intervention by targeting the shared pathophysiology of HLH and SAA. However, given the inherent limitations of a single case, the generalizability of our findings and the efficacy of allogeneic hematopoietic stem cell transplantation require validation through larger, controlled studies.
2025-10-02 | [Aplastic anemia in children: recent advances in diagnosis and treatment].
Pediatric aplastic anemia (AA) is a rare bone marrow failure that requires several special considerations for its diagnosis and treatment compared with adult AA. Accurate differential diagnosis is crucial, and distinguishing acquired AA from inherited bone marrow failure syndromes is particularly important. In addition to detailed morphological evaluation, comprehensive diagnostic workups incorporating genetic analysis using next-generation sequencing have become increasingly important for guiding treatment decisions. When discussing treatment strategies for pediatric AA, the long-term sequelae and level of hematopoietic recovery should also be considered, although the survival rates now exceed 90% following immunosuppressive therapy or hematopoietic cell transplantation (HCT). Recent advances in HCT include improved conditioning regimens, successful upfront HCT from matched unrelated donors, and expanded salvage treatment options such as unrelated cord blood transplantation or haploidentical HCT. This review outlines these recent advances in the diagnosis and treatment of AA in children based on the latest data.
2025-04-21 | From severe aplastic anemia with TERT variant to Wilson disease - associations or not.
Severe aplastic anemia is a life-threatening ineffective hematopoiesis, arising from inherited or acquired traits. Wilson disease is a rare congenital metabolic disorder with copper accumulation. Here we report a rare case of a 15-year-old boy, who presented with bone marrow failure. Whole exome sequencing revealed several gene mutations in ATP7B and TERT. Based on the phenotypes, telomere lengths and pedigree of his family, the patient was diagnosed with severe aplastic anemia accompanied by Wilson disease. Allogeneic hematopoietic stem cell transplantation and anti-copper therapy helped him achieve transfusion independence and restore relatively normal copper metabolism. We discussed the possible associations between the two rare conditions and optimal management in this situation.
2024-07-22 | Anti-human leukocyte antigen-DPB1 antibody-associated transfusion-related acute lung injury after hematopoietic stem cell infusion.
Although relatively rare among transfusion reactions, transfusion-related acute lung injury (TRALI) is a life-threatening condition, making its prevention, recognition, and early intervention extremely important. Although many etiological factors have been identified, the most common reasons are anti-human leukocyte antigen (anti-HLA) and anti-human neutrophil antigen antibodies that pass from the donor to the recipient during transfusion. TRALI was shown with transfusion of all kinds of blood products, however, it is rarely seen after stem cell infusion. Despite an adult case who developed TRALI after stem cell infusion, there is no pediatric case of TRALI associated with hematopoietic stem cell infusion in the previous literature. Here, we report a pediatric case with TRALI after infusion of the hematopoietic stem cell product from his female donor who has recently given birth 6 months ago. A 9-year-old patient with acquired aplastic anemia was admitted for hematopoietic stem cell transplantation (HSCT) from an ABO and 10/10 HLA compatible 21-year-old sister donor the unmanipulated stem cell product was planned to be infused in 4 h. At the last hour of infusion, the patient had acute hypoxemia, tachycardia, and bilateral pulmonary edema. He was diagnosed with TRALI and completely recovered with supportive therapy in 48 h. The anti-HLA antibody analysis of the donor showed positivity of anti-HLA-DPB1 antibodies. We wanted to emphasize the need for examination of anti-HLA antibodies of the donor and plasma depletion of the product to avoid TRALI in HSCTs from multiparous female donors.
gene therapies
2026-03-25 | Epidemiology of Acquired Bone Marrow Failure
Abstract Acquired Aplastic Anemia (AA) is a rare immune-mediated disorder characterized by peripheral blood cytopenias resulting from a hypocellular marrow. Significant advances have been made to characterize the dysregulated immune system and responses to understand the pathogenesis of AA, which in turn have unraveled the genetic predisposition markers (host) and the causal role of environmental factors, and more importantly, the interplay between them in a proportion of these cases. National registries and retrospective studies have identified a marked variation in disease incidence among certain ethnic populations and geographical regions where polymorphism for various Human leukocyte antigen (HLA) alleles has subsequently been found. Idiosyncratic reaction of the bone marrow to certain drugs and toxins has led to better pharmacovigilance practices, better monitoring, and the judicious use of these agents in clinical practice. AA following viral infections, including post-hepatitis AA, other autoimmune disorders, pregnancy, and following vaccination, all highlight a disturbed immune milieu in the body toward disease predisposition. Autoimmunity remains at the core of acquired AA, but we highlight important epidemiological influences that give context and a better understanding of the disordered nature of this autoimmune disease.
2026-02-20 | Assessment of characteristics and treatment patterns of adult patients with acquired aplastic anemia in Turkiye (PLANE-TR).
Acquired aplastic anemia (AA) is a rare blood disorder causing hypocellular bone marrow due to immune damage to hematopoietic stem cells, leading to low blood cell counts. This study investigates the demographics, treatment patterns, and clinical outcomes of AA in Turkiye. In this non-interventional, retrospective descriptive study, data of 274 patients (Female/Male: 4/5) diagnosed with AA between September 1, 2011, and September 1, 2021, were collected from 16 centers. Severe and very severe AA was diagnosed in 72% and 27.7% of patients, respectively. The mean time from diagnosis to first treatment was 119 ± 287 days, while time to hematopoietic stem cell transplantation (HSCT) was 212 ± 321 days, and to Anti-Thymocyte Globulin (ATG) was 87 ± 242.5 days. The mean time to response after first-line and second-line treatment was 172.9 ± 264.6 days and 191.9 ± 211.9 days, respectively. The mean overall survival of patients with AA was 3.56 ± 3.12 years, with a 5-year overall survival rate of 72.6%. HSCT and other initial treatments led to full or partial remission for most patients, improving survival rates for over half of them. The study observed comparable patterns to previous studies, providing vital insights into Turkiye's acquired AA treatment landscape.
2025-11-05 | Aplastic Anemia in Focus: Insights into Diagnosis and Emerging Therapies.
