Camille Simard, Grégoire Le Gal, Alejandro Lazo-Langner, Vicky Tagalakis, Keerat Grewal, Francis Nguyen, Tzu-Fei Wang, Deborah M. Siegal, Mehran Anvari, Aristithes G. Doumouras, Aurélien Delluc
Obesity is a known risk factor for venous thromboembolism (VTE), but the long-term effect of weight-loss interventions such as bariatric surgery on VTE risk is uncertain. We conducted a population-based matched cohort study using administrative health data from Ontario, Canada. Adults who underwent bariatric surgery between 2010 and 2016 were matched 1:1 to controls on age, sex, body mass index (BMI), and diabetes status. The primary outcome was incident VTE (deep vein thrombosis or pulmonary embolism), measured after a 3-month landmark period. Hazard ratios (HRs) were estimated using Cox models adjusted for confounders, including time-varying VTE risk factors. We included 13 502 patients who underwent bariatric surgery and 13 502 matched controls. The mean age was 45.0 years (SD 11.1), and 81.4% were women. Median follow-up was 8.4 years. VTE incidence was 0.24 per 100 person-years in the surgical group and 0.26 in the control group. Bariatric surgery was associated with a 21% reduced risk of VTE (HR 0.79; 95% CI 0.66–0.96). Risk reduction was more pronounced in men (HR 0.59; 95% CI 0.36–0.96) and in patients with BMI < 50 kg/m2. No benefit was observed in patients with BMI ≥ 50 kg/m2 or those who had sleeve gastrectomy. Bariatric surgery is associated with a long-term reduction in VTE risk, particularly among men and individuals with moderate obesity. These findings support the reversibility of obesity-related thrombosis risk and inform long-term VTE prevention strategies.
肥胖是已知的静脉血栓栓塞（VTE）的危险因素，但减肥干预措施（如减肥手术）对VTE风险的长期影响尚不确定。我们使用来自加拿大安大略省的行政卫生数据进行了一项基于人群的匹配队列研究。在2010年至2016年期间接受减肥手术的成年人在年龄、性别、体重指数（BMI）和糖尿病状况方面与对照组进行了1:1的匹配。主要终点是VTE（深静脉血栓形成或肺栓塞）的发生率，在3个月的里程碑期后测量。使用Cox模型对混杂因素（包括时变静脉血栓栓塞危险因素）进行校正，估计风险比（hr）。我们纳入了13 502名接受减肥手术的患者和13 502名匹配的对照组。平均年龄45.0岁（SD 11.1）， 81.4%为女性。中位随访时间为8.4年。手术组静脉血栓栓塞发生率为0.24 / 100人年，对照组为0.26 / 100人年。减肥手术与静脉血栓栓塞风险降低21%相关（HR 0.79; 95% CI 0.66-0.96）。风险降低在男性（HR 0.59; 95% CI 0.36-0.96）和BMI为2的患者中更为明显。BMI≥50 kg/m2的患者或进行袖式胃切除术的患者未观察到任何益处。减肥手术与静脉血栓栓塞风险的长期降低有关，尤其是在男性和中度肥胖人群中。这些发现支持肥胖相关血栓形成风险的可逆性，并为长期静脉血栓形成预防策略提供信息。
{"title":"Association Between Bariatric Surgery and the Long-Term Risk for Venous Thromboembolism: A Population-Based Matched Cohort Study","authors":"Camille Simard, Grégoire Le Gal, Alejandro Lazo-Langner, Vicky Tagalakis, Keerat Grewal, Francis Nguyen, Tzu-Fei Wang, Deborah M. Siegal, Mehran Anvari, Aristithes G. Doumouras, Aurélien Delluc","doi":"10.1002/ajh.70186","DOIUrl":"10.1002/ajh.70186","url":null,"abstract":"<p>Obesity is a known risk factor for venous thromboembolism (VTE), but the long-term effect of weight-loss interventions such as bariatric surgery on VTE risk is uncertain. We conducted a population-based matched cohort study using administrative health data from Ontario, Canada. Adults who underwent bariatric surgery between 2010 and 2016 were matched 1:1 to controls on age, sex, body mass index (BMI), and diabetes status. The primary outcome was incident VTE (deep vein thrombosis or pulmonary embolism), measured after a 3-month landmark period. Hazard ratios (HRs) were estimated using Cox models adjusted for confounders, including time-varying VTE risk factors. We included 13 502 patients who underwent bariatric surgery and 13 502 matched controls. The mean age was 45.0 years (SD 11.1), and 81.4% were women. Median follow-up was 8.4 years. VTE incidence was 0.24 per 100 person-years in the surgical group and 0.26 in the control group. Bariatric surgery was associated with a 21% reduced risk of VTE (HR 0.79; 95% CI 0.66–0.96). Risk reduction was more pronounced in men (HR 0.59; 95% CI 0.36–0.96) and in patients with BMI < 50 kg/m<sup>2</sup>. No benefit was observed in patients with BMI ≥ 50 kg/m<sup>2</sup> or those who had sleeve gastrectomy. Bariatric surgery is associated with a long-term reduction in VTE risk, particularly among men and individuals with moderate obesity. These findings support the reversibility of obesity-related thrombosis risk and inform long-term VTE prevention strategies.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 3","pages":"487-496"},"PeriodicalIF":9.9,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146049938","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}
