cell therapies

2026-07-30 | Living Donor Liver Transplantation as Salvage Therapy for Steroid-Refractory Chronic Hepatic GVHD Following Allogeneic Hematopoietic Stem Cell Transplantation.

Hepatic graft-versus-host disease (GVHD) is a rare but life-threatening complication following allogeneic hematopoietic stem cell transplantation (HSCT). Steroid-refractory hepatic GVHD carries a high risk of mortality with limited salvage options. Liver transplantation after HSCT poses unique challenges due to dual alloimmunity and is rarely pursued, particularly in pediatric patients. We report a pediatric patient with steroid-refractory chronic hepatic GVHD successfully treated with living donor liver transplantation (LDLT) from a parental donor. A 13-year-old male underwent allogeneic HSCT for idiopathic severe aplastic anemia and developed progressive chronic hepatic GVHD characterized by ductopenia and severe cholestasis. His disease was refractory to corticosteroids and multiple additional therapies, including ruxolitinib, mesenchymal stromal cells, infliximab, sirolimus, anti-thymocyte globulin, alpha-1 antitrypsin, cyclophosphamide, and emapalumab. His course was complicated by Epstein-Barr virus (EBV) associated post-transplant lymphoproliferative disorder (PTLD), successfully treated with rituximab. Fifteen months after HSCT, and seven months after clearance of EBV viremia, he underwent LDLT from a parental donor. Donor selection preserved the option for future donor-derived EBV-specific cytotoxic T lymphocyte therapy if needed. Eleven months following LDLT, the patient remains clinically well, with normal liver function, sustained full donor chimerism, and no evidence of recurrent GVHD or PTLD. LDLT may represent a viable option in select pediatric patients with irreversible chronic hepatic GVHD. This case underscores the importance of early multidisciplinary planning and highlights the absence of liver-specific biomarkers or targeted therapies to guide management. Dedicated research into preventive and regenerative strategies is warranted.

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2026-01-29 | Alpha/beta-T-cell depleted hematopoietic stem cell transplantation from unrelated and haploidentical donors in children with idiopathic aplastic anemia

Introduction. Hematopoietic stem cell transplantation (HSCT) from an alternative donor is the main treatment option for patients with severe acquired aplastic anemia (AAA) refractory to combined immunosuppressive therapy with anti-thymocyte globulin and cyclosporine A. Although the outcomes of unrelated and haploidentical HSCTs have improved over the years, graft-versus-host disease (GVHD) continues to pose a major clinical challenge associated with significant morbidity and mortality. Aim: to present the outcomes of unrelated and haploidentical HSCTs with TCRαβ-depleted grafts in patients with AAA. Materials and methods. Eighty patients (42 males and 38 females) with AAA underwent HSCT between September 2012 and February 2022. The median age at transplantation was 10 (2.3–22.7) years. Seventy-eight patients received HSCT after relapse or refractory disease after one (n = 14) or two (n = 18) courses of immunosuppressive therapy. Two patients underwent HSCT as first-line treatment. The median time from diagnosis to transplantation was 1 (0.1–11.8) year. Conditioning regimen included cyclophosphamide (100–150 mg/kg), fludarabine (150 mg/kg), antithymocyte globulin (ATGAM (100 mg/kg) or thymoglobulin (5–10 mg/kg)), and thoracoabdominal irradiation (2–6 Gy). In some cases, additional medications such as melphalan (140 mg/m2), thiophosphamide (5–10 mg/kg), and rituximab (200 mg/m2) were used. Patients with paroxysmal nocturnal hemoglobinuria (n = 6) received eculizumab at a dose of 600 mg from day –7 to day +14 (every 7 days). Post-transplant GVHD prophylaxis included calcineurin inhibitors. TCRαβ/CD19 depletion was performed using a CliniMACS Plus system (Miltenyi Biotec, Bergish Gladbach, Germany). The median CD34+ cell dose in the graft was 10 (2.7–23.0) × 10⁶/kg, and the median TCRαβ+ cell dose was 26.6 (0.85–316.00) × 10³/kg. Results. The cumulative incidence of engraftment was 0,95 (95% confidence interval (CI) 0.9–1.0) with the median time to neutrophil recovery being 13 (9–24) days and to platelet recovery – 12 (7–25) days. Graft rejection occurred in 9 patients, the cumulative incidence of rejection was 0,11 (95% CI 0.06–0.20). Three of these patients underwent successful retransplantation. The cumulative incidence of grade II–III acute GVHD was 0,12 (95% CI 0.05–0.27) in the patients who had undergone unrelated donor HSCT versus 0,42 (95% CI 0.29–0.61) in the haploidentical HSCT recipients (p = 0.003). The cumulative incidence of chronic GVHD was 0,5 (95% CI 0.01–0.20) in the unrelated donor HSCT group and 0,21 (95% CI 0.12–0.38) in the haploidentical HSCT group (p = 0.02). The median follow-up was 6.4 years. Twenty-two (27.5%) patients died. Sixteen of them died of complications after the first HSCT; 4 deaths occurred due to complications associated with repeat HSCT. Two patients died after graft rejection due to infectious complications. The overall survival was 0,79 (95% CI 66–91) in the unrelated donor HSCT group and 0,66 (95% CI 51–81) in the haploidentical donor HSCT group. Conclusion. The use of TCRαβ/CD19-depleted HSCT from alternative donors ensured high engraftment rates and reduced the incidence of severe GVHD. However, there were no significant improvements in graft rejection or mortality.

