François Therme, Jean Francois Viallard, Manuela Rueter, Thibault Comont, Stephane Cheze, Sylvain Audia, Mikael Ebbo, Matthieu Mahevas, Louis Terriou, Quitterie Reynaud, Pierre-Yves Jeandel, Thomas Moulinet, Delphine Gobert, Philippe Guilpain, Clément Gourguechon, Ailsa Robbins, Marc Ruivard, Laurie Chabbert, Bernard Bonnotte, Bertrand Godeau, Maryse Lapeyre-Mestre, Yoann Zadro, Marc Michel, Guillaume Moulis, The Carmen-France Investigators Group
Adult patients with immune thrombocytopenia (ITP) have an increased risk of venous thrombosis as compared to the general population. The management of ITP in the context of anticoagulation is challenging. We conducted an observational study in the prospective, multicenter, national CARMEN-France registry. Adult patients with newly diagnosed ITP between June 2013 and May 2022 were selected. We assessed the cumulative incidence of venous thrombosis during follow-up with death as a competing event, described these events, and assessed patient outcomes depending on management strategies, with a focus on thromboses that occurred during treatment with thrombopoietin receptor agonists (TPO-RA). Among the 1303 patients selected for this study, 53 experienced venous thrombosis. The cumulative incidence of venous thrombosis was 2.6% (95% CI: 1.8–3.7) at 1 year and 8.6% (95% CI: 5.8–12.0) at 5 years. In patients exposed to TPO-RA, the cumulative incidence was 9.3% (95% CI: 6.2–13.2) and 13.4% (95% CI: 8.6–19.2) at 1 and 5 years of exposure, respectively. Patients who experienced thrombosis were older, had more frequently a history of venous thrombosis and secondary ITP, a more severe ITP, and were more frequently treated with TPO-RAs. Twenty (37.7%) of the 53 events were atypical, including five cerebral venous thromboses. Four patients died, and seven experienced major bleeding. The analysis of different managements of ITP after the thrombotic event suggested that the safest strategy was to promptly control ITP to enable early anticoagulation, including using TPO-RAs. Long-term anticoagulation therapy should be considered in patients treated with TPO-RAs and persistent risk factors for thrombosis.
{"title":"Incidence, Characteristics, and Management of Venous Thrombosis in Adult Patients With Immune Thrombocytopenia: Results From the Multicenter, Prospective Registry CARMEN-France","authors":"François Therme, Jean Francois Viallard, Manuela Rueter, Thibault Comont, Stephane Cheze, Sylvain Audia, Mikael Ebbo, Matthieu Mahevas, Louis Terriou, Quitterie Reynaud, Pierre-Yves Jeandel, Thomas Moulinet, Delphine Gobert, Philippe Guilpain, Clément Gourguechon, Ailsa Robbins, Marc Ruivard, Laurie Chabbert, Bernard Bonnotte, Bertrand Godeau, Maryse Lapeyre-Mestre, Yoann Zadro, Marc Michel, Guillaume Moulis, The Carmen-France Investigators Group","doi":"10.1002/ajh.70192","DOIUrl":"10.1002/ajh.70192","url":null,"abstract":"<div>\u0000 \u0000 <p>Adult patients with immune thrombocytopenia (ITP) have an increased risk of venous thrombosis as compared to the general population. The management of ITP in the context of anticoagulation is challenging. We conducted an observational study in the prospective, multicenter, national CARMEN-France registry. Adult patients with newly diagnosed ITP between June 2013 and May 2022 were selected. We assessed the cumulative incidence of venous thrombosis during follow-up with death as a competing event, described these events, and assessed patient outcomes depending on management strategies, with a focus on thromboses that occurred during treatment with thrombopoietin receptor agonists (TPO-RA). Among the 1303 patients selected for this study, 53 experienced venous thrombosis. The cumulative incidence of venous thrombosis was 2.6% (95% CI: 1.8–3.7) at 1 year and 8.6% (95% CI: 5.8–12.0) at 5 years. In patients exposed to TPO-RA, the cumulative incidence was 9.3% (95% CI: 6.2–13.2) and 13.4% (95% CI: 8.6–19.2) at 1 and 5 years of exposure, respectively. Patients who experienced thrombosis were older, had more frequently a history of venous thrombosis and secondary ITP, a more severe ITP, and were more frequently treated with TPO-RAs. Twenty (37.7%) of the 53 events were atypical, including five cerebral venous thromboses. Four patients died, and seven experienced major bleeding. The analysis of different managements of ITP after the thrombotic event suggested that the safest strategy was to promptly control ITP to enable early anticoagulation, including using TPO-RAs. Long-term anticoagulation therapy should be considered in patients treated with TPO-RAs and persistent risk factors for thrombosis.</p>\u0000 </div>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 3","pages":"456-466"},"PeriodicalIF":9.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931490","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}
Abhishek A. Mangaonkar, Kelly L. Bolton, Mrinal M. Patnaik
Condition Overview
Clonal hematopoiesis (CH) refers to the presence of somatic variants in hematopoietic stem and progenitor cells (HSPC) that result in expansion over time.