{"title":"Reassessing the Duration of Induction Therapy for Newly Diagnosed, Transplant-Eligible Myeloma Patients in the Context of Quadruple CD38 Monoclonal Antibody-Based Regimens: Is 24 Weeks Optimal?","authors":"Meera Mohan, Sabarinath Radhakrishnan, Carolina Schinke, Eirini Katodritou, Rafeal Fonseca","doi":"10.1002/ajh.70215","DOIUrl":"https://doi.org/10.1002/ajh.70215","url":null,"abstract":"","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":" ","pages":""},"PeriodicalIF":9.9,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146049884","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}
Lorella Maria Antonia Melillo,Valentina Arena,Alfonso Piciocchi,Anna Candoni,Valeria Calafiore,Roberto Cairoli,Paolo de Fabritiis,Gabriella Storti,Prassede Salutari,Francesco Lanza,Giovanni Martinelli,Mario Luppi,Saveria Capria,Raffaele Palmieri,Luca Maurillo,Maria Ilaria Del Principe,Maria Teresa Voso,Francesco Buccisano,Paola Fazi,Adriano Venditti
{"title":"Associations Between Sex, Disease Features and Outcome in Patients With Acute Myeloid Leukemia: A Sex-Stratified Analysis of the GIMEMA AML1310 Trial.","authors":"Lorella Maria Antonia Melillo,Valentina Arena,Alfonso Piciocchi,Anna Candoni,Valeria Calafiore,Roberto Cairoli,Paolo de Fabritiis,Gabriella Storti,Prassede Salutari,Francesco Lanza,Giovanni Martinelli,Mario Luppi,Saveria Capria,Raffaele Palmieri,Luca Maurillo,Maria Ilaria Del Principe,Maria Teresa Voso,Francesco Buccisano,Paola Fazi,Adriano Venditti","doi":"10.1002/ajh.70209","DOIUrl":"https://doi.org/10.1002/ajh.70209","url":null,"abstract":"","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"66 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033616","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}
<p>In this issue of the American Journal of Hematology, Liu et al. [<span>1</span>] report how childhood artery morphology impacts blood flow and stroke risk in sickle cell disease (SCD).</p><p>Stroke is a very severe complication of SCD with a unique epidemiology for this disease. Natural history data from the landmark Cooperative Study of Sickle Cell Disease (CSSCD) showed that the risk of stroke peaks in children aged 2–5 [<span>2</span>], then decreases until a second increase after 30 [<span>2, 3</span>]. This high risk in young children is uncommon among SCD-associated organ complications and the underlying mechanisms have long been a conundrum.</p><p>The knowledge of stroke pathophysiology in SCD has much improved in the last few decades. While hemorrhagic strokes can occur [<span>3</span>], most SCD-associated strokes are ischemic. Several mechanisms can lead to cerebral ischemia, including low cardiac output or anemia exacerbation, often resulting in watershed ischemia [<span>4</span>]. However, the main cause of stroke has been identified as the progressive stenosis of large arteries (internal carotid artery [ICA] and anterior and middle cerebral arteries). This characterizes cerebral vasculopathy (CV), despite the lack of a uniform definition of this term [<span>5</span>]. One major step forward in understanding CV was the identification that arterial blood flow is accelerated before the onset of stenosis. This characteristic provided a unique opportunity for early CV screening and pre-emptive intervention. Transcranial Doppler (TCD) monitoring of arterial velocity has proven highly effective at detecting children at high risk of stroke, and it is now a cornerstone of SCD care [<span>6</span>]. The increased velocity before the development of stenosis also provided significant pathophysiological insights by showing that abnormal flow was the cause and not only the consequence of CV (although stenosis can further alter blood flow in a vicious circle).