Petruta Gurban, Cristina Mambet, Anca Botezatu, Laura G. Necula, Lilia Matei, Ana Iulia Neagu, Ioana Pitica, Marius Ataman, Aurelia Tatic, Alexandru Bardas, Mihnea A. Gaman, Camelia Dobrea, Mihaela Dragomir, Cecilia Ghimici, Silvana Angelescu, Doina Barbu, Oana Stanca, Marina Danila, Nicoleta Berbec, Andrei Colita, Ana Maria Vladareanu, Saviana Nedeianu, Mihaela Chivu-Economescu, Coralia Bleotu, Daniel Coriu, Elise Sepulchre, Gabriela Anton, Carmen C. Diaconu, Stefan N. Constantinescu
<p><i>BCR::ABL1</i>-negative myeloproliferative neoplasms (MPNs) can evolve to secondary acute myeloid leukemia (sAML) or blast-phase (BP) MPN, a very severe condition with lack of effective therapy.<span><sup>1</sup></span> Leukemic transformation (LT) of MPNs displays a variable incidence according to MPN phenotype: 9%–13% in primary myelofibrosis (PMF), 3%–7% in polycythemia vera (PV), and 1%–4% in essential thrombocythemia (ET).<span><sup>1</sup></span> Here, we investigated the mutational landscape, copy number variations (CNVs), and uniparental disomy (UPD) events in BP-MPN cases that were diagnosed over a 6-year period of monitoring in three different hematology units (Fundeni Clinical Institute, Coltea Hospital and Emergency University Hospitals, Bucharest, Romania) and the patterns of clonal evolution in a subset of patients with available paired chronic phase (CP)-BP DNA samples.</p><p>The study was approved by the local ethics committee (No. 136/06.02.2017 rev. no.131/18.01.2019) and was performed in conformity with the Declaration of Helsinki. A written informed consent was provided by each patient at collection of samples that were referred to Stefan S Nicolau Institute of Virology, Romania, for molecular analysis. Clinical, morphological, and immunophenotypic data were provided from the medical records for all recruited patients. Peripheral blood or bone marrow (BM) mononuclear cells were isolated and processed to obtain various cell fractions. CD3+ T cells were used as reference for germline mutations. Molecular testing for MPN-driver mutations, targeted next-generation sequencing (NGS), whole-exome sequencing (WES), single nucleotide polymorphism (SNP) microarray analysis, and multiplex ligation-dependent probe amplification (MLPA) were performed as described by manufacturers (see Supplemental file; Data S1 for a complete description of methods).</p><p>A total of 33 patients (median age, 63 years; 57.6% males) were diagnosed with BP-MPN between 2017 and 2023, in the above-mentioned centers, including 20 post-PMF (60.4%), and 13 post-ET/PV (39.4%) cases (Table S1). A prior stage of secondary myelofibrosis was confirmed by BM biopsy in 8 out of 13 post-ET/PV AML (61.5%) patients. According to morphologic and immunophenotypic data, sAML cases were classified as AML with myelodysplasia-related changes (<i>n</i> = 4, 12.1%) and AML, not otherwise specified (<i>n</i> = 29, 87.9%), as follows: AML with minimal differentiation (<i>n</i> = 6, 18.2%), AML without maturation (<i>n</i> = 12, 36.4%), acute myelomonocytic leukemia (<i>n</i> = 6, 18.2%), acute monocytic leukemia (<i>n</i> = 1, 3%), pure erythroid leukemia (<i>n</i> = 1, 3%), and acute megakaryoblastic leukemia (<i>n</i> = 3, 9.1%). Concerning the MPN drivers detected at CP, 60.6% of patients carried <i>JAK2</i> V617F mutation, 21.2% harbored calreticulin (<i>CALR</i>) mutations (5 type1/type 1-like, 2 type2/type-2 like), and 18.2% were classified as triple-negative (TN-MPNs). We
