Monitoring and Treatment of Paroxysmal Nocturnal Hemoglobinuria in Patients with Aplastic Anemia in Asia: An Expert Consensus.

Paroxysmal nocturnal hemoglobinuria (PNH) clones can be identified in a significant proportion of patients with aplastic anemia (AA). Screening for PNH clones at the time of an AA diagnosis is recommended by national and international guidelines. In this report, an expert panel of physicians discusses current best practices and provides recommendations for managing PNH in patients with AA in the Asia-Pacific region.

Differential detection of megakaryocytic and erythroid DNA in plasma in hematological disorders.

The tissues of origin of plasma DNA can be revealed by methylation patterns. However, the relative DNA contributions from megakaryocytes and erythroblasts into plasma appeared inconsistent among studies. To shed light into this phenomenon, we developed droplet digital PCR (ddPCR) assays for the differential detection of contributions from these cell types in plasma based on megakaryocyte-specific and erythroblast-specific methylation markers.

Improvements in hematologic markers and decreases in fatigue with pegcetacoplan for patients with paroxysmal nocturnal hemoglobinuria and mild or moderate anemia (hemoglobin ≥10 g/dL) who had received eculizumab or were naive to complement inhibitors.

Background: Although complement component 5 inhibitors (C5is) eculizumab and ravulizumab improve paroxysmal nocturnal hemoglobinuria (PNH) outcomes, patients may experience persistent anemia. This post hoc analysis investigated whether the complement component 3-targeted therapy pegcetacoplan also improved hematologic outcomes and reduced fatigue in patients with PNH and mild/moderate anemia.

Methods: Patients with PNH and hemoglobin ≥10.

A whole-body mechanistic physiologically-based pharmacokinetic modeling of intravenous iron.

Iron is essential for every cell of the mammalian organism. Iron deficiency is a major public health issue worldwide. Intravenous (IV) iron therapy has been used to treat anemia.

Unmet Needs in the First-Line Treatment of Diffuse Large B-cell Lymphoma: Expert Recommendations From the Asia-Pacific Region With a Focus on the Challenging Subtypes.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, accounting for around 30-60% of all cases. The management of DLBCL in Asia has several unmet needs due to the diversity of the population, the heterogeneity of local clinical guidelines for DLBCL and the wide disparity in resources and healthcare systems across different regions. Rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) is widely recognized as the standard first-line treatment for DLBCL; however, alternative regimens are required to improve patient outcomes in challenging subtypes, such as patients with high International Prognostic Index scores, old/frail patients, and patients with double-hit and double-expressor DLBCL or concurrent central nervous system disease.

Erythropoietin hyporesponsiveness in non-alcoholic fatty liver disease.

Treatment with erythropoietin (EPO) can correct anaemia in chronic kidney disease (CKD) patients; however, up to 10% exhibit resistance or hyporesponsiveness to EPO. Non-alcoholic fatty liver disease (NAFLD), prevalent liver disease in CKD patients, may limit EPO response because of thrombopoietin deficiency, iron homeostasis disorder and inflammation. Therefore, we hypothesized NAFLD is a risk factor for EPO responsiveness.

Early erythroferrone levels can predict the long-term haemoglobin responses to erythropoiesis-stimulating agents.

Background And Purpose: Our previous study reported that erythroferrone (ERFE), a newly identified hormone produced by erythroblasts, responded to recombinant human erythropoietin (rHuEPO) sensitively but its dynamics was complicated by double peaks and circadian rhythm. This study intends to elucidate the underlying mechanisms for the double peaks of ERFE dynamics and further determine whether early ERFE measurements can predict haemoglobin responses to rHuEPO.

Experimental Approach: By using the purified recombinant rat ERFE protein and investigating its deposition in rats, the production of ERFE was deconvoluted.

A novel electronic health record-based, machine-learning model to predict severe hypoglycemia leading to hospitalizations in older adults with diabetes: A territory-wide cohort and modeling study.

Background: Older adults with diabetes are at high risk of severe hypoglycemia (SH). Many machine-learning (ML) models predict short-term hypoglycemia are not specific for older adults and show poor precision-recall. We aimed to develop a multidimensional, electronic health record (EHR)-based ML model to predict one-year risk of SH requiring hospitalization in older adults with diabetes.

