再生不良性貧血

The RACE study (NCT02009747) compared horse antithymocyte globulin (hATG) plus cyclosporine A (CsA) ± eltrombopag as initial immunosuppressive treatment (IST) for severe aplastic anemia. Here we report the final 2-year analysis of this prospective randomized phase III study. One hundred ninety-seven treatment-naive patients were randomized to standard IST (hATG 40 mg/kg × 4 days and CsA 5 mg/kg/day; arm A; n = 101) or standard IST + eltrombopag at the dose of 150 mg/day (arm B; n = 96) from day +14 until 6 months (or 3 months, in case of complete response). The median follow-up was 23.2 months. The 2-year cumulative incidence of complete response was significantly superior in arm B (62.4% vs. 35.3%; p < 0.001). The 2-year overall survival (OS) was 86% in arm A and 91% in arm B (p = 0.081), with hazard ratio (HR), adjusted for age and disease severity, of 0.54 (p = 0.064). The 2-year disease-free survival (DFS) was 56% vs. 37% (adjusted HR = 0.49; p < 0.001), while event-free survival (EFS) was 48% vs. 32% (p < 0.001), with adjusted HR = 0.54 (p < 0.001), both significantly superior for arm B. The cumulative incidence of relapse was comparable in the two arms, while evolution to clinical paroxysmal nocturnal hemoglobinuria was 8% in arm A and 1% in arm B (p = 0.041). The risk of clonal evolution remained negligible, with one patient in arm A and two in arm B developing karyotypic abnormalities. The initial hematological response benefit of eltrombopag added to IST as front-line treatment of AA is associated with better 2-year OS, DFS, and EFS without increased risk of secondary myeloid malignancies.

BACKGROUND: Fulminant hepatitis is a rare but highly lethal complication associated with various drugs, including antithyroid thionamides used for hyperthyroidism. While propylthiouracil (PTU) is more commonly linked to severe hepatotoxicity, methimazole can also cause acute liver failure and, rarely, bone marrow suppression such as aplastic anemia or agranulocytosis. Drug-induced liver injury accounts for a significant proportion of acute liver failure cases requiring transplantation, with antithyroid drugs occasionally implicated. The pathogenesis is thought to be immune-mediated and potentially dose-dependent, with cross-reactivity between thionamides. Simultaneous occurrence of severe hepatotoxicity and aplastic anemia is exceptionally rare, particularly with methimazole. CASE REPORT: A 37-year-old man with Graves' disease, on methimazole for 4 years without recent follow-up, presented in February 2024 with jaundice, choluria, and acholic stools. Investigations revealed hyperbilirubinemia, elevated transaminases, negative viral/autoimmune serologies, and normal imaging. Liver biopsy confirmed drug-induced injury with ductopenia, portal fibrosis, inflammation, and bilirubinostasis. Methimazole was discontinued. One month later, progressive pancytopenia developed, unresponsive to corticosteroids. Bone marrow biopsy showed hypocellularity consistent with aplastic anemia, requiring transfusions. Liver failure progressed to grade II encephalopathy, bilirubin 30.23 mg/dL (516.93 µmol/L), MELD 29, meeting King's College Criteria. He underwent urgent cadaveric orthotopic liver transplantation on June 13, 2024. Post-transplant, aplastic anemia was managed with erythropoietin, G-CSF, eltrombopag, and transfusions. An opportunistic CMV infection was treated with ganciclovir. Hematopoietic support was eventually discontinued without further transfusions, and the patient was discharged with stable graft and hematological recovery. CONCLUSION: This case illustrates the rare simultaneous occurrence of methimazole-induced fulminant hepatitis and aplastic anemia necessitating liver transplantation. It underscores the challenges in perioperative management of profound pancytopenia and posttransplant complications in such patients. Multidisciplinary care was key to successful outcome, highlighting the need for vigilant monitoring of antithyroid drug therapy and avoidance of cross-use in cases of severe adverse reactions.