</p><p>How abnormal blood flow leads to stenosis is not fully understood. Post-mortem pathology studies revealed that stenosis was composed of intimal hyperplasia due to fibroblast and smooth muscle proliferation, internal membrane defects, and a superimposed thrombus [<span>7</span>]. This vascular lesion is likely promoted by the vascular adhesion of sickled red blood cells and activated white blood cells and platelets, resulting in endothelial dysfunction. Inflammation, hypoxia, decreased nitrite oxide bioavailability, and altered blood rheology also contribute to stenosis formation [<span>8</span>]. Several risk factors have been identified as increasing the risk of CV: hemoglobin SS or S-beta<sup>0</sup>-thalassemia type [<span>2</span>], lower hemoglobin level [<span>2</span>], high reticulocyte count [<span>9</span>], high systolic blood pressure [<span>2</span>], frequent acute chest syndrome [<span>2</span>], low fetal hemoglobin [<span>10</span>]. Several of these risk factors may
{"title":"Blame It on My (Arterial) Youth: How Childhood Vascular Morphology Shapes the Risk of Cerebral Vasculopathy in Sickle Cell Disease","authors":"Thomas Pincez","doi":"10.1002/ajh.70214","DOIUrl":"10.1002/ajh.70214","url":null,"abstract":"<p>In this issue of the American Journal of Hematology, Liu et al. [<span>1</span>] report how childhood artery morphology impacts blood flow and stroke risk in sickle cell disease (SCD).</p><p>Stroke is a very severe complication of SCD with a unique epidemiology for this disease. Natural history data from the landmark Cooperative Study of Sickle Cell Disease (CSSCD) showed that the risk of stroke peaks in children aged 2–5 [<span>2</span>], then decreases until a second increase after 30 [<span>2, 3</span>]. This high risk in young children is uncommon among SCD-associated organ complications and the underlying mechanisms have long been a conundrum.</p><p>The knowledge of stroke pathophysiology in SCD has much improved in the last few decades. While hemorrhagic strokes can occur [<span>3</span>], most SCD-associated strokes are ischemic. Several mechanisms can lead to cerebral ischemia, including low cardiac output or anemia exacerbation, often resulting in watershed ischemia [<span>4</span>]. However, the main cause of stroke has been identified as the progressive stenosis of large arteries (internal carotid artery [ICA] and anterior and middle cerebral arteries). This characterizes cerebral vasculopathy (CV), despite the lack of a uniform definition of this term [<span>5</span>]. One major step forward in understanding CV was the identification that arterial blood flow is accelerated before the onset of stenosis. This characteristic provided a unique opportunity for early CV screening and pre-emptive intervention. Transcranial Doppler (TCD) monitoring of arterial velocity has proven highly effective at detecting children at high risk of stroke, and it is now a cornerstone of SCD care [<span>6</span>]. The increased velocity before the development of stenosis also provided significant pathophysiological insights by showing that abnormal flow was the cause and not only the consequence of CV (although stenosis can further alter blood flow in a vicious circle).