Aplastic anaemia (AA) is a rare and life-threatening condition characterized by the failure of bone marrow to produce adequate blood cells. An autoimmune reaction of T lymphocytes against hematopoietic stem cells (HSCs) is the primary etiology. However, less commonly, a congenital deficiency or an acquired injury to these cells can also suppress their division and differentiation. Guidelines for practitioners to manage AA are frequently ambiguous. Close follow-up and monitoring are essential in managing patients with AA, necessitating physicians to comprehend the etiopathology of the disease. Clinical hematologists frequently provide specific treatments, but the physician must stay informed and cognisant of the latest management guidelines for the condition. In the management of AA, both specific and auxiliary modalities hold considerable significance. The databases that were used for the literature study were PubMed/Medline, Embase, Scopus, and Web of Science. Search terms included "Aplastic anaemia." Articles from after 2006 that were relevant to diagnosis and management instructions were the only ones that were used. The things that were not allowed were scholarly posters, abstracts, and studies with nonhuman subjects. In recent years, there has been a substantial evolution in the concepts related to treating AA. This is attributable to improved outcomes in both familial and nonfamilial donor HSC transplants, alongside current advancements in immunosuppressive and gene therapy. This review article presents the current scientific insights by emphasizing the diagnostic protocols and developments in therapies, including the impacts of gene therapy, immunosuppressive agents, and HSC transplantation.
2011-02-03 | Lentiviral gene transfer regenerates hematopoietic stem cells in a mouse model for Mpl-deficient aplastic anemia
Abstract Thpo/Mpl signaling plays an important role in the maintenance of hematopoietic stem cells (HSCs) in addition to its role in megakaryopoiesis. Patients with inactivating mutations in Mpl develop thrombocytopenia and aplastic anemia because of progressive loss of HSCs. Yet, it is unknown whether this loss of HSCs is an irreversible process. In this study, we used the Mpl knockout (Mpl−/−) mouse model and expressed Mpl from newly developed lentiviral vectors specifically in the physiologic Mpl target populations, namely, HSCs and megakaryocytes. After validating lineage-specific expression in vivo using lentiviral eGFP reporter vectors, we performed bone marrow transplantation of transduced Mpl−/− bone marrow cells into Mpl−/− mice. We show that restoration of Mpl expression from transcriptionally targeted vectors prevents lethal adverse reactions of ectopic Mpl expression, replenishes the HSC pool, restores stem cell properties, and corrects platelet production. In some mice, megakaryocyte counts were atypically high, accompanied by bone neo-formation and marrow fibrosis. Gene-corrected Mpl−/− cells had increased long-term repopulating potential, with a marked increase in lineage−Sca1+cKit+ cells and early progenitor populations in reconstituted mice. Transcriptome analysis of lineage−Sca1+cKit+ cells in Mpl-corrected mice showed functional adjustment of genes involved in HSC self-renewal.
2006-10-19 | Identification of novel regulators in T-cell differentiation of aplastic anemia patients
Aplastic anemia (AA) is a bone marrow failure syndrome mostly characterized by an immune-mediated destruction of marrow hematopoietic progenitor/stem cells. The resulting hypocellularity limits a detailed analysis of the cellular immune response. To overcome this technical problem we performed a microarray analysis of CD3+ T-cells derived from bone marrow aspirates and peripheral blood samples of newly diagnosed AA patients and healthy volunteers. Two AA patients were additionally analyzed after achieving a partial remission following immunosuppression. The regulation of selected candidate genes was confirmed by real-time RT-PCR. Among more than 22.200 transcripts, 583 genes were differentially expressed in the bone marrow of AA patients compared to healthy controls. Dysregulated genes are involved in T-cell mediated cytotoxicity, immune response of Th1 differentiated T-cells, and major regulators of immune function. In hematological remission the expression levels of several candidate genes tend to normalize, such as immune regulators and genes involved in proinflammatory immune response. Our study suggests a pivotal role of Th1/Tc1 differentiated T-cells in immune-mediated marrow destruction of AA patients. Most importantly, immune regulatory genes could be identified, which are likely involved in the recovery of hematopoiesis and may help to design new therapeutic strategies in bone marrow failure syndromes.
antibodies
2025-10-20 | Early and Long-Lasting Hematologic Recovery in a Young Adult With Severe Aplastic Anemia Treated With Romiplostim, Horse-Anti-Thymocyte Globulin (ATG), and Cyclosporine A: A Case Report.
Aplastic anemia (AA) is a rare but potentially life-threatening bone marrow failure syndrome, typically characterized by peripheral pancytopenia and marked marrow hypocellularity. In acquired cases, immune-mediated destruction of hematopoietic stem cells is the predominant mechanism; however, intrinsic stem cell defects may also contribute to marrow failure, particularly in inherited bone marrow failure syndromes. Other etiologies, such as drug-induced marrow suppression, viral infections, and radiation exposure, should also be considered in the differential diagnosis. We present the case of a 22-year-old male with newly diagnosed severe AA, who exhibited pancytopenia and hypocellular marrow devoid of dysplastic features or blast cells. Cytogenetic studies and viral serologies yielded unremarkable results. Inherited marrow failure syndromes were excluded based on clinical phenotype, cytogenetic analysis, and absence of family history, supporting the diagnosis of acquired AA. Given the lack of an HLA-matched sibling donor, combination therapy consisting of horse anti-thymocyte globulin (hATG), cyclosporine A (CsA), and romiplostim (ROMI) was promptly initiated. Hematologic improvement was observed by week two, and complete response, defined as hemoglobin ≥100 g/L, absolute neutrophil count ≥1.0 ×10⁹/L, and platelet count ≥100 ×10⁹/L-was achieved by week five. Transfusion independence was attained early in the course, and no serious adverse events were observed. This case underscores the potential utility of early triple immunosuppressive therapy (IST) in treatment-naïve severe AA, particularly among younger patients, where prompt immunosuppressive intervention may accelerate hematologic recovery and support the preservation of marrow architecture.
2025-06-16 | Hematopoietic Stem Cell Transplantation and Immune System Suppression in Severe Aplastic Anemia
Aplastic anemia (AA) is characterized by pancytopenia and hypocellular bone marrow and can be either acquired or constitutional. Acquired AA results from autoimmune-mediated destruction of hematopoietic stem cells, often triggered by toxic agents inducing neo or cryptic antigens that activate immune responses. Although rare, acquired AA remains a serious condition typically managed with immunosuppressive therapy and supportive care. Constitutional forms, such as Fanconi anemia (FA) and Dyskeratosis Congenita (DC), are also uncommon and associated with genetic defects in DNA repair or telomere maintenance. Accurate differentiation between acquired and constitutional AA is critical for effective management. In our center, 15 patients were diagnosed with AA between 2016 and 2021 (acquired = 5, constitutional = 10). Patients with acquired AA received immunosuppressive therapy. Those with constitutional AA and HLA-matched donors underwent bone marrow transplantation following a conditioning regimen of busulfan, cyclophosphamide, and rabbit ATG. Cyclosporine was initiated two days prior to transplantation and continued for 6–12 months or longer. Despite the high mortality risk associated with untreated AA, all patients achieved favorable outcomes with no mortality, underscoring the critical role of early diagnosis and individualized treatment in improving survival in AA.