C-terminal binding protein 2 is a novel tumor suppressor targeting the MYC-IRF4 axis in multiple myeloma.

Multiple myeloma (MM) cells are addicted to MYC and its direct transactivation targets IRF4 for proliferation and survival. MYC and IRF4 are still considered "undruggable," as most small-molecule inhibitors suffer from low potency, suboptimal pharmacokinetic properties, and undesirable off-target effects. Indirect inhibition of MYC/IRF4 emerges as a therapeutic vulnerability in MM.

Thrombopoietin treats erythropoietin resistance by correcting EPO-induced progenitorcell depletion.

Recombinant human erythropoietin (rHuEPO) is a prevalent treatment for anemia in patients with chronic kidney disease. However, up to 10% of these patients exhibit EPO resistance or hyporesponsiveness, which may be caused by the depletion of erythroid progenitor cells. Thrombopoietin (TPO) has the potential to promote the growth of early progenitor cells and correct the depletion.

Novel Combination of Erythropoietin and Romiplostim to Treat Chemotherapy-Induced Anemia and Thrombocytopenia via Pharmacodynamic Interaction on Hematopoietic Stem and Progenitor Cells.

Chemotherapy-induced anemia and thrombocytopenia (CIAT) in cancer patients are often caused by the damage of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. We have previously shown that romiplostim, a thrombopoietin receptor agonist that could stimulate the expansion of HSPCs, could synergize with recombinant human erythropoietin (rHuEPO) to promote erythropoiesis in addition to stimulating platelet production, whereas rHuEPO could influence the platelet count through stem cell competition. Therefore, we hypothesize that a combination of romiplostim with rHuEPO can alleviate CIAT simultaneously, while minimizing the risk of thrombosis.

The Influence of Precursor Depletion and dose Regimens on Resistance to Erythropoiesis-Stimulating Agents: Insights from Simulations with Instantaneous Dose-Adaptation Algorithm.

Erythropoiesis-stimulating agents (ESAs) have been a common treatment for anemia associated with chronic kidney disease (CKD), while 10-20 % of patients continue to suffer from persistent anemia despite receiving ESA treatments. Our previous findings suggested that intensive ESA usage can cause resistance by depleting the erythroid precursor cells. Here, we used a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model of ESAs and conducted simulations to evaluate the influence of dose regimens and other factors (such as administration route, individual PK/PD parameters, types of ESAs, and disease status) on ESA resistance with instantaneous dose adaptations in healthy populations and anemic patients.

Clinical, neuroimaging, and behavioural risk factors for neurocognitive impairment in Chinese patients with haemophilia: A multicentre study.

Background: Few studies have evaluated the impact of subclinical microstructural changes and psychosocial factors on cognitive function in patients with haemophilia.

Objectives: To determine the prevalence and characteristics of cognitive impairment in patients with haemophilia, and identify associated risk factors.

Methods: We recruited haemophilia A or B patients who were aged ≥10 years old from three public hospitals in Hong Kong.

SPINK2 Protein Expression Is an Independent Adverse Prognostic Marker in AML and Is Potentially Implicated in the Regulation of Ferroptosis and Immune Response.

There is an urgent need for the identification as well as clinicopathological and functional characterization of potent prognostic biomarkers and therapeutic targets in acute myeloid leukemia (AML). Using immunohistochemistry and next-generation sequencing, we investigated the protein expression as well as clinicopathological and prognostic associations of serine protease inhibitor Kazal type 2 (SPINK2) in AML and examined its potential biological functions. High SPINK2 protein expression was an independent adverse biomarker for survival and an indicator of elevated therapy resistance and relapse risk.

Pegcetacoplan controls hemolysis in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis. Pegcetacoplan is the first C3-targeted therapy approved for adults with PNH (United States), adults with PNH with inadequate response or intolerance to a C5 inhibitor (Australia), and adults with anemia despite C5-targeted therapy for ≥3 months (European Union). PRINCE was a phase 3, randomized, multicenter, open-label, controlled study to evaluate the efficacy and safety of pegcetacoplan vs control (supportive care only; eg, blood transfusions, corticosteroids, and supplements) in complement inhibitor-naive patients with PNH.

Scaling Pharmacodynamics from Rats to Humans to Support Erythropoietin and Romiplostim Combination Therapy to Treat Erythropoietin-Resistant Anemia.