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2026-01-01 | Umbilical Cord Blood Transplantation for Patients with Idiopathic and Inherited Bone Marrow Failure Disorders

Abstract Umbilical cord blood transplantation (UCBT) offers a viable hematopoietic stem cell source for patients with idiopathic and inherited bone marrow failure (BMF) syndromes lacking matched related donors (MRDs) or matched unrelated donors (MUDs). Although its use has declined with the rise of haploidentical transplantation, UCBT remains crucial for select patients, especially children. The approach is associated with rapid donor availability, low graft versus host disease (GvHD) risk, and favorable outcomes in matched settings. Retrospective data and prospective trials demonstrate encouraging survival, particularly with appropriate cell dose, minimal human leukocyte antigen (HLA) mismatch, and fludarabine (Flu)-based reduced-intensity conditioning (RIC) regimens. Specific syndromes such as Fanconi anemia (FA), severe aplastic anemia (SAA), dyskeratosis congenita (DC), and Diamond–Blackfan anemia (DBA) highlight distinct challenges and considerations in UCBT application. While matched sibling UCBT shows excellent outcomes, unrelated UCBT requires careful patient selection and transplant expertise. As research advances and transplant protocols evolve, UCBT remains a critical option in the curative landscape for patients with BMF syndromes.

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2025-08-11 | Autologous Cord Blood Transplantation for Idiopathic Severe Aplastic Anemia

Cord blood units are seldom used for autologous transplantation and selection criteria have not been defined. A 6-year-old male with severe aplastic anemia received an autologous cord blood transplantation containing total nucleated cells (TNC) 2.0×107/kg and CD34+0.32×105/kg. However, he lost the graft and was rescued with a second, haploidentical donor graft. Together with those reported in the literature, 15 children with aplastic anemia received autologous cord blood transplantation. Thirteen children succeeded but 2 failed. Successful transplantation can be predicted by TNC doses of >2.5×107/kg (12/12 vs. 1/3; P=0.029), but not by CD34+ dose or patient's age. Cord blood units with adequate TNC are valid products for autologous transplantation.

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2024-10-22 | Features of the course and tactics of pregnancy management in a patient with relapse of idiopathic aplastic anemia

A clinical observation of the course of pregnancy in a patient with relapse of idiopathic aplastic anemia is presented. The peculiarities of pregnancy management, approaches to therapy, as well as outcomes for mother and fetus are analyzed. The authors concluded that the use of modern methods of diagnosis, treatment, and blood transfusion support can prolong pregnancy to term and reduce the risks of adverse maternal and fetal outcomes.

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small molecules

2026-05-01 | Two Sides of the Same Coin, Pathogenic RTEL1 Mutations

Background Regulator of telomere elongation helicase 1 (RTEL1) is a gene that encodes a DNA helicase crucial for DNA repair and telomere maintenance. It belongs to a family of genes associated with telomere biology disorders (TBD). The phenotypic spectrum of RTEL1 mutations is highly variable, encompassing bone marrow failure, idiopathic pulmonary fibrosis, cirrhosis, and malignancy due to excessive telomere erosion. Objective We describe two patients at opposite ends of age, both with pathogenic variants in RTEL1. Clinical Case Descriptions Patient 1 was admitted to the hospital at 3 years of age due to failure to thrive and chronic diarrhea, found to have refractory CMV colitis and CMV and HHV6 viremia. She developed toxic megacolon secondary to CMV, requiring a subtotal colectomy. She underwent a reduced-intensity conditioning matched sibling donor bone marrow transplant (BMT) and ileorectal anastomosis. She was referred at age 4 for immune evaluation due to severe inflammatory bowel disease (IBD)-like gastrointestinal (GI) disease with suboptimal response to steroids and vedolizumab. She was treated with danazol with resolution of her diarrhea and, interestingly, hair regrowth. Patient 2 is a 61-year-old female with leukopenia and recurrent fevers without infection. She was previously healthy with no history of autoimmunity or recurrent infections. She had atypical CD8-positive T cell lymphoid infiltration on liver biopsy with elevated inflammatory cytokines and was referred for immune dysregulation. Investigations Patient 1 had an elevated fecal calprotectin of 889 ug/g and had a homozygous pathogenic RTEL1 variant c.2869C>T (P.Arg957Trp). Patient 2 had an expanded CD8+ T cell population (74%) with a low CD4/CD8 ratio (0.19) and reduced B cells (1%), while immunoglobulin levels remained within the normal range. Cytokine studies showed elevated IFN-y (49pg/mL), elevated CXCL9 (32, 454pg/mL), and elevated soluble IL-2 receptor (5,899 pg/mL) with no evidence of hemophagocytic lymphohistiocytosis (HLH) or granulomas on bone marrow biopsy. She had a heterozygous pathogenic RTEL1 variant: c.3791G>A (p.Arg1264His). Discussion These two cases highlight the phenotypically distinct presentations of pathogenic RTEL1 across the age spectrum. When discovered in older adults, it raises the question of somatic mutations, though germline heterozygous pathogenic variants have been described. Danazol and BMT are being considered in patient 2. Figure 1. Schematic representation of RTEL1 variants with respect to functional protein domains. Variants in P1 and P2 with respect to the RTEL1 function protein domains. HD, N-terminal helicase domain; HHD1 and HHD2, harmonin homology domains 1 and 2; PIP, PCNA-interacting protein box; RING, C-terminal C4C4 type RING domain. Reference transcript NM_001283009.2, adapted from (1). Created using Biorender.com.