Diagnosis
CH of indeterminate potential (CHIP) is operationally defined as pathogenic variants in oncogenic driver genes occurring in HSPCs at variant allele frequencies ≥ 2%.
Clinical Associations
CH is associated with increased risk for progressive cytopenias (also called clonal cytopenia of undetermined significance), hematological (predominantly myeloid but also lymphoid) neoplasms, cytosis (including monocytosis), and nonhematological conditions such as atherosclerotic cardiovascular and cerebrovascular disease. CH is linked to numerous other diseases including venous thromboembolism, type 2 diabetes mellitus, chronic obstructive pulmonary disease, osteoporosis, and gout, with a potential protective impact in Alzheimer's disease (AD).
Management Recommendations
CH detection is becoming increasingly common due to the ubiquitous use of somatic and germline sequencing in clinical practice, particularly, in oncology. The clinical implications of CH are most relevant in therapy-related myeloid neoplasms (t-MN), with antecedent CH clones in genes such as TP53, PPM1D, and/or CHEK2 having a clear selection advantage. Furthermore, genetic predisposition to CH has provided some clarity on the origin and evolution of CH. We are currently defining the role for CH assessment in individuals with persistent (≥ 4 months) unexplained cytopenias, in patients with malignancies prior to adjuvant cytotoxic chemotherapy and/or radiation or radionuclide therapy, screening prior to autologous hematopoietic stem cell transplantation or chimeric antigen receptor T cell (CAR-T) therapy, and to work-up potentially germline mosaic variants.
{"title":"Clonal Hematopoiesis of Indeterminate Potential and Clonal Cytopenias of Undetermined Significance: 2026 Update on Clinical Associations and Management Recommendations","authors":"Abhishek A. Mangaonkar, Kelly L. Bolton, Mrinal M. Patnaik","doi":"10.1002/ajh.70205","DOIUrl":"10.1002/ajh.70205","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Condition Overview</h3>\u0000 \u0000 <p>Clonal hematopoiesis (CH) refers to the presence of somatic variants in hematopoietic stem and progenitor cells (HSPC) that result in expansion over time.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Diagnosis</h3>\u0000 \u0000 <p>CH of indeterminate potential (CHIP) is operationally defined as pathogenic variants in oncogenic driver genes occurring in HSPCs at variant allele frequencies ≥ 2%.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Clinical Associations</h3>\u0000 \u0000 <p>CH is associated with increased risk for progressive cytopenias (also called clonal cytopenia of undetermined significance), hematological (predominantly myeloid but also lymphoid) neoplasms, cytosis (including monocytosis), and nonhematological conditions such as atherosclerotic cardiovascular and cerebrovascular disease. CH is linked to numerous other diseases including venous thromboembolism, type 2 diabetes mellitus, chronic obstructive pulmonary disease, osteoporosis, and gout, with a potential protective impact in Alzheimer's disease (AD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Management Recommendations</h3>\u0000 \u0000 <p>CH detection is becoming increasingly common due to the ubiquitous use of somatic and germline sequencing in clinical practice, particularly, in oncology. The clinical implications of CH are most relevant in therapy-related myeloid neoplasms (t-MN), with antecedent CH clones in genes such as <i>TP53, PPM1D,</i> and/or <i>CHEK2</i> having a clear selection advantage. Furthermore, genetic predisposition to CH has provided some clarity on the origin and evolution of CH. We are currently defining the role for CH assessment in individuals with persistent (≥ 4 months) unexplained cytopenias, in patients with malignancies prior to adjuvant cytotoxic chemotherapy and/or radiation or radionuclide therapy, screening prior to autologous hematopoietic stem cell transplantation or chimeric antigen receptor T cell (CAR-T) therapy, and to work-up potentially germline mosaic variants.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 3","pages":"550-565"},"PeriodicalIF":9.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70205","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gian Luca Forni, Emanuela Stampone, Valeria Maria Pinto, Laura Silvestri, Debora Bencivenga, Sara Sarnelli, Marilena Di Finizio, Paolo Ricchi, Sabrina Quintino, Ugo Salvadori, Domenico Girelli, Fulvio Della Ragione, Adriana Borriello