Recombinant human erythropoietin (rHuEPO) is one of the most effective drugs for the treatment of anemia in patients with chronic kidney disease. However, EPO-resistance is an important contributor to the increased risk of adverse effects. We previously showed that EPO treatment could induce precursor cell depletion, resulting in EPO-resistance.

Eltrombopag in patients with chronic immune thrombocytopenia in Asia-Pacific, the Middle East, and Turkey: final analysis of CITE.

CITE was a prospective, noninterventional study in adult patients with chronic immune thrombocytopenia treated with eltrombopag under routine clinical care in Asia-Pacific, the Middle East, and Turkey. Data to assess eltrombopag usage, compliance, and outcomes were collected from May 2017 to December 2020. Platelet response was defined as platelet count ≥50 × 103/μL in the absence of rescue medications and splenectomy.

Pharmacogenomic Profiling of Pediatric Acute Myeloid Leukemia to Identify Therapeutic Vulnerabilities and Inform Functional Precision Medicine.

Unlabelled: Despite the expanding portfolio of targeted therapies for adults with acute myeloid leukemia (AML), direct implementation in children is challenging due to inherent differences in underlying genetics. Here we established the pharmacologic profile of pediatric AML by screening myeloblast sensitivity to approved and investigational agents, revealing candidates of immediate clinical relevance. Drug responses ex vivo correlated with patient characteristics, exhibited age-specific alterations, and concorded with activities in xenograft models.

Safety and efficacy of pegcetacoplan in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, hematologic disease characterized by complement-mediated hemolysis, thrombosis, and various degrees of bone marrow dysfunction. Until recently, C5 inhibition with eculizumab or ravulizumab represented the only therapies approved for patients with PNH by the United States Food and Drug Administration (US FDA). Although C5-inhibitors reduce PNH-related signs and symptoms, many patients continue to exhibit persistent anemia and require frequent blood transfusions.

Inhibition of C3 with pegcetacoplan results in normalization of hemolysis markers in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder characterized by complement-mediated hemolysis. C5 inhibitors (eculizumab/ravulizumab) control intravascular hemolysis but do not prevent residual extravascular hemolysis. The newly approved complement inhibitor, pegcetacoplan, inhibits C3, upstream of C5, and has the potential to improve control of complement-mediated hemolysis.

Mutational spectrum and prognosis in Chinese patients with prefibrotic primary myelofibrosis.

Prefibrotic primary myelofibrosis (Pre-PMF) has been classified as a separate entity of myeloproliferative neoplasms (MPNs). Pre-PMF is clinically heterogeneous but a specific prognostic model is lacking. Gene mutations have emerged as useful tools for stratification of myelofibrosis patients.

Treatment Adherence and Health-Related Quality of Life in Patients with Hemophilia in Hong Kong.

Background: This study aims to identify factors affecting health-related quality of life (HRQoL) in Chinese patients with hemophilia in Hong Kong, and to examine the association between treatment adherence and HRQoL outcomes. Methods: Patients with hemophilia A or B from a non-governmental organization reported their HRQoL and treatment adherence to prophylactic therapy using validated tools. Univariate tests and multivariable regression analysis were used to compare differences in outcomes across clinically relevant subgroups.

A Novel Combination Therapy of Erythropoietin and Thrombopoietin to Treat Erythropoietin-Resistance anemia.

Purpose: Treatment with recombinant human erythropoietin (rHuEPO) may correct anemia in patients with chronic kidney disease. However, up to 10% of these patients exhibit EPO resistance or hyporesponsiveness, which may be caused by the depletion of erythroid progenitor cells. Thrombopoietin (TPO) stimulates the self-renewal of stem cells and promotes the growth of early erythroid progenitor cells.

Dynamics of Erythroferrone Response to Erythropoietin in Rats.

Erythroferrone (ERFE) is a hormone identified recently as a master regulator connecting iron homeostasis and erythropoiesis. Serum ERFE concentrations significantly increase in animals and humans with normal or impaired kidney function after receiving exogenous erythropoiesis-stimulating agents (ESAs), which suggests it might be a predictive factor for erythropoiesis. To evaluate whether ERFE is an early, sensitive biomarker for long-term erythropoietic effects of ESAs, we investigated the relationship between ERFE dynamics and time courses of major erythropoietic responses to ESA treatment.