</p><p>How abnormal blood flow leads to stenosis is not fully understood. Post-mortem pathology studies revealed that stenosis was composed of intimal hyperplasia due to fibroblast and smooth muscle proliferation, internal membrane defects, and a superimposed thrombus [<span>7</span>]. This vascular lesion is likely promoted by the vascular adhesion of sickled red blood cells and activated white blood cells and platelets, resulting in endothelial dysfunction. Inflammation, hypoxia, decreased nitrite oxide bioavailability, and altered blood rheology also contribute to stenosis formation [<span>8</span>]. Several risk factors have been identified as increasing the risk of CV: hemoglobin SS or S-beta<sup>0</sup>-thalassemia type [<span>2</span>], lower hemoglobin level [<span>2</span>], high reticulocyte count [<span>9</span>], high systolic blood pressure [<span>2</span>], frequent acute chest syndrome [<span>2</span>], low fetal hemoglobin [<span>10</span>]. Several of these risk factors may","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 3","pages":"415-417"},"PeriodicalIF":9.9,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70214","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033613","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}
Lucie Lanikova,Dusan Hrckulak,Veronika Zimolova,Felipe R Lorenzo,Jihyun Song,Katerina Vecerkova,Olga Babosova,Linda Berkova,Vladimir Korinek,Steve Elliott,Josef T Prchal
We previously reported a five-generation kindred with autosomal dominant erythrocytosis associated with a novel germline promoter variant in the erythropoietin (EPO) gene (EPO c.-136 G>A). This mutation creates a new hypoxia response element (HRE) consensus sequence on the reverse strand suggesting a gain of function mutation. CRISPR/Cas9-edited Hep3B cells harboring the c.-136 G>A variant had increased EPO mRNA and protein expression under both normoxic and hypoxic conditions compared to wild-type cells; functional assays confirmed the activity of the c.-136 G>A variant-induced EPO. Isoelectric focusing analyses of patient urine and plasma showed a more basic EPO isoform pattern, consistent with the reduced sulfated N-glycan contribution, suggesting decreased renal and increased non-renal expression. Luciferase reporter assays confirmed increased transcriptional activation of the mutant promoter. However, chromatin immunoprecipitation did not verify direct hypoxia-inducible factor (HIF)-1/2 binding, suggesting the possible involvement of alternative regulatory elements. These findings support a model in which the EPO c.-136 G>A promoter variant introduces a new HRE that overrides the normal kidney expression resulting in persistent or ectopic non-renal EPO production postnatally. This study expands the spectrum of molecular mechanisms underlying hereditary erythrocytosis and provides novel mechanistic insights into EPO regulation, including its tissue-specific expression.
我们之前报道了一个常染色体显性红细胞增多症的五代亲缘关系，该亲缘关系与促红细胞生成素（EPO）基因（EPO c.-136 G> a）的一种新的种系启动子变异有关。该突变在反向链上产生了一个新的缺氧反应元件（HRE）共识序列，表明功能突变的增加。与野生型细胞相比，CRISPR/ cas9编辑的含有c -136 G>A变体的Hep3B细胞在常氧和缺氧条件下都增加了EPO mRNA和蛋白的表达；功能分析证实c - 136g>a变异体诱导的EPO具有活性。患者尿液和血浆等电聚焦分析显示更基本的EPO异构体模式，与巯基n-聚糖的减少一致，表明肾脏表达减少，非肾脏表达增加。荧光素酶报告基因检测证实突变启动子的转录激活增加。然而，染色质免疫沉淀未证实直接缺氧诱导因子(HIF)-1/2结合，提示可能涉及其他调节元件。这些发现支持了EPO c -136 G bbbba启动子变异引入新的HRE的模型，该HRE覆盖正常肾脏表达，导致出生后持续或异位的非肾脏EPO产生。这项研究扩展了遗传性红细胞增多症的分子机制，并为EPO调控提供了新的机制见解，包括其组织特异性表达。
{"title":"Autosomal Dominant Erythrocytosis Caused by Non-Renal Erythropoietin (EPO) Due to EPO c.-136 G>A Germline Mutation.","authors":"Lucie Lanikova,Dusan Hrckulak,Veronika Zimolova,Felipe R Lorenzo,Jihyun Song,Katerina Vecerkova,Olga Babosova,Linda Berkova,Vladimir Korinek,Steve Elliott,Josef T Prchal","doi":"10.1002/ajh.70208","DOIUrl":"https://doi.org/10.1002/ajh.70208","url":null,"abstract":"We previously reported a five-generation kindred with autosomal dominant erythrocytosis associated with a novel germline promoter variant in the erythropoietin (EPO) gene (EPO c.