Eculizumab is Associated With Increased Infection Rates and Infection Related Mortality in Children With Thrombotic Microangiopathy After HCT.

Complement C5 inhibition can be used to treat hematopoietic cell transplant-associated thrombotic microangiopathy (TA-TMA) but may impact infectious organism clearance, impeding opsonization and lysis. The infectious risks of eculizumab exposure after hematopoietic cell transplant (HCT) are unknown. In this single center, retrospective case-control study, we included allogeneic HCT recipients transplanted from January 2019 to January 2023.

Characterizing pregnancy outcomes in a humanized mouse model of sickle cell disease.

Although increased risk for adverse pregnancy outcomes has been well characterized in women with sickle cell disease (SCD), there remains unexplored value in the characterization of a preclinical model which could minimize human risk. This study aimed to characterize pregnancy outcomes in the SCD mouse model with emphasis on analogous clinical correlates and biological contributors. As such, we identified worsened outcomes including reduced litter sizes (haemoglobin HbSS (SS) 5.

Complement is activated in patients with acute chest syndrome caused by sickle cell disease and represents a therapeutic target.

Despite being the first genetic disease described, sickle cell disease (SCD) continues to result in severe complications. Of these complications, acute chest syndrome (ACS), a form of acute lung injury, leads all-cause mortality. However, the pathophysiology of ACS remains incompletely understood, resulting in patients with ACS receiving only supportive measures.

CD47 regulates antigen modulation and red blood cell clearance following an incompatible transfusion.

Red blood cell (RBC) alloantibodies can result in the rapid removal of incompatible RBCs following transfusion. However, antibody-mediated clearance of RBCs is not the inevitable outcome of an incompatible transfusion. Antibody engagement can also result in the modulation of the target antigen, often rendering RBCs resistant to antibody-mediated removal.

Real-world insights from a cohort of approximately 2000 individuals who were analysed using a freely available next-generation sequencing anaemia screening programme.

Data from a large cohort of individuals referred for NGS testing evaluate the utility of next-generation sequencing in clinical practice for diagnosing hereditary haemolytic anaemias.

Harnessing the potential of red blood cells in immunotherapy.

Red blood cell (RBC) transfusion represents one of the earliest and most widespread forms of cellular therapy. While the primary purpose of RBC transfusions is to enhance the oxygen-carrying capacity of the recipient, RBCs also possess unique properties that make them attractive vehicles for inducing antigen-specific immune tolerance. Preclinical studies have demonstrated that RBC transfusion alone, in the absence of inflammatory stimuli, often fails to elicit detectable alloantibody formation against model RBC antigens.

Comparative clinical efficacy and safety of biosimilar ABP 959 and eculizumab reference product in patients with paroxysmal nocturnal hemoglobinuria.

ABP 959 is a biosimilar to the eculizumab reference product (RP), which is approved for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH). This multicenter, randomized, double-blind, active-controlled, two-period crossover study randomized eculizumab RP-treated patients with PNH to one of two treatment sequences (ABP 959/eculizumab RP or eculizumab RP/ABP 959) to evaluate the clinical similarity of ABP 959 when compared with eculizumab RP. This study evaluated the efficacy of ABP 959 when compared with eculizumab RP based on control of intravascular hemolysis as measured by lactate dehydrogenase (LDH) and by the time-adjusted area under the effect curve of LDH.

Real-World Application of Recently Proposed ASTCT/CIBMTR/EBMT/APBMT Consensus Risk Stratification for Transplantation-Associated Thrombotic Microangiopathy in Children.

Consensus diagnostic and risk stratification of transplantation-associated thrombotic microangiopathy (TA-TMA) was recently achieved from international transplantation groups. Although the proposed diagnostic criteria have been applied to multiple pediatric cohorts, there are scant data applying the novel risk stratification approach in children with TA-TMA. In this retrospective cohort study, all children undergoing an allogeneic HCT or autologous HCT for neuroblastoma were prospectively screened for TA-TMA, diagnosed, and risk-stratified using the Jodele criteria from August 2019 to October 2023.

Pharmacokinetics, pharmacodynamics, efficacy, and safety of ravulizumab in pediatric paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease of uncontrolled terminal complement activation leading to intravascular hemolysis, thrombotic events and increased morbidity and mortality. This phase 3, open-label, single-arm, multicenter study evaluated ravulizumab treatment in eculizumab-naive or -experienced pediatric patients (aged <18 years) with PNH over a 26-week primary evaluation period (PEP) and 4-year extension period (EP). Patients included in the study received weight-based intravenous ravulizumab dosing.