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2026-04-30 | Efficacy and safety of cyclosporine plus luspatercept versus cyclosporine in newly diagnosed non-transfusion-dependent non-severe aplastic anemia: A prospective randomized trial.

The clinical need for treating anemia in aplastic anemia (AA) patients remains unmet. Luspatercept has been shown to be effective in myelodysplastic neoplasms (MDS). Patients who were newly diagnosed with non-transfusion-dependent non-severe AA (NTD-NSAA) were randomly assigned to receive either cyclosporine (CsA) combined with luspatercept or CsA monotherapy at a 1:1 ratio. This study (ClinicalTrials.gov NCT05399732) aimed to compare their treatment responses, safety, disease progression, and outcomes. In total, 58 patients participated in the final analysis, with 29 receiving CsA+luspatercept and 29 receiving CsA monotherapy. With a median follow-up of 12 months (range: 6-25) and 12 months (range: 7-25), respectively, the overall response rates (ORRs) were 69.0% vs. 37.9% (p = 0.018) at the 3rd month, 79.3% vs. 51.7% (p = 0.027) at the 6th month, and 72.4% vs. 51.7% (p = 0.104) at the end of follow-up. Patients receiving CsA+luspatercept had a shorter time to achieve a positive response than those receiving CsA alone (p = 0.004). A post hoc subgroup analysis based on age (< 60 vs. ≥60 years) showed no significant difference in ORRs for those < 60 years old. However, for patients ≥ 60 years old receiving CsA+luspatercept, a significantly greater ORR was demonstrated at both the 3rd month (p = 0.032) and 6th month (p = 0.046) compared with CsA monotherapy. Compared with CsA monotherapy, the combination of CsA and luspatercept resulted in a higher response rate and a shorter time to response for patients with NTD-NSAA, with an acceptable safety profile. The benefit of CsA+luspatercept was most pronounced in older patients.

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2026-01-01 | complementary use of homeopathy with conventional therapy in aplastic anemia: a case reports

Aplastic anemia (AA) is a life-threatening hematological disease evident by impaired bone marrow function and subsequent pancytopenia, often leading to considerable clinical complications. Conventional treatments include immunosuppressive therapy and/or stem cell transplantation. Compared to younger patients, elderly AA patients have been associated to lower survival rates, a higher risk of dysplastic development, lesser response to first-line treatment and more severe thrombocytopenia. Some patients pursue complementary therapies alongside standard care to enhance recovery and reduce treatment-related stress. A 69-year-old woman with symptoms of fatigue, petechial hemorrhage and gingival bleeding was diagnosed with idiopathic severe aplastic anemia after a laboratory examination. She had conventional immunosuppressive treatment and adopted homeopathy as a supplemental therapy. Individualized Homeopathic Medicine Phosphorus in 30c potency along with supportive homeopathic medicines Lecithin in 6c potency and Ferrum Metallicum in 30c potency was prescribed to her during treatment. Over 2 years, the patient demonstrated significant hematological improvement and enhanced quality of life. This case illustrates the safe and potentially beneficial integration of classical homeopathy with standard treatment in aplastic anemia. Continued research efforts are essential to formulate integrative care frameworks that incorporate homeopathic support alongside conventional treatment to optimize clinical results and patient well-being.