{"title":"Dominance of mutations in epigenetic regulators and a diversity of signaling alterations in blast-phase BCR::ABL1-negative myeloproliferative neoplasms","authors":"Petruta Gurban, Cristina Mambet, Anca Botezatu, Laura G. Necula, Lilia Matei, Ana Iulia Neagu, Ioana Pitica, Marius Ataman, Aurelia Tatic, Alexandru Bardas, Mihnea A. Gaman, Camelia Dobrea, Mihaela Dragomir, Cecilia Ghimici, Silvana Angelescu, Doina Barbu, Oana Stanca, Marina Danila, Nicoleta Berbec, Andrei Colita, Ana Maria Vladareanu, Saviana Nedeianu, Mihaela Chivu-Economescu, Coralia Bleotu, Daniel Coriu, Elise Sepulchre, Gabriela Anton, Carmen C. Diaconu, Stefan N. Constantinescu","doi":"10.1002/ajh.27503","DOIUrl":"10.1002/ajh.27503","url":null,"abstract":"<p><i>BCR::ABL1</i>-negative myeloproliferative neoplasms (MPNs) can evolve to secondary acute myeloid leukemia (sAML) or blast-phase (BP) MPN, a very severe condition with lack of effective therapy.<span><sup>1</sup></span> Leukemic transformation (LT) of MPNs displays a variable incidence according to MPN phenotype: 9%–13% in primary myelofibrosis (PMF), 3%–7% in polycythemia vera (PV), and 1%–4% in essential thrombocythemia (ET).<span><sup>1</sup></span> Here, we investigated the mutational landscape, copy number variations (CNVs), and uniparental disomy (UPD) events in BP-MPN cases that were diagnosed over a 6-year period of monitoring in three different hematology units (Fundeni Clinical Institute, Coltea Hospital and Emergency University Hospitals, Bucharest, Romania) and the patterns of clonal evolution in a subset of patients with available paired chronic phase (CP)-BP DNA samples.</p><p>The study was approved by the local ethics committee (No. 136/06.02.2017 rev. no.131/18.01.2019) and was performed in conformity with the Declaration of Helsinki. A written informed consent was provided by each patient at collection of samples that were referred to Stefan S Nicolau Institute of Virology, Romania, for molecular analysis. Clinical, morphological, and immunophenotypic data were provided from the medical records for all recruited patients. Peripheral blood or bone marrow (BM) mononuclear cells were isolated and processed to obtain various cell fractions. CD3+ T cells were used as reference for germline mutations. Molecular testing for MPN-driver mutations, targeted next-generation sequencing (NGS), whole-exome sequencing (WES), single nucleotide polymorphism (SNP) microarray analysis, and multiplex ligation-dependent probe amplification (MLPA) were performed as described by manufacturers (see Supplemental file; Data S1 for a complete description of methods).</p><p>A total of 33 patients (median age, 63 years; 57.6% males) were diagnosed with BP-MPN between 2017 and 2023, in the above-mentioned centers, including 20 post-PMF (60.4%), and 13 post-ET/PV (39.4%) cases (Table S1). A prior stage of secondary myelofibrosis was confirmed by BM biopsy in 8 out of 13 post-ET/PV AML (61.5%) patients. According to morphologic and immunophenotypic data, sAML cases were classified as AML with myelodysplasia-related changes (<i>n</i> = 4, 12.1%) and AML, not otherwise specified (<i>n</i> = 29, 87.9%), as follows: AML with minimal differentiation (<i>n</i> = 6, 18.2%), AML without maturation (<i>n</i> = 12, 36.4%), acute myelomonocytic leukemia (<i>n</i> = 6, 18.2%), acute monocytic leukemia (<i>n</i> = 1, 3%), pure erythroid leukemia (<i>n</i> = 1, 3%), and acute megakaryoblastic leukemia (<i>n</i> = 3, 9.1%). Concerning the MPN drivers detected at CP, 60.6% of patients carried <i>JAK2</i> V617F mutation, 21.2% harbored calreticulin (<i>CALR</i>) mutations (5 type1/type 1-like, 2 type2/type-2 like), and 18.2% were classified as triple-negative (TN-MPNs). We","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 1","pages":"168-171"},"PeriodicalIF":10.1,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27503","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449401","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}
Yoshito Nishimura, Thomas Atwell, Matthew Callstrom, Patrick McGarrah, Matthew Howard, Rebecca L. King, Angela Dispenzieri
Laboratory findings and timeline of treatments. Day 0 is the day of the initial consult at our institution. CRP, C-reactive protein; IgG, immunoglobulin G.
