Children with non-malignant hematological disorders (NMHD) often require numerous red blood cell transfusions prior to hematopoietic stem cell transplant (HSCT), leading to iron overload. Ferritin and liver iron concentration (LIC) are used to estimate the degree of iron overload to determine eligibility for HSCT, but neither marker has been definitively associated with poorer HSCT outcomes in pediatric cohorts. We conducted a multicenter retrospective cohort study using PEDSnet to examine the association between elevated pre-HSCT ferritin and LIC and HSCT outcomes, and to evaluate iron reduction therapy post-transplant. 580 patients with a pre-HSCT ferritin and 260 patients with a pre-HSCT LIC were studied. Patients with high pre-HSCT ferritin >2500 ng/mL had decreased 3-year overall survival (adjusted HR 2.31, 1.06-5.04). A sensitivity analysis demonstrated this trend only in patients with severe aplastic anemia (SAA). Elevated ferritin was associated with a markedly increased risk of bacteremia after HSCT in patients with SAA (HR 3.33, 1.72 - 6.44). Elevated pre-HSCT LIC >5 mg Fe/g dry weight was not associated with decreased survival, bacteremia, graft failure, or veno-occlusive disease (VOD). VOD was assessed only in patients undergoing busulfan-based transplant. Post-transplant, 63% of patients in the multicenter analysis had an elevated ferritin, while 68% had an elevated LIC. Chelation and phlebotomy were equally effective in reducing post-HSCT iron. These results challenge the use of LIC as the gold standard for iron-related risk stratification in HSCT. Further research into peri-HSCT iron management is necessary in an era of expanding availability of HSCT for NMHD.

Neurofibromatosis type I -related severe aplastic anemia: an unusual association with a complicated bone marrow transplantation course.

Bone marrow transplantation from matched and mismatched unrelated donors with post-transplant cyclophosphamide for patients with severe aplastic anemia.

Who is the best allogeneic hematopoietic stem cell transplant donor for severe aplastic anemia? Data from the Chinese Bone Marrow Transplantation Registry Group (CBMTRG).

Discussion remains concerning the safety and tolerability of anti-thymocyte globulin (ATG)-based immunosuppressive therapy (IST) in older patients with aplastic anaemia (AA). Using data of 127 consecutive patients from the Dutch adult AA registry, we evaluated long-term treatment success of standard ATG-based IST as first-line treatment with a multi-state model. Only one death was potentially associated with ATG. Overall survival at 5 years was 79%. We defined Transplantation-, Treatment- and Disease-Free Survival (TT-DFS) as the ultimate success of this treatment. This means that a patient is alive, is currently transfusion-independent without having received an allogeneic stem cell transplantation, has not developed AML or MDS, and has stopped all medication for AA. The probability of TT-DFS was 42% at 5 years after start of IST. In patients younger than 40 years (n = 36) and in patients aged 60 or above (n = 53), this was 58% and 34%, respectively. Older age, more severe AA and absence of a PNH-clone of ≥ 1% all reduced the likelihood of reaching TT-DFS. These analyses on unselected nationwide data indicate that ATG-based IST is effective and safe also in older patients. They suggest that age, AA severity and presence of a PNH-clone should be taken into account when considering this treatment in older patients.

Hepatitis-associated aplastic anaemia is a rare entity that can sometimes be life-threatening due to its rapid progression to liver failure, necessitating an urgent liver transplantation (LT). Treating severe aplastic anaemia following an LT can be very challenging. While immunosuppressive therapy (IST) has been reported to have some success, the vulnerable state of these patients in addition to the time taken for IST to work makes this a less suitable option for the majority of patients. Haematopoietic stem cell transplantation (HSCT) with matched related donors has been reported as a curative option; there has been less success using alternate donors. Here, we present our experience of predominantly alternate donor HSCT following liver transplantation in an extremely high-risk group of 10 children. Overall survival was 90% at a median of 38 months post-LT. Surviving children have normal blood counts, normal liver function and performance status. No liver-related complications or significant graft versus host disease were encountered. Multiple infective and non-infective post-HSCT complications were successfully treated with excellent multidisciplinary input. Upfront HSCT, even with alternate donors, can be lifesaving if performed in a timely manner, following close liaison between liver transplantation and HSCT teams and with the appropriate multidisciplinary support.