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2026-01-01 | Paroxysmal Nocturnal Hemoglobinuria: Bone Marrow Failure and Beyond

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is embedded with idiopathic/immune aplastic anemia (AA) because of both common pathophysiology and clinical association. Indeed, over 40% of AA patients may exhibit a PNH population within their mature blood cells, and the expansion of hematopoietic progenitors carrying the PIGA mutation (the somatic mutation eventually accounting for PNH) is not considered a random phenomenon in AA since PIGA -mutated cells are thought likely to be able to escape from the (auto)immune attack causing AA (Ref Neal/jarek and Luzzatto/rotoli, plus notaro/gargiulo). Clinically speaking, the spectrum of overlap between PNH (which is clinically characterized by the triad of hemolysis, thrombophilia, and bone marrow failure (BMF)) and AA ranges from classical PNH with nonmeaningful cytopenia to typical AA with nonmeaningful PNH clonal populations (i.e., subclinical PNH). Meaningful clinical overlap between PNH and AA is described as AA/PNH syndrome or intermediate PNH, depending on the severity of cytopenia. Here, we will focus on the diagnosis and management of bone marrow failure associated with PNH, highlighting that the management of these patients is not different from that of patients with isolated AA (i.e., in the absence of meaningful PNH clonal populations). Except for the higher risk of thrombosis, patients with AA and a PNH clone should be managed the same way as compared to patients with idiopathic anemia without a clone. Sibling transplantation is mandatory for patients aged less than 40–50 when a matched family donor is available; immunosuppression using the association of horse antithymocyte globulin (ATG), cyclosporine, and eltrombopag (paying attention to the increased risk of thromboembolic complications) is the reference treatment for other patients. In some very rare cases, a significant intravascular hemolysis is associated, which may justify associating a treatment with complement inhibitors. Considering the recent advances in the field of anticomplement therapies, we will also briefly describe the novel data with new complement inhibitors, introducing the concept of proximal inhibitors as well as describing their possible role in changing the treatment paradigm of hemolytic PNH.

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2025-11-05 | Overrepresentation of Germline Immune-Related Gene Variants in Patients with Acquired Bone Marrow Failure.

Bone marrow failure (BMF) in idiopathic aplastic anemia (AA) and hypoplastic myelodysplastic neoplasms (MDS-h) results from the destruction of hematopoietic progenitors by autoreactive T cells; however, the molecular events driving the pathogenesis of these disorders remain unclear. We therefore applied whole-exome sequencing (WES) in AA and MDS-h patients to identify acquired and inherited gene variants presumed to have functional consequences for BMF. We also used transcriptome profiling to investigate the molecular mechanisms underlying the aberrant T cell response. WES was performed on DNA from 42 patients at diagnosis. Transcriptome profiling of CD3⁺ cells was conducted in 21 patients and 10 healthy donors. Peripheral blood cell populations were analyzed by flow cytometry. Pathogenic/likely pathogenic (P/LP) somatic gene variants were detected in 79% of patients and were functionally associated with BMF-relevant processes such as antigen processing/presentation, T cell-mediated immunity, and DNA repair. P/LP germline gene variants were found in all patients, almost half of whom harbored variants associated with inborn errors of immunity. Patient T cells displayed expression signatures of increased inflammation, apoptosis, hypoxia response, and decreased oxidative phosphorylation. Dysregulated long noncoding RNAs were predicted to primarily regulate the differentiation of T helper 17 cells. Patients also showed significantly lower frequencies of immature progenitors and natural killer cells compared with controls. Patients with idiopathic AA and MDS-h carried multiple germline immune-related gene variants that may increase susceptibility to immune-mediated BMF. Furthermore, patient T cells exhibited altered energy metabolism, which may represent a therapeutic target for modulating immune responses in autoimmune diseases.

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proteins

2021-11-29 | A Review of Romiplostim Mechanism of Action and Clinical Applicability.

Thrombocytopenia results from a variety of conditions, including radiation, chemotherapy, autoimmune disease, bone marrow disorders, pathologic conditions associated with surgical procedures, hematopoietic stem cell transplant (HSCT), and hematologic disorders associated with severe aplastic anemia. Immune thrombocytopenia (ITP) is caused by immune reactions that accelerate destruction and reduce production of platelets. Thrombopoietin (TPO) is a critical component of platelet production pathways, and TPO receptor agonists (TPO-RAs) are important for the management of ITP by increasing platelet production and reducing the need for other treatments. Romiplostim is a TPO-RA approved for use in patients with ITP in the United States, European Union, Australia, and several countries in Africa and Asia, as well as for use in patients with refractory aplastic anemia in Japan and Korea. Romiplostim binds to and activates the TPO receptor on megakaryocyte precursors, thus promoting cell proliferation and viability, resulting in increased platelet production. Through this mechanism, romiplostim reduces the need for other treatments and decreases bleeding events in patients with thrombocytopenia. In addition to its efficacy in ITP, studies have shown that romiplostim is effective in improving platelet counts in various settings, thereby highlighting the versatility of romiplostim. The efficacy of romiplostim in such disorders is currently under investigation. Here, we review the structure, mechanism, pharmacokinetics, and pharmacodynamics of romiplostim. We also summarize the clinical evidence supporting its use in ITP and other disorders that involve thrombocytopenia, including chemotherapy-induced thrombocytopenia, aplastic anemia, acute radiation syndrome, perisurgical thrombocytopenia, post-HSCT thrombocytopenia, and liver disease.

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2021-03-17 | Treg sensitivity to FasL and relative IL-2 deprivation drive idiopathic aplastic anemia immune dysfunction.

