Lydian A. de Ligt, Sanjay R. Thakoerdin, Maud Zwolsman, Gaby Stegemann, Hanke Matlung, Taco W. Kuijpers, Bart J. Biemond, Karin Fijnvandraat, Robin van Bruggen, Erfan Nur
Sickle cell disease (SCD) is a chronic inflammatory state, characterized by increased plasma values of inflammatory and angiogenic proteins. Although red blood cell (RBC) transfusion is known to have immunomodulatory effects in other conditions, its potential effects on the inflammatory state in SCD remain largely unknown. This study aimed to explore the longitudinal effects of RBC transfusion on plasma inflammatory and angiogenic proteins in chronically transfused patients with SCD. Plasma samples were collected from SCD patients treated with either exchange ( N = 12) or top‐up ( N = 12) transfusion prior to transfusion and 1 h, 24–72 h, 1 and 2 weeks post‐transfusion. Proximity Extension Assay technology was used to measure plasma values of 21 proteins at each of these timepoints. Exchange transfusion resulted in decreased values of proteins released during inflammasome activation (IL‐1β, IL‐18), B cell survival and activation (TNFRSF13B/TACI, TNFRSF13C/BAFFR, TNFSF13/APRIL), angiogenesis (ANGPT2, VEGFA, KDR, CXCL12), and neutrophil differentiation, recruitment and activation (G‐CSF, G‐CSFR, CXCL1, CXCL5, CXCL6), at 1 h post‐transfusion, returning gradually to values comparable to pre‐transfusion values during 2 weeks post‐transfusion. In contrast, top‐up transfusion resulted in increased values of EPO and ANGPT1. While exchange transfusion seems to reduce the activation of pro‐inflammatory and pro‐angiogenic pathways, top‐up transfusion might result in reduced hypoxia and increased vascular stability as suggested by the increased values of EPO and ANGPT1. These results enhance our understanding of the effects of RBC transfusion on inflammatory and angiogenic pathways and suggest that exchange transfusion has a stronger effect on these pathways in SCD patients compared to top‐up transfusion.
{"title":"Effect of Red Blood Cell Transfusion on Inflammatory and Angiogenic Pathways in Patients With Sickle Cell Disease","authors":"Lydian A. de Ligt, Sanjay R. Thakoerdin, Maud Zwolsman, Gaby Stegemann, Hanke Matlung, Taco W. Kuijpers, Bart J. Biemond, Karin Fijnvandraat, Robin van Bruggen, Erfan Nur","doi":"10.1002/ajh.70193","DOIUrl":"https://doi.org/10.1002/ajh.70193","url":null,"abstract":"Sickle cell disease (SCD) is a chronic inflammatory state, characterized by increased plasma values of inflammatory and angiogenic proteins. Although red blood cell (RBC) transfusion is known to have immunomodulatory effects in other conditions, its potential effects on the inflammatory state in SCD remain largely unknown. This study aimed to explore the longitudinal effects of RBC transfusion on plasma inflammatory and angiogenic proteins in chronically transfused patients with SCD. Plasma samples were collected from SCD patients treated with either exchange ( <jats:italic>N</jats:italic> = 12) or top‐up ( <jats:italic>N</jats:italic> = 12) transfusion prior to transfusion and 1 h, 24–72 h, 1 and 2 weeks post‐transfusion. Proximity Extension Assay technology was used to measure plasma values of 21 proteins at each of these timepoints. Exchange transfusion resulted in decreased values of proteins released during inflammasome activation (IL‐1β, IL‐18), B cell survival and activation (TNFRSF13B/TACI, TNFRSF13C/BAFFR, TNFSF13/APRIL), angiogenesis (ANGPT2, VEGFA, KDR, CXCL12), and neutrophil differentiation, recruitment and activation (G‐CSF, G‐CSFR, CXCL1, CXCL5, CXCL6), at 1 h post‐transfusion, returning gradually to values comparable to pre‐transfusion values during 2 weeks post‐transfusion. In contrast, top‐up transfusion resulted in increased values of EPO and ANGPT1. While exchange transfusion seems to reduce the activation of pro‐inflammatory and pro‐angiogenic pathways, top‐up transfusion might result in reduced hypoxia and increased vascular stability as suggested by the increased values of EPO and ANGPT1. These results enhance our understanding of the effects of RBC transfusion on inflammatory and angiogenic pathways and suggest that exchange transfusion has a stronger effect on these pathways in SCD patients compared to top‐up transfusion.