Revisiting the Diagnostic Approach to Epstein-Barr Virus-associated Severe Aplastic Anemia in Children.

The efficacy of a triple combination of rabbit anti-human thymocyte immunoglobulin (rATG), ciclosporin and eltrombopag (EPAG) was prospectively evaluated in patients with severe or transfusion-dependent non-severe aplastic anaemia (SAA) across 29 institutions in Japan. Sixty patients were enrolled, of whom 48 had SAA. The primary end-point, the haematological overall response rate at 12 weeks, was 52.6% (95% confidence interval, 39.0%-66.0%), increasing to 67.9% at 26 weeks. The most frequent grade 3/4 adverse event was febrile neutropenia (20.0%). One elderly patient with severe neutropenia died of sepsis. Progression to myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) was observed in one patient each. There was no association between the haematological response and high thrombopoietin levels, presence of paroxysmal nocturnal haemoglobinuria-type cells or Human Leukocyte Antigen (HLA)class I allele-lacking cells. Five patients (8.5%) had chromosomal abnormalities at baseline with no subsequent progression to MDS or AML. By 26 weeks, chromosomal abnormalities had emerged or expanded in eight patients (17.4%), although abnormalities of chromosome 7 were not observed within 52 weeks. These results suggest that triple therapy with rATG may be as effective as that with horse anti-human thymocyte immunoglobulin. Notably, the addition of EPAG did not induce chromosomal abnormalities associated with poor prognosis.

Long-term outcomes of αβ T-cell/CD19 B-cell-depleted peripheral blood stem cell transplantation from unrelated donors in pediatric and adolescent patients with severe aplastic anemia: a single-center study.

Hematopoietic stem cell transplantation (HSCT) has been the therapy of choice for treating some hematologic malignancies and selected non-malignant disorders for decades. With the introduction of novel immunotherapeutic and cell-mediated approaches, the role of autologous HSCT (auto-HSCT) and allogeneic HSCT (allo-HSCT) should be redefined. Auto-HSCT remains the standard of treatment for multiple myeloma, Hodgkin?s lymphoma, and non- Hodgkin?s lymphoma. The use of novel agents, including proteasome inhibitors, immunomodulatory drugs, monoclonal and bispecific antibodies, enhances the intensity and efficacy of the therapeutic response and opens debate on an optimized timing for HSCT. Allo-HSCT represents the most effective type of adoptive immunotherapy, ensuring complete and long-term hematopoietic reconstitution, of-ten accompanied by the graft-versus-leukemia effect. It re-mains the main curative treatment for acute leukemias, high-risk myelodysplastic and myeloproliferative syndromes, and severe aplastic anemia. Improvements in stem cell (SC) donor selection, ex vivo manipulations of harvested cells, and graft engineering with superior immune monitoring have broadened and expanded their applicability, while improving safety and clinical outcome. Despite rapid progress in cellular and other immunotherapies, HSCT continues to play an essential role in the treatment of numerous hematologic disorders. A combination of HSCT with novel drugs and other immunotherapies offers the potential for personalized and safer treatment with long-term positive clinical outcomes, ensuring that HSCT remains a highly relevant method in modern medicine. The aim of this re-view was to summarize current biological concepts of SCs, as well as important advances in the rapidly developing fields of SC research, and to determine the place and efficacy of HSCT nowadays, in the era of new therapeutic approaches and agents.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for severe aplastic anemia (SAA). In China, the number of SAA patients undergoing allo-HSCT has risen considerably. However, owing to variations in clinical practices between China and other countries, certain aspects of transplantation demonstrate unique and distinct characteristics. To address these unique challenges and standardize clinical practice, we developed evidence-based guidelines tailored to the management of Chinese SAA patients undergoing allo-HSCT. This clinical practice guideline was developed using the Evidence to Decision framework and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to formulate evidence-based recommendations. In instances where high-quality evidence was lacking, the Delphi method was used to integrate expert opinions. The guidelines adhere to the Appraisal of Guidelines for Research and Evaluation II (AGREE II) framework and the Reporting Items for Practice Guidelines in Health Care (RIGHT) statement to ensure methodological rigor and transparency. The guidelines present 32 recommendations encompassing key aspects of allo-HSCT for SAA, including patient eligibility criteria, donor and graft selection, pretransplant assessment and conditioning strategies, graft-versus-host disease prophylaxis, early management of posttransplant complications, and long-term follow-up. These recommendations are based on the latest clinical evidence and expert consensus, offering a structured approach to optimize transplantation outcomes. These guidelines establish standardized protocols to enhance allo-HSCT management for SAA in China by integrating current evidence and expert consensus. Its widespread adoption is expected to improve donor selection strategies, conditioning regimen applications, posttransplant care, and long-term patient outcomes. Ultimately, these recommendations aim to increase the quality of patient care, improve survival rates, and contribute to the advancement of national health care standards.