Voxelotor improves red blood cell functionality in children with sickle cell anaemia: An ancillary study of the HOPE-KIDS 1 trial.

Introduction: Sickle haemoglobin (HbS) polymerisation perturbs red blood cell (RBC) rheology and drives sickle cell disease (SCD) pathophysiology. Voxelotor is an HbS polymerisation inhibitor that increases haemoglobin (Hb)-oxygen affinity.

Methods/results: In this 48-week, prospective, single-centre translational study, 10 children aged 4-11 years with SCD were treated with voxelotor.

D-dimer and sinusoidal obstructive syndrome-novel poor prognostic features of thrombotic microangiopathy in children after hematopoietic cellular therapy in a single institution prospective cohort study.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a common, severe complication of allogeneic hematopoietic cellular therapy (HCT). Even when treated in many studies, morbidity and mortality rates are high. This prospective single-institution cohort study serially enrolled all allogeneic HCT recipients from August 2019-August 2022.

Pediatric transplant-associated thrombotic microangiopathy health care utilization and implications of eculizumab therapy.

The health care use (HCU) burden of transplant-associated thrombotic microangiopathy (TA-TMA) and its treatments are unknown. The objective of this study was to investigate inpatient costs associated with meeting criteria for TA-TMA in the first year after hematopoietic cell transplant (HCT). This institutional review board-approved retrospective multicenter study included serial children who underwent HCT from 1 January 2015 to 1 July 2019.

Frequency of HLA-DRCD38 T cells identifies and quantifies T-cell activation in hemophagocytic lymphohistiocytosis, hyperinflammation, and immune regulatory disorders.

Background: Quantifying T-cell activation is essential for the diagnosis and evaluation of treatment response in various hyperinflammatory and immune regulatory disorders, including hemophagocytic lymphohistiocytosis. Plasma soluble IL-2 receptor (sIL-2R) is a well-established biomarker for evaluating systemic T-cell activation. However, the limited availability of sIL-2R testing could result in delayed diagnosis.

Antibody-mediated antigen loss switches augmented immunity to antibody-mediated immunosuppression.

Antibodies against fetal red blood cell (RBC) antigens can cause hemolytic disease of the fetus and newborn (HDFN). Reductions in HDFN due to anti-RhD antibodies have been achieved through use of Rh immune globulin (RhIg), a polyclonal antibody preparation that causes antibody-mediated immunosuppression (AMIS), thereby preventing maternal immune responses against fetal RBCs. Despite the success of RhIg, it is only effective against 1 alloantigen.

Storage differentially impacts alloimmunization to distinct red cell antigens following transfusion in mice.

Introduction: The impact of blood storage on red blood cell (RBC) alloimmunization remains controversial, with some studies suggesting enhancement of RBC-induced alloantibody production and others failing to observe any impact of storage on alloantibody formation. Since evaluation of storage on RBC alloimmunization in patients has examined antibody formation against a broad range of alloantigens, it remains possible that different clinical outcomes reflect a variable impact of storage on alloimmunization to specific antigens.

Methods: RBCs expressing two distinct model antigens, HEL-OVA-Duffy (HOD) and KEL, separately or together (HOD × KEL), were stored for 0, 8, or 14 days, followed by detection of antigen levels prior to transfusion.

Pulmonary Manifestations and Vascular Changes in Pediatric Transplantation-Associated Thrombotic Microangiopathy.

Although transplant-associated thrombotic microangiopathy (TA-TMA) commonly complicates pediatric hematopoietic cellular therapy (HCT), pulmonary manifestations and histology of TA-TMA (pTA-TMA) are rarely reported, with scant data available on timing, risk factors, pathogenesis, and outcomes. Pulmonary hypertension (PH) and diffuse alveolar hemorrhage (DAH) are recognized manifestations of pTA-TMA. The objective of this study was to characterize the pathologic findings, outcomes, and coincident diagnoses preceding biopsy-proven pTA-TMA.

Sickle cell disease is a risk factor for transplant-associated thrombotic microangiopathy in children.

Transplant-associated thrombotic microangiopathy (TA-TMA) and sickle cell disease (SCD) share features of endothelial and complement activation. Thus, we hypothesized that SCD is a risk factor for TA-TMA and that prehematopoietic cellular transplantation (HCT) markers of endothelial dysfunction and complement activation would be higher in patients with SCD. Children who underwent initial haploidentical or matched sibling donor HCT between January 2015 and June 2020 were included in this institutional review board-approved, single institution, retrospective study.