Allogeneic hematopoietic stem cell transplantation (HSCT) is one of the principal curative approaches in the treatment of acute myeloid leukemia (AML); however, relapse after transplantation remains a catastrophic event with poor prognosis. The incidence of relapse has remained unchanged over the last 3 decades despite an evolving understanding of the immunobiology of the graft-versus-leukemia effect and the immune escape mechanisms that lead to post-HSCT relapse. The approach to posttransplant relapse is highly individualized and is dictated both by disease biology and genomics as well as the patient's clinical status at the time of relapse and the interval between relapse and transplantation. With the help of 3 illustrative cases, we discuss our approach to early, late, and incipient relapse. Current therapeutic strategies incorporate immunosuppression taper when feasible, a variety of targeted and nontargeted chemotherapeutic agents, and consolidative cellular therapies including donor lymphocyte infusions or a second allogeneic transplant. We then summarize evolving frontiers in the treatment and prognostication of relapse, including the critical role of measurable residual disease. Finally, we emphasize enrollment on clinical trials and thoughtful discussions regarding goals of care and supporting frail patients as universal principles that should be incorporated in approaches to treatment of AML relapse after transplantation.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the (oligo)clonal expansion of myeloid progenitor cells. Despite advances in treatment, AML remains challenging to cure, particularly in patients with specific genetic abnormalities. Menin inhibitors have emerged as a promising therapeutic approach, targeting key genetic drivers of AML, such as KMT2A (lysine methyl transferase 2A) rearrangements and NPM1 mutations. Here, we review the clinical value of menin inhibitors, highlighting their mechanism of action, efficacy, safety, and potential to transform AML treatment.

We found 20 patients with an immunophenotype consistent with classic hairy cell leukemia and BRAF mutations other than just V600E. Fourteen had 1 non-V600E BRAF mutation and 6 had V600E with 1 (n = 5) or 2 (n = 1) non-V600E BRAF comutations. This study was registered at https://clinicaltrials.gov as #NCT01087333.

Hypercalcemia in monoclonal gammopathy of undetermined significance (MGUS) presents a clinical challenge because it may indicate progression to multiple myeloma (MM) but could also be due to a multitude of unrelated disorders. To inform the approach to this clinical challenge, we conducted a nested cohort study within the Iceland Screens, Treats, or Prevents Multiple Myeloma screening study. Of the 75 422 Icelanders aged 40 years and above who underwent screening for MGUS, we included 2546 with MGUS who were in active follow-up, including regular serum calcium measurements. In total, 191 individuals (7.5%) had hypercalcemia detected at least once, of whom 93 had persistent hypercalcemia (48.7%). MM was found in 3 participants with persistent hypercalcemia (3.2%); all had concurrent bone disease and other end-organ damage. The most common causes of hypercalcemia were primary hyperparathyroidism (56.0%) and malignancies other than MM (16.0%). In this first comprehensive study on hypercalcemia in MGUS, we observed that hypercalcemia rarely indicated MGUS progression and never in the absence of other symptoms of MM. More than half of hypercalcemia cases were transient, and the underlying causes were similar to those in the general population. We conclude that hypercalcemia in MGUS should be approached in the same way as in those without MGUS.

Complement C5 inhibitor treatment with ravulizumab or eculizumab for paroxysmal nocturnal hemoglobinuria (PNH) improves outcomes and survival. Some patients remain anemic due to clinically significant extravascular hemolysis (cs-EVH; hemoglobin [Hb] ≤9.5 g/dL and absolute reticulocyte count [ARC] ≥120 × 109/L). In the phase 3 ALPHA trial, participants received oral factor D inhibitor danicopan (150 mg 3 times daily) or placebo plus ravulizumab or eculizumab during the 12-week, double-blind treatment period 1 (TP1); those receiving placebo switched to danicopan during the subsequent 12-week, open-label TP2 and continued during the 2-year long-term extension (LTE). There were 86 participants randomized in the study, of whom 82 entered TP2, and 80 entered LTE. The primary end point was met, with Hb improvements from baseline at week 12 (least squares mean change, 2.8 g/dL) with danicopan. For participants switching from placebo to danicopan at week 12, improvements in mean Hb were observed at week 24. Similar trends were observed for the proportion of participants with ≥2 g/dL Hb increase, ARC, proportion of participants achieving transfusion avoidance, and Functional Assessment of Chronic Illness Therapy-Fatigue scale scores. Improvements were maintained up to week 72. No new safety signals were observed. The breakthrough hemolysis rate was 6 events per 100 patient-years. These long-term data demonstrate sustained efficacy and safety of danicopan plus ravulizumab/eculizumab for continued control of terminal complement activity, intravascular hemolysis, and cs-EVH in PNH. This trial was registered at www.clinicaltrials.gov as #NCT04469465.