Mesenchymal stem cells (MSCs) are multipotent stem cells with critical functions, including immunomodulation, multidirectional differentiation, anti-inflammatory activity, tissue repair, and regeneration. Recent studies demonstrate that MSCs can enhance hematopoietic stem cell engraftment, mitigate graft-versus-host disease (GVHD), address transplant-related complications, and treat conditions such as immune thrombocytopenia (ITP) and severe aplastic anemia (SAA). These therapeutic effects are largely attributable to the immunomodulatory and anti-inflammatory properties of MSCs. However, in hematologic malignancies, MSCs can exert both pro-tumor and anti-tumor influences. Exosomes, which are extracellular vesicles derived from MSCs (MSC-EVs), not only replicate many MSC functions but also exhibit greater chemical stability and lower immunogenicity. These characteristics make MSC-EVs particularly significant in the context of hematopoietic stem cell transplantation (HSCT). This review provides a detailed overview of the roles and clinical applications of MSCs in hematologic diseases, the properties of MSC-EVs, and their emerging significance in HSCT.

ObjectivesHepatitis‐associated aplastic anemia (HAAA) is described as acute severe hepatitis of unknown origin followed by bone marrow failure (BMF). We aimed to provide a comprehensive picture of pediatric HAAA.MethodsTwo‐center retrospective analysis was performed using data from children diagnosed with acquired BMF, including severe aplastic anemia (SAA) and myelodysplastic syndrome type refractory cytopenia of childhood (RCC). The assessment of the subcohort of HAAA included clinical features indicative of diagnosis and disease progression, with additional data from previously published case series.ResultsCohort comprised 62 children with acquired BMF and 22 children with HAAA. Median age of HAAA patients was 13.5 years. Potentially triggering viral infections were detected in 45%. The median interval from hepatitis onset to cytopenia was 3 weeks. All cases presented with severe hepatitis (median alanine transaminase 2127 U/L) and all but one with hyperbilirubinemia (median bilirubin 15.3 mg/dL). Coagulopathy was variable (median international normalized ratio 1.5). Four patients (18%) developed acute liver failure, two (9%) required liver transplantation. Hepatic parameters normalized within a median of 8.5 weeks. There was no statistically significant difference in the course of hepatitis between patients with SAA and RCC. Early lymphopenia was a key finding in patients with HAAA, progressing from a median of 905/µL at hepatitis onset to 530/µL within 4 weeks.ConclusionsHAAA occurs in both SAA and RCC. Most cases present with severe acute cholestatic hepatitis and variable coagulopathy. Hepatic recovery is common. Lymphopenia at disease onset is frequent and may serve as a diagnostic marker.