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"40 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stefan Markus Dendorfer, Katharina Schmidt‐Brücken, Michael Kramer, Björn Steffen, Christoph Schliemann, Jan‐Henrik Mikesch, Nael Alakel, Regina Herbst, Mathias Hänel, Maher Hanoun, Martin Kaufmann, Barbora Weinbergerova, Kerstin Schäfer‐Eckart, Tim Sauer, Andreas Neubauer, Andreas Burchert, Claudia D. Baldus, Jolana Mertová, Edgar Jost, Dirk Niemann, Jan Novák, Stefan W. Krause, Sebastian Scholl, Andreas Hochhaus, Gerhard Held, Tomáš Szotkowski, Andreas Rank, Christoph Schmid, Lars Fransecky, Sabine Kayser, Markus Schaich, Frank Fiebig, Annett Haake, Johannes Schetelig, Jan Moritz Middeke, Friedrich Stölzel, Uwe Platzbecker, Christian Thiede, Carsten Müller‐Tidow, Wolfgang E. Berdel, Gerhard Ehninger, Jiri Mayer, Hubert Serve, Martin Bornhäuser, Christoph Röllig
Anthracyclines are an essential component of induction therapy for acute myeloid leukemia (AML), but their optimal dosing and the associated risk for cardiotoxicity remain under debate. The DaunoDouble trial compared daunorubicin at 60 (Dauno60) versus 90 mg/m 2 (Dauno90) in combination with cytarabine (100 mg/m 2 for 7 days) in newly diagnosed AML patients aged 18–65 years. Cardiac function was assessed by left ventricular ejection fraction (LVEF) and cardiac biomarkers (high‐sensitivity troponin T [hsTnT], NT‐proBNP) before treatment and on Day 15 in 317 randomized patients. Median LVEF declined significantly from 65% [IQR 60%–68.5%] to 61% [IQR 58%–67.8%] across all patients ( p < 0.01), without significant differences between treatment arms. NT‐proBNP levels measured after induction therapy correlated negatively with LVEF at the same time point ( ρ = −0.24, p = 0.02), but did not change significantly during induction—neither between Day 1 and 15 nor between treatment arms. HsTnT levels increased significantly from 5 [IQR 4–8] to 8 ng/L [IQR 6–14] across all patients ( p < 0.01), with higher post‐induction values in the Dauno90 group (9.5 ng/L [IQR 7–14]) compared to Dauno60 (7 ng/L [IQR 5–14]; p < 0.01). In exploratory subgroup analyses, post‐induction hsTnT levels were also significantly higher in patients with obesity and arterial hypertension. These findings provide evidence of a dose‐dependent cardiotoxic effect of daunorubicin, already apparent at standard induction doses, and underscore the importance of early cardiac monitoring. Long‐term follow‐up will be essential to determine the clinical significance of these early changes. Trial Registration: ClinicalTrials.gov identifier: NCT02140242
{"title":"Randomized Comparison of Cardiotoxicity With 60 Versus 90 mg Daunorubicin in AML Induction Therapy","authors":"Stefan Markus Dendorfer, Katharina Schmidt‐Brücken, Michael Kramer, Björn Steffen, Christoph Schliemann, Jan‐Henrik Mikesch, Nael Alakel, Regina Herbst, Mathias Hänel, Maher Hanoun, Martin Kaufmann, Barbora Weinbergerova, Kerstin Schäfer‐Eckart, Tim Sauer, Andreas Neubauer, Andreas Burchert, Claudia D. Baldus, Jolana Mertová, Edgar Jost, Dirk Niemann, Jan Novák, Stefan W. Krause, Sebastian Scholl, Andreas Hochhaus, Gerhard Held, Tomáš Szotkowski, Andreas Rank, Christoph Schmid, Lars Fransecky, Sabine Kayser, Markus Schaich, Frank Fiebig, Annett Haake, Johannes Schetelig, Jan Moritz Middeke, Friedrich Stölzel, Uwe Platzbecker, Christian Thiede, Carsten Müller‐Tidow, Wolfgang E. Berdel, Gerhard Ehninger, Jiri Mayer, Hubert Serve, Martin Bornhäuser, Christoph Röllig","doi":"10.1002/ajh.70160","DOIUrl":"https://doi.org/10.1002/ajh.70160","url":null,"abstract":"Anthracyclines are an essential component of induction therapy for acute myeloid leukemia (AML), but their optimal dosing and the associated risk for cardiotoxicity remain under debate. The DaunoDouble trial compared daunorubicin at 60 (Dauno60) versus 90 mg/m <jats:sup>2</jats:sup> (Dauno90) in combination with cytarabine (100 mg/m <jats:sup>2</jats:sup> for 7 days) in newly diagnosed AML patients aged 18–65 years. Cardiac function was assessed by left ventricular ejection fraction (LVEF) and cardiac biomarkers (high‐sensitivity troponin T [hsTnT], NT‐proBNP) before treatment and on Day 15 in 317 randomized patients. Median LVEF declined significantly from 65% [IQR 60%–68.5%] to 61% [IQR 