2024-09-02 | Dynamics of T cell subpopulation in patients with aplastic anemia during immunosuppressive therapy
Background. Aplastic anemia (AA) is a non-tumor and rare disease of the blood system, characterized by deep pancytopenia due to the development of bone marrow aplasia with immune-mediated damage of hematopoietic stem cells. Research results indicate the presence of antigenic effects leading to pathological activation and dysregulation of the T cells in the bone marrow with increased production of pro-inflammatory cytokines that damage hematopoietic stem cells. The triggering factor that initiates the cascade of immune reactions is currently unknown. The high efficiency of immunosuppressive therapy (IST), which allows achieving remission in the majority of AA patients, is evidence of the immune genesis of the disease. The pathogenesis of AA is currently being actively studied. The participation of T cell subpopulations in immune response is beyond doubt, but the issues of their significance in the AA pathogenesis have not been fully studied. A more detailed understanding of the AA development mechanisms is necessary for the development of long-term effective treatment. Aim. To investigate the T cells subpopulation in bone marrow of AA patients during IST. Materials and methods. The study included 41 patients over 18 years of age with newly diagnosed acquired AA without previous IST. Treatment was carried out according to a protocol including horse antithymocyte globulin and cyclosporine. Flow cytometry was used to detect T cell subpopulations. Bone marrow examination was performed at three time points: initially, 3 and 6 months after initiation of combined IST. Results. Multidirectional changes in the T cell subpopulations ratio before the start of IST were found in all AA patients included in the prospective study: most patients had a higher proportion of effector CD4 + and CD8 + T cells (61 and 83 % of patients, respectively), memory CD4 + T cells (63 % of patients), and a lower proportion of naive CD4 + and CD8 + T cells (81 and 51 % of patients, respectively) compared to donors ( p <0.05). The abnormal T cell subpopulation ratios that cause abnormal immune response are most pronounced in the very severe form of AA. When responding to treatment, no significant changes in T cells subpopulation were found either before the start of IST or 6 months after compared with donors. In the absence of treatment response, a higher proportion of effector CD4 + and CD8 + T cells, memory CD4 + T cells, and a lower proportion of naive CD4 + and CD8 + T cells were detected compared to donors already before the start of IST ( p <0.05). Of all cytometric parameters, a significant relationship was obtained between effector CD8 + T cells dynamics and response to treatment ( p = 0.040). The number of these cells at the onset and control points significantly correlated with the response to IST. In patients who have not responded to treatment by the 3rd month from IST initiated, there is a further increase in effector CD8 + T cells number, despite the IST continuation, which dictates the need to intensify IST in the shortest possible time (between the 3rd and 6th months) in these patients, namely, a 2nd course of equine antithymocyte globulin and continuation of cyclosporine therapy or individual consideration of alternative treatment (allogeneic hematopoietic stem cell transplantation). Conclusion. Studying the T cells subpopulation dynamics, in particular effector T cells, allows us to determine the tactics of further treatment in the early stages of IST in order to select the optimal treatment program for each AA patient.
2024-04-04 | Hematopoiesis post anti-CD117 monoclonal antibody treatment in wild-type and Fanconi anemia settings
Anti-CD117 monoclonal antibody (mAb) agents have emerged as exciting alternative conditioning strategies to traditional genotoxic irradiation or chemotherapy conditioning for both allogeneic and autologous gene-modified hematopoietic stem cell transplantation. Further, these agents are concurrently being explored in the treatment of mast cell disorders. Despite promising results in animal models and more recently in patients, the short-term and long-term effects of these treatments have not been fully explored. We conducted rigorous assessments to evaluate the effects of antagonistic anti-mCD117 mAb, ACK2, on hematopoiesis in wild-type (WT) and Fanconi Anemia (FA) mice. Importantly, we found no evidence of short-term DNA damage in either setting following this treatment suggesting that ACK2 does not induce immediate genotoxicity, providing crucial insights into its safety profile. Surprisingly, FA mice exhibited an increase in colony formation post-ACK2 treatment without accompanying DNA damage, indicating a potential targeting of hematopoietic stem cells (HSCs) and expansion of hematopoietic progenitor cells. Moreover, the long-term phenotypic and functional changes in hematopoietic stem and progenitor cells did not significantly differ between the ACK2-treated and control groups, in either setting, supporting that ACK2 does not adversely affect hematopoietic capacity. These finding underscore the safety of these agents when utilized as a short-course treatment in the conditioning context, as they did not induce significant changes in DNA damage amongst hematopoietic stem or progenitor cells. However, through a comparison of gene expression via single-cell RNA sequencing between untreated and treated mice, it was revealed that the ACK2 mAb, via c-Kit downregulation, effectively modulated the MAPK pathway with Fos down-regulation in WT and FA mice. Importantly, this modulation was achieved without causing prolonged disruptions. These findings validate the safety of the treatment and also enhance our understanding of its intricate mode of action at the molecular level.
2024-02-15 | When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms
Aplastic anemia (AA) and hypoplastic myelodysplastic syndrome are paradigms of autoimmune hematopoietic failure (AHF). Myelodysplastic syndrome and acute myeloid leukemia are unequivocal myeloid neoplasms (MNs). Currently, AA is also known to be a clonal hematological disease. Genetic aberrations typically observed in MNs are detected in approximately one-third of AA patients. In AA patients harboring MN-related genetic aberrations, a poor response to immunosuppressive therapy (IST) and an increased risk of transformation to MNs occurring either naturally or after IST are predicted. Approximately 10%–15% of patients with severe AA transform the disease phenotype to MNs following IST, and in some patients, leukemic transformation emerges during or shortly after IST. Phenotypic transformations between AHF and MNs can occur reciprocally. A fraction of advanced MN patients experience an aplastic crisis during which leukemic blasts are repressed. The switch that shapes the disease phenotype is a change in the strength of extramedullary inflammation. Both AHF and MNs have an immune-active bone marrow (BM) environment (BME). In AHF patients, an inflamed BME can be evoked by infiltrated immune cells targeting neoplastic molecules, which contributes to the BM-specific autoimmune impairment. Autoimmune responses in AHF may represent an antileukemic mechanism, and inflammatory stressors strengthen antileukemic immunity, at least in a significant proportion of patients who have MN-related genetic aberrations. During active inflammatory episodes, normal and leukemic hematopoieses are suppressed, which leads to the occurrence of aplastic cytopenia and leukemic cell regression. The successful treatment of underlying infections mitigates inflammatory stress-related antileukemic activities and promotes the penetration of leukemic hematopoiesis. The effect of IST is similar to that of treating underlying infections. Investigating inflammatory stress-powered antileukemic immunity is highly important in theoretical studies and clinical practice, especially given the wide application of immune-activating agents and immune checkpoint inhibitors in the treatment of hematological neoplasms.