A vertebrojugular fistula (VJF) is a vascular malformation characterised by abnormal communication between the vertebral artery (VA) and the internal jugular vein (IJV). It can occur following neck trauma, iatrogenic injury or spontaneously in connective tissue disorders, and rarely, it can be congenital. A young adult man in his early 20s with aplastic anaemia was planned for allogeneic haematopoietic stem cell transplantation (Allo-HSCT) for which right IJV cannulation was planned. After a single attempt at straightforward IJV cannulation, high flow was observed through all lumens; an anomalous arteriovenous connection was suspected; therefore, the catheter was removed immediately. The left IJV was successfully cannulated and the patient underwent urgent Allo-HSCT because of limited curative treatment options. Two days later, he presented with neck pain and small neck swelling and was investigated and found to have a VJF, which required coil embolisation of the fistula and sacrifice of the right VA. This report highlights the importance of pre-cannulation ultrasound screening of major neck vessels to study the IJV anatomy and its relationship with other neck vessels, compressibility and flow characteristics of the IJV using Doppler ultrasound (colour, pulsed wave and spectral wave Doppler patterns) to rule out thrombus or an anomalous arteriovenous connection, especially in patients with a history of prior IJV cannulation.

Refractory immune-mediated cytopenias (IMCs) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are a challenging complication with limited therapeutic options. Although preexisting human leukocyte antigen (HLA) antibodies, particularly donor-specific antibodies (DSAs), are well-established risk factors for graft failure, the clinical significance and mechanistic role of de novo HLA antibodies emerging after transplantation remain poorly defined. Whether such antibodies are associated with posttransplant IMCs has not been systematically explored. We report two patients with severe aplastic anemia who developed refractory IMCs after allo-HSCT in association with high-titer de novo HLA antibodies and preserved full donor chimerism. In case 1, combined HLA class I and II antibodies were detected in association with trilineage cytopenia. Rituximab, corticosteroids and plasma exchange reduced HLA class II antibodies (including DSAs), whereas persistent HLA class I antibodies were linked to ongoing pancytopenia despite multi-agent treatment. In case 2, isolated high-titer de novo HLA class II antibodies were detected in association with late-onset thrombocytopenia, refractory to corticosteroids and rituximab. In both patients, plasma cell-directed therapy with daratumumab led to definitive clearance of de novo HLA antibodies and was followed by rapid and sustained hematologic recovery, including coordinated trilineage recovery in case 1 and selective platelet recovery in case 2. These cases provide initial hypothesis-generating observations that de novo HLA antibodies are associated with and may contribute to refractory IMCs after allo-HSCT. The concordance across antibody class, lineage-specific or multilineage hematopoietic injury, and lineage-matched recovery after antibody clearance suggests a functional immunophenotype-hematopoietic phenotype coupling that warrants further investigation.

Acquired aplastic anemia (AA) serves as a life-threatening hematopoietic disorder with certain morbidity and mortality, which is caused by the immunologic attack-induced lymphocyte destruction of hematopoietic stem/progenitor cells (HSPCs). Longitudinal studies have highlighted the immunodysfunction in the relapse of AA, yet the dissection of natural killer (NK) cell-related pathogenesis remains largely obscure. In this study, we enriched bone marrow blood-derived mononuclear cells (BM-MNCs) for 20 AA patients and 20 healthy donors (HD), and detected the content and immunophenotyping of resident NK cells (rHD-NKs, rAA-NKs) by cell counting and flow cytometry (FCM) assay. Meanwhile, we utilized our well-established "3ILs"-based protocol for the ex vivo induction of expanded NK cells from BM-MNCs (eHD-NKs, eAA-NKs). Besides the cellular phenotyping analyses of eHD-NKs and eAA-NKs, we further compared the cellular viability and the ex vivo cytotoxicity upon tumor cell lines. Finally, with the aid of RNA-sequencing (RNA-SEQ) and bioinformatics analyses, the transcriptomic signatures of eHD-NKs and eAA-NKs were verified, including gene expression profiling and genetic spectrum. Compared to the corresponding HD-NKs (rHD-NKs, eHD-NKs), both the resident and expanded AA-NKs (rAA-NKs, eAA-NKs) were consistently declined in content of total CD3-CD56+ NK cells and the NKp46+ activated subset, while the CD3-CD56+CD16+ NK cells and the relative subsets revealed different trends (e.g., CD25+, NKp44+ NK subsets). Meanwhile, eHD-NKs and eAA-NKs exhibited multifaceted conservations and alterations in gene expression pattern and somatic variation signatures. Overall, these data indicated the similarities and diversities of cellular phenotype and transcriptomic signatures between HD-NKs and AA-NKs in the bone marrow microenvironment. Our findings provided useful references for the bone marrow failure (BMF)-related cytogenetic characterization of AA-NKs, which would facilitate the further development of NK cell-based precise diagnosis and targeted therapeutics for AA in the future.