{"title":"Cryoablation for unresectable unicentric Castleman disease","authors":"Yoshito Nishimura, Thomas Atwell, Matthew Callstrom, Patrick McGarrah, Matthew Howard, Rebecca L. King, Angela Dispenzieri","doi":"10.1002/ajh.27507","DOIUrl":"10.1002/ajh.27507","url":null,"abstract":"<p>Laboratory findings and timeline of treatments. Day 0 is the day of the initial consult at our institution. CRP, C-reactive protein; IgG, immunoglobulin G.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 1","pages":"149-151"},"PeriodicalIF":10.1,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27507","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440373","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}
Ali Zidan, Adham H. El-Sherbini, Abdelrahman Noureldin, David K. C. Cooper, Maha Othman
The recent report of the first pig kidney transplant in a living human brings hope to thousands of people with end-stage kidney failure. The scientific community views this early success with caution as kidney xenotransplantation exhibits many challenges and barriers. One of these is coagulation dysregulation. This includes (i) pig von Willebrand Factor (vWF) interaction with human platelets, which can induce abnormal clotting responses, heightening the risk of graft failure, (ii) the inefficiency of pig thrombomodulin in activating human protein C, which emphasizes the species-specific variations that aggravate coagulation challenges, and (iii) the development of thrombotic microangiopathy in the pig grafts and the occurrence of systemic consumptive coagulopathy in the recipients. Indeed, coagulation dysregulation largely results from differences in endothelial cell response and incompatibilities between pig and human coagulation–anticoagulation pathways. These barriers can be resolved by modifications to pig vWF and the expression of human thrombomodulin and endothelial protein C receptors in pig cells, serving as strategic interventions to align the coagulation systems of the two species more closely. These coagulation challenges have clinical implications in how they affect graft survival and patient outcome. Genetic engineering of the organ-source pig and the administration of various drugs have assisted in correcting this coagulation dysregulation. Hence, comprehending and controlling coagulation dysregulation is crucial for progress in xenotransplantation as a viable option for treating patients with terminal kidney disease.
最近首例猪肾活体移植的报道为成千上万肾衰竭晚期患者带来了希望。科学界对这一早期成功持谨慎态度，因为肾脏异种移植面临许多挑战和障碍。其中之一就是凝血失调。这包括：(i) 猪冯-威廉因子（vWF）与人类血小板相互作用，可诱发异常凝血反应，增加移植失败的风险；(ii) 猪血栓调节蛋白在激活人类蛋白 C 方面效率低下，这强调了物种特异性变异，加剧了凝血挑战；(iii) 猪移植物出现血栓性微血管病，受体出现全身消耗性凝血病。事实上，凝血失调在很大程度上是由于内皮细胞反应的差异以及猪和人类凝血抗凝途径的不相容性造成的。这些障碍可以通过修改猪 vWF 以及在猪细胞中表达人血栓调节蛋白和内皮蛋白 C 受体来解决，从而使两个物种的凝血系统更加接近。这些凝血难题对移植物存活率和患者预后的影响具有临床意义。器官来源猪的基因工程和各种药物的应用有助于纠正这种凝血失调。因此，理解和控制凝血失调对于异种移植作为治疗晚期肾病患者的可行方案的进展至关重要。
{"title":"Characterizing coagulation responses in humans and nonhuman primates following kidney xenotransplantation—A narrative review","authors":"Ali Zidan, Adham H. El-Sherbini, Abdelrahman Noureldin, David K. C. Cooper, Maha Othman","doi":"10.1002/ajh.27506","DOIUrl":"https://doi.org/10.1002/ajh.27506","url":null,"abstract":"The recent report of the first pig kidney transplant in a living human brings hope to thousands of people with end-stage kidney failure. The scientific community views this early success with caution as kidney xenotransplantation exhibits many challenges and barriers. One of these is coagulation dysregulation. This includes (i) pig von Willebrand Factor (vWF) interaction with human platelets, which can induce abnormal clotting responses, heightening the risk of graft failure, (ii) the inefficiency of pig thrombomodulin in activating human protein C, which emphasizes the species-specific variations that aggravate coagulation challenges, and (iii) the development of thrombotic microangiopathy in the pig grafts and the occurrence of systemic consumptive coagulopathy in the recipients. Indeed, coagulation dysregulation largely results from differences in endothelial cell response and incompatibilities between pig and human coagulation–anticoagulation pathways. These barriers can be resolved by modifications to pig vWF and the expression of human thrombomodulin and endothelial protein C receptors in pig cells, serving as strategic interventions to align the coagulation systems of the two species more closely. These coagulation challenges have clinical implications in how they affect graft survival and patient outcome. Genetic engineering of the organ-source pig and the administration of various drugs have assisted in correcting this coagulation dysregulation. Hence, comprehending and controlling coagulation dysregulation is crucial for progress in xenotransplantation as a viable option for treating patients with terminal kidney disease.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"78 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436453","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}