other
2023-02-22 | Allogeneic hematopoietic stem cell transplantation in the COVID-19 era
Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) recipients are especially vulnerable to coronavirus disease 19 (COVID-19), because of their profound immunodeficiency. Indeed, the first pandemic wave was marked by a high mortality rate in this population. Factors increasing immunodepression such as older age, immunosuppressive treatments or a short delay between transplant and infection appear to worsen the prognosis. Many changes in clinical practice had to be implemented in order to limit this risk, including postponing of transplant for non-malignant diseases, preference for local rather than international donations and for peripheral blood as stem cell source, and the widespread use of cryopreservation. The great revolution in the COVID-19 pandemic came from the development of mRNA vaccines that have shown to be able to prevent severe forms of the disease. More than 75% of allo-HSCT recipients develop seroconversion after 2 doses of vaccine. Multiple studies have identified lymphopenia, exposure to immunosuppressive or anti-CD20 therapies, and a short post-transplant period as factors associated with a poor response to vaccination. The use of repeated injections of the vaccine, including a third dose, not only improves the seroconversion rate but also intensifies the immune response, both in B cells and T cells. Vaccines are an effective and well-tolerated method in this high-risk population. Some studies investigated the possibility of immune protection being transferred from a vaccinated donor to a recipient, with encouraging initial results. However, dynamic mutations and immune escape of the virus can lead to breakthrough infections with new variants in vaccinated individuals and still represent a threat of severe disease in allo-HSCT recipients. New challenges include the need to adapt vaccine protection to emerging variants.
small molecules
2026-08-13 | Real-world retrospective analysis of clinical outcomes in pediatric acquired aplastic anemia: a single-center 10-year cohort study
Introduction Pediatric aplastic anemia (AA), a rare and potentially fatal disease, demonstrates significant heterogeneity in pathogenesis, disease severity, therapeutic regimens, and clinical outcomes. Methods In this study, clinical features and outcomes of 70 children with AA, including severe AA (SAA, n = 30), very severe AA (vSAA, n = 21) and nonsevere AA (nSAA, n = 19), were retrospectively analyzed, with a median follow-up of 60.7 months (range, 0.4-136.5 months). Results Patients with nSAA were mainly treated with cyclosporine A, whereas SAA/vSAA patients primarily received allogeneic hematopoietic stem cell transplantation (HSCT) followed by standard immunosuppressive therapy (IST). Ultimate therapy regimens differed significantly between patients with SAA/vSAA and nSAA ( p = 0.001). SAA/vSAA group exhibited a higher overall response rate at the 2-year follow-up (85.5% vs. 55.6%, p = 0.019). The 2-year overall survival (OS) and event-free survival (EFS) for the entire cohort were 97.1% and 48.5%, respectively. In patients with SAA/vSAA, HSCT was associated with higher and faster cumulative complete response (CR) rate ( p < 0.0001) and superior EFS ( p = 0.0297) compared with IST. Two IST-resistant patients were observed to achieved CR with eltrombopag (EPAG) salvage therapy. Discussion pediatric AA carries excellent OS but suboptimal EFS. HSCT tends to yield more favorable EFS compared with IST in SAA/vSAA patients, and EPAG may act as an effective salvage option for appropriately selected IST-resistant individuals. Further multicenter prospective research is warranted prior to implementing these findings in routine clinical practice.
2026-04-01 | American Society of Hematology 2026 Guidelines for the Diagnosis and Management of Severe Acquired Aplastic Anemia.
Aplastic anemia is a rare, life-threatening condition marked by pancytopenia and bone marrow hypocellularity. Despite therapeutic advances, clinical practice remains variable, and uncertainties persist regarding diagnosis and optimal management. To address these gaps, the American Society of Hematology (ASH) developed evidence-based guidelines to provide standardized, patient-centered recommendations. The recommendations are intended to support patients, clinicians and other health care professionals in their decisions about the management and diagnosis of severe and very severe immune acquired aplastic anemia. ASH formed a multidisciplinary guideline panel of content experts, methodologists and a patient representative. An evidence synthesis team supported the guideline development process by conducting systematic evidence reviews. The panel prioritized clinical questions and used the GRADE approach, including the Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. The panel agreed on 33 recommendations and 4 good practice statements addressing the use of diagnostic tests, treatment strategies and supportive care. Additional recommendations covered the incorporation of eltrombopag into immunosuppressive regimens and the use of antimicrobial prophylaxis in high-risk patients. For most clinical questions, the certainty of the evidence was rated as low or very low, largely due to the reliance on small, non-randomized studies. Recommendations emphasize prioritizing hematopoietic cell transplantation for younger individuals with an available matched sibling or unrelated donor and as a second-line option following failure of immunosuppressive therapy. The panel also recommended adding eltrombopag to immunosuppressive regimens and using antibiotic and antifungal prophylaxis in neutropenic patients.
2026-03-13 | Successful Treatment of Aplastic Anemia With Eltrombopag During Pregnancy: A Short Report.
Aplastic anemia (AA) is a rare bone marrow failure syndrome with pancytopenia, mainly due to immune-mediated stem cell destruction. First-line therapy for acquired severe AA ≥ 50 years/non-severe AA (NSAA) requiring treatment is immunosuppressive therapy with horse anti-thymocyte globulin, cyclosporine A (CSA), and eltrombopag (EPAG). In pregnancy, cytopenia may worsen, while therapeutic options are limited. We report the first case of a pregnant patient with NSAA/PNH receiving full-dose EPAG (150 mg/d). Counts remained stable, delivery was uneventful, and the child was healthy. Postpartum, EPAG was discontinued, CSA tapered, and transfusion independence achieved. EPAG may represent a feasible option in selected pregnancies.
2026-01-05 | Efficacy and safety of avatrombopag in aplastic anemia: a comprehensive review of clinical evidence.
Aplastic anemia is a bone marrow failure disorder marked by cytopenias that impair oxygen delivery, immune defense, and hemostasis. Standard therapy traditionally combines immunosuppression with or without hematopoietic stem cell transplantation, and more recently incorporates thrombopoietin receptor agonists to stimulate residual hematopoiesis. Eltrombopag improved outcomes when added to immunosuppressive therapy, but its association with hepatotoxicity limits its suitability for patients with underlying liver disease or elevated baseline liver enzymes. Avatrombopag is a newer oral thrombopoietin receptor agonist that does not require dietary restrictions and does not undergo significant hepatic metabolism, which offers a potential therapeutic advantage in settings where liver function is compromised. This review evaluated ten clinical studies published from 2023 to October 2025 that investigated avatrombopag in acquired aplastic anemia across varied patient populations, including treatment-naive, relapsed or refractory cases, older adults, and patients with secondary aplastic anemia related to chemoradiation. Across these studies, overall response rates ranged from 55% to 85%, and complete response rates reached up to one-third of treated patients. Response onset typically occurred within 1-2 months, which aligns with clinical decision timelines for assessing therapeutic benefit. Avatrombopag supported reductions in transfusion requirements and sustained hematologic improvement in both severe and non-severe disease. Patients previously intolerant or non-responsive to eltrombopag also demonstrated clinical improvement, which suggests pharmacologic differences translate into meaningful therapeutic effects. Importantly, avatrombopag demonstrated a favorable safety profile in all reviewed settings. Reports did not identify clinically relevant hepatotoxicity, clonal evolution, or treatment-limiting adverse effects. Its tolerability in patients with liver dysfunction distinguishes it from earlier agents in this drug class. Ongoing trials will clarify optimal dosing strategies and define its future role within first-line therapy and salvage treatment pathways for aplastic anemia.
