Nomogram establishment for short-term survival prediction in ICU patients with aplastic anemia based on the MIMIC-IV database.

OBJECTIVE: To establish an efficient nomogram model to predict short-term survival in ICU patients with aplastic anemia (AA). METHODS: The data of AA patients in the MIMIC-IV database were obtained and randomly assigned to the training set and testing set in a ratio of 7:3. Independent prognosis factors were identified through univariate and multivariate Cox regression analyses. The variance inflation factor was calculated to detect the correlation between variables. A nomogram model was built based on independent prognostic factors and risk scores for factors were generated. Model performance was tested using C-index, receiver operating characteristic (ROC) curve, calibration curve, decision curve analysis (DCA) and Kaplan-Meier curve. RESULTS: A total of 1,963 AA patients were included. A nomogram model with 7 variables was built, including SAPS II, chronic pulmonary obstructive disease, body temperature, red cell distribution width, saturation of peripheral oxygen, age and mechanical ventilation. The C-indexes in the training set and testing set were 0.642 and 0.643 respectively, indicating certain accuracy of the model. ROC curve showed favorable classification performance of nomogram. The calibration curve reflected that its probabilistic prediction was reliable. DCA revealed good clinical practicability of the model. Moreover, the Kaplan-Meier curve showed that receiving mechanical ventilation could improve the survival status of AA patients in the short term but did not in the later period. CONCLUSION: The nomogram model of the short-term survival rate of AA patients was built based on clinical characteristics, and early mechanical ventilation could help improve the short-term survival rate of patients.

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Hematopoietic stem cell transplantation (HSCT) is a therapeutic option for various potentially life-threatening malignant and non-malignant diseases in children, such as malignancies, immunodeficiency syndromes, severe aplastic anemia, and inherited metabolic disorders. During transplantation, many factors can affect the nutritional status of the children, including radiotherapy, chemotherapy, gastrointestinal disorders, graft-versus-host disease, and medications. Malnutrition has been associated with decreased overall survival and increased complications in children undergoing HSCT, making nutritional support a crucial component of their management. However, currently, there is a lack of guidelines or consensus on nutritional support for children undergoing HSCT in China. Therefore, this review summarizes the progress in nutritional support for children undergoing HSCT, aiming to provide clinical guidance.

Donor-type bone marrow aplasia following hematopoietic stem cell transplantation in a child with a novel SAMD9L variant.

Pathogenic variants in the genes SAMD9 (sterile a-motif domain containing protein - 9) and SAMD9L (SAMD9-like) cause bone marrow failure with characteristic syndromic features. We report a case of a previously healthy, 3-year-old boy with no dysmorphology, who presented with severe aplastic anemia and a novel variant in the SAMD9L gene. His father, elder brother and sister who harbored the same variant were completely healthy. In the absence of a matched unrelated donor, he underwent a stem cell transplant from his sister, a 10/10 match. Almost 2 years later he developed donor type aplasia and succumbed to an invasive fungal infection after a failed haplograft from his mother. This case highlights the pathogenicity of this previously undescribed germline variation of uncertain significance in the SAMD9L gene and the value of comprehensive genetic testing for inherited bone marrow failures even in the absence of a positive family history or characteristic congenital abnormalities.

Transformation of Severe Aplastic Anemia into Donor Cell Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation: A Rare Case Report.

BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important treatment for severe aplastic anemia (SAA). It is known that SAA can evolve into malignant clonal diseases, such as acute myeloblastic leukemia (AML) or myelodysplastic syndrome. However, the transformation of SAA into AML after allo-HSCT is a rare phenomenon. Here, we report a case of SAA transformed into AML after patient received human leucocyte antigen (HLA)-matched sibling peripheral blood stem cell transplantation. CASE REPORT A 51-year-old female patient presented with petechiae and fatigue and received a diagnosis of idiopathic SAA. The immunosuppressive therapy combined with umbilical cord blood transplantation failed for this patient. Then, she received HLA-matched sibling allogeneic peripheral blood stem cell transplantation (allo-PBSCT). However, 445 days after allo-PBSCT, the patient had a diagnosis of AML by bone marrow puncture. Donor-recipient chimerism monitoring and cytogenetic analysis confirmed that the leukemia was donor cell origin. Notably, a new HOXA11 mutation was detected in the peripheral blood of the patient after transplantation by whole-exome sequencing, which was the same gene mutation detected in the donor. The patient received 1 cycle of induction chemotherapy with azacytidine and achieved complete remission. However, the leukemia relapsed after 2 cycles of consolidation chemotherapy. Unfortunately, the patient died of leukemia progression 575 days after allo-HSCT. CONCLUSIONS The mechanism of how normal donor hematopoietic cells transform to leukemia in the host remains unclear. Donor cell leukemia provides a unique opportunity to examine genetic variations in donors and hosts with regards to the progression to malignancy.

Safety and efficacy of eltrombopag in patients with aplastic anemia: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: This article conducts a systematic review of eltrombopag combined with immunosuppressive therapy for the treatment of aplastic anemia (AA), to demonstrate the effectiveness and safety of eltrombopag. METHODS: PubMed, Cochrane Library, Embase, OVID, Web of Science, China National Knowledge Infrastructure, and Wanfang databases were searched. Studies that met the inclusion criteria were collected, ranging from the establishment of the database to August 2023. Two reviewers performed meta-analyses using the Cochrane systematic review method and RevMan 5.3 software. RESULTS: This meta-analysis enrolled 5 studies with a total of 542 AA patients, including 274 in the experimental group and 268 in the control group. Meta-analyses were performed for efficacy and adverse reactions. The endpoint of effects included 6-month complete response (CR), 6-month partial response (PR), and 6-month overall response (OR). Eltrombopag combined with immunotherapy showed significant improvements in 6-month CR (OR: 2.20; 95% CI;1.54-3.12; P < 0.0001) and 6-month OR (OR = 3.66, 95% CI 2.39-5.61, P < 0.001)compared to immunosuppressive therapy for AA patients. In terms of safety, eltrombopag combined with immunosuppressive therapy showed significantly increased pigment deposition and abnormal liver function compared to immunosuppressive therapy alone. CONCLUSION: Compared to immunosuppressive therapy alone, eltrombopag combined with immunosuppressive therapy showed significant improvements in 6-month CR and 6-month OR. However, it also resulted in increased pigment deposition and abnormal liver function in terms of safety.

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.

Haploidentical Hematopoietic Stem Cell Transplantation for Patients with Severe Aplastic Anemia-Single-Centre Experience.

Severe aplastic anemia (SAA) is a life-threatening type of aplastic anemia for which allogeneic stem cell transplantation or immunosuppressive therapy are the principal treatment modalities. Only about 25-30% of patients have a matched sibling donor, and finding an unrelated donor in ethnic minorities is a challenge. The use of related haploidentical donor transplants in severe aplastic anemia is uncommon. We would like to report our experience with the first four patients who underwent haploidentical transplants for severe aplastic anemia. This is a retrospective study. We collected data from our transplant database of all haploidentical hematopoietic stem cell transplants for SAA from 1 January 2020 to 31 December 2021. The transplant protocol used was the Hopkins' protocol. There were three patients who underwent haploidentical transplants as primary therapy for SAA. A fourth patient received a haploidentical transplant after immunosuppressive therapy failure. The median age of the patients at transplant was 24 y (range 20-29). All patients were engrafted. Neutrophil engraftment occurred at a median of 21 days (range 17-22). Any active infections resolved with the recovery of blood counts. The median hospitalization time was 27 days (range 22-41). Only one patient had grade 2 acute GVHD involving the skin. There was no chronic GVHD. All patients had complete lymphoid and myeloid donor chimerism on day 60. Based on our experience and the emerging literature, haplo-identical transplantation should be considered for select young patients with SAA who have low chances of responding to immunosuppressive therapy.