Quantitative fibrinogen disorders, including afibrinogenemia and hypofibrinogenemia, are defined by the complete absence or reduction of fibrinogen, respectively. The diagnosis is based on the measurement of fibrinogen activity and antigen levels, which define the severity of this monogenic disorder. Afibrinogenemia is the result of homozygosity or combined heterozygosity for the causative mutations, whereas monoallelic mutations lead to hypofibrinogenemia. The bleeding phenotype varies in accordance with fibrinogen levels, ranging generally from frequent and often life-threatening bleeding in afibrinogenemia to the absence of symptoms, or mild bleeding symptoms in mild hypofibrinogenemia. The main treatment for quantitative fibrinogen disorders is fibrinogen supplementation. Despite low fibrinogen levels, a tendency for thrombosis is a characteristic of these disorders and may be exacerbated by fibrinogen supplementation. The management of surgery and pregnancy presents significant challenges regarding the amount of fibrinogen replacement and the need for thromboprophylaxis. The objective of this article is to present 4 clinical scenarios that illustrate common clinical challenges and to propose strategies for managing bleeding, thrombosis, surgery, and pregnancy.

The advent of chimeric antigen receptor (CAR) T cells has revolutionized the treatment landscape for hematologic malignancies, and emerging evidence suggests their potential in autoimmune diseases (AIDs). This article evaluates the early successes and future implications of B-cell-targeting CAR T-cell therapy in AIDs. Initial applications, particularly in refractory systemic lupus erythematosus, have demonstrated significant and durable clinical remissions, with accompanying evaluation of the immune system suggesting a so-called "reset" of innate inflammation and adaptive autoimmunity. This has generated widespread interest in expanding this therapeutic approach. CAR T cells offer unique advantages over other treatment modalities, including very deep B-cell depletion and unique therapeutic activity within inflamed tissues and associated lymphoid structures. However, the field must address key concerns, including long-term toxicity, particularly the risk of secondary malignancies, and future accessibility given the higher prevalence of AIDs compared with malignancies. Technological advances in cell therapy, such as next-generation CAR T cells, allogeneic off-the-shelf products, and alternative cell types, such as regulatory CAR T cells, are being explored in AIDs to improve efficacy and safety. In addition, bispecific antibodies are emerging as potential alternatives or complements to CAR T cells, potentially offering comparable efficacy without the need for complex logistics, lymphodepletion, and the risk of insertional mutagenesis. As the field evolves, cellular therapists will play a critical role in the multidisciplinary teams managing these complex cases. The transformative potential of CAR T cells in AIDs is undeniable, but careful consideration of safety, efficacy, and implementation is essential as this novel therapeutic approach moves forward.