58%–67.8%] across all patients ( <jats:italic>p</jats:italic> < 0.01), without significant differences between treatment arms. NT‐proBNP levels measured after induction therapy correlated negatively with LVEF at the same time point ( <jats:italic>ρ</jats:italic> = −0.24, <jats:italic>p</jats:italic> = 0.02), but did not change significantly during induction—neither between Day 1 and 15 nor between treatment arms. HsTnT levels increased significantly from 5 [IQR 4–8] to 8 ng/L [IQR 6–14] across all patients ( <jats:italic>p</jats:italic> < 0.01), with higher post‐induction values in the Dauno90 group (9.5 ng/L [IQR 7–14]) compared to Dauno60 (7 ng/L [IQR 5–14]; <jats:italic>p</jats:italic> < 0.01). In exploratory subgroup analyses, post‐induction hsTnT levels were also significantly higher in patients with obesity and arterial hypertension. These findings provide evidence of a dose‐dependent cardiotoxic effect of daunorubicin, already apparent at standard induction doses, and underscore the importance of early cardiac monitoring. Long‐term follow‐up will be essential to determine the clinical significance of these early changes. Trial Registration: ClinicalTrials.gov identifier: NCT02140242","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"185 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ali Abdelhay, Mouna Reghis, Tamer Salhab, Nagesh Jadhav, Michelle Sholzberg, Peter Kouides
Iron deficiency, with or without anemia (IDA or IDWA, respectively), is one of the most prevalent and underdiagnosed conditions globally, particularly in women. In September 2023, Rochester Regional Health (RRH) increased the lower limit of normal (LLN) for ferritin from 10 ng/mL in women and 22 ng/mL in men to a unified threshold of 30 ng/mL, aligning with emerging consensus guidelines. This study evaluates the impact of this clinical laboratory intervention on IDWA/IDA diagnosis and treatment patterns. We conducted a retrospective cohort study using Epic's SlicerDicer tool, comparing patients with ferritin levels < 30 ng/mL during two 1.5‐year periods before and after ferritin LLN update. Primary outcome was the rate of IDWA or IDA diagnoses. Secondary outcomes included individual diagnosis rates, rates of IDWA or IDA diagnosis in males and females, iron prescriptions, hematology referrals, number of patients undergoing endoscopy procedures, and number of packed red blood cells (pRBCs) transfusions. Relative risks (RR) with multiplicity corrected confidence intervals (CI) were calculated for the primary and secondary outcomes. Subgroup analyses were stratified by sex, age, race, ferritin levels, and ordering department. Changes in mean ferritin and hematocrit levels at 3–6 months post‐test were also compared using Welch's t ‐test. Among patients with ferritin levels < 30 ng/mL, 22 478 were identified in the pre‐intervention period and 27 699 in the post‐intervention period. The rate of IDWA or IDA diagnosis increased from 51.0% to 58.5% (RR 1.15; CI: 1.12–1.17; p < 0.001). This increase was more pronounced among females (49.4% to 58.0%; RR 1.17; CI: 1.14–1.21) compared to males (57.0% to 60.2%; RR 1.06; CI: 1.01–1.11). Diagnoses of IDWA rose by 47% (RR 1.47; CI: 1.38–1.57), while IDA increased by 7% (RR 1.07; CI: 1.04–1.10). Prescriptions for oral and IV iron increased by 15% and 17%, respectively, while endoscopy procedures increased by 23%. Among department specialties, surgical departments had the highest relative increase in IDWA/IDA diagnosis rates (RR 1.34; 95% CI: 1.21–1.49). Ferritin levels increased more substantially after the intervention at the 3–6‐month follow‐up (mean difference: 6.9 ng/mL; 95% CI: 5.7–8.1), with a more pronounced rise among females (mean difference: 8.2 ng/mL; 95% CI: 6.9–9.5) compared to males (mean difference: 4.0 ng/mL; 95% CI: 1.4–6.6). Hematocrit levels showed a modest increase in both periods, though the differences were not clinically significant. Transitioning to an evidence‐based higher, sex‐independent ferritin LLN significantly improved the identification and treatment of iron deficiency, particularly among women and non‐anemic patients. These findings support broader adoption of revised ferritin thresholds to enhance early detection and intervention for iron deficiency in clinical practice.