Idiopathic aplastic anemia (AA) has 2 key characteristics: an autoimmune response against hematopoietic stem/progenitor cells and regulatory T-cells (Tregs) deficiency. We have previously demonstrated reduction in a specific subpopulation of Treg in AA, which predicts response to immunosuppression. The aims of the present study were to define mechanisms of Treg subpopulation imbalance and identify potential for therapeutic intervention. We have identified 2 mechanisms that lead to skewed Treg composition in AA: first, FasL-mediated apoptosis on ligand interaction; and, second, relative interleukin-2 (IL-2) deprivation. We have shown that IL-2 augmentation can overcome these mechanisms. Interestingly, when high concentrations of IL-2 were used for in vitro Treg expansion cultures, AA Tregs were able to expand. The expanded populations expressed a high level of p-BCL-2, which makes them resistant to apoptosis. Using a xenograft mouse model, the function and stability of expanded AA Tregs were tested. We have shown that these Tregs were able to suppress the macroscopic clinical features and tissue manifestations of T-cell-mediated graft-versus-host disease. These Tregs maintained their suppressive properties as well as their phenotype in a highly inflammatory environment. Our findings provide an insight into the mechanisms of Treg reduction in AA. We have identified novel targets with potential for therapeutic interventions. Supplementation of ex vivo expansion cultures of Tregs with high concentrations of IL-2 or delivery of IL-2 directly to patients could improve clinical outcomes in addition to standard immunosuppressive therapy.

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1996-05-01 | Recombinant Interleukin-1 Followed by immunosuppressive therapy for aplastic anemia

American Journal of HematologyVolume 52, Issue 1 p. 61-62 Letters and CorrespondenceFree Access Recombinant Interleukin-1 Followed by immunosuppressive therapy for aplastic anemia Kristine Doney, Kristine Doney Division of Clinical Research, Fred Hutchinson Cancer Research Center, Department of Medicine, University of Washington, Seattle, WashingtonSearch for more papers by this authorRainer Store, Rainer Store Division of Clinical Research, Fred Hutchinson Cancer Research Center, Department of Medicine, University of Washington, Seattle, WashingtonSearch for more papers by this authorKathy Lilleby, Kathy Lilleby Division of Clinical Research, Fred Hutchinson Cancer Research Center, Department of Medicine, University of Washington, Seattle, WashingtonSearch for more papers by this authorFrederick R. Appeleaum, Frederick R. Appeleaum Division of Clinical Research, Fred Hutchinson Cancer Research Center, Department of Medicine, University of Washington, Seattle, WashingtonSearch for more papers by this author Kristine Doney, Kristine Doney Division of Clinical Research, Fred Hutchinson Cancer Research Center, Department of Medicine, University of Washington, Seattle, WashingtonSearch for more papers by this authorRainer Store, Rainer Store Division of Clinical Research, Fred Hutchinson Cancer Research Center, Department of Medicine, University of Washington, Seattle, WashingtonSearch for more papers by this authorKathy Lilleby, Kathy Lilleby Division of Clinical Research, Fred Hutchinson Cancer Research Center, Department of Medicine, University of Washington, Seattle, WashingtonSearch for more papers by this authorFrederick R. Appeleaum, Frederick R. Appeleaum Division of Clinical Research, Fred Hutchinson Cancer Research Center, Department of Medicine, University of Washington, Seattle, WashingtonSearch for more papers by this author First published: May 1996 https://doi.org/10.1002/1096-8652(199605)52:1<61::AID-AJH2830520102>3.0.CO;2-4Citations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume52, Issue1May 1996Pages 61-62 ReferencesRelatedInformation

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1992-03-30 | A trial of recombinant human interleukin-1 in patients with severe refractory aplastic anaemia.

We report here the effects of in vivo administration of recombinant interleukin-1 alpha (rIL-1 alpha) to patients with severe, idiopathic aplastic anaemia. Four patients who were refractory to immunosuppressive therapy and were not bone marrow transplantation candidates received daily doses of 0.03 microgram/kg and 0.10 microgram/kg intravenously as 5 d courses. No significant changes in either peripheral blood counts or bone marrow cellularity were observed at either dose during or following therapy. Two patients showed increased numbers of bone marrow progenitor colonies. Lymphocyte phenotyping demonstrated an elevated percentage of CD8+/DR+ activated suppressor T lymphocytes prior to therapy. After rIL-1 alpha administration, the percentage of CD8+/DR+ cells was reduced or returned to normal in all patients. Significant side-effects included fever, rigours, fatigue, headache and nausea. Transient hypotension was observed at both doses in all patients. These results suggest that while rIL-1 alpha can be safely administered, no significant haematologic improvement was observed in patients with severe aplastic anaemia.