Exploring strategies to optimise outcomes in hepatitis-associated aplastic anaemia patients following haematopoietic stem cell transplantation.

This study aimed to assess haematopoietic stem cell transplantation (HSCT) safety and efficacy while exploring strategies for optimising outcomes in patients with hepatitis-associated aplastic anaemia (HAAA). We retrospectively reviewed 35 HAAA patients who underwent HSCT at a large Chinese blood disease hospital between 2008 and 2022. HAAA patients receiving HSCT typically presented with severe (28.6%) and very severe (65.7%) AA. Male patients predominated (68.6%), with a median onset age of 23 years (range, 9-44). Haploidentical donor-HSCT and matched sibling donor-HSCT were in comparable proportions. The 5-year overall survival (OS) rate was 74.0%, with cumulative incidences of grade II-IV acute and chronic graft-versus-host disease (GVHD) at 37.1% and 22.4%, respectively. A diagnosis-to-HSCT interval ≥ 75 days, acute GVHD, and post-HSCT liver events (e.g., hepatic GVHD and a three-fold increase in aminotransferase or bilirubin) significantly worsened 5-year OS. In the multivariate models, recipients with sex-matched grafts had better OS, and those with younger male donors had a lower incidence of II-IV aGVHD. Higher HLA matching degree (HLA > = 7/10) was an independent prognostic factor associated with better OS and GFFS. A diagnosis-to-HSCT interval ≥ 75 days was predictive of post-transplant liver events in HAAA patients. In conclusion, HSCT was a safe and effective treatment for HAAA. Early transplantation, careful donor selection and improving post-transplant liver events were crucial to optimise outcomes.

Aplastic anemia: history and recent developments in diagnosis and treatment.

Acquired aplastic anemia is an immune-mediated disease that targets hematopoietic stem cells, which is diagnosed by findings of peripheral blood pancytopenia and hypocellular bone marrow. Although the diagnostic definition is simple, differential diagnosis from other overlapping hematopoietic disorders such as hypoplastic myelodysplastic syndrome and inherited bone marrow failure syndrome is not easy. Immune suppressive therapy and allogeneic hematopoietic stem cell transplantation are important treatment approaches for aplastic anemia, and both have advanced in recent years. This issue of Progress in Hematology covers four topics related to aplastic anemia: (1) laboratory markers to identify immune pathophysiology and their role on differential diagnosis and prognosis, (2) the path to combination therapy with horse anti-thymocyte globulin, cyclosporine A, and eltrombopag, (3) more than 60 years of history and recent trends in allogeneic HSCT, and (4) genetic testing for differential diagnosis from IBMFS and novel approaches to transplantation for children including fludarabine/melphalan-based conditioning.

Metagenomic Next-Generation Sequencing (mNGS) of cerebrospinal fluid for diagnosis of human herpesvirus 6B encephalitis following transplantation for severe aplastic anemia.

INTRODUCTION: Human herpesvirus 6B (HHV-6B) encephalitis is common in immunosuppressed patients and presents a diagnostic challenge for physicians. Metagenomic next-generation sequencing (mNGS) may facilitate early diagnosis of HHV-6B encephalitis. Herein, we described a case of HHV-6B encephalitis following transplantation for severe aplastic anemia (SAA) diagnosed by mNGS. CASE SUMMARY: A 31-year-old male underwent myeloablative haploid hematopoietic stem cell transplantation for the treatment of SAA. On day + 21 after transplantation, the patient developed symptoms such as sudden epilepsy, drowsiness, memory dislocation, and memory loss. HHV-6B encephalitis was confirmed based on cranial MRI and mNGS of cerebrospinal fluid. Following antiviral therapy with sodium foscarnet, the symptoms improved and HHV-6B was negative by mNGS. There were no serious sequelae. Currently, the patient is in good health and is still under follow-up. CONCLUSIONS: A case of HHV-6B encephalitis after SAA transplantation was diagnosed by mNGS of cerebrospinal fluid in time and was effectively treated with sodium foscarnet.