<p>Transferrin-Immune Complex Disease (TICD) is an acquired monoclonal gammopathy characterized by the presence of anti-transferrin (TF) autoantibodies, leading to remarkable hypertransferrinemia and hypersideremia [<span>1-8</span>]. The condition is not benign since TICD patients present a high risk of developing hemochromatosis and multiple myeloma. Anemia might contemporaneously occur. So far, few cases of TICD have been reported (Table 1), but the disease's frequency is likely underestimated. Here, we identified two novel TICD cases (patients 10 and 11, Table 1) and reported mechanistic studies aimed at characterizing the pathophysiology of the disease.</p><p> <i>Patient 10</i> is a 65-year-old man presenting with hypersideremia (706 μg/mL), hypertransferrinemia (652 mg/dL), high TF saturation (76%), and a monoclonal IgG-κ peak (2740 mg/dL). Liver Iron Concentration (LIC) quantification by Magnetic Resonance T2* (MR-T2*) confirmed iron overload (8 mg Fe/g liver dry weight, normal range < 3.2 mg Fe/g liver dry weight). Due to mild anemia, the patient underwent moderate phlebotomies (200 mL each time). In spite of the hypersideremia, hepcidin was extremely low (< 0.5 ng/100 mL). Erythroferrone (ERFE) was remarkably high (7.4 ng/mL).</p><p> <i>Patient 11</i> is a 72-year-old woman with hypersideremia (580 μg/mL), hypertransferrinemia (445 mg/dL), high TF saturation (70%), and a monoclonal IgG-κ peak (2232 mg/dL). She was identified as having MGUS since the age of 55. MR-T2* LIC quantification showed mild iron overload (6.4 mg Fe/g liver dry weight). After diagnosis, the patient developed progressive anemia, and phlebotomy therapy became poorly tolerated. No data on hepcidin and ERFE levels are available.</p><p>Patient 10 IgGs were purified by protein A/G and analyzed by SDS/PAGE, showing a light chain with an abnormally higher molecular weight and the presence of a large amount of TF. Through these data and direct laboratory analyses (Supporting Information: 1, SM1), we established that about 70% of TF was IgG-bound and determined the stoichiometry of the immunocomplex, containing two IgG molecules for each TF molecule (Table S1). Iron co-purified with the TF-immunocomplexes. Using the same procedure, patient 11 IgGs were only partially purified, and the fraction of IgG-bound TF could not be precisely estimated. No molecular weight alteration of the κ-light chain was evident.</p><p>We investigated in vitro whether the IgG/TF occurrence affects iron supply to cells. 10% control, or patient 10 sera were added to Hep-G2, a human hepatocellular carcinoma-derived cell line. An immunofluorescence punctate pattern (Supporting Information: SM2) demonstrated TF incorporation. Thus, the TF-immunocomplex does not hamper TF entry. Intriguingly, we evidenced TF localization at the mid-body (Supporting Information: SM2), suggesting TF's still unknown roles. Hep-G2 cells were then incubated with patient 11 serum as well, and cyto
