The use of therapeutic plasma exchange in tandem with continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO) has been well described; however, evidence showing the use of extracorporeal photopheresis (ECP) in tandem is lacking. Here we report a consult to perform ECP in tandem with CRRT for a 26-year-old female with a history of severe aplastic anemia who underwent allogeneic hematopoietic stem cell transplant, complicated by steroid-refractory acute graft-versus-host disease, vaso-occlusive disease, thrombotic microangiopathy, adenoviremia, and acute renal and respiratory failure. We performed six tandem ECP procedures (seven total) over 19 days, until the patient's decline resulted in compassionate discontinuation of care. During our procedures, CRRT managed the ionized calcium and adjusted the calcium infusion rate accordingly. We encountered red blood cell and optic bowl sensor alarms during ECP. This case, to our knowledge, is the first to describe the inpatient use of ECP in tandem with CRRT.

Eltrombopag combined with horse antithymocyte globulin and cyclosporine A (CSA) is the standard of care for patients with severe aplastic anemia who are not eligible for stem cell transplantation. No consensus exists on the optimal treatment of moderate aplastic anemia (MAA). The "Eltrombopag for MAA" (EMAA) trial is an investigator-initiated, prospective, randomized, placebo-controlled, double-blind, multicenter, phase III trial and compared eltrombopag+CSA (n=41) with placebo+CSA (n=44) as a first-line therapy for MAA patients with clinically significant cytopenia. In patients with evaluable response at week 24 (n=75), the overall response rate (ORR), including partial response (PR) and complete response (CR), was significantly higher in the eltrombopag+CSA arm (71.4%; 95% confidence interval [CI], 54.8%-83.8%) than in the placebo+CSA arm (42.5%; 95% CI, 28.5%-57.8%) (p=0.011, Fisher's exact test; primary endpoint). After response assessment at week 24 and unblinding, patients in the placebo arm without CR were switched to receive eltrombopag in addition to continued CSA. This group achieved an ORR of 73.5% by week 48 (p=0.009, McNemar test, comparing response at 24 vs. 48 weeks). Relapse rate and failure-free survival did not differ significantly among the arms. Eltrombopag was well tolerated without new safety concerns. Adding eltrombopag to CSA for first-line treatment of MAA significantly improves trilineage hematologic response at week 24 and addition of eltrombopag in patients without CR after 24 weeks of single-agent CSA treatment also significantly improves the ORR. The trial was registered at www.clinicaltrials.gov as #NCT02773225 and at European Union Drug Regulating Authorities Clincial Trials as EudraCT2014-000174-19.

Severe aplastic anemia (SAA) is a serious medical condition that is characterized by its abrupt onset, rapid progression of the disease, and alarmingly high mortality rate, making it a significant concern in the field of hematology. Intensive immunosuppressive therapy (IST) is one of the primary therapeutic options; however, some SAA patients do not respond to initial IST treatment. For these patients, salvage treatment remains a significant challenge. Consequently, predicting the efficacy of IST for SAA at initial diagnosis and developing the optimal curative regimen could potentially enhance treatment outcomes. The concurrent presence of trisomy 8 and a BCL6 corepressor (BCOR) mutation in SAA is uncommon and may independently predict the efficacy of IST. In this case report, we presented a SAA patient exhibiting both trisomy 8 and a BCOR mutation at diagnosis. The bone marrow (BM) aspirate showed hypocellular BM and the bone marrow biopsy revealed a severe hypocellular bone marrow (15% cellularity). The patient experienced rapid clinical improvement, evidenced by reduced transfusion requirements and a favorable response to IST. Approximately two year's post-IST, a follow-up biopsy indicated remission, with the volume of hematopoietic tissue increasing to 40%. Cytogenetic analysis showed a normal karyotype, and no BCOR mutation was detected by next-generation sequencing (NGS). Complete blood cell count results also showed improvement. In conclusion, we are the first to report a rare case of SAA characterized by the simultaneous presence of chromosome 8 abnormality and BCOR mutation in detail, which may represent a new distinct entity in SAA.

Fanconi anemia (FA) is a rare disease with a deficient homologous recombination DNA repair pathway and high sensitivity to mitomycin C (MMC). In FA cells, hydroxyurea (HU), when applied in the G2 phase of the cell cycle, exacerbates the chromosomal aberrations (CAs) induced by MMC. Here, we study how exposure to HU in the G2 phase results in an increased CAs frequency in FA cells with or without prior treatment with MMC. We performed chromosome aberration analysis, flow cytometry, and mRNA and protein expression in lymphoblastoid cell lines. We found that HU alone induces post-replicative DNA damage in the form of DNA double-strand breaks (DSBs) in both wild-type and FA cells and a similar increase in the activation of DSBs marker ɣH2AX. HU potentiates the amount of CAs only in MMC-treated FA cells by multiple mechanisms, including (1) hindering the ɣH2AX signal, (2) impairing the translocation of ribonucleotide reductase (RNR) into the cell nucleus, and (3) promoting the activity of WIP1 phosphatase. Concomitantly, increased levels of cell death were observed in FA cell cultures. HU induces DNA damage and potentiates pre-existent damage in FA cells by preventing the translocation of the RNR component p53R2 into the nucleus and activating checkpoint recovery, thus allowing the survival of a proportion of FA cells that have adapted to DNA damage.