{"title":"Impact of Optimizing the Lower Limit of Normal for Ferritin on Iron Deficiency Diagnosis and Treatment Patterns: A Pre and Post‐Intervention Study Using EHR Data","authors":"Ali Abdelhay, Mouna Reghis, Tamer Salhab, Nagesh Jadhav, Michelle Sholzberg, Peter Kouides","doi":"10.1002/ajh.70198","DOIUrl":"https://doi.org/10.1002/ajh.70198","url":null,"abstract":"Iron deficiency, with or without anemia (IDA or IDWA, respectively), is one of the most prevalent and underdiagnosed conditions globally, particularly in women. In September 2023, Rochester Regional Health (RRH) increased the lower limit of normal (LLN) for ferritin from 10 ng/mL in women and 22 ng/mL in men to a unified threshold of 30 ng/mL, aligning with emerging consensus guidelines. This study evaluates the impact of this clinical laboratory intervention on IDWA/IDA diagnosis and treatment patterns. We conducted a retrospective cohort study using Epic's SlicerDicer tool, comparing patients with ferritin levels < 30 ng/mL during two 1.5‐year periods before and after ferritin LLN update. Primary outcome was the rate of IDWA or IDA diagnoses. Secondary outcomes included individual diagnosis rates, rates of IDWA or IDA diagnosis in males and females, iron prescriptions, hematology referrals, number of patients undergoing endoscopy procedures, and number of packed red blood cells (pRBCs) transfusions. Relative risks (RR) with multiplicity corrected confidence intervals (CI) were calculated for the primary and secondary outcomes. Subgroup analyses were stratified by sex, age, race, ferritin levels, and ordering department. Changes in mean ferritin and hematocrit levels at 3–6 months post‐test were also compared using Welch's <jats:italic>t</jats:italic> ‐test. Among patients with ferritin levels < 30 ng/mL, 22 478 were identified in the pre‐intervention period and 27 699 in the post‐intervention period. The rate of IDWA or IDA diagnosis increased from 51.0% to 58.5% (RR 1.15; CI: 1.12–1.17; <jats:italic>p</jats:italic> < 0.001). This increase was more pronounced among females (49.4% to 58.0%; RR 1.17; CI: 1.14–1.21) compared to males (57.0% to 60.2%; RR 1.06; CI: 1.01–1.11). Diagnoses of IDWA rose by 47% (RR 1.47; CI: 1.38–1.57), while IDA increased by 7% (RR 1.07; CI: 1.04–1.10). Prescriptions for oral and IV iron increased by 15% and 17%, respectively, while endoscopy procedures increased by 23%. Among department specialties, surgical departments had the highest relative increase in IDWA/IDA diagnosis rates (RR 1.34; 95% CI: 1.21–1.49). Ferritin levels increased more substantially after the intervention at the 3–6‐month follow‐up (mean difference: 6.9 ng/mL; 95% CI: 5.7–8.1), with a more pronounced rise among females (mean difference: 8.2 ng/mL; 95% CI: 6.9–9.5) compared to males (mean difference: 4.0 ng/mL; 95% CI: 1.4–6.6). Hematocrit levels showed a modest increase in both periods, though the differences were not clinically significant. Transitioning to an evidence‐based higher, sex‐independent ferritin LLN significantly improved the identification and treatment of iron deficiency, particularly among women and non‐anemic patients. These findings support broader adoption of revised ferritin thresholds to enhance early detection and intervention for iron deficiency in clinical practice.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"19 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
France Debaugnies, Frank Goetzinger, Fleur Wolff, Francis Impens, Sara Dufour, Delphi Van Haver, Philippe Gottignies, Raphaël La Schiazza, Bhavna Mahadeb, Nathalie Meuleman, Carole Nagant, Laurence Rozen, Patricia Borde, Francis Corazza
<p>A wide range of conditions, including malignancies, infections, autoimmune autoinflammatory diseases, and more recently described adverse effects of immunotherapies, can trigger a cytokine storm responsible for a devastating dysregulated immune response. Among cytokine storm syndromes, hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory hyperferritinemic syndrome resulting from a highly stimulated but ineffective immune response, leading to potentially fatal multiorgan damage [<span>1</span>]. HLH can be suspected based on elevated serum ferritin levels [<span>2, 3</span>] but the very high levels of ferritin specific to hyperinflammatory states are reached when the disease progression is too advanced to be of any clinical use. Among the patients with hyperferritinemia admitted to intensive care units, HLH is found in 1.5% [<span>4</span>]. Other frequently encountered causes of hyperferritinemia in critically ill patients are sepsis, liver diseases, and hematological malignancies, conditions that may either mimic or trigger HLH [<span>5</span>]. As the clinical and laboratory features of HLH and sepsis frequently overlap, a reliable marker to differentiate HLH is needed.