Guidelines for the diagnosis and management of adult aplastic anaemia: A British Society for Haematology Guideline.

Pancytopenia with hypocellular bone marrow is the hallmark of aplastic anaemia (AA) and the diagnosis is confirmed after careful evaluation, following exclusion of alternate diagnosis including hypoplastic myelodysplastic syndromes. Emerging use of molecular cyto-genomics is helpful in delineating immune mediated AA from inherited bone marrow failures (IBMF). Camitta criteria is used to assess disease severity, which along with age and availability of human leucocyte antigen compatible donor are determinants for therapeutic decisions. Supportive care with blood and platelet transfusion support, along with anti-microbial prophylaxis and prompt management of opportunistic infections remain key throughout the disease course. The standard first-line treatment for newly diagnosed acquired severe/very severe AA patients is horse anti-thymocyte globulin and ciclosporin-based immunosuppressive therapy (IST) with eltrombopag or allogeneic haemopoietic stem cell transplant (HSCT) from a matched sibling donor. Unrelated donor HSCT in adults should be considered after lack of response to IST, and up front for young adults with severe infections and a readily available matched unrelated donor. Management of IBMF, AA in pregnancy and in elderly require special attention. In view of the rarity of AA and complexity of management, appropriate discussion in multidisciplinary meetings and involvement of expert centres is strongly recommended to improve patient outcomes.

Second haploidentical bone marrow transplantation with antithymocyte antibody-containing conditioning regimen for graft failure in eight patients with severe aplastic anemia.

The effects of a second haploidentical bone marrow transplantation with an antithymocyte antibody-containing conditioning regimen after graft failure in patients with severe aplastic anemia remain unclear. Eight severe aplastic anemia patients with graft failure with a median age of 12.5 (range, 3-22) years were retrospectively reviewed. At the second transplantation, they received a median mononuclear cell number of 15.7 (range, 11.2-20.9) × 108/kg or a median CD34+ cell number of 6.2 (range, 2.5-17.5) × 106/kg. They were all successfully engrafted, with a median time of 12.5 (range, 11-16) days for neutrophils and 24 (range, 14-50) days for platelets. Three patients developed skin acute graft-versus-host disease Grades I-II, and another 3 developed limited chronic graft-versus-host disease. All patients successfully recovered after treatment with methylprednisolone (0.5-1 mg/kg/day) and tacrolimus. One patient each died of respiratory failure caused by multidrug-resistant Klebsiella pneumoniae at 8 months and invasive fungal disease at 23 months after transplantation. Six patients survived with a 5-year estimated overall survival of 75% and a median follow-up time of 61 (range, 8-129) months. A second haploidentical bone marrow transplantation with an antithymocyte antibody-containing conditioning regimen was feasible for saving severe aplastic anemia patients with graft failure.

A multicentre ambispective observational study into the incidence and clinical management of aplastic anaemia in Spain (IMAS study).

Aplastic anemia (AA) is a rare, life-threatening hematological disease, with a poorly defined incidence. As the data available on AA varies substantially worldwide, a multicenter, ambispective, observational study was carried out between 2010 and 2019 to assess the incidence, clinical management and survival of AA at seven Spanish hospitals. The incidence of AA was 2.83 per million inhabitants per year, consistent with that reported previously in Europe, with a median age at diagnosis of 61 years-old (range 12-86), and a similar number of males and females. The initial diagnosis was severe or very severe AA in 55.8% of cases and 93.7% required transfusion. The most frequent first line therapy was anti-thymocyte globulin (ATG) plus cyclosporin A (CsA, 44.2%), followed by other CsA-based regimes (46.3%), with hematopoietic stem cell transplantation an infrequent 1st line therapy. The 6-month response rate was 68.2%, which then increased over a median follow-up of 3.9 years. The 5-year overall survival (5OS) was 73.6%, similar in severe (78.6%) and very severe AA patients (74.6%) but lower in moderate AA (MAA) patients (68.4%). The 5OS was 100% in 0-25 year-old patients but dropping to 58.3% in patients ≥ 60 years-old. At the last contact, 75.8% of the patients were alive. In conclusion, the incidence, characteristics and management of AA in our study are consistent with that reported previously. In terms of survival, although the global long-term OS rate was good, there is room for improvement, particularly in older patients. Finally, what appears to be a worse long-term survival of MAA patients, as reported previously, reinforces the importance of not underestimating this condition when diagnosed as MAA.