{"title":"Iron Overload and Anemia in Transferrin Immune Complex Disease, an Overlooked Monoclonal Gammopathy of Clinical Significance","authors":"Gian Luca Forni, Emanuela Stampone, Valeria Maria Pinto, Laura Silvestri, Debora Bencivenga, Sara Sarnelli, Marilena Di Finizio, Paolo Ricchi, Sabrina Quintino, Ugo Salvadori, Domenico Girelli, Fulvio Della Ragione, Adriana Borriello","doi":"10.1002/ajh.70187","DOIUrl":"10.1002/ajh.70187","url":null,"abstract":"<p>Transferrin-Immune Complex Disease (TICD) is an acquired monoclonal gammopathy characterized by the presence of anti-transferrin (TF) autoantibodies, leading to remarkable hypertransferrinemia and hypersideremia [<span>1-8</span>]. The condition is not benign since TICD patients present a high risk of developing hemochromatosis and multiple myeloma. Anemia might contemporaneously occur. So far, few cases of TICD have been reported (Table 1), but the disease's frequency is likely underestimated. Here, we identified two novel TICD cases (patients 10 and 11, Table 1) and reported mechanistic studies aimed at characterizing the pathophysiology of the disease.</p><p>\u0000 <i>Patient 10</i> is a 65-year-old man presenting with hypersideremia (706 μg/mL), hypertransferrinemia (652 mg/dL), high TF saturation (76%), and a monoclonal IgG-κ peak (2740 mg/dL). Liver Iron Concentration (LIC) quantification by Magnetic Resonance T2* (MR-T2*) confirmed iron overload (8 mg Fe/g liver dry weight, normal range < 3.2 mg Fe/g liver dry weight). Due to mild anemia, the patient underwent moderate phlebotomies (200 mL each time). In spite of the hypersideremia, hepcidin was extremely low (< 0.5 ng/100 mL). Erythroferrone (ERFE) was remarkably high (7.4 ng/mL).</p><p>\u0000 <i>Patient 11</i> is a 72-year-old woman with hypersideremia (580 μg/mL), hypertransferrinemia (445 mg/dL), high TF saturation (70%), and a monoclonal IgG-κ peak (2232 mg/dL). She was identified as having MGUS since the age of 55. MR-T2* LIC quantification showed mild iron overload (6.4 mg Fe/g liver dry weight). After diagnosis, the patient developed progressive anemia, and phlebotomy therapy became poorly tolerated. No data on hepcidin and ERFE levels are available.</p><p>Patient 10 IgGs were purified by protein A/G and analyzed by SDS/PAGE, showing a light chain with an abnormally higher molecular weight and the presence of a large amount of TF. Through these data and direct laboratory analyses (Supporting Information: 1, SM1), we established that about 70% of TF was IgG-bound and determined the stoichiometry of the immunocomplex, containing two IgG molecules for each TF molecule (Table S1). Iron co-purified with the TF-immunocomplexes. Using the same procedure, patient 11 IgGs were only partially purified, and the fraction of IgG-bound TF could not be precisely estimated. No molecular weight alteration of the κ-light chain was evident.</p><p>We investigated in vitro whether the IgG/TF occurrence affects iron supply to cells. 10% control, or patient 10 sera were added to Hep-G2, a human hepatocellular carcinoma-derived cell line. An immunofluorescence punctate pattern (Supporting Information: SM2) demonstrated TF incorporation. Thus, the TF-immunocomplex does not hamper TF entry. Intriguingly, we evidenced TF localization at the mid-body (Supporting Information: SM2), suggesting TF's still unknown roles. Hep-G2 cells were then incubated with patient 11 serum as well, and cyto","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 3","pages":"586-591"},"PeriodicalIF":9.9,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70187","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nicolas Lecornec,Flore Sicre de Fontbrune,Edouard Forcade,Loïc Garçon,Louis Terriou,Pierre Cougoul,Karen Delavigne,Isabelle Marie,Isabelle Brindel,Éric Deconinck,Étienne Daguindau,Shanti Amé,Marie-Pierre Ledoux,Laurence Sanhes,Stanislas Nimubona,Guy Leverger,Marianne de Montalembert,Régis Peffault de Latour,Jean-Hugues Dalle,Pierre Fenaux,Lydie Da Costa,Thierry Leblanc