</p> <p>The human ferritin is a ubiquitous iron-storage protein, composed of 24 subunits with 2 types of peptide chains: light (FeL) or heavy (FeH). The ratio of FeL:FeH subunits varies according to the physiological status of the cell and tissue function [<span>6, 7</span>]. In normal conditions, the serum ferritin is predominantly composed of the L subunit and positively correlated with the size of the total body iron stores [<span>8</span>]. Immunoassays used in clinical laboratories recognize solely the L subunit of ferritin. However, inflammatory conditions have been shown to modulate the relative expression of the H and L subunits of ferritin, with most studied pro-inflammatory stimuli preferentially upregulating FeH synthesis [<span>9</span>]. Increased levels of FeH have been observed in ex vivo models, in bone marrow and liver tissue from patients with HLH [<span>10</span>], and its pro-inflammatory properties have been demonstrated on human macrophage cultures [<span>11</span>]. To our knowledge, quantification of circulating FeH in blood has not yet been reported, especially during acute inflammatory processes [<span>11-13</span>].</p> <p>To improve the specificity of ferritin's assay, we used mass spectrometry (MS)-based proteomics to quantify both L-Ferritin (FeL) and H-Ferritin (FeH) in human sera.</p> <p>Starting from an untargeted liquid chromatography-tandem MS (LC–MS/MS) analysis, we developed a targeted LC–MS/MS method based on multiple reaction monitoring (MRM).</p> <p>First, we performed untargeted shotgun analysis of 6 sera of patients with hyperferritinemia (> 5000 μg/L), to maximize our chances of identifying tryptic signature peptides of FeL and FeH among peptides from other more abundant sera proteins. Among identified peptides, we sele
{"title":"Serum H-Ferritin-To-Ferritin Ratio as a Biomarker of Hemophagocytic Lymphohistiocytosis in Critically Ill Patients With Hyperferritinemia","authors":"France Debaugnies, Frank Goetzinger, Fleur Wolff, Francis Impens, Sara Dufour, Delphi Van Haver, Philippe Gottignies, Raphaël La Schiazza, Bhavna Mahadeb, Nathalie Meuleman, Carole Nagant, Laurence Rozen, Patricia Borde, Francis Corazza","doi":"10.1002/ajh.70189","DOIUrl":"https://doi.org/10.1002/ajh.70189","url":null,"abstract":"<p>A wide range of conditions, including malignancies, infections, autoimmune autoinflammatory diseases, and more recently described adverse effects of immunotherapies, can trigger a cytokine storm responsible for a devastating dysregulated immune response. Among cytokine storm syndromes, hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory hyperferritinemic syndrome resulting from a highly stimulated but ineffective immune response, leading to potentially fatal multiorgan damage [<span>1</span>]. HLH can be suspected based on elevated serum ferritin levels [<span>2, 3</span>] but the very high levels of ferritin specific to hyperinflammatory states are reached when the disease progression is too advanced to be of any clinical use. Among the patients with hyperferritinemia admitted to intensive care units, HLH is found in 1.5% [<span>4</span>]. Other frequently encountered causes of hyperferritinemia in critically ill patients are sepsis, liver diseases, and hematological malignancies, conditions that may either mimic or trigger HLH [<span>5</span>]. As the clinical and laboratory features of HLH and sepsis frequently overlap, a reliable marker to differentiate HLH is needed.</p>\u0000<p>The human ferritin is a ubiquitous iron-storage protein, composed of 24 subunits with 2 types of peptide chains: light (FeL) or heavy (FeH). The ratio of FeL:FeH subunits varies according to the physiological status of the cell and tissue function [<span>6, 7</span>]. In normal conditions, the serum ferritin is predominantly composed of the L subunit and positively correlated with the size of the total body iron stores [<span>8</span>]. Immunoassays used in clinical laboratories recognize solely the L subunit of ferritin. However, inflammatory conditions have been shown to modulate the relative expression of the H and L subunits of ferritin, with most studied pro-inflammatory stimuli preferentially upregulating FeH synthesis [<span>9</span>]. Increased levels of FeH have been observed in ex vivo models, in bone marrow and liver tissue from patients with HLH [<span>10</span>], and its pro-inflammatory properties have been demonstrated on human macrophage cultures [<span>11</span>]. To our knowledge, quantification of circulating FeH in blood has not yet been reported, especially during acute inflammatory processes [<span>11-13</span>].