Mathis Mottelson, Jens Helby, Jesper Petersen, Børge Grønne Nordestgaard, Stig Egil Bojesen, Selma Kofoed Bendtsen, Maria Rossing, Andreas Ørslev Rasmussen, Andreas Glenthøj
<p>Hereditary spherocytosis (HS) is caused by mutations in genes such as <i>ANK1</i>, <i>EPB42</i>, <i>SLC4A1</i>, <i>SPTA1</i>, or <i>SPTB</i>,<span><sup>1</sup></span> leading to altered red blood cell (RBC) membrane proteins, reduced deformability, and decreased RBC lifespan. Dehydrated hereditary stomatocytosis (xerocytosis) is caused by variants in the <i>PIEZO1</i> gene and, less commonly, <i>KCNN4</i> variants, affecting RBC hydration and stability.<span><sup>2</sup></span></p><p>The prevalence of HS is generally reported around 1:2000, while dehydrated hereditary stomatocytosis estimates range from 1:10 000 to 1:50 000, though mostly based on sporadic cases or older studies lacking comprehensive diagnostic methods.<span><sup>1, 2</sup></span> Current prevalence estimates may be inaccurate due to underdiagnosis, referral bias, and the lack of systematic population-based testing. A study analyzing complete blood counts of 48 million North American patients suggested that up to 1:8000 individuals could potentially have dehydrated hereditary stomatocytosis based on specific biochemical markers, although definitive confirmation through genetic or specialized testing was not feasible.<span><sup>3</sup></span> Interestingly, a study identified a gain-of-function <i>PIEZO1</i> allele in one-third of African Americans, which, in a mouse model, induced a phenotype resembling dehydrated hereditary stomatocytosis and provided significant resistance to malaria.<span><sup>4</sup></span></p><p>We tested the hypothesis that both hereditary spherocytosis and dehydrated hereditary stomatocytosis are more frequent in the white general population than previously estimated. For this purpose, we studied 109 039 white individuals of Danish descent from the Copenhagen General Population Study(H-KF 01-144/01) examined between 2003 and 2015.<span><sup>5</sup></span> All individuals had hemoglobin, red cell distribution width (RDW), and MCHC measured, and all individuals had DNA obtained for further genetic analysis. Individuals with biochemical signs of hemolysis were genetically tested for the most frequent causes of hereditary hemolysis. All individuals aged 40–100 years and 25% of inhabitants aged 20–39 years living in a suburban part of the Capital Region of Denmark were invited, of these 43% participated. All participating individuals underwent a physical examination, had blood samples drawn, and completed a questionnaire on lifestyle and health on the day of enrollment. Blood samples for hemoglobin, mean corpuscular volume, and MCHC were drawn at enrollment and analyzed fresh on an ADVIA 120 Hematology System. RDW was calculated as standard deviation of mean corpuscular volume divided by mean corpuscular volume multiplied by 100. As previously proposed by Kaufman et al.<span><sup>3</sup></span> potential hemolysis was considered in individuals with RBC indices suggesting hemolysis: increased MCHC and high RDW (as a sign of reticulocytosis), or increased MCHC
{"title":"Hereditary stomatocytosis in the general population: A genetically based prevalence estimate from a 109 039 individual Danish cohort","authors":"Mathis Mottelson, Jens Helby, Jesper Petersen, Børge Grønne Nordestgaard, Stig Egil Bojesen, Selma Kofoed Bendtsen, Maria Rossing, Andreas Ørslev Rasmussen, Andreas Glenthøj","doi":"10.1002/ajh.27508","DOIUrl":"10.1002/ajh.27508","url":null,"abstract":"<p>Hereditary spherocytosis (HS) is caused by mutations in genes such as <i>ANK1</i>, <i>EPB42</i>, <i>SLC4A1</i>, <i>SPTA1</i>, or <i>SPTB</i>,<span><sup>1</sup></span> leading to altered red blood cell (RBC) membrane proteins, reduced deformability, and decreased RBC lifespan. Dehydrated hereditary stomatocytosis (xerocytosis) is caused by variants in the <i>PIEZO1</i> gene and, less commonly, <i>KCNN4</i> variants, affecting RBC hydration and stability.<span><sup>2</sup></span></p><p>The prevalence of HS is generally reported around 1:2000, while dehydrated hereditary stomatocytosis estimates range from 1:10 000 to 1:50 000, though mostly based on sporadic cases or older studies lacking comprehensive diagnostic methods.