Upfront Umbilical Cord Blood Transplantation Versus Immunosuppressive Therapy for Pediatric Patients With Idiopathic Severe Aplastic Anemia.

Umbilical cord blood transplantation (UCBT) has been rarely reported as a first-line treatment for idiopathic severe aplastic anemia (SAA) patients lacking HLA-matched sibling donors (MSD). Our study aimed to compare the clinical outcomes of pediatric SAA patients who received UCBT and immunosuppressive therapy (IST) upfront. A retrospective analysis was performed on 43 consecutive patients who received frontline IST (n = 17) or UCBT (n = 26) between July 2017 and April 2022. The 3-year overall survival (OS) was comparable between the UCBT and IST groups (96.2% versus 100%, P = .419), while the 3-year event-free survival (EFS) was significantly better in the former than in the latter (88.5% versus 58.8%, P = .048). In the UCBT group, 24 patients achieved successful engraftment, 2 patients developed severe acute graft-versus-host disease (aGVHD), no extensive chronic GVHD (cGVHD), and a high GVHD-free, failure-free survival (GFFS) of 84.6% at 3 years. After 1 year of treatment, 12 patients in the IST group responded, while 5 patients did not achieve remission and 2 patients had disease relapse. At both 3 and 6 months after treatment, the proportion of transfusion-independent patients was higher in the UCBT group than in the IST group. Faster immune recovery and earlier transfusion independence further reduced the risk of infection and bleeding, thereby improving health-related quality of life in the UCBT-treated group. Our results suggested that UCBT as upfront therapy may be an effective and safe option for pediatric SAA patients, with favorable outcomes in experienced centers.

Diagnostic evaluation in bone marrow failure disorders: what have we learnt to help inform the transplant decision in 2024 and beyond?

Aplastic anemia (AA) is the prototypical bone marrow failure syndrome. In the current era of readily available 'molecular annotation', application of comprehensive next-generation sequencing panels has generated novel insights into underlying pathogenetic mechanisms, potentially leading to improvements in personalized therapeutic approaches. New evidence has emerged as to the role of somatic loss of HLA class I allele expression in 'immune-mediated' AA, associated molecular aberrations, and risk of clonal evolution. A deeper understanding has emerged regarding the role of 'myeloid' gene mutations in this context, translating patho-mechanistic insights derived from wider clinical and translational research within the myeloid disorder arena. Here, we review contemporary 'tools' which aid in confirmation of a diagnosis of AA, with an additional focus on their potential in guiding therapeutic options. A specific emphasis is placed upon interpretation and integration of this detailed diagnostic information and how this may inform optimal transplantation strategies.

Current use of androgens in bone marrow failure disorders: a report from the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation.