</p>\u0000<p>To improve the specificity of ferritin's assay, we used mass spectrometry (MS)-based proteomics to quantify both L-Ferritin (FeL) and H-Ferritin (FeH) in human sera.</p>\u0000<p>Starting from an untargeted liquid chromatography-tandem MS (LC–MS/MS) analysis, we developed a targeted LC–MS/MS method based on multiple reaction monitoring (MRM).</p>\u0000<p>First, we performed untargeted shotgun analysis of 6 sera of patients with hyperferritinemia (> 5000 μg/L), to maximize our chances of identifying tryptic signature peptides of FeL and FeH among peptides from other more abundant sera proteins. Among identified peptides, we sele","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"32 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sichen Liang, Guilin Tang, Melanie Klausner, Jen Ghabrial, Victoria Stinnett, Patty Long, Laura Morsberger, Rena R. Xian, Carol Ann Huff, Syed Abbas Ali, Philip H. Imus, Christian B. Gocke, Ying S. Zou
{"title":"Optical Genome Mapping for Cytogenetic Analysis in Multiple Myeloma: Real‐World Evidence","authors":"Sichen Liang, Guilin Tang, Melanie Klausner, Jen Ghabrial, Victoria Stinnett, Patty Long, Laura Morsberger, Rena R. Xian, Carol Ann Huff, Syed Abbas Ali, Philip H. Imus, Christian B. Gocke, Ying S. Zou","doi":"10.1002/ajh.70175","DOIUrl":"https://doi.org/10.1002/ajh.70175","url":null,"abstract":"","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"43 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Non-severe aplastic anemia (NSAA) is a heterogeneous bone marrow failure syndrome with limited standardized treatment options. Cyclosporine A (CsA) monotherapy often yields suboptimal responses, highlighting an unmet clinical need for more effective therapies. Thrombopoietin receptor agonists (TPO-RAs) have shown satisfying outcomes in severe aplastic anemia (SAA), but data on their frontline use in NSAA remain scarce. We enrolled 54 adults with newly diagnosed NSAA, including 25 with transfusion-dependent NSAA (TD-NSAA) in the prospective, single-arm Phase 2 trial (NCT05660785) to evaluate the efficacy and safety of hetrombopag, an oral TPO-RA, in combination with CsA. At 24 weeks, the overall response rate (ORR) was 81.5% (44/54), comprising 72.2% partial responses and 9.3% complete responses (CRs). Notably, CR and robust partial response (robust PR) were achieved in 46.3% (25/54) of patients. In the TD-NSAA subgroup, the ORR was even higher at 88.0% (22/25) with substantial improvements in hematologic parameters and quality of life. Extending treatment from 16 to 24 weeks increased the CR and robust PR rate from 24.0% to 44.0%. The median time to achieve an initial response was 6, and 14 weeks for robust PR. Adverse events occurred in 35% of patients, predominantly Grade 1 or 2 and were manageable. Importantly, no clonal progression to myelodysplastic syndrome or leukemia was observed. These findings support hetrombopag plus CsA as a potential first-line therapeutic intervention for NSAA, especially in TD-NSAA patients.
{"title":"Hetrombopag Added to Cyclosporine as the First-Line Treatment for Patients With Non-Severe Aplastic Anemia: A Phase 2 Multicenter Trial.","authors":"Lele Zhang,Ruonan Li,Qian Liang,Weiwang Li,Hong Pan,Zhen Gao,Liwei Fang,Jingyu Zhao,Xiao Yu,Zhexiang Kuang,Neng Nie,Jianping Li,Jinbo Huang,Xin Zhao,Meili Ge,Yizhou Zheng,Jun Li,Hong Zhang,Jun Shi","doi":"10.1002/ajh.70183","DOIUrl":"https://doi.org/10.1002/ajh.70183","url":null,"abstract":"Non-severe aplastic anemia (NSAA) is a heterogeneous bone marrow failure syndrome with limited standardized treatment options. Cyclosporine A (CsA) monotherapy often yields suboptimal responses, highlighting an unmet clinical need for more effective therapies. Thrombopoietin receptor agonists (TPO-RAs) have shown satisfying outcomes in severe aplastic anemia (SAA), but data on their frontline use in NSAA remain scarce. We enrolled 54 adults with newly diagnosed NSAA, including 25 with transfusion-dependent NSAA (TD-NSAA) in the prospective, single-arm Phase 2 trial (NCT05660785) to evaluate the efficacy and safety of hetrombopag, an oral TPO-RA, in combination with CsA. At 24 weeks, the overall response rate (ORR) was 81.5% (44/54), comprising 72.2% partial responses and 9.3% complete responses (CRs). Notably, CR and robust partial response (robust PR) were achieved in 46.3% (25/54) of patients. In the TD-NSAA subgroup, the ORR was even higher at 88.0% (22/25) with substantial improvements in hematologic parameters and quality of life. Extending treatment from 16 to 24 weeks increased the CR and robust PR rate from 24.0% to 44.0%. The median time to achieve an initial response was 6, and 14 weeks for robust PR. Adverse events occurred in 35% of patients, predominantly Grade 1 or 2 and were manageable. Importantly, no clonal progression to myelodysplastic syndrome or leukemia was observed. These findings support hetrombopag plus CsA as a potential first-line therapeutic intervention for NSAA, especially in TD-NSAA patients.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"128 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Li Huang, Qian Wang, He‐Lian Li, Wen Peng, Li Yang, Lin Liu, Li Wang, Xiao‐Hua Luo