<span><sup>1, 2</sup></span> Current prevalence estimates may be inaccurate due to underdiagnosis, referral bias, and the lack of systematic population-based testing. A study analyzing complete blood counts of 48 million North American patients suggested that up to 1:8000 individuals could potentially have dehydrated hereditary stomatocytosis based on specific biochemical markers, although definitive confirmation through genetic or specialized testing was not feasible.<span><sup>3</sup></span> Interestingly, a study identified a gain-of-function <i>PIEZO1</i> allele in one-third of African Americans, which, in a mouse model, induced a phenotype resembling dehydrated hereditary stomatocytosis and provided significant resistance to malaria.<span><sup>4</sup></span></p><p>We tested the hypothesis that both hereditary spherocytosis and dehydrated hereditary stomatocytosis are more frequent in the white general population than previously estimated. For this purpose, we studied 109 039 white individuals of Danish descent from the Copenhagen General Population Study(H-KF 01-144/01) examined between 2003 and 2015.<span><sup>5</sup></span> All individuals had hemoglobin, red cell distribution width (RDW), and MCHC measured, and all individuals had DNA obtained for further genetic analysis. Individuals with biochemical signs of hemolysis were genetically tested for the most frequent causes of hereditary hemolysis. All individuals aged 40–100 years and 25% of inhabitants aged 20–39 years living in a suburban part of the Capital Region of Denmark were invited, of these 43% participated. All participating individuals underwent a physical examination, had blood samples drawn, and completed a questionnaire on lifestyle and health on the day of enrollment. Blood samples for hemoglobin, mean corpuscular volume, and MCHC were drawn at enrollment and analyzed fresh on an ADVIA 120 Hematology System. RDW was calculated as standard deviation of mean corpuscular volume divided by mean corpuscular volume multiplied by 100. As previously proposed by Kaufman et al.<span><sup>3</sup></span> potential hemolysis was considered in individuals with RBC indices suggesting hemolysis: increased MCHC and high RDW (as a sign of reticulocytosis), or increased MCHC","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 1","pages":"152-157"},"PeriodicalIF":10.1,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27508","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431727","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}
Suheil Albert Atallah-Yunes, Matthew J. Rees, Raphael Mwangi, Robyn L. Kuchler, Grzegorz S. Nowakowski, Thomas M. Habermann, Yucai Wang, Carrie A. Thompson, Andrew L. Feldman, Matthew J. Maurer, James R. Cerhan, Stephen M. Ansell, Thomas E. Witzig
Differences in characteristics and outcomes between incidental and symptomatic presentations of Large B-Cell Lymphoma.
偶然出现的大 B 细胞淋巴瘤与无症状出现的大 B 细胞淋巴瘤在特征和预后上的差异。
{"title":"Characteristics and outcomes of incidentally diagnosed diffuse large B-cell lymphoma and implications for cancer screening","authors":"Suheil Albert Atallah-Yunes, Matthew J. Rees, Raphael Mwangi, Robyn L. Kuchler, Grzegorz S. Nowakowski, Thomas M. Habermann, Yucai Wang, Carrie A. Thompson, Andrew L. Feldman, Matthew J. Maurer, James R. Cerhan, Stephen M. Ansell, Thomas E. Witzig","doi":"10.1002/ajh.27504","DOIUrl":"10.1002/ajh.27504","url":null,"abstract":"<p>Differences in characteristics and outcomes between incidental and symptomatic presentations of Large B-Cell Lymphoma.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 1","pages":"158-162"},"PeriodicalIF":10.1,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27504","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431710","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}
Rayan Bou-Fakhredin, Maria Domenica Cappellini, Ali T. Taher, Lucia De Franceschi
Beta (β)-thalassemia and sickle cell disease (SCD) are characterized by a hypercoagulable state, which can significantly influence organ complication and disease severity. While red blood cells (RBCs) and erythroblasts continue to play a central role in the pathogenesis of thrombosis in β-thalassemia and SCD, additional factors such as free heme, inflammatory vasculopathy, splenectomy, among other factors further contribute to the complexity of thrombotic risk. Thus, understanding the role of the numerous factors driving this hypercoagulable state will enable healthcare practitioners to enhance preventive and treatment strategies and develop novel therapies for the future. We herein describe the pathogenesis of thrombosis in patients with β-thalassemia and SCD. We also identify common mechanisms underlying the procoagulant profile of hemoglobinopathies translating into thrombotic events. Finally, we review the currently available prevention and clinical management of thrombosis in these patient populations.