Treatment algorithms for severe aplastic anemia (SAA) are evolving. A hematopoietic cell transplant (HCT) from a matched sibling donor is preferred for younger patients with SAA, whereas immunosuppressive treatment (IST) has traditionally been recommended for older patients. Because of the toxicity and risk associated with HCTs from alternative donors (ie, matched unrelated donors, haploidentical donors, or umbilical cord blood units), this approach has generally been reserved for patients who have experienced relapse after IST or have proved refractory to it. However, the recent development of reduced-toxicity conditioning regimens and the use of posttransplant cyclophosphamide as prophylaxis for graft-versus-host disease have significantly reduced the risk of morbidity and mortality after HCT. These changes have also expanded the pool of donors such that alternative donors are now increasingly being used for HCTs for patients with SAA. With the use of these novel HCT regimens and improved supportive care practices, overall survival and disease-free survival after HCT have improved over the last few decades, and disease-free survival after HCT may now be superior to that after IST. Several ongoing clinical trials are evaluating the use of matched unrelated donors and have expanded the use of haploidentical donors in the up-front setting for treatment-naive patients, thereby challenging the equipoise that has existed in this field for decades. These advances may usher in a paradigm shift in the management of SAA in the coming years.

Hematopoetic Stem Cell Transplantation (HSCT) in pediatric patients with Severe Aplastic Anemia (SAA): the Greek experience

Background: Severe aplastic anemia (SAA) is a potentially fatal disorder of bone marrow failure with a high risk of life-threatening infections and bleeding. While matched sibling donor transplantation remains the preferred therapy, immunosuppressive treatment with horse anti-thymocyte globulin (hATG), cyclosporine, and eltrombopag is the standard first-line option for non-transplant candidates. However, a significant proportion of patients fail to respond, and access to allogeneic transplantation is severely restricted in resource-limited settings due to prohibitive costs and infrastructure constraints. In such scenarios, rabbit anti-T lymphocyte globulin (rATLG) emerges as an important second-line salvage therapy.Methods: This hospital-based retrospective study included 10 patients with SAA or very severe aplastic anemia (VSAA), aged ≥13 years, treated at King George’s Medical University, Lucknow, between 2020 and 2024. All patients had relapsed or refractory disease following hATG and were ineligible for transplantation. rATLG was administered at 3.5 mg/kg/day for five days alongside cyclosporine and eltrombopag. Responses were assessed at three, six, and 12 months, with survival analysed using Kaplan-Meier (KM) estimates (censoring applied for patients alive or lost to follow-up at the last contact).Results: The cohort had a median age of 23 years, with 70% (7/10 patients) classified as SAA and 30% (3/10 patients) as VSAA. Four had refractory disease, six had relapsed disease, and three harboured a PNH clone. At 12 months, 40% (4/10 patients) achieved partial response; no complete responses were observed. Overall survival (OS) at two years was 78% (95% CI: 40.3-94.9) by KM estimate. The most common adverse events were fever, pruritus, hepatic dysfunction, and infections.Conclusion: Although modest in efficacy, rATLG offers a clinically meaningful salvage option in transplant-ineligible SAA patients, particularly in low-resource settings where curative transplantation is often inaccessible. Our findings underscore the role of rATLG as a bridge therapy, while highlighting the urgent need for wider access to definitive curative options in developing countries.