Androgens represent the historical therapeutic backbone of bone marrow failure (BMF) syndromes. However, their role has rarely been analyzed in a prospective setting, and systematic and long-term data regarding their usage, effectiveness and toxicity in both acquired and inherited BMF are currently unavailable. Here, taking advantage of a unique disease-specific international dataset, we retrospectively analyzed the largest cohort so far of BMF patients who received androgens before or in the absence of an allogeneic hematopoietic cell transplantation (HCT), re-evaluating their current use in these disorders. We identified 274 patients across 82 European Society for Blood and Marrow Transplantation (EBMT) affiliated centers: 193 with acquired (median age 32 years) and 81 with inherited (median age 8 years) BMF. With a median duration of androgen treatment of 5.6 and 20 months, respectively, complete and partial remission rates at 3 months were 6% and 29% in acquired and 8% and 29% in inherited disorders. Five-year overall survival and failure-free survival (FFS) were respectively 63% and 23% in acquired and 78% and 14% in inherited BMF. Androgen initiation after second-line treatments for acquired BMF, and after >12 months post diagnosis for inherited BMF were identified as factors associated with improved FFS in multivariable analysis. Androgen use was associated with a manageable incidence of organ-specific toxicity, and low rates of solid and hematologic malignancies. Sub-analysis of transplant-related outcomes after exposure to these compounds showed probabilities of survival and complications similar to other transplanted BMF cohorts. This study delivers a unique opportunity to track androgen use in BMF syndromes and represents the basis for general recommendations on this category of therapeutics on behalf of the Severe Aplastic Anemia Working Party of the EBMT.

The Protective Effect of Chronic Intermittent Hypobaric Hypoxia on Preventing the Destruction of CD34+ Haematopoietic Stem Cells in Aplastic Anaemia by Modulating the Th1/Th2 Balance.

Aplastic anaemia (AA) is a haematopoietic disorder caused by immune-mediated attack on haematopoietic stem cells (HSCs). Stem cell transplantation and immunosuppressive therapy remain the major treatment choice for AA patients but have limited benefits and undesired side effects. The aim of our study was to clarify the protective role of immunity of chronic intermittent hypobaric hypoxia (CIHH) and the underlying mechanism in AA. Our integrative analysis demonstrated that CIHH pre-treatment significantly improved haematopoiesis and survival in an AA rat model. We further confirmed that CIHH pre-treatment was closely associated with the Th1/Th2 balance and a large number of negative regulatory haematopoietic factors, such as TNF-α and IFN-γ, produced by hyperactive Th1 lymphocytes released in AA rats, which induced the death program in a large number of CD34+ HSCs by activating the Fas/FasL apoptosis pathway, while CIHH pre-treatment effectively downregulated the expression of TNF-α and IFN-γ, resulting in a reduction in Fas antigen expression in CD34+ HSCs. In summary, this study provides evidence that CIHH has good protective effect against AA by modulating immune balance in Th1/Th2 cells and may provide a new therapeutic strategy.

Comparison of Stem Cell Transplantation Using Unrelated, Haploidentical, and Sibling Donors for Patients with Acquired Severe Aplastic Anemia: A Single-Center Retrospective Cohort Study.

The preferred donor (haploidentical donor [HID] versus matched unrelated donor [URD]) choice in patients with acquired severe aplastic anemia (SAA) who lack an HLA-matched sibling donor (MSD) and fail upfront immunosuppressive treatment (IST) therapy is unknown. We retrospectively investigated SAA patients (n = 58) who underwent allogeneic stem cell transplantation (allo-SCT) between January 2012 and October 2022. The 5-year overall survival (OS) and 5-year failure-free survival (FFS) were comparable among the URD (n = 8), HID (n = 25), and MSD (n = 25) cohorts (OS: mean, 87.5 ± 11.7% versus 98.0 ± 6.5% versus 83.3 ± 7.6% [P = .926]; FFS: mean, 60.0 ± 18.2% versus 87.0 ± 7.0% versus 78.3 ± 8.6% [P = .222]). Multivariate analysis revealed that primary engraftment failure independently predicted OS and secondary graft failure predicted FFS among SAA patients who underwent allo-SCT, but donor type and age were not predictive of these outcomes. An urgent second SCT for patients with engraftment failure may be an effective salvage treatment. Our findings show that an alternative donor SCT is indicated for eligible SAA patients without an MSD even if age ≥40 years.