2026-01-01 | Gut Microbiome Alterations in Aplastic Anemia: Mechanistic Insights, Immune-Hematopoietic Crosstalk and Therapeutic Potential
Aplastic anemia (AA) is a rare hematological disorder characterized by peripheral cytopenias and hypocellular bone marrow resulting from failed hematopoiesis. The condition may arise from inherited genetic defects in hematopoietic stem cells (HSCs) or from acquired immune-mediated mechanisms. In acquired AA, immune dysregulation leads to the destruction of hematopoietic stem and progenitor cells (HSPCs), with immunosuppressive therapy remaining the cornerstone of treatment. Emerging evidence highlights the gut microbiome as a critical modulator of immune function and hematopoiesis. Disruptions in gut microbial composition have been linked to autoimmune and inflammatory diseases, yet their specific role in AA pathogenesis is not fully understood. The gut microbiome may influence immune responses, hematopoietic recovery and disease progression. Profiling the gut microbiome could also serve as a non-invasive method for monitoring disease progression, identifying microbial patterns associated with treatment response and assessing individual risk for relapse. Despite these promising insights, clinical trials specifically targeting the gut microbiome in AA remain limited, revealing a significant gap in research. A deeper understanding of the interactions between the gut microbiome, immune system and hematopoiesis is essential for identifying novel biomarkers and therapeutic strategies. These insights could complement existing immunosuppressive therapies and enable more personalized treatment approaches. This review thus synthesizes current evidence on gut microbiome alterations in AA, exploring their potential role in immune regulation, hematopoietic recovery and therapeutic interventions.
cell therapies
2026-01-01 | Management of Acquired Aplastic Anemia in Children
Abstract Acquired aplastic anemia (AA) in children is a rare, life-threatening disorder characterized by pancytopenia and hypocellular bone marrow. Early referral to specialized centers ensures accurate diagnosis and timely treatment. Differential diagnosis must exclude inherited bone marrow failure syndromes and immune-related disorders using comprehensive genetic and immunologic testing. Hematopoietic stem cell transplantation (HSCT) from a matched sibling donor remains the first-line treatment when available, offering high survival rates. In the absence of a suitable donor, immunosuppressive therapy (IST) with horse antithymocyte globulin and cyclosporine is the standard. Upfront matched unrelated donor transplantation is increasingly used due to improved outcomes. Supportive care, including transfusions, infection prophylaxis, and iron chelation, remains critical. Emerging options such as haploidentical transplantation and thrombopoietin receptor agonists provide alternatives for refractory cases. Despite therapeutic advances, long-term follow-up is essential to monitor clonal evolution and late effects. Personalized, risk-adapted strategies are pivotal to optimizing pediatric AA management.
2025-10-31 | Hemophagocytic lymphohistiocytosis in the context of hepatitis-associated severe aplastic anemia: A case report
Rationale: Hemophagocytic lymphohistiocytosis (HLH) is a severe immune dysregulation syndrome. Hepatitis-associated severe aplastic anemia (SAA) is a specific subtype of acquired aplastic anemia characterized by concomitant hepatitis, leading to a challenging diagnosis and poor prognosis. Here, we present a rare case of HLH in the context of hepatitis-associated SAA, emphasizing the need for early recognition and individualized management. Patient concerns: The patient, a 19-year-old male, presented with recurrent fever, jaundice, and cytopenias, indicative of hepatitis. Diagnoses: Bone marrow aspiration and biopsy suggested SAA, while peripheral blood next-generation sequencing detected Candida tropicalis infection on 2 separate occasions. Despite combination antifungal therapy with amphotericin B and posaconazole, the bilirubin level continued to rise. Additional tests revealed an elevated soluble CD25 level of 3659 U/mL, decreased natural killer cell activity of 1.8%, and a serum ferritin level > 2000 μg/L. The final diagnosis was HLH. Interventions: Dexamethasone and ruxolitinib were administered to control the fever. Subsequently, the patient underwent HLA-matched allogeneic bone marrow and peripheral blood hematopoietic stem cell transplantation for SAA. Outcomes: The patient’s symptoms, including fever and fatigue, resolved. Lessons: This case highlights that HLH should be considered in SAA patients with unexplained fever, poor response to anti-infectives, and elevated bilirubin. A treatment strategy addressing both bone marrow failure and hyperinflammation is essential. In this patient, allogeneic hematopoietic stem cell transplantation served as a successful curative intervention by targeting the shared pathophysiology of HLH and SAA. However, given the inherent limitations of a single case, the generalizability of our findings and the efficacy of allogeneic hematopoietic stem cell transplantation require validation through larger, controlled studies.
2025-10-02 | [Aplastic anemia in children: recent advances in diagnosis and treatment].
Pediatric aplastic anemia (AA) is a rare bone marrow failure that requires several special considerations for its diagnosis and treatment compared with adult AA. Accurate differential diagnosis is crucial, and distinguishing acquired AA from inherited bone marrow failure syndromes is particularly important. In addition to detailed morphological evaluation, comprehensive diagnostic workups incorporating genetic analysis using next-generation sequencing have become increasingly important for guiding treatment decisions. When discussing treatment strategies for pediatric AA, the long-term sequelae and level of hematopoietic recovery should also be considered, although the survival rates now exceed 90% following immunosuppressive therapy or hematopoietic cell transplantation (HCT). Recent advances in HCT include improved conditioning regimens, successful upfront HCT from matched unrelated donors, and expanded salvage treatment options such as unrelated cord blood transplantation or haploidentical HCT. This review outlines these recent advances in the diagnosis and treatment of AA in children based on the latest data.
2025-04-21 | From severe aplastic anemia with TERT variant to Wilson disease - associations or not.