-136 G>A). This mutation creates a new hypoxia response element (HRE) consensus sequence on the reverse strand suggesting a gain of function mutation. CRISPR/Cas9-edited Hep3B cells harboring the c.-136 G>A variant had increased EPO mRNA and protein expression under both normoxic and hypoxic conditions compared to wild-type cells; functional assays confirmed the activity of the c.-136 G>A variant-induced EPO. Isoelectric focusing analyses of patient urine and plasma showed a more basic EPO isoform pattern, consistent with the reduced sulfated N-glycan contribution, suggesting decreased renal and increased non-renal expression. Luciferase reporter assays confirmed increased transcriptional activation of the mutant promoter. However, chromatin immunoprecipitation did not verify direct hypoxia-inducible factor (HIF)-1/2 binding, suggesting the possible involvement of alternative regulatory elements. These findings support a model in which the EPO c.-136 G>A promoter variant introduces a new HRE that overrides the normal kidney expression resulting in persistent or ectopic non-renal EPO production postnatally. This study expands the spectrum of molecular mechanisms underlying hereditary erythrocytosis and provides novel mechanistic insights into EPO regulation, including its tissue-specific expression.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"58 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021677","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}
{"title":"Are Current Exposure Models Sufficient to Link Pollution to MDS Progression?: The Impact of Overlooked Social and Environmental Confounders.","authors":"Howard Lopes Ribeiro Junior,Jonas Nogueira Ferreira Maciel Gusmão,João Vitor Caetano Goes,Danielle Calheiros Campelo Maia","doi":"10.1002/ajh.70211","DOIUrl":"https://doi.org/10.1002/ajh.70211","url":null,"abstract":"","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"36 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015349","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}
Rami S. Komrokji, Sheida Hayati, Manuel Ugidos, Guillermo Garcia-Manero, Matteo Giovanni Della Porta, Amer M. Zeidan, Valeria Santini, Uwe Platzbecker, Anita K. Gandhi, Rajasekhar N. V. S. Suragani
The COMMANDS trial established luspatercept as a first-line treatment for anemia in transfusion-dependent lower-risk (LR) myelodysplastic syndromes (MDS). Here we report red blood cell (RBC) transfusion response analysis based on somatic mutations profile and disease risk for patients treated with luspatercept or epoetin alfa in the COMMANDS trial. Of 350 evaluable patients, 238 (68.0%) had MDS with multiple lineage dysplasia and ring sideroblasts (RS) according to World Health Organization 2016 criteria, and 320 (91.4%) had somatic mutations in ≥ 1 gene (median, 2) with median variant allele frequencies (VAF) of 2%–59%. Mutation profiles were similar in the treatment groups. Luspatercept had superior responses versus epoetin alfa across multiple mutations (risk difference; RD, [95% confidence interval; CI] 0.25 [0.15–0.35]), including in SF3B1-mutated (0.38 [0.25–0.50]) and SF3B1 wild-type (0.09 [−0.11 to 0.30]). Luspatercept demonstrated superior responses in patients with VAF ≥ 10% (random effect, 0.36 [95% CI, 0.28–0.44]), and in those with 1 (63% vs. 40%; p = 0.040), 2 (70% vs. 27%; p < 0.001), and 3 (72% vs. 40%; p = 0.018) mutations, and across the low (75% vs. 38%), moderate low (61% vs. 38%), moderate high (44% vs. 21%), and high (36% vs. 24%) Molecular International Prognostic Scoring System risk groups (summary effect RD, 0.26 [95% CI, 0.14–0.37]). Across most mutations luspatercept responses were superior (random effect, 0.34 [95% CI, 0.24–0.44]) in patients with RS but were similar between treatments in RS-negative patients. Luspatercept represents an effective treatment option in various mutational backgrounds in LR MDS.