Information about Diamond-Blackfan anemia syndrome (DBAS), a ribosomopathy associated with anemia, congenital anomalies and cancer predisposition is limited in adults. Using the French DBAS registry, 235 adult patients with DBAS were analyzed for hematological outcomes. At last follow-up, anemia, neutropenia, thrombocytopenia, and pancytopenia affected respectively 78%, 31%, 15%, and 11% of the patients. There was no severe aplastic anemia outside of clonal evolution. Among patients without DBAS-specific treatment (e.g., steroids or red blood cell transfusions), the incidence of anemia, neutropenia, and thrombocytopenia was 52%, 35%, and 10%, highlighting that treatment independence does not mean hematologic remission. Four patients developed myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), all associated with poor-risk features and dismal outcomes. Observed to expected ratios were 155 for MDS and 55.4 for AML, confirming a major risk-excess despite stringent criteria for MDS diagnosis. With a median follow-up of 32.2 years (IQR 26-44), overall survival (OS) was 98.0% (95% CI, 95.8-100), 90.6% (95% CI, 84.2-97.5), and 70.7% (95% CI, 57.3-87.2) at 30, 40, and 50 years respectively. Solid and hematologic cancers were the main cause of death. This study demonstrates, in a large cohort of adults with DBAS, that cytopenias beyond anemia are frequent and persistent. Myeloid neoplasms occur with a high incidence and dismal outcomes. These findings highlight the need for risk stratification, tailored surveillance, and optimized therapeutic strategies in this vulnerable population.
{"title":"Hematologic Landscape of Adult Patients With Diamond-Blackfan Anemia Syndrome.","authors":"Nicolas Lecornec,Flore Sicre de Fontbrune,Edouard Forcade,Loïc Garçon,Louis Terriou,Pierre Cougoul,Karen Delavigne,Isabelle Marie,Isabelle Brindel,Éric Deconinck,Étienne Daguindau,Shanti Amé,Marie-Pierre Ledoux,Laurence Sanhes,Stanislas Nimubona,Guy Leverger,Marianne de Montalembert,Régis Peffault de Latour,Jean-Hugues Dalle,Pierre Fenaux,Lydie Da Costa,Thierry Leblanc","doi":"10.1002/ajh.70197","DOIUrl":"https://doi.org/10.1002/ajh.70197","url":null,"abstract":"Information about Diamond-Blackfan anemia syndrome (DBAS), a ribosomopathy associated with anemia, congenital anomalies and cancer predisposition is limited in adults. Using the French DBAS registry, 235 adult patients with DBAS were analyzed for hematological outcomes. At last follow-up, anemia, neutropenia, thrombocytopenia, and pancytopenia affected respectively 78%, 31%, 15%, and 11% of the patients. There was no severe aplastic anemia outside of clonal evolution. Among patients without DBAS-specific treatment (e.g., steroids or red blood cell transfusions), the incidence of anemia, neutropenia, and thrombocytopenia was 52%, 35%, and 10%, highlighting that treatment independence does not mean hematologic remission. Four patients developed myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), all associated with poor-risk features and dismal outcomes. Observed to expected ratios were 155 for MDS and 55.4 for AML, confirming a major risk-excess despite stringent criteria for MDS diagnosis. With a median follow-up of 32.2 years (IQR 26-44), overall survival (OS) was 98.0% (95% CI, 95.8-100), 90.6% (95% CI, 84.2-97.5), and 70.7% (95% CI, 57.3-87.2) at 30, 40, and 50 years respectively. Solid and hematologic cancers were the main cause of death. This study demonstrates, in a large cohort of adults with DBAS, that cytopenias beyond anemia are frequent and persistent. Myeloid neoplasms occur with a high incidence and dismal outcomes. These findings highlight the need for risk stratification, tailored surveillance, and optimized therapeutic strategies in this vulnerable population.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"39 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907676","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}
Peter N. Benotti, G. Craig Wood, Jila Kaberi‐Otarod, Christopher D. Still, Glenn S. Gerhard, Bruce R. Bistrian