{"title":"Flu/Cy Plus PTCy Conditioning Regimen in Haplo‐ HSCT of Severe Aplastic Anemia","authors":"Li Huang, Qian Wang, He‐Lian Li, Wen Peng, Li Yang, Lin Liu, Li Wang, Xiao‐Hua Luo","doi":"10.1002/ajh.70176","DOIUrl":"https://doi.org/10.1002/ajh.70176","url":null,"abstract":"","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"359 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Salam Idriss, David Hoogewijs, François Girodon, Betty Gardie
Erythropoietin (EPO) is a circulating glycoprotein hormone essential for red blood cell production. The history of EPO stretches from early observations of hypoxia in the mid‐19th century to its gene cloning and the clinical use of recombinant forms. Structurally, EPO's extensive glycosylation shapes stability, receptor binding, and therapeutic potential, inspiring engineered analogs with distinct pharmacokinetics. Developmentally, EPO expression shifts from embryonic neural crest and fetal hepatocytes to renal interstitial fibroblasts after birth. EPO gene regulation integrates hypoxia‐inducible factors, transcriptional repressors, enhancers, with HIF‐2α as the principal activator, and post‐translational mechanisms. Recent findings reveal genetic variants within the EPO gene in patients with erythrocytosis. Isoelectric focusing profiles of EPO in these patients was similar to the hepatic‐derived EPO profiles in premature newborns, highlighting a dynamic and context‐dependent regulation. These findings suggest that reactivation of EPO expression in the liver could be therapeutically valuable, given that hepatic‐derived EPO exhibits enhanced activity. Clinically, erythropoiesis‐stimulating agents transformed anemia management but raised safety concerns, leading to refined guidelines. The recent introduction of hypoxia‐inducible factor prolyl hydroxylase inhibitors represents a new strategy that restores endogenous EPO production and coordinates iron metabolism through transient HIF stabilization. Outstanding challenges include the absence of faithful human EPO‐producing cell models and incomplete understanding of the full molecular mechanisms controlling EPO expression and production. Combining insights from developmental biology, genetics, and epigenomics may open new avenues for therapies targeting disorders of erythropoiesis and oxygen homeostasis.
{"title":"Erythropoietin Expression and Regulation: Piecing Together Known Mechanisms and Emerging Insights ","authors":"Salam Idriss, David Hoogewijs, François Girodon, Betty Gardie","doi":"10.1002/ajh.70173","DOIUrl":"https://doi.org/10.1002/ajh.70173","url":null,"abstract":"Erythropoietin (EPO) is a circulating glycoprotein hormone essential for red blood cell production. The history of EPO stretches from early observations of hypoxia in the mid‐19th century to its gene cloning and the clinical use of recombinant forms. Structurally, EPO's extensive glycosylation shapes stability, receptor binding, and therapeutic potential, inspiring engineered analogs with distinct pharmacokinetics. Developmentally, EPO expression shifts from embryonic neural crest and fetal hepatocytes to renal interstitial fibroblasts after birth. <jats:italic>EPO</jats:italic> gene regulation integrates hypoxia‐inducible factors, transcriptional repressors, enhancers, with HIF‐2α as the principal activator, and post‐translational mechanisms. Recent findings reveal genetic variants within the <jats:italic>EPO</jats:italic> gene in patients with erythrocytosis. Isoelectric focusing profiles of EPO in these patients was similar to the hepatic‐derived EPO profiles in premature newborns, highlighting a dynamic and context‐dependent regulation. These findings suggest that reactivation of <jats:italic>EPO</jats:italic> expression in the liver could be therapeutically valuable, given that hepatic‐derived EPO exhibits enhanced activity. Clinically, erythropoiesis‐stimulating agents transformed anemia management but raised safety concerns, leading to refined guidelines. The recent introduction of hypoxia‐inducible factor prolyl hydroxylase inhibitors represents a new strategy that restores endogenous EPO production and coordinates iron metabolism through transient HIF stabilization. Outstanding challenges include the absence of faithful human EPO‐producing cell models and incomplete understanding of the full molecular mechanisms controlling <jats:italic>EPO</jats:italic> expression and production. Combining insights from developmental biology, genetics, and epigenomics may open new avenues for therapies targeting disorders of erythropoiesis and oxygen homeostasis.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"27 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ashley E Benson, Kylee L Martens, Monica Rincon, Lucy Ward, Thalia P Kelley, Elinor L Sullivan, Adam K Lewkowitz, Methodius G Tuuli, Jason A Graham, Joseph J Shatzel, Jamie O Lo
