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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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 | 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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