Coagulation is related to inflammation, but the key pathway, especially innate immune system and coagulation regulation, is not well understood and need to be further explored. Here, we demonstrated that neutrophil gelatinase-associated lipocalin (NGAL), an innate immune inflammatory mediator, is upregulated in patients with thrombosis. Furthermore, it contributes to the initiation and amplification of coagulation, hemostasis, and thrombosis. This occurs by enhancing tissue factor expression on the cell surface, potentiating various clotting factors such as thrombin, kallikrein, factor XIa (FXIa), and FVIIa, promoting thrombin-induced platelet aggregation, and inhibiting antithrombin. NGAL knockout led to strikingly prolonged clot reaction time and kinetic time in thromboelastography analysis, along with reduced thrombus generation angle and lower thrombus maximum amplitude, which were in line with remarkably prolonged activated partial thromboplastin time and prothrombin time. In several mouse hemostasis and thrombosis models, NGAL overexpression or IV administration promoted coagulation and hemostasis and aggravated thrombosis, whereas NGAL knockout or treatment with anti-NGAL monoclonal antibody significantly prolonged bleeding time and alleviated thrombus formation. Notably, NGAL knockout prolonged mouse tail bleeding time or artery occlusion time to over 40 or 60 minutes, respectively, resembling uncontrollable bleeding and clotting disorder seen in hemophilic mice. Furthermore, anti-NGAL monoclonal antibody treatment markedly reduced the formation of blood clots in inflammation-induced thrombosis models. Collectively, these findings unveil a previously unidentified role of NGAL in the processes of coagulation, hemostasis, and thrombosis, as well as the cross talk between innate immunity, inflammation, and coagulation. Thus, modulating NGAL levels could potentially help balance thrombotic and hemorrhagic risks.

Accumulation of free α-globin is a critical factor in the pathogenesis of β-thalassemia. Autophagy plays a crucial role in clearing toxic free α-globin, thereby reducing disease severity. However, the impact of natural mutations in autophagy-related genes (ATGs) on the phenotypic variability of β-thalassemia remains unclear. In this study, we systematically investigated the relationship between variants in ATGs and disease phenotypes in a cohort of 1022 patients with β-thalassemia, identifying 4 missense mutations in the autophagy and beclin 1 regulator 1 (AMBRA1) gene. Disruption of the Ambra1 gene in β-thalassemic mice was found to reduce autophagic clearance of α-globin in red blood cell precursors, exacerbating disease phenotypes. Functional characterization of the AMBRA1 gene and these mutations in patient-derived CD34+ cells, edited human umbilical cord blood-derived erythroid progenitor 2 (HUDEP-2) cells, and engineered HUDEP-2 β-thalassemic cells confirmed that AMBRA1 facilitates the autophagic clearance of free α-globin in human erythroid cells. Functional studies demonstrated that AMBRA1 missense mutants destabilize Unc-51-like kinase 1 protein, inhibit light chain 3 protein lipidation, and subsequently hinder autophagic flux, leading to increased α-globin deposition. Additionally, these mutations were associated with erythrotoxic effects in vitro, including increased intracellular reactive oxygen species levels, higher apoptosis rates, and impaired erythroid differentiation and maturation. This study sheds light on the molecular association between mutations in ATGs and the exacerbation of β-thalassemia, highlighting the potential role of the AMBRA1 gene as a promising diagnostic and therapeutic target for β-hemoglobinopathies.

The oral microbiota, second in abundance to the gut, is implicated in chronic systemic diseases, but its specific role in graft-versus-host disease (GVHD) pathogenesis has been unclear. Our study finds that mucositis-induced oral dysbiosis in patients after hematopoietic cell transplantation (HCT) associated with increased chronic GVHD (cGVHD), even in patients receiving posttransplant cyclophosphamide. In murine HCT models, oral dysbiosis caused by bilateral molar ligatures exacerbated cGVHD and increased bacterial load in the oral cavity and gut, with Enterococcaceae significantly increasing in both organs. In this model, the migration of Enterococcaceae to cervical lymph nodes both before and after transplantation activated antigen-presenting cells, thereby promoting the expansion of donor-derived inflammatory T cells. Based on these results, we hypothesize that pathogenic bacteria increase in the oral cavity might not only exacerbate local inflammation but also enhance systemic inflammation throughout the HCT course. Additionally, these bacteria translocated to the gut and formed ectopic colonies, further amplifying systemic inflammation. Furthermore, interventions targeting the oral microbiome mitigated murine cGVHD. Collectively, our findings highlight the importance of oral dysbiosis in cGVHD and suggest that modulation of the oral microbiome during transplantation may be an effective approach for preventing or treating cGVHD.