{"title":"Hypercoagulability in hemoglobinopathies: Decoding the thrombotic threat","authors":"Rayan Bou-Fakhredin, Maria Domenica Cappellini, Ali T. Taher, Lucia De Franceschi","doi":"10.1002/ajh.27500","DOIUrl":"10.1002/ajh.27500","url":null,"abstract":"<p>Beta (β)-thalassemia and sickle cell disease (SCD) are characterized by a hypercoagulable state, which can significantly influence organ complication and disease severity. While red blood cells (RBCs) and erythroblasts continue to play a central role in the pathogenesis of thrombosis in β-thalassemia and SCD, additional factors such as free heme, inflammatory vasculopathy, splenectomy, among other factors further contribute to the complexity of thrombotic risk. Thus, understanding the role of the numerous factors driving this hypercoagulable state will enable healthcare practitioners to enhance preventive and treatment strategies and develop novel therapies for the future. We herein describe the pathogenesis of thrombosis in patients with β-thalassemia and SCD. We also identify common mechanisms underlying the procoagulant profile of hemoglobinopathies translating into thrombotic events. Finally, we review the currently available prevention and clinical management of thrombosis in these patient populations.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 1","pages":"103-115"},"PeriodicalIF":10.1,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431709","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}
Cristina Pascual-Izquierdo, Blanca Sánchez-González, Mariana-Isabel Canaro-Hirnyk, Gloria García-Donas, María Menor-Gómez, Juan-José Gil-Fernández, Silvia Monsalvo-Saornil, Almudena de-Laiglesia, María-Teresa Álvarez-Román, Isidro Jarque-Ramos, María-José Llácer, Begoña Pedrote-Amador, Denis Zafra-Torres, Isabel Caparrós-Miranda, Ariana Ortúzar-Pasalodos, Nuria Revilla-Calvo, José-María Bastida, Esther Chica-Gullón, Montserrat Alvarellos, Reyes Jiménez-Bárcenas, Silvia Bernat, Daniel Martínez-Carballeira, Sunil Lakhwani, Elsa López-Ansoar, María-Esperanza Moreno-Beltrán, Álvaro Lorenzo-Vizcaya, María-Aránzazu Aguirre, Maialen Lasa-Eguialde, Marta Canet, Isabel-Teresa González-Gascón-y-Marín, Gonzalo Caballero-Navarro, Amalia Cuesta, Marta Díaz-López, Teresa Arquero, Marta Moreno-Carbonell, María-Eva Mingot-Castellano, the Spanish ITP Group (GEPTI) of the Spanish Society of Hematology and Hemotherapy (SEHH)
Avatrombopag is the newest thrombopoietin receptor agonist (TPO-RA) approved to treat immune thrombocytopenia (ITP). Real-world evidence regarding effectiveness/safety is limited. The Spanish ITP Group (GEPTI) performed a retrospective study with patients starting avatrombopag for the first time. A total of 268 ITP patients were recruited. The median (interquartile range [IQR]) follow-up time was 47.5 (30.4–58.9) weeks. Among the 193 patients with baseline platelet counts <50 × 109/L, 174 (90.1%) of them achieved response (PC ≥50 × 109/L), and 113 (87.6%) of the 129 who persisted on avatrombopag at last visit had platelet levels above such threshold. Results were similar when only those patients switching to avatrombopag due to previous treatment failure were considered (n = 104). Patients reached response in 13 (7–21) days. Among patients with baseline levels ≥50 × 109/L, 73/75 (97.3%) reported response, which was maintained by 53 (94.6%) of the 56 who continued on avatrombopag at the end of the study. Loss-of-response was always <10%. ITP duration did not influence response. Approximately 79% (34/43) of heavily pretreated (≥4 lines) patients with baseline platelet counts <50 × 109/L switching after previous failure achieved PC ≥50 × 109/L. Previous use of eltrombopag and/or romiplostim did not influence response, regardless of whether previous TPO-RA(s) succeeded or failed. Avatrombopag allowed dose-reduction/suspension of corticosteroids in 40/50 (80.0%) patients with baseline platelet counts <50 × 109/L. Overall, 40/268 (14.9%) thrombocytosis and 12/268 (4.5%) thromboembolic events were reported. Our real-world cohort supports the use of avatrombopag to manage ITP, regardless of disease severity and treatment history.