Iron deficiency (ID) is the most common nutritional deficiency following metabolic and bariatric surgery. Preoperative anemia and/or low serum levels of ferritin, which are common among candidates for metabolic and bariatric surgery (MBS), are associated with increased risk of developing severe postoperative ID. This study investigates iron status among candidates for MBS and its relationship to the development of severe postoperative anemia. From an established bariatric surgery registry, surgery candidates with iron assessment as well as longitudinal anemia follow‐up were identified. The relationship between ferritin levels < 30 ng/mL stratified by levels of transferrin saturation < 20% and < 15% was analyzed to identify risk factors associated with the onset of severe postoperative anemia (hemoglobin level < 8 g/dL). Four thousand seven hundred and nine patients were studied. 14.6% had ferritin concentrations < 30 ng/mL and another 20% 30–99 ng/dL coupled with transferrin saturations (TSATs) < 20% to indicate absolute ID and functional ID. The overall prevalence of ID was 35%. The overall risk of severe postoperative anemia was 10.5% at 5 years and 19.8% at 10 years. Ferritin levels of < 30 ng/mL and TSAT < 20% were each associated with greater risk of developing severe anemia ( p < 0.0001). Patients with ferritins < 30 ng/mL and TSATs < 15% had the most severe ID with the greatest risk of developing earlier and more severe anemia which was confirmed after adjusted analysis ( p < 0.0001). A preoperative ferritin level < 30 ng/mL with TSAT < 15% is an excellent predictor for severe postoperative anemia.
{"title":"Preoperative Iron Status and the Risk of Severe Postoperative Anemia After Metabolic and Bariatric Surgery","authors":"Peter N. Benotti, G. Craig Wood, Jila Kaberi‐Otarod, Christopher D. Still, Glenn S. Gerhard, Bruce R. Bistrian","doi":"10.1002/ajh.70191","DOIUrl":"https://doi.org/10.1002/ajh.70191","url":null,"abstract":"Iron deficiency (ID) is the most common nutritional deficiency following metabolic and bariatric surgery. Preoperative anemia and/or low serum levels of ferritin, which are common among candidates for metabolic and bariatric surgery (MBS), are associated with increased risk of developing severe postoperative ID. This study investigates iron status among candidates for MBS and its relationship to the development of severe postoperative anemia. From an established bariatric surgery registry, surgery candidates with iron assessment as well as longitudinal anemia follow‐up were identified. The relationship between ferritin levels < 30 ng/mL stratified by levels of transferrin saturation < 20% and < 15% was analyzed to identify risk factors associated with the onset of severe postoperative anemia (hemoglobin level < 8 g/dL). Four thousand seven hundred and nine patients were studied. 14.6% had ferritin concentrations < 30 ng/mL and another 20% 30–99 ng/dL coupled with transferrin saturations (TSATs) < 20% to indicate absolute ID and functional ID. The overall prevalence of ID was 35%. The overall risk of severe postoperative anemia was 10.5% at 5 years and 19.8% at 10 years. Ferritin levels of < 30 ng/mL and TSAT < 20% were each associated with greater risk of developing severe anemia ( <jats:italic>p</jats:italic> < 0.0001). Patients with ferritins < 30 ng/mL and TSATs < 15% had the most severe ID with the greatest risk of developing earlier and more severe anemia which was confirmed after adjusted analysis ( <jats:italic>p</jats:italic> < 0.0001). A preoperative ferritin level < 30 ng/mL with TSAT < 15% is an excellent predictor for severe postoperative anemia.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"14 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902505","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}
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}
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":"10.1002/ajh.70198","url":null,"abstract":"<div>\u0000 \u0000 <p>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 <i>t</i>-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; <i>p</i> < 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.</p>\u0000 </div>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 3","pages":"439-446"},"PeriodicalIF":9.9,"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 selected