Severe aplastic anemia is a life-threatening ineffective hematopoiesis, arising from inherited or acquired traits. Wilson disease is a rare congenital metabolic disorder with copper accumulation. Here we report a rare case of a 15-year-old boy, who presented with bone marrow failure. Whole exome sequencing revealed several gene mutations in ATP7B and TERT. Based on the phenotypes, telomere lengths and pedigree of his family, the patient was diagnosed with severe aplastic anemia accompanied by Wilson disease. Allogeneic hematopoietic stem cell transplantation and anti-copper therapy helped him achieve transfusion independence and restore relatively normal copper metabolism. We discussed the possible associations between the two rare conditions and optimal management in this situation.
2024-07-22 | Anti-human leukocyte antigen-DPB1 antibody-associated transfusion-related acute lung injury after hematopoietic stem cell infusion.
Although relatively rare among transfusion reactions, transfusion-related acute lung injury (TRALI) is a life-threatening condition, making its prevention, recognition, and early intervention extremely important. Although many etiological factors have been identified, the most common reasons are anti-human leukocyte antigen (anti-HLA) and anti-human neutrophil antigen antibodies that pass from the donor to the recipient during transfusion. TRALI was shown with transfusion of all kinds of blood products, however, it is rarely seen after stem cell infusion. Despite an adult case who developed TRALI after stem cell infusion, there is no pediatric case of TRALI associated with hematopoietic stem cell infusion in the previous literature. Here, we report a pediatric case with TRALI after infusion of the hematopoietic stem cell product from his female donor who has recently given birth 6 months ago. A 9-year-old patient with acquired aplastic anemia was admitted for hematopoietic stem cell transplantation (HSCT) from an ABO and 10/10 HLA compatible 21-year-old sister donor the unmanipulated stem cell product was planned to be infused in 4 h. At the last hour of infusion, the patient had acute hypoxemia, tachycardia, and bilateral pulmonary edema. He was diagnosed with TRALI and completely recovered with supportive therapy in 48 h. The anti-HLA antibody analysis of the donor showed positivity of anti-HLA-DPB1 antibodies. We wanted to emphasize the need for examination of anti-HLA antibodies of the donor and plasma depletion of the product to avoid TRALI in HSCTs from multiparous female donors.
gene therapies
2026-03-25 | Epidemiology of Acquired Bone Marrow Failure
Abstract Acquired Aplastic Anemia (AA) is a rare immune-mediated disorder characterized by peripheral blood cytopenias resulting from a hypocellular marrow. Significant advances have been made to characterize the dysregulated immune system and responses to understand the pathogenesis of AA, which in turn have unraveled the genetic predisposition markers (host) and the causal role of environmental factors, and more importantly, the interplay between them in a proportion of these cases. National registries and retrospective studies have identified a marked variation in disease incidence among certain ethnic populations and geographical regions where polymorphism for various Human leukocyte antigen (HLA) alleles has subsequently been found. Idiosyncratic reaction of the bone marrow to certain drugs and toxins has led to better pharmacovigilance practices, better monitoring, and the judicious use of these agents in clinical practice. AA following viral infections, including post-hepatitis AA, other autoimmune disorders, pregnancy, and following vaccination, all highlight a disturbed immune milieu in the body toward disease predisposition. Autoimmunity remains at the core of acquired AA, but we highlight important epidemiological influences that give context and a better understanding of the disordered nature of this autoimmune disease.
2026-02-20 | Assessment of characteristics and treatment patterns of adult patients with acquired aplastic anemia in Turkiye (PLANE-TR).
Acquired aplastic anemia (AA) is a rare blood disorder causing hypocellular bone marrow due to immune damage to hematopoietic stem cells, leading to low blood cell counts. This study investigates the demographics, treatment patterns, and clinical outcomes of AA in Turkiye. In this non-interventional, retrospective descriptive study, data of 274 patients (Female/Male: 4/5) diagnosed with AA between September 1, 2011, and September 1, 2021, were collected from 16 centers. Severe and very severe AA was diagnosed in 72% and 27.7% of patients, respectively. The mean time from diagnosis to first treatment was 119 ± 287 days, while time to hematopoietic stem cell transplantation (HSCT) was 212 ± 321 days, and to Anti-Thymocyte Globulin (ATG) was 87 ± 242.5 days. The mean time to response after first-line and second-line treatment was 172.9 ± 264.6 days and 191.9 ± 211.9 days, respectively. The mean overall survival of patients with AA was 3.56 ± 3.12 years, with a 5-year overall survival rate of 72.6%. HSCT and other initial treatments led to full or partial remission for most patients, improving survival rates for over half of them. The study observed comparable patterns to previous studies, providing vital insights into Turkiye's acquired AA treatment landscape.
2025-11-05 | Aplastic Anemia in Focus: Insights into Diagnosis and Emerging Therapies.
Aplastic anaemia (AA) is a rare and life-threatening condition characterized by the failure of bone marrow to produce adequate blood cells. An autoimmune reaction of T lymphocytes against hematopoietic stem cells (HSCs) is the primary etiology. However, less commonly, a congenital deficiency or an acquired injury to these cells can also suppress their division and differentiation. Guidelines for practitioners to manage AA are frequently ambiguous. Close follow-up and monitoring are essential in managing patients with AA, necessitating physicians to comprehend the etiopathology of the disease. Clinical hematologists frequently provide specific treatments, but the physician must stay informed and cognisant of the latest management guidelines for the condition. In the management of AA, both specific and auxiliary modalities hold considerable significance. The databases that were used for the literature study were PubMed/Medline, Embase, Scopus, and Web of Science. Search terms included "Aplastic anaemia." Articles from after 2006 that were relevant to diagnosis and management instructions were the only ones that were used. The things that were not allowed were scholarly posters, abstracts, and studies with nonhuman subjects. In recent years, there has been a substantial evolution in the concepts related to treating AA. This is attributable to improved outcomes in both familial and nonfamilial donor HSC transplants, alongside current advancements in immunosuppressive and gene therapy. This review article presents the current scientific insights by emphasizing the diagnostic protocols and developments in therapies, including the impacts of gene therapy, immunosuppressive agents, and HSC transplantation.
2011-02-03 | Lentiviral gene transfer regenerates hematopoietic stem cells in a mouse model for Mpl-deficient aplastic anemia
Abstract Thpo/Mpl signaling plays an important role in the maintenance of hematopoietic stem cells (HSCs) in addition to its role in megakaryopoiesis. Patients with inactivating mutations in Mpl develop thrombocytopenia and aplastic anemia because of progressive loss of HSCs. Yet, it is unknown whether this loss of HSCs is an irreversible process. In this study, we used the Mpl knockout (Mpl−/−) mouse model and expressed Mpl from newly developed lentiviral vectors specifically in the physiologic Mpl target populations, namely, HSCs and megakaryocytes. After validating lineage-specific expression in vivo using lentiviral eGFP reporter vectors, we performed bone marrow transplantation of transduced Mpl−/− bone marrow cells into Mpl−/− mice. We show that restoration of Mpl expression from transcriptionally targeted vectors prevents lethal adverse reactions of ectopic Mpl expression, replenishes the HSC pool, restores stem cell properties, and corrects platelet production. In some mice, megakaryocyte counts were atypically high, accompanied by bone neo-formation and marrow fibrosis. Gene-corrected Mpl−/− cells had increased long-term repopulating potential, with a marked increase in lineage−Sca1+cKit+ cells and early progenitor populations in reconstituted mice. Transcriptome analysis of lineage−Sca1+cKit+ cells in Mpl-corrected mice showed functional adjustment of genes involved in HSC self-renewal.