{"title":"Impact of Mutational Landscape and Burden on RBC Transfusion Response in Patients With Lower-Risk Myelodysplastic Syndromes (LR-MDS) in the COMMANDS Study","authors":"Rami S. Komrokji, Sheida Hayati, Manuel Ugidos, Guillermo Garcia-Manero, Matteo Giovanni Della Porta, Amer M. Zeidan, Valeria Santini, Uwe Platzbecker, Anita K. Gandhi, Rajasekhar N. V. S. Suragani","doi":"10.1002/ajh.70171","DOIUrl":"10.1002/ajh.70171","url":null,"abstract":"<p>The COMMANDS trial established luspatercept as a first-line treatment for anemia in transfusion-dependent lower-risk (LR) myelodysplastic syndromes (MDS). Here we report red blood cell (RBC) transfusion response analysis based on somatic mutations profile and disease risk for patients treated with luspatercept or epoetin alfa in the COMMANDS trial. Of 350 evaluable patients, 238 (68.0%) had MDS with multiple lineage dysplasia and ring sideroblasts (RS) according to World Health Organization 2016 criteria, and 320 (91.4%) had somatic mutations in ≥ 1 gene (median, 2) with median variant allele frequencies (VAF) of 2%–59%. Mutation profiles were similar in the treatment groups. Luspatercept had superior responses versus epoetin alfa across multiple mutations (risk difference; RD, [95% confidence interval; CI] 0.25 [0.15–0.35]), including in <i>SF3B1</i>-mutated (0.38 [0.25–0.50]) and <i>SF3B1</i> wild-type (0.09 [−0.11 to 0.30]). Luspatercept demonstrated superior responses in patients with VAF ≥ 10% (random effect, 0.36 [95% CI, 0.28–0.44]), and in those with 1 (63% vs. 40%; <i>p</i> = 0.040), 2 (70% vs. 27%; <i>p</i> < 0.001), and 3 (72% vs. 40%; <i>p</i> = 0.018) mutations, and across the low (75% vs. 38%), moderate low (61% vs. 38%), moderate high (44% vs. 21%), and high (36% vs. 24%) Molecular International Prognostic Scoring System risk groups (summary effect RD, 0.26 [95% CI, 0.14–0.37]). Across most mutations luspatercept responses were superior (random effect, 0.34 [95% CI, 0.24–0.44]) in patients with RS but were similar between treatments in RS-negative patients. Luspatercept represents an effective treatment option in various mutational backgrounds in LR MDS.</p><p>\u0000 <b>Trial Registration:</b> ClinicalTrials.gov Identifier: NCT03682536.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 3","pages":"427-438"},"PeriodicalIF":9.9,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70171","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994874","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}
Emilia D'Angelo, Giorgia Mandrile, Nicolò Tesio, Francesco Cecere, Teresa Ceglie, Rosa Maria De Maria, Simona Mellone, Mara Giordano, Neha Sanjay Kargutar, Flavia Cerrato, Andrea Riccio, Giovanni Battista Ferrero
<p>Thalassemias, the most common inherited anemias, are a heterogenous group of genetic disorders resulting from a decreased synthesis of alpha or beta chains of hemoglobin. Beta-thalassemia results from mutations in the <i>HBB</i> gene on chromosome 11, leading to reduced (β<sup>+</sup>) or absent (β<sup>0</sup>) synthesis of beta-globin chains. Over 200 different <i>HBB</i>-causing mutations have been identified, resulting in complex genotype–phenotype correlations and wide clinical presentations classified in three main clinical diagnoses, ranging from asymptomatic carriers (beta-thalassemia minor) to Non-Transfusion-Dependent Thalassemia (NTDT—Thalassemia Intermedia) and Transfusion-Dependent Thalassemia (TDT—Thalassemia Major) [<span>1</span>].</p><p>Late-onset beta-thalassemia major is extremely rare, with only five cases identified so far [<span>2-4</span>]. In all these cases, the recessive <i>HBB</i> mutation became homozygous due to somatic paternal uniparental isodisomy of the 11p15 chromosome region (patUPiD11p15) in blood cells. Four cases of late-onset NTDT have also been identified, all harboring a somatic maternal 11p15 deletion that causes the hemizygous state of a beta-globin mutation in blood [<span>5-7</span>]. Interestingly, maternal deletions and patUPiD of chr11p15 are typical molecular defects of the growth- and cancer-associated disorder, Beckwith-Wiedemann syndrome spectrum (BWSp, [<span>8</span>]), which results from the dysregulation of imprinted genes controlling growth and proliferation, including <i>IGF2</i>, expressed on the paternal chromosome, <i>H19</i> and <i>CDKN1C</i>, both expressed on the maternal chromosome [<span>9</span>].</p><p>Here, we present the case of a man who developed adult-onset beta-thalassemia major due to a paternal nonsense <i>HBB</i> mutation becoming homozygous in the bone marrow following a clonal somatic segmental pat UPiD. This case highlights the contribution of imprinted genes in the pathogenesis of hemoglobinopathies and defines adult-onset Thalassemias as acquired imprinting defects.