{"title":"Avatrombopag in immune thrombocytopenia: A real-world study of the Spanish ITP Group (GEPTI)","authors":"Cristina Pascual-Izquierdo, Blanca Sánchez-González, Mariana-Isabel Canaro-Hirnyk, Gloria García-Donas, María Menor-Gómez, Juan-José Gil-Fernández, Silvia Monsalvo-Saornil, Almudena de-Laiglesia, María-Teresa Álvarez-Román, Isidro Jarque-Ramos, María-José Llácer, Begoña Pedrote-Amador, Denis Zafra-Torres, Isabel Caparrós-Miranda, Ariana Ortúzar-Pasalodos, Nuria Revilla-Calvo, José-María Bastida, Esther Chica-Gullón, Montserrat Alvarellos, Reyes Jiménez-Bárcenas, Silvia Bernat, Daniel Martínez-Carballeira, Sunil Lakhwani, Elsa López-Ansoar, María-Esperanza Moreno-Beltrán, Álvaro Lorenzo-Vizcaya, María-Aránzazu Aguirre, Maialen Lasa-Eguialde, Marta Canet, Isabel-Teresa González-Gascón-y-Marín, Gonzalo Caballero-Navarro, Amalia Cuesta, Marta Díaz-López, Teresa Arquero, Marta Moreno-Carbonell, María-Eva Mingot-Castellano, the Spanish ITP Group (GEPTI) of the Spanish Society of Hematology and Hemotherapy (SEHH)","doi":"10.1002/ajh.27498","DOIUrl":"10.1002/ajh.27498","url":null,"abstract":"<p>Avatrombopag is the newest thrombopoietin receptor agonist (TPO-RA) approved to treat immune thrombocytopenia (ITP). Real-world evidence regarding effectiveness/safety is limited. The Spanish ITP Group (GEPTI) performed a retrospective study with patients starting avatrombopag for the first time. A total of 268 ITP patients were recruited. The median (interquartile range [IQR]) follow-up time was 47.5 (30.4–58.9) weeks. Among the 193 patients with baseline platelet counts <50 × 10<sup>9</sup>/L, 174 (90.1%) of them achieved response (PC ≥50 × 10<sup>9</sup>/L), and 113 (87.6%) of the 129 who persisted on avatrombopag at last visit had platelet levels above such threshold. Results were similar when only those patients switching to avatrombopag due to previous treatment failure were considered (<i>n</i> = 104). Patients reached response in 13 (7–21) days. Among patients with baseline levels ≥50 × 10<sup>9</sup>/L, 73/75 (97.3%) reported response, which was maintained by 53 (94.6%) of the 56 who continued on avatrombopag at the end of the study. Loss-of-response was always <10%. ITP duration did not influence response. Approximately 79% (34/43) of heavily pretreated (≥4 lines) patients with baseline platelet counts <50 × 10<sup>9</sup>/L switching after previous failure achieved PC ≥50 × 10<sup>9</sup>/L. Previous use of eltrombopag and/or romiplostim did not influence response, regardless of whether previous TPO-RA(s) succeeded or failed. Avatrombopag allowed dose-reduction/suspension of corticosteroids in 40/50 (80.0%) patients with baseline platelet counts <50 × 10<sup>9</sup>/L. Overall, 40/268 (14.9%) thrombocytosis and 12/268 (4.5%) thromboembolic events were reported. Our real-world cohort supports the use of avatrombopag to manage ITP, regardless of disease severity and treatment history.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"99 12","pages":"2328-2339"},"PeriodicalIF":10.1,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27498","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142415779","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}
Antonio M. Risitano, Camilla Frieri, Luana Marano, Eleonora Urciuoli, Ada Sanseverino, Caterina Nannelli, Rosario Notaro
<p>The treatment of paroxysmal nocturnal hemoglobinuria (PNH) is undergoing a second revolution with the introduction of proximal complement inhibitors.<span><sup>1</sup></span> Indeed, recent clinical studies have shown that molecules targeting either the C3, the complement factor B, or the complement factor D (this latter in association with anti-C5 therapy) have been effective in increasing hemoglobin levels in PNH patients with residual anemia despite standard anti-C5 treatment.<span><sup>2-4</sup></span> The effectiveness of this class of complement inhibitors is achieved by preventing C3-mediated extravascular hemolysis, which we have identified as the major factor limiting hemoglobin normalization in PNH patients treated with anti-C5.<span><sup>1, 5</sup></span> Indeed, unlike C5 inhibitors, proximal complement inhibitors are able to almost completely normalize the lifespan of PNH erythrocytes, leading to the paradox that a better hematological response is associated with a significant and large increase in both the proportion and the mass of the population of ‘crippled’ PNH erythrocytes. Eventually, the increased size of the population of PNH erythrocytes resulting from the therapeutic effectiveness of proximal complement inhibitors has raised the concern that clinically severe intravascular breakthrough hemolysis (BTH) may occur if the therapeutic blockade is lost, even temporarily. An interesting debate on the risk of BTH is currently ongoing, spurring discussions about whether proximal complement inhibitors should be used as monotherapy or in a combination with anti-C5.