BackgroundHaploidentical hematopoietic stem cell transplantation (HID-HSCT) serves as an alternative treatment for severe aplastic anemia (SAA) patients lacking a suitable HLA-identical sibling donor. Compared to HLA-matched HSCT, HID-HSCT has higher rates of graft failure (GF) and graft-versus-host disease (GVHD). Recent studies suggest promising clinical outcomes when Mesenchymal stem cells (MSCs) are combined with HID-HSCT for SAA treatment.MethodsThis study retrospectively analyzed clinical data from 190 SAA patients who underwent HID-HSCT with or without MSCs co-infusion. Patients were divided into two groups: the HID group (100 patients receiving only HID-HSCT) and the HID+MSC group (90 patients receiving HID-HSCT combined with MSC co-infusion).ResultsThe analysis revealed that the HID+MSC group had a significantly higher 5-year overall survival rate compared to the HID group (86.6% vs. 75.0%, p = 0.036) and a significantly improved GRFS rate (76.6% vs. 64.0%, p = 0.048). While MSCs co-infusion did not significantly reduce the incidence of aGVHD or cGVHD, a downward trend was observed, particularly for cGVHD (16.6% vs. 26.0%). Both groups showed high cumulative engraftment rates for NE and PLT within 28 days post-transplant, with no significant differences. Regarding viral reactivation, EBV and CMV reactivation rates were similar between the two groups, though four patients in the HID group developed EBV-associated PTLD.ConclusionThis study demonstrates that combining HID-HSCT with MSCs co-infusion is a safe and effective therapeutic strategy that significantly improves survival rates and quality of life in SAA patients.

Wartime conditions present major challenges to the timely diagnosis and management of severe aplastic anemia (SAA). We describe 3 previously healthy military service members who developed idiopathic SAA during active duty. In all 3 patients, no chronic illnesses were documented in the medical records, and no specific toxin exposures or prior hepatitis were recorded. All experienced a gradual onset of cytopenias accompanied by hemorrhagic symptoms, initial misclassification as immune thrombocytopenia or myelodysplastic syndrome, and war-related delays to definitive therapy. Each required prolonged transfusion support and broad-spectrum antibiotics for neutropenic complications. Two patients received immunosuppressive therapy (antithymocyte globulin plus cyclosporine A) four to 5 months after diagnosis, while the youngest underwent urgent allogeneic bone marrow transplantation. Despite severe logistical constraints, all survived the acute phase but remained transfusion-dependent at discharge. These cases underscore the need to strengthen medical logistics and ensure early access to specialized hematologic care to improve SAA outcomes during wartime.

Acquired severe aplastic anemia is a rare, life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow. It shows a bimodal age distribution, with approximately 70–80% of cases classified as idiopathic. Recent advances in hematopoietic cell transplantation, immunosuppressive therapy, biological agents, and supportive care have greatly improved survival rates, reaching a 95% cure rate. Differential diagnoses include refractory cytopenia of childhood, inherited bone marrow failure syndromes, and other blood disorders. The aim of this article was to update the Brazilian consensus previously published by the Brazilian Society of Cellular Therapy and Bone Marrow Transplantation in 2021, highlighting the latest developments in the treatment and monitoring of severe aplastic anemia patients undergoing hematopoietic cell transplantation.

ABSTRACTBackgroundThe use of romiplostim, a thrombopoietin agonist, has increased in the last decade for the treatment of immune mediated thrombocytopenia and severe aplastic anemia. Its utility has been explored in the management of delayed platelet engraftment and secondary platelet failure during stem cell transplant (SCT), but its use has remained largely anecdotal in pediatric allogeneic SCT.MethodsIn this single centre, retrospective study we report the largest pediatric SCT cohort use of romiplostim.ResultsRomiplostim was used in 17 children for several indications, principally including poor graft function (PGF) and immune‐mediated cytopenia (IMC), including multi‐lineage cytopenia. The overall response rate (ORR) was 76.5% and the median time to achieve OR was 42 days. No toxicity was observed with romiplostim including marrow fibrosis, clonal evolution and thrombosis with a median follow‐up of 18 months. Romiplostim averted the need for second allogeneic SCT in two patients with late graft failure and the need for stem cell boost (SCB) in three patients.ConclusionWe propose that romiplostim can be safely used in the cytopenia in pediatric SCT to good effect.