Iron deficiency anemia (IDA) is prevalent in pregnancy, yet oral iron therapies are associated with poor adherence and many intravenous (IV) iron formulations require multiple doses for treatment. Ferric derisomaltose (FDI) is a newer IV iron formulation that is safe and efficacious in non-pregnant individuals, yet pregnancy data is lacking. We evaluated the safety, efficacy, and maternal and neonatal outcomes associated with a single 1000 mg IV dose of FDI in pregnant individuals with IDA. We conducted a prospective, single-arm interventional trial of FDI administered in the second or third trimester of pregnancy from January 2024 to July 2025. The primary outcome was efficacy (hemoglobin increase of ≥ 1 g/dL). Secondary outcomes included safety, other hematologic parameters, patient-reported quality of life, and maternal and neonatal outcomes. Among 78 participants enrolled, 75 received FDI. From baseline to delivery, mean hemoglobin increased by 1.3 g/dL, with significant improvements (p < 0.001) in ferritin and transferrin saturation through 6 weeks postpartum. Patient-reported fatigue scores improved (p < 0.001), as did Edinburgh Postnatal Depression Scale scores (p = 0.003). The mean FDI infusion time was 24 min. Cord blood ferritin and hemoglobin values suggested enhanced neonatal iron status. No major infusion reactions or hospitalizations occurred. Minor infusion-related symptoms were uncommon and self-limited: chest tightness (6.7%), flushing (5.3%), mild shortness of breath (4%), urticaria (2.7%), rash (1.3%). Two patients (2.6%) did not complete the infusion due to reaction. These findings support single-dose IV FDI as a safe and effective option for late-pregnancy IDA, meriting further evaluation in larger controlled trials.
{"title":"Efficacy of Single-Dose Intravenous Ferric Derisomaltose for Iron Deficiency Anemia in Pregnancy.","authors":"Ashley E Benson, Kylee L Martens, Monica Rincon, Lucy Ward, Thalia P Kelley, Elinor L Sullivan, Adam K Lewkowitz, Methodius G Tuuli, Jason A Graham, Joseph J Shatzel, Jamie O Lo","doi":"10.1002/ajh.70190","DOIUrl":"https://doi.org/10.1002/ajh.70190","url":null,"abstract":"<p><p>Iron deficiency anemia (IDA) is prevalent in pregnancy, yet oral iron therapies are associated with poor adherence and many intravenous (IV) iron formulations require multiple doses for treatment. Ferric derisomaltose (FDI) is a newer IV iron formulation that is safe and efficacious in non-pregnant individuals, yet pregnancy data is lacking. We evaluated the safety, efficacy, and maternal and neonatal outcomes associated with a single 1000 mg IV dose of FDI in pregnant individuals with IDA. We conducted a prospective, single-arm interventional trial of FDI administered in the second or third trimester of pregnancy from January 2024 to July 2025. The primary outcome was efficacy (hemoglobin increase of ≥ 1 g/dL). Secondary outcomes included safety, other hematologic parameters, patient-reported quality of life, and maternal and neonatal outcomes. Among 78 participants enrolled, 75 received FDI. From baseline to delivery, mean hemoglobin increased by 1.3 g/dL, with significant improvements (p < 0.001) in ferritin and transferrin saturation through 6 weeks postpartum. Patient-reported fatigue scores improved (p < 0.001), as did Edinburgh Postnatal Depression Scale scores (p = 0.003). The mean FDI infusion time was 24 min. Cord blood ferritin and hemoglobin values suggested enhanced neonatal iron status. No major infusion reactions or hospitalizations occurred. Minor infusion-related symptoms were uncommon and self-limited: chest tightness (6.7%), flushing (5.3%), mild shortness of breath (4%), urticaria (2.7%), rash (1.3%). Two patients (2.6%) did not complete the infusion due to reaction. These findings support single-dose IV FDI as a safe and effective option for late-pregnancy IDA, meriting further evaluation in larger controlled trials.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":" ","pages":""},"PeriodicalIF":9.9,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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