2006-10-19 | Identification of novel regulators in T-cell differentiation of aplastic anemia patients
Aplastic anemia (AA) is a bone marrow failure syndrome mostly characterized by an immune-mediated destruction of marrow hematopoietic progenitor/stem cells. The resulting hypocellularity limits a detailed analysis of the cellular immune response. To overcome this technical problem we performed a microarray analysis of CD3+ T-cells derived from bone marrow aspirates and peripheral blood samples of newly diagnosed AA patients and healthy volunteers. Two AA patients were additionally analyzed after achieving a partial remission following immunosuppression. The regulation of selected candidate genes was confirmed by real-time RT-PCR. Among more than 22.200 transcripts, 583 genes were differentially expressed in the bone marrow of AA patients compared to healthy controls. Dysregulated genes are involved in T-cell mediated cytotoxicity, immune response of Th1 differentiated T-cells, and major regulators of immune function. In hematological remission the expression levels of several candidate genes tend to normalize, such as immune regulators and genes involved in proinflammatory immune response. Our study suggests a pivotal role of Th1/Tc1 differentiated T-cells in immune-mediated marrow destruction of AA patients. Most importantly, immune regulatory genes could be identified, which are likely involved in the recovery of hematopoiesis and may help to design new therapeutic strategies in bone marrow failure syndromes.
antibodies
2025-10-20 | Early and Long-Lasting Hematologic Recovery in a Young Adult With Severe Aplastic Anemia Treated With Romiplostim, Horse-Anti-Thymocyte Globulin (ATG), and Cyclosporine A: A Case Report.
Aplastic anemia (AA) is a rare but potentially life-threatening bone marrow failure syndrome, typically characterized by peripheral pancytopenia and marked marrow hypocellularity. In acquired cases, immune-mediated destruction of hematopoietic stem cells is the predominant mechanism; however, intrinsic stem cell defects may also contribute to marrow failure, particularly in inherited bone marrow failure syndromes. Other etiologies, such as drug-induced marrow suppression, viral infections, and radiation exposure, should also be considered in the differential diagnosis. We present the case of a 22-year-old male with newly diagnosed severe AA, who exhibited pancytopenia and hypocellular marrow devoid of dysplastic features or blast cells. Cytogenetic studies and viral serologies yielded unremarkable results. Inherited marrow failure syndromes were excluded based on clinical phenotype, cytogenetic analysis, and absence of family history, supporting the diagnosis of acquired AA. Given the lack of an HLA-matched sibling donor, combination therapy consisting of horse anti-thymocyte globulin (hATG), cyclosporine A (CsA), and romiplostim (ROMI) was promptly initiated. Hematologic improvement was observed by week two, and complete response, defined as hemoglobin ≥100 g/L, absolute neutrophil count ≥1.0 ×10⁹/L, and platelet count ≥100 ×10⁹/L-was achieved by week five. Transfusion independence was attained early in the course, and no serious adverse events were observed. This case underscores the potential utility of early triple immunosuppressive therapy (IST) in treatment-naïve severe AA, particularly among younger patients, where prompt immunosuppressive intervention may accelerate hematologic recovery and support the preservation of marrow architecture.
2025-06-16 | Hematopoietic Stem Cell Transplantation and Immune System Suppression in Severe Aplastic Anemia
Aplastic anemia (AA) is characterized by pancytopenia and hypocellular bone marrow and can be either acquired or constitutional. Acquired AA results from autoimmune-mediated destruction of hematopoietic stem cells, often triggered by toxic agents inducing neo or cryptic antigens that activate immune responses. Although rare, acquired AA remains a serious condition typically managed with immunosuppressive therapy and supportive care. Constitutional forms, such as Fanconi anemia (FA) and Dyskeratosis Congenita (DC), are also uncommon and associated with genetic defects in DNA repair or telomere maintenance. Accurate differentiation between acquired and constitutional AA is critical for effective management. In our center, 15 patients were diagnosed with AA between 2016 and 2021 (acquired = 5, constitutional = 10). Patients with acquired AA received immunosuppressive therapy. Those with constitutional AA and HLA-matched donors underwent bone marrow transplantation following a conditioning regimen of busulfan, cyclophosphamide, and rabbit ATG. Cyclosporine was initiated two days prior to transplantation and continued for 6–12 months or longer. Despite the high mortality risk associated with untreated AA, all patients achieved favorable outcomes with no mortality, underscoring the critical role of early diagnosis and individualized treatment in improving survival in AA.
2024-09-02 | Dynamics of T cell subpopulation in patients with aplastic anemia during immunosuppressive therapy
Background. Aplastic anemia (AA) is a non-tumor and rare disease of the blood system, characterized by deep pancytopenia due to the development of bone marrow aplasia with immune-mediated damage of hematopoietic stem cells. Research results indicate the presence of antigenic effects leading to pathological activation and dysregulation of the T cells in the bone marrow with increased production of pro-inflammatory cytokines that damage hematopoietic stem cells. The triggering factor that initiates the cascade of immune reactions is currently unknown. The high efficiency of immunosuppressive therapy (IST), which allows achieving remission in the majority of AA patients, is evidence of the immune genesis of the disease. The pathogenesis of AA is currently being actively studied. The participation of T cell subpopulations in immune response is beyond doubt, but the issues of their significance in the AA pathogenesis have not been fully studied. A more detailed understanding of the AA development mechanisms is necessary for the development of long-term effective treatment. Aim. To investigate the T cells subpopulation in bone marrow of AA patients during IST. Materials and methods. The study included 41 patients over 18 years of age with newly diagnosed acquired AA without previous IST. Treatment was carried out according to a protocol including horse antithymocyte globulin and cyclosporine. Flow cytometry was used to detect T cell subpopulations. Bone marrow examination was performed at three time points: initially, 3 and 6 months after initiation of combined IST. Results. Multidirectional changes in the T cell subpopulations ratio before the start of IST were found in all AA patients included in the prospective study: most patients had a higher proportion of effector CD4 + and CD8 + T cells (61 and 83 % of patients, respectively), memory CD4 + T cells (63 % of patients), and a lower proportion of naive CD4 + and CD8 + T cells (81 and 51 % of patients, respectively) compared to donors ( p <0.05). The abnormal T cell subpopulation ratios that cause abnormal immune response are most pronounced in the very severe form of AA. When responding to treatment, no significant changes in T cells subpopulation were found either before the start of IST or 6 months after compared with donors. In the absence of treatment response, a higher proportion of effector CD4 + and CD8 + T cells, memory CD4 + T cells, and a lower proportion of naive CD4 + and CD8 + T cells were detected compared to donors already before the start of IST ( p <0.05). Of all cytometric parameters, a significant relationship was obtained between effector CD8 + T cells dynamics and response to treatment ( p = 0.040). The number of these cells at the onset and control points significantly correlated with the response to IST. In patients who have not responded to treatment by the 3rd month from IST initiated, there is a further increase in effector CD8 + T cells number, despite the IST continuation, which dictates the need to intensify IST in the shortest possible time (between the 3rd and 6th months) in these patients, namely, a 2nd course of equine antithymocyte globulin and continuation of cyclosporine therapy or individual consideration of alternative treatment (allogeneic hematopoietic stem cell transplantation). Conclusion. Studying the T cells subpopulation dynamics, in particular effector T cells, allows us to determine the tactics of further treatment in the early stages of IST in order to select the optimal treatment program for each AA patient.