{"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":"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><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 selected","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 3","pages":"648-653"},"PeriodicalIF":9.9,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70189","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marina Konopleva, Courtney D. DiNardo, Yan Sun, Paul Jung, Sanam Loghavi, Jalaja Potluri, Monique Dail, Brenda Chyla, Daniel A. Pollyea
<p>Acute myeloid leukemia (AML) is a heterogeneous malignancy with variable outcomes to treatment. Frontline therapy typically consists of high-dose chemotherapy followed by stem cell transplant for patients who are able to tolerate high-intensity treatment, or low-dose chemotherapy (e.g., cytarabine or hypomethylating agents, like azacitidine) for patients who are older and/or have comorbid conditions, although the exact treatment course used for a given patient depends upon disease biology and evolving research. Venetoclax-azacitidine increased response rates versus azacitidine monotherapy among patients with AML who are ineligible for intensive chemotherapy [<span>1</span>], leading to Food and Drug Administration approval in 2018 and has since become the standard of care for this patient population. Venetoclax-azacitidine has shown broad efficacy across patient subgroups, including those with primary or secondary AML, intermediate or poor cytogenetic risk, and mutation subgroups (e.g., <i>IDH1/2</i>-mutated AML treated with or without IDH inhibitor) [<span>1-3</span>]. However, patients with monocytic AML have been reported to have primary and secondary resistance to and/or suboptimal response with venetoclax-based therapy [<span>4</span>]. In a study of 100 patients, those with French–American–British (FAB) M5 AML subtype [<span>5</span>], a more differentiated phenotype of monocytic AML, were suggested to be less sensitive to treatment with venetoclax-azacitidine [<span>6</span>]. Other studies, both in vivo and ex vivo, have shown similar results [<span>4, 7, 8</span>]. An emerging 4-gene prognostic signature for AML highlights the influence of mutations in <i>TP53</i>, <i>FLT3-</i>ITD, <i>NRAS</i>, and <i>KRAS</i> on patient outcomes, of which <i>N/KRAS</i> mutations are commonly associated with monocytic AML [<span>9, 10</span>]. Here, we report findings by AML differentiation state using the FAB classification system (M4, M5) and baseline gene expression profiling (GEP) to define monocytic-like AML in a post hoc analysis of venetoclax-azacitidine in patients ineligible for intensive chemotherapy from a pooled analysis of Phase 1b M14-358 and Phase 3 VIALE-A studies.</p><p>Patients from the Phase 1b M14-358 (NCT02203773) and Phase 3 VIALE-A (NCT02993523) studies [<span>1, 11</span>] who received venetoclax-azacitidine were included (Figure S1, Tables S1 and S2). Two methods were used to define monocytic AML: pathologic assignment of FAB subtyping (M4, M5, non-M4/M5; <i>n</i> = 197) per investigator and baseline GEP in patients with > 30% AML blasts (<i>n</i> = 153). Seventy-seven patients had FAB and GEP data. For GEP, a 13-gene panel of common myeloid markers (<i>ANPEP</i>, <i>CD14</i>, <i>CD300e</i>, <i>CD33</i>, <i>CD34</i>, <i>CD4</i>, <i>CD68</i>, <i>CR1</i>, <i>FCGR1A</i>, <i>FCGR1B</i>, <i>FCGR1CP</i>, <i>ITGAM</i>, and <i>KIT</i>) was used (Figure 1A). The expression levels of 4 of these genes associated with monocytic differe
{"title":"Analysis of Patients With Monocytic and Monocytic-Like Acute Myeloid Leukemia, Including AML-M4 and AML-M5, Treated With Venetoclax Plus Azacitidine","authors":"Marina Konopleva, Courtney D. DiNardo, Yan Sun, Paul Jung, Sanam Loghavi, Jalaja Potluri, Monique Dail, Brenda Chyla, Daniel A. Pollyea","doi":"10.1002/ajh.70161","DOIUrl":"10.1002/ajh.70161","url":null,"abstract":"<p>Acute myeloid leukemia (AML) is a heterogeneous malignancy with variable outcomes to treatment. Frontline therapy typically consists of high-dose chemotherapy followed by stem cell transplant for patients who are able to tolerate high-intensity treatment, or low-dose chemotherapy (e.g., cytarabine or hypomethylating agents, like azacitidine) for patients