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gene therapies

2026-05-01 | C29-13 Somatic Variants Rescue Bone Marrow Failure, But Not Lung Disease in Patients With Germline Variants in TINF2

Abstract Introduction Telomeres are essential for genome maintenance. Rare variants disrupting telomere maintenance genes cause a spectrum of short telomere syndromes, with idiopathic pulmonary fibrosis (IPF) as the most common phenotype. Variants in the shelterin component TIN2 typically cause severe pediatric dyskeratosis congenita (DC) and bone marrow failure. However, a subset of patients with germline TINF2 variants presents with less severe, adult-onset disease, including IPF, suggesting the presence of modifying factors. Methods We identified three patients with pathogenic germline TINF2 hotspot variants evaluated at the University of Pittsburgh Medical Center for lung transplantation. Two had a family history of DC; one had a sporadic presentation. Clinical genetic testing and deep exome sequencing was used to identify somatic variants. We validated the function of somatic variants in vitro using CRISPR/Cas9-mediated genome editing in multiple cell lines and in patient-derived induced pluripotent stem cells (iPSCs). Results All three patients had somatic variants in the DNA-binding domain of POT1 where tumor-specific variants have been previously reported. Edited cells showed no signs of DNA damage, genomic instability, or altered growth kinetics. Telomeres progressively lengthened in all edited lines. iPSCs reprogrammed from patient PBMCs, which harbored both the germline TINF2 and somatic POT1 variants, also demonstrated gradual telomere lengthening, verifying the POT1 variants are functional and sufficient for telomere elongation, even in the context of the pathogenic TINF2 variant. Conclusions Somatic POT1 variants appear to rescue hematopoietic function and cause telomere lengthening in vitro. POT1 editing is efficient and does not appear to influence genome stability. We propose that genetically modifying POT1 may be an effective therapy to rescue the bone marrow of patients with short telomeres. This abstract is funded by: NA

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2025-08-23 | Identification of molecular heterogeneity in telomere maintenance pathway of aplastic anemia.

AIM: Aplastic anemia (AA) is a hematological disorder accompanying with hypocellular marrow and heterogenous characteristics of bi or pancytopenia. This study was undertaken to identify the genetic and epigenetic heterogeneity in telomere maintenance pathway in AA. MATERIALS AND METHODS: Peripheral blood samples were collected from idiopathic AA cases (n = 60) and age-matched healthy subjects (n = 43). To evaluate genetic factors, whole exome and targeted resequencing was performed among AA cases and age-matched healthy subjects. Differential gene expression of telomere maintenance pathway and evaluation of predicted miRNA, hsa-miR-1202 was assessed through SYBR green based quantitative real-time PCR. The results were then correlated with clinical parameters. RESULTS: Majority (95%) of AA cases exhibited significantly reduced average telomere length (p value < 0.001) compared to age-matched healthy subjects except 5% of AA cases. 25 genetic variations in 15 genes were observed exclusively among AA cases with shorter telomere, that may be associated with pathogenesis of Aplastic anemia. Specifically, a heterozygous deleterious variation in TMEM173 gene (NM_198282: exon7: c. G878A: p. R293Q, rs7380824) was found exclusively among cases with short telomere that might be used as a possible marker to identify the pathogenic scenarios of bone marrow. Positive correlation of upregulated hsa-miR-1202 was found to be associated with their target genes (RAPGEF5 and MANEA). Additionally, these altered genes and the miR1202 also have a significant negative correlation with platelet count. CONCLUSION: Estimation of average telomere length, genetic variation and gene expression pattern might indicate a novel diagnostic approach towards new treatment regimen of idiopathic AA cases with an emphasis on telomere maintenance pathway.

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2025-04-11 | Clinical and genetic spectrum of SBDS and DNAJC21 gene variants in bone marrow failure cases: Atypical and cryptic presentations.

Shwachman-Diamond syndrome (SDS) is a rare bone marrow failure disorder presenting with early onset cytopenia, chronic diarrhea, and failure to thrive with biallelic pathogenic variants in the SBDS (SDS1; 260400) gene. Recently, biallelic variants in DNAJC21 (BMFS3; 617052) and ELF1 genes have also been shown to be related to SDS-like phenotype. Additionally, a monoallelic variant of the SBDS gene has been linked to the development of idiopathic aplastic anemia (IAA). We screened 405 marrow failure cases and noted 10 different SDS gene variants in 3 % (11/405) cases, of which 2 (20 %) were novel; DNAJC21 variant c.98-2delA and SBDS variant c.359T>C. In this report, we highlight the detailed phenotype and genotype of these cases and emphasize cryptic and atypical presentations.

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2025-04-04 | Inherited aplastic anaemia/bone marrow failure syndromes

The inherited bone marrow (BM) failure syndromes are a diverse group of disorders characterised by BM failure usually in association with one or more extra-haemopoietic abnormality. The BM failure, which can involve one or more cell lineages, often presents in childhood. Furthermore, some patients initially labelled as having ‘idiopathic aplastic anaemia’ or ‘myelodysplasia’ represent cryptic presentations of these syndromes. Significant advances in the genetics of these syndromes have been made with more than 100 disease genes identified. These advances have given insights into normal haemopoiesis and how this is disrupted in patients with BM failure. In the clinic, genetic tests stemming from the recent advances are facilitating diagnosis. Haemopoietic stem cell transplantation using fludarabine-based protocols have improved outcomes significantly particularly for patients with FA and DC. Management of some of the other complications, such as cancer, remains a challenge. Recent studies suggest the possibility of new and potentially more efficacious therapies. This includes renewed focus on haemopoietic gene therapy and drugs that target disease-specific defects.