</p><p>The male patient, a 45 years old beta-thalassemia carrier, was admitted to our Centre after the occasional finding of anemia and hyperbilirubinemia. He reported several episodes of mild jaundice not associated with hyperchromic urine, nor gallstones, associated with a mean hemoglobin (Hb) concentration of 12 g/dL, a mean corpuscular volume (MCV) of 65 fL, and a mean corpuscular hemoglobin concentration (MCHC) of 22 pg/dL. A glucose-6-phosphate dehydrogenase (G6PD) deficiency screening yielded normal results. Serological tests for hepatitis C virus (HCV) and hepatitis B virus (HBV) were negative.</p><p>At our first examination, pallor, latent jaundice and enlarged spleen were noted, with the following hematological parameter: Hb 9.2 g/dL, MCV 73.4 fL, MCH 23 pg, reticulocytes 138 000/ul, total bilirubin 8.1 mg/dL (indirect 7.63), Lactate Dehydrogenase (LDH) 451 U/L, HbA2: 3.4%, HbF 39.8%, iron 224
{"title":"Adult-Onset β-Thalassemia Major as Acquired Imprinting Disorder","authors":"Emilia D'Angelo, Giorgia Mandrile, Nicolò Tesio, Francesco Cecere, Teresa Ceglie, Rosa Maria De Maria, Simona Mellone, Mara Giordano, Neha Sanjay Kargutar, Flavia Cerrato, Andrea Riccio, Giovanni Battista Ferrero","doi":"10.1002/ajh.70177","DOIUrl":"10.1002/ajh.70177","url":null,"abstract":"<p>Thalassemias, the most common inherited anemias, are a heterogenous group of genetic disorders resulting from a decreased synthesis of alpha or beta chains of hemoglobin. Beta-thalassemia results from mutations in the <i>HBB</i> gene on chromosome 11, leading to reduced (β<sup>+</sup>) or absent (β<sup>0</sup>) synthesis of beta-globin chains. Over 200 different <i>HBB</i>-causing mutations have been identified, resulting in complex genotype–phenotype correlations and wide clinical presentations classified in three main clinical diagnoses, ranging from asymptomatic carriers (beta-thalassemia minor) to Non-Transfusion-Dependent Thalassemia (NTDT—Thalassemia Intermedia) and Transfusion-Dependent Thalassemia (TDT—Thalassemia Major) [<span>1</span>].</p><p>Late-onset beta-thalassemia major is extremely rare, with only five cases identified so far [<span>2-4</span>]. In all these cases, the recessive <i>HBB</i> mutation became homozygous due to somatic paternal uniparental isodisomy of the 11p15 chromosome region (patUPiD11p15) in blood cells. Four cases of late-onset NTDT have also been identified, all harboring a somatic maternal 11p15 deletion that causes the hemizygous state of a beta-globin mutation in blood [<span>5-7</span>]. Interestingly, maternal deletions and patUPiD of chr11p15 are typical molecular defects of the growth- and cancer-associated disorder, Beckwith-Wiedemann syndrome spectrum (BWSp, [<span>8</span>]), which results from the dysregulation of imprinted genes controlling growth and proliferation, including <i>IGF2</i>, expressed on the paternal chromosome, <i>H19</i> and <i>CDKN1C</i>, both expressed on the maternal chromosome [<span>9</span>].</p><p>Here, we present the case of a man who developed adult-onset beta-thalassemia major due to a paternal nonsense <i>HBB</i> mutation becoming homozygous in the bone marrow following a clonal somatic segmental pat UPiD. This case highlights the contribution of imprinted genes in the pathogenesis of hemoglobinopathies and defines adult-onset Thalassemias as acquired imprinting defects.</p><p>The male patient, a 45 years old beta-thalassemia carrier, was admitted to our Centre after the occasional finding of anemia and hyperbilirubinemia. He reported several episodes of mild jaundice not associated with hyperchromic urine, nor gallstones, associated with a mean hemoglobin (Hb) concentration of 12 g/dL, a mean corpuscular volume (MCV) of 65 fL, and a mean corpuscular hemoglobin concentration (MCHC) of 22 pg/dL. A glucose-6-phosphate dehydrogenase (G6PD) deficiency screening yielded normal results. Serological tests for hepatitis C virus (HCV) and hepatitis B virus (HBV) were negative.</p><p>At our first examination, pallor, latent jaundice and enlarged spleen were noted, with the following hematological parameter: Hb 9.2 g/dL, MCV 73.4 fL, MCH 23 pg, reticulocytes 138 000/ul, total bilirubin 8.1 mg/dL (indirect 7.63), Lactate Dehydrogenase (LDH) 451 U/L, HbA2: 3.4%, HbF 39.8%, iron 224","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 3","pages":"633-638"},"PeriodicalIF":9.9,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70177","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986503","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}