Platelet products are essential for preventing and treating bleeding in patients with thrombocytopenia. However, their short shelf life and reliance on voluntary blood donations pose significant challenges to maintaining a stable supply. To overcome these limitations, induced pluripotent stem cell-derived platelets (iPSC-PLTs) have emerged as a promising alternative. The clinical application of iPSC-PLTs succeeded in demonstrating safety in an autologous transfusion setting; however, allogeneic applications remain unexplored. Here, we report the world's first clinical evaluation of an allogeneic iPSC-PLT product. An immortalized megakaryocyte cell line (imMKCL) was established from an iPSC line by introducing 3 inducible genes-c-MYC, BMI1, and BCL-XL-and subsequently generating master and working cell banks. Using the working cell bank and turbulent flow bioreactors, an allogeneic iPSC-PLT product, MEG-002, was successfully produced with clinically relevant quality and yield. MEG-002 underwent comprehensive structural and functional characterization, including in vivo efficacy testing in rabbit models, which confirmed its functionality. Preclinical safety studies revealed no concerns. A clinical trial was conducted in accordance with ethical and regulatory standards in Japan. MEG-002 was infused into a patient with aplastic anemia at a dose of 6 × 1010 platelets. No adverse events were reported, and no clinically significant changes were observed in any assessments. Furthermore, a transient increase in platelet count and evidence of iPSC-PLT circulation were observed. Despite being descriptive observations from a single subject, these findings suggest the safety and potential efficacy of allogeneic iPSC-PLTs in humans. The clinical trial is registered with the Japan Registry of Clinical Trials (jRCT2053210068).

Chicken infectious anemia virus (CIAV) is a major immunosuppressive pathogen of poultry, causing aplastic anaemia, lymphoid atrophy, and severe haematopoietic dysfunction in young chicks, thereby posing a substantial threat to global poultry health and production. In this study, a novel highly pathogenic CIAV strain, designated CIAV-GDHY230813, was isolated from young Mahuang chickens in China and subjected to comprehensive molecular and pathogenic characterization. Whole-genome sequencing and phylogenetic analysis revealed that CIAV-GDHY230813 belongs to I-a branch. Notably, the VP1 protein harbored a glutamine residue at position 394, a molecular marker strongly associated with high virulence, together with multiple amino acid substitutions, insertions, and deletions across the coding regions. Pathogenicity experiments in specific-pathogen-free (SPF) chicks demonstrated that infection with CIAV-GDHY230813 resulted in pronounced growth retardation, severe damage to immune organs, and increased mortality. From 3 to 21 days post-infection (dpi), body weights of infected chicks were significantly lower than those of the control group (p < 0.01). Marked thymic and bursal atrophy, splenomegaly, and significantly reduced haematocrit levels were observed, indicating severe anaemia. Furthermore, CIAV infection led to a marked reduction in antibody titres against Newcastle disease virus vaccination by 4-fold to 8-fold, reflecting substantial suppression of humoral immune responses. Quantitative analysis of viral distribution showed significantly elevated viral loads in blood, liver, thymus, spleen, and bursa of Fabricius at both 14 and 21 dpi (p < 0.001), with peak levels detected at 21 dpi. Collectively, these findings demonstrate the strong replicative capacity and high pathogenic potential of CIAV-GDHY230813, providing valuable insights into the molecular epidemiology and pathogenic mechanisms of CIAV in China, supporting improved surveillance and control strategies, and laying a solid foundation for the development of effective vaccines against CIAV.

Fanconi anemia (FA) is characterized by defective DNA repair and chronic p53 activation, predisposing to acute myeloid leukemia through persistent genomic instability. The molecular adaptations enabling cell survival under chronic stress remain poorly understood. This study investigates the role of ZMAT3, a p53 responsive RNA binding protein overexpressed in FA deficient cells, to elucidate its role in cellular adaptation. Using FA patient fibroblasts and Fancg KO mouse models, we launched transcriptomic profiling, lipidomic, and functional analyses. RNA-seq and lipidomic analyses revealed unexpected alterations in sphingolipid metabolism upon ZMAT3 depletion, linked to ceramide accumulation and downregulation of ASAH1 (acid ceramidase). Functionally, ZMAT3 depletion increased DNA damage and enhanced ferroptosis susceptibility, an iron dependent cell death mechanism. Mechanistically, our results showed that ZMAT3 promotes ASAH1 expression, limits ceramide accumulation and protects cells from ferroptosis induced death which could participate to preleukemic clonal evolution and pointing to areas for further exploration in FA-associated malignancies.