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2023-11-25 | Pediatric Bone Marrow Failure: A Broad Landscape in Need of Personalized Management.

Irreversible severe bone marrow failure (BMF) is a life-threatening condition in pediatric patients. Most important causes are inherited bone marrow failure syndromes (IBMFSs) and (pre)malignant diseases, such as myelodysplastic syndrome (MDS) and (idiopathic) aplastic anemia (AA). Timely treatment is essential to prevent infections and bleeding complications and increase overall survival (OS). Allogeneic hematopoietic stem cell transplantation (HSCT) provides a cure for most types of BMF but cannot restore non-hematological defects. When using a matched sibling donor (MSD) or a matched unrelated donor (MUD), the OS after HSCT ranges between 60 and 90%. Due to the introduction of post-transplantation cyclophosphamide (PT-Cy) to prevent graft versus host disease (GVHD), alternative donor HSCT can reach similar survival rates. Although HSCT can restore ineffective hematopoiesis, it is not always used as a first-line therapy due to the severe risks associated with HSCT. Therefore, depending on the underlying cause, other treatment options might be preferred. Finally, for IBMFSs with an identified genetic etiology, gene therapy might provide a novel treatment strategy as it could bypass certain limitations of HSCT. However, gene therapy for most IBMFSs is still in its infancy. This review summarizes current clinical practices for pediatric BMF, including HSCT as well as other disease-specific treatment options.

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other

2026-08-01 | Idiopathic AA Renal Amyloidosis Treated with Tocilizumab — A Case Report

Background Amyloidosis represents a heterogeneous group of disorders characterized by the deposition of misfolded protein. Among its subtypes, serum amyloid A (AA) amyloidosis arises when persistent systemic inflammation drives hepatic production of SAA. Excess SAA misfolds into insoluble fibrils that deposit in organs such as the kidneys, causing progressive proteinuria, loss of renal function and eventual renal failure. Standard management aims to control the underlying inflammation to reduce SAA production and halt further amyloid deposition. For example, interleukin-6 blockade with tocilizumab, which suppresses SAA production, has shown encouraging results in small series of patients with secondary amyloidosis. [1,2] In rare cases without an identifiable source of inflammation, however, no targeted therapies have been shown to be effective. Case Report We report a 48-year-old female first found incidentally at the age of 37 to have renal impairment. Over the past decade, her eGFR had declined to 12mL/min/1.73m 2 , with 3g/L of proteinuria. Renal biopsy in 2020 confirmed widespread AA amyloid deposits with severe interstitial fibrosis and 11/16 glomeruli globally sclerosed, with SAA concentrations exceeding 16,000ng/mL. Throughout her entire course, she had no infectious, rheumatologic or constitutional symptoms. Other than a RF titer of 30 IUx103/L, extensive investigations were negative, including bone marrow biopsy, rheumatologic markers (CCP, ANA, dsDNA, C3/C4, ANCA, ESR, CRP) and infectious serologies (hepatitis, syphilis, schistosoma, strongyloides, whipples, tuberculosis, HIV, HTLV, filariasis). A thorough genetic investigation was also negative including sequencing for the SAA1 gene, panels containing genes associated with hereditary amyloidosis and autoinflammatory diseases, as well as a research exome. A brief trial of colchicine was initially trialed but stopped due to worsening kidney function. Tocilizumab 160mg SC every 2 weeks was initiated in December 2024 in an attempt to suppress hepatic SAA production. A year after, SAA levels fell from >16,000 to 5,427ng/mL. Her GFR stabilized at 13 mL/min/1.73m 2 , and dialysis has not yet been required at the time of writing. Conclusion Idiopathic AA amyloidosis is a therapeutic challenge due to the condition’s rarity and lack of standard therapies. While there are numerous publications demonstrating the efficacy of tocilizumab in secondary AA amyloidosis,[1-3] our case is the first we are aware of, describing this therapeutic effect in idiopathic AA amyloidosis. This case underscores the central role of interleukin-6 in SAA production and may form the foundation for future studies with more patients over a longer duration to further explore the disease-modifying benefits of tocilizumab in idiopathic AA amyloidosis. References [1.] Okuda Y. Mod Rheumatol 2019;29:268-74. [2.] Courties A. Amyloid 2015;22:84-92. [3.] Yamagata A. BMC Nephrol 2017;18:377.