2024-04-04 | Hematopoiesis post anti-CD117 monoclonal antibody treatment in wild-type and Fanconi anemia settings
Anti-CD117 monoclonal antibody (mAb) agents have emerged as exciting alternative conditioning strategies to traditional genotoxic irradiation or chemotherapy conditioning for both allogeneic and autologous gene-modified hematopoietic stem cell transplantation. Further, these agents are concurrently being explored in the treatment of mast cell disorders. Despite promising results in animal models and more recently in patients, the short-term and long-term effects of these treatments have not been fully explored. We conducted rigorous assessments to evaluate the effects of antagonistic anti-mCD117 mAb, ACK2, on hematopoiesis in wild-type (WT) and Fanconi Anemia (FA) mice. Importantly, we found no evidence of short-term DNA damage in either setting following this treatment suggesting that ACK2 does not induce immediate genotoxicity, providing crucial insights into its safety profile. Surprisingly, FA mice exhibited an increase in colony formation post-ACK2 treatment without accompanying DNA damage, indicating a potential targeting of hematopoietic stem cells (HSCs) and expansion of hematopoietic progenitor cells. Moreover, the long-term phenotypic and functional changes in hematopoietic stem and progenitor cells did not significantly differ between the ACK2-treated and control groups, in either setting, supporting that ACK2 does not adversely affect hematopoietic capacity. These finding underscore the safety of these agents when utilized as a short-course treatment in the conditioning context, as they did not induce significant changes in DNA damage amongst hematopoietic stem or progenitor cells. However, through a comparison of gene expression via single-cell RNA sequencing between untreated and treated mice, it was revealed that the ACK2 mAb, via c-Kit downregulation, effectively modulated the MAPK pathway with Fos down-regulation in WT and FA mice. Importantly, this modulation was achieved without causing prolonged disruptions. These findings validate the safety of the treatment and also enhance our understanding of its intricate mode of action at the molecular level.
2024-02-15 | When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms
Aplastic anemia (AA) and hypoplastic myelodysplastic syndrome are paradigms of autoimmune hematopoietic failure (AHF). Myelodysplastic syndrome and acute myeloid leukemia are unequivocal myeloid neoplasms (MNs). Currently, AA is also known to be a clonal hematological disease. Genetic aberrations typically observed in MNs are detected in approximately one-third of AA patients. In AA patients harboring MN-related genetic aberrations, a poor response to immunosuppressive therapy (IST) and an increased risk of transformation to MNs occurring either naturally or after IST are predicted. Approximately 10%–15% of patients with severe AA transform the disease phenotype to MNs following IST, and in some patients, leukemic transformation emerges during or shortly after IST. Phenotypic transformations between AHF and MNs can occur reciprocally. A fraction of advanced MN patients experience an aplastic crisis during which leukemic blasts are repressed. The switch that shapes the disease phenotype is a change in the strength of extramedullary inflammation. Both AHF and MNs have an immune-active bone marrow (BM) environment (BME). In AHF patients, an inflamed BME can be evoked by infiltrated immune cells targeting neoplastic molecules, which contributes to the BM-specific autoimmune impairment. Autoimmune responses in AHF may represent an antileukemic mechanism, and inflammatory stressors strengthen antileukemic immunity, at least in a significant proportion of patients who have MN-related genetic aberrations. During active inflammatory episodes, normal and leukemic hematopoieses are suppressed, which leads to the occurrence of aplastic cytopenia and leukemic cell regression. The successful treatment of underlying infections mitigates inflammatory stress-related antileukemic activities and promotes the penetration of leukemic hematopoiesis. The effect of IST is similar to that of treating underlying infections. Investigating inflammatory stress-powered antileukemic immunity is highly important in theoretical studies and clinical practice, especially given the wide application of immune-activating agents and immune checkpoint inhibitors in the treatment of hematological neoplasms.
other
2023-02-22 | Allogeneic hematopoietic stem cell transplantation in the COVID-19 era
Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) recipients are especially vulnerable to coronavirus disease 19 (COVID-19), because of their profound immunodeficiency. Indeed, the first pandemic wave was marked by a high mortality rate in this population. Factors increasing immunodepression such as older age, immunosuppressive treatments or a short delay between transplant and infection appear to worsen the prognosis. Many changes in clinical practice had to be implemented in order to limit this risk, including postponing of transplant for non-malignant diseases, preference for local rather than international donations and for peripheral blood as stem cell source, and the widespread use of cryopreservation. The great revolution in the COVID-19 pandemic came from the development of mRNA vaccines that have shown to be able to prevent severe forms of the disease. More than 75% of allo-HSCT recipients develop seroconversion after 2 doses of vaccine. Multiple studies have identified lymphopenia, exposure to immunosuppressive or anti-CD20 therapies, and a short post-transplant period as factors associated with a poor response to vaccination. The use of repeated injections of the vaccine, including a third dose, not only improves the seroconversion rate but also intensifies the immune response, both in B cells and T cells. Vaccines are an effective and well-tolerated method in this high-risk population. Some studies investigated the possibility of immune protection being transferred from a vaccinated donor to a recipient, with encouraging initial results. However, dynamic mutations and immune escape of the virus can lead to breakthrough infections with new variants in vaccinated individuals and still represent a threat of severe disease in allo-HSCT recipients. New challenges include the need to adapt vaccine protection to emerging variants.
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Drug Discovery Landscape
1 orphan drug designation for Rare acquired aplastic anemia.
1 orphan drug designation for Rare acquired aplastic anemia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Romiplostim | proteins | FDA | Amgen Inc. |
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