Angela C Weyand,Jourdan E Triebwasser,Alexander Chaitoff
{"title":"Prevalence of Iron Deficiency and Iron Deficiency Anemia in US Pregnant Individuals, 2003-2023.","authors":"Angela C Weyand,Jourdan E Triebwasser,Alexander Chaitoff","doi":"10.1002/ajh.70207","DOIUrl":"https://doi.org/10.1002/ajh.70207","url":null,"abstract":"","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"1 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986450","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}
Calreticulin (CALR) mutations are prevalent in 20%-30% of patients with BCR::ABL1-negative myeloproliferative neoplasms (MPN). Mutant calreticulin (mutCALR), presented by the thrombopoietin receptor (MPL, also known as TPOR or CD110) on the surface of the disease-initiating MPN progenitors, represents an ideal target for curative immunotherapies including monoclonal antibodies, bispecific T cell engaging antibodies (TCE), and CAR-T cell therapies. Despite that two clinical TCE candidates have advanced into phase 1 trials in recent 2 years, depletion of mutCALR+ hematopoietic stem cells and normalization of hematopoiesis remained absent in preclinical evaluation. Here, we developed a bispecific T cell engager DX1-2C11 that specifically and efficiently eradicates mutCALR-expressing cells via recruiting polyclonal T cells. DX1-2C11 depleted Ba/F3 cells expressing mutCALR, as well as primary murine myeloid cells in a dose-dependent manner in vitro. In CALRdel52 transgenic mice, a single dose of DX1-2C11 activated CD4+ and CD8+ T cells in the peripheral blood, spleen and bone marrow within 24 h. Furthermore, a single dose of DX1-2C11 reduced platelet counts in the periphery and decreased mutant stem/progenitor cell populations in the spleen and bone marrow by Day 7 posttreatment. Notably, the reduction of mutant burden was durably maintained in secondary recipient mice. In the disseminated NSG model, DX1-2C11 delivered immediate tumor burden reduction and significantly prolonged the overall survival of mice compared to the control group. Taken together, these data suggest that bispecific T cell engaging antibody targeting mutCALR represents a curative strategy that efficiently eliminates mutant MPN stem cells in vivo.
{"title":"A Murine Bispecific Antibody Efficiently Redirects T Cells Against Calr Mutated Stem Cells In Vivo.","authors":"Shengen Xiong,Tamara Wais,Cecilia Varga,Christina Schueller,Sarada Achyutuni,Robert Kralovics","doi":"10.1002/ajh.70206","DOIUrl":"https://doi.org/10.1002/ajh.70206","url":null,"abstract":"Calreticulin (CALR) mutations are prevalent in 20%-30% of patients with BCR::ABL1-negative myeloproliferative neoplasms (MPN). Mutant calreticulin (mutCALR), presented by the thrombopoietin receptor (MPL, also known as TPOR or CD110) on the surface of the disease-initiating MPN progenitors, represents an ideal target for curative immunotherapies including monoclonal antibodies, bispecific T cell engaging antibodies (TCE), and CAR-T cell therapies. Despite that two clinical TCE candidates have advanced into phase 1 trials in recent 2 years, depletion of mutCALR+ hematopoietic stem cells and normalization of hematopoiesis remained absent in preclinical evaluation. Here, we developed a bispecific T cell engager DX1-2C11 that specifically and efficiently eradicates mutCALR-expressing cells via recruiting polyclonal T cells. DX1-2C11 depleted Ba/F3 cells expressing mutCALR, as well as primary murine myeloid cells in a dose-dependent manner in vitro. In CALRdel52 transgenic mice, a single dose of DX1-2C11 activated CD4+ and CD8+ T cells in the peripheral blood, spleen and bone marrow within 24 h. Furthermore, a single dose of DX1-2C11 reduced platelet counts in the periphery and decreased mutant stem/progenitor cell populations in the spleen and bone marrow by Day 7 posttreatment. Notably, the reduction of mutant burden was durably maintained in secondary recipient mice. In the disseminated NSG model, DX1-2C11 delivered immediate tumor burden reduction and significantly prolonged the overall survival of mice compared to the control group. Taken together, these data suggest that bispecific T cell engaging antibody targeting mutCALR represents a curative strategy that efficiently eliminates mutant MPN stem cells in vivo.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"26 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961447","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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