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2024-11-05 | Characterization of Complement and Immunoglobulin Deposition in Bone Marrow Trephine Biopsies of Patients with Cytopenias

Cytopenias can be categorized in “peripheral”, such as autoimmune hemolytic anemias (AIHA), immune thrombocytopenic purpura (ITP), and chronic idiopathic/autoimmune neutropenia (CIN/AIN), and “central”, including disorders such as aplastic anemia (AA) and myelodysplastic neoplasms (MDS). Several overlaps exist between the two forms, with a clear role of the humoral and complement immune response in the former, that is however less known in the latter. We assessed complement fractions C3 and C4, IgM and IgG deposits by immunohistochemistry on bone marrow biopsies from 162 cytopenic patients diagnosed between 2016 and 2023 at a tertiary hematologic center, reference for immune cytopenias, in Milan, Italy. Deposits were expressed using a semiquantitative scale from 0 to +3 by an expert hemopathologist. The topographical distribution was then evaluated and categorized as serous versus precursors pattern. We collected laboratory data at diagnosis to evaluate a correlation with the immunohistochemical data. Overall, 28 AIHA, 15 ITP, 58 CIN/AIN, 12 AA, and 49 lower-risk MDS were accrued. A significantly greater deposition of C3 and C4 (≥2+) was found in AA and MDS versus peripheral cytopenias (42% and 33% in AA, 49% and 41% in MDS versus 21% and 14% in all peripheral cytopenias, p=0.004 and p=0.002, respectively). Ig deposition was significantly greater (≥ 3+) in MDS and AA (63% and 42% for IgM and 49% and 33% for IgG, respectively) versus peripheral cytopenias (39% for IgM and 11% for IgG, respectively, p &lt; 0.05); notably, IgM deposition was particularly evident in AIHA, ≥ 3+ in 50% of cases. Topographically, most of C3 and C4 deposition showed a serous pattern, while deposition on precursors was observed in 25% of MDS cases (mainly C3) and 42% of AIHA (mainly C4). IgG/M deposits were equally distributed on serum and precursors in all disease category. Hb and reticulocytes values were negatively correlated with C4 deposits in MDS patients (r= -0.031, p=0.01 for Hb and r= -0.29, p=0.02 for reticulocytes). Bone marrow cellularity negatively correlated with IgM deposits in AA (r= -0.72, p=0.004). Finally, platelet counts negatively correlated with IgM deposits in ITP (r=-0.5, p=0.02). In conclusion, our data demonstrated a significant deposition of complement and Ig in bone marrow of patients with “peripheral” and “central” cytopenias, more marked in the latter. The correlation with hematological parameters hints for a role of the immune attack against bone marrow precursors in all these conditions and might foster innovative therapeutic approaches.

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2021-09-24 | Detection and treatment of cerebral toxoplasmosis in an aplastic pediatric post-allogeneic hematopoietic cell transplant patient: a case report.

Cerebral toxoplasmosis infection presents with non-specific neurologic symptoms in immunocompromised patients. With lack of measurable adaptive immune responses and reluctance to sample affected brain tissue, expedient diagnosis to guide directed treatment is often delayed. We describe the use of cerebrospinal fluid polymerase chain reaction and plasma cell-free DNA technologies to supplement neuroimaging in the diagnosis of cerebral toxoplasmosis in an immunocompromised pediatric patient following allogeneic hematopoietic cell transplantation for idiopathic severe aplastic anemia. Successful cerebral toxoplasmosis treatment included antibiotic therapy for 1 year following restoration of cellular immunity with an allogeneic stem cell boost. Plasma cell-free DNA technology provides a non-invasive method of rapid diagnosis, improving the likelihood of survival from often lethal opportunistic infection in a high risk, immunocompromised patient population.

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2019-05-14 | Evaluating the Efficacy and Anti-infective Effect of High-dose Intravenous Immunoglobulin Adjuvant Therapy for Acquired Aplastic Anemia Children.

The efficacy and anti-infective effect of high-dose intravenous immunoglobulin (HDIVIG) in severe or very severe aplastic anemia children were evaluated. In total, 61 patients who underwent immunosuppressive therapy were retrospectively reviewed. The non-IVIG group (30 cases) received rabbit-antithymocyte protein (R-ATG, 3 to 5 mg/kg/d, for 5 consecutive days)+cyclosporin A (CSA), and the HDIVIG group (31 cases) underwent R-ATG+CSA+immunoglobulin (1 g/kg/d, for 2 consecutive days, once a month, 6 times). The early effective rate was higher in the HDIVIG group (P=0.020). However, the long-term effective rate and the 5-year overall survival rates difference were not statistically significant (P=0.717, 0.419). The infection rate and severe infection rate in the HDIVIG group were lower (P=0.003, 0.008). The infection-related mortality differences were not statistically significant after ATG application (P>0.05). In the HDIVIG group, 9 patients were nonresponders. Among the nonresponders, 8 patients' first-dose IVIG was given within 7 days before ATG. HDIVIG may increase the early effective rate and reduce early infection and serious infection for aplastic anemia children, but failed to reduce the infection-related mortality.

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