who are older and/or have comorbid conditions, although the exact treatment course used for a given patient depends upon disease biology and evolving research. Venetoclax-azacitidine increased response rates versus azacitidine monotherapy among patients with AML who are ineligible for intensive chemotherapy [<span>1</span>], leading to Food and Drug Administration approval in 2018 and has since become the standard of care for this patient population. Venetoclax-azacitidine has shown broad efficacy across patient subgroups, including those with primary or secondary AML, intermediate or poor cytogenetic risk, and mutation subgroups (e.g., <i>IDH1/2</i>-mutated AML treated with or without IDH inhibitor) [<span>1-3</span>]. However, patients with monocytic AML have been reported to have primary and secondary resistance to and/or suboptimal response with venetoclax-based therapy [<span>4</span>]. In a study of 100 patients, those with French–American–British (FAB) M5 AML subtype [<span>5</span>], a more differentiated phenotype of monocytic AML, were suggested to be less sensitive to treatment with venetoclax-azacitidine [<span>6</span>]. Other studies, both in vivo and ex vivo, have shown similar results [<span>4, 7, 8</span>]. An emerging 4-gene prognostic signature for AML highlights the influence of mutations in <i>TP53</i>, <i>FLT3-</i>ITD, <i>NRAS</i>, and <i>KRAS</i> on patient outcomes, of which <i>N/KRAS</i> mutations are commonly associated with monocytic AML [<span>9, 10</span>]. Here, we report findings by AML differentiation state using the FAB classification system (M4, M5) and baseline gene expression profiling (GEP) to define monocytic-like AML in a post hoc analysis of venetoclax-azacitidine in patients ineligible for intensive chemotherapy from a pooled analysis of Phase 1b M14-358 and Phase 3 VIALE-A studies.</p><p>Patients from the Phase 1b M14-358 (NCT02203773) and Phase 3 VIALE-A (NCT02993523) studies [<span>1, 11</span>] who received venetoclax-azacitidine were included (Figure S1, Tables S1 and S2). Two methods were used to define monocytic AML: pathologic assignment of FAB subtyping (M4, M5, non-M4/M5; <i>n</i> = 197) per investigator and baseline GEP in patients with > 30% AML blasts (<i>n</i> = 153). Seventy-seven patients had FAB and GEP data. For GEP, a 13-gene panel of common myeloid markers (<i>ANPEP</i>, <i>CD14</i>, <i>CD300e</i>, <i>CD33</i>, <i>CD34</i>, <i>CD4</i>, <i>CD68</i>, <i>CR1</i>, <i>FCGR1A</i>, <i>FCGR1B</i>, <i>FCGR1CP</i>, <i>ITGAM</i>, and <i>KIT</i>) was used (Figure 1A). The expression levels of 4 of these genes associated with monocytic differe","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 3","pages":"577-580"},"PeriodicalIF":9.9,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70161","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","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/m2 (Dauno90) in combination with cytarabine (100 mg/m2 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.
{"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":"10.1002/ajh.70160","url":null,"abstract":"<p>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<sup>2</sup> (Dauno90) in combination with cytarabine (100 mg/m<sup>2</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 (<i>p</i> < 0.01), without significant differences between treatment arms. NT-proBNP levels measured after induction therapy correlated negatively with LVEF at the same time point (<i>ρ</i> = −0.24, <i>p</i> = 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 (<i>p</i> < 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]; <i>p</i> < 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.</p><p>\u0000 <b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT02140242</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 3","pages":"512-520"},"PeriodicalIF":9.9,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70160","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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