<span><sup>6</sup></span> These discussions are based on comparisons of different clinical trials but suffer from the paucity of data. In addition, there is an almost complete lack of knowledge about the clinical course of BTH in patients with very large proportions of PNH erythrocytes (even higher than 90%) because, simply, this condition has never been observed in PNH patients before the introduction of treatments with proximal complement inhibitors. Thus, even index cases provide valuable insights that enhance the understanding of this novel condition within the PNH community.</p><p>We report the unique circumstance of three PNH patients treated with the factor D inhibitor vemircopan as monotherapy within the clinical trial NCT04170023.<span><sup>7</sup></span> The trial was unexpectedly terminated by the sponsor's decision, following an interim analysis claiming that vemircopan monotherapy “Did not appropriately control IVH; significantly increased rates of BTH and LDH excursions (LDH excursions is defined by LDH values >x2ULN) compared with ravulizumab” (https://clinicaltrials.gov/study/NCT04170023). Consequently, these patients, despite achieving a very good hematological response associated with a large population of PNH erythrocytes, were compelled to discontinue this effective treatment, and to be switched to standard-of-care anti-C5 treatment (single 2700 mg
{"title":"Massive hemolysis in paroxysmal nocturnal hemoglobinuria after switching from proximal complement inhibitor to anti-C5 therapy: A lesson not to be forgotten","authors":"Antonio M. Risitano, Camilla Frieri, Luana Marano, Eleonora Urciuoli, Ada Sanseverino, Caterina Nannelli, Rosario Notaro","doi":"10.1002/ajh.27502","DOIUrl":"10.1002/ajh.27502","url":null,"abstract":"<p>The treatment of paroxysmal nocturnal hemoglobinuria (PNH) is undergoing a second revolution with the introduction of proximal complement inhibitors.<span><sup>1</sup></span> Indeed, recent clinical studies have shown that molecules targeting either the C3, the complement factor B, or the complement factor D (this latter in association with anti-C5 therapy) have been effective in increasing hemoglobin levels in PNH patients with residual anemia despite standard anti-C5 treatment.<span><sup>2-4</sup></span> The effectiveness of this class of complement inhibitors is achieved by preventing C3-mediated extravascular hemolysis, which we have identified as the major factor limiting hemoglobin normalization in PNH patients treated with anti-C5.<span><sup>1, 5</sup></span> Indeed, unlike C5 inhibitors, proximal complement inhibitors are able to almost completely normalize the lifespan of PNH erythrocytes, leading to the paradox that a better hematological response is associated with a significant and large increase in both the proportion and the mass of the population of ‘crippled’ PNH erythrocytes. Eventually, the increased size of the population of PNH erythrocytes resulting from the therapeutic effectiveness of proximal complement inhibitors has raised the concern that clinically severe intravascular breakthrough hemolysis (BTH) may occur if the therapeutic blockade is lost, even temporarily. An interesting debate on the risk of BTH is currently ongoing, spurring discussions about whether proximal complement inhibitors should be used as monotherapy or in a combination with anti-C5.<span><sup>6</sup></span> These discussions are based on comparisons of different clinical trials but suffer from the paucity of data. In addition, there is an almost complete lack of knowledge about the clinical course of BTH in patients with very large proportions of PNH erythrocytes (even higher than 90%) because, simply, this condition has never been observed in PNH patients before the introduction of treatments with proximal complement inhibitors. Thus, even index cases provide valuable insights that enhance the understanding of this novel condition within the PNH community.</p><p>We report the unique circumstance of three PNH patients treated with the factor D inhibitor vemircopan as monotherapy within the clinical trial NCT04170023.<span><sup>7</sup></span> The trial was unexpectedly terminated by the sponsor's decision, following an interim analysis claiming that vemircopan monotherapy “Did not appropriately control IVH; significantly increased rates of BTH and LDH excursions (LDH excursions is defined by LDH values >x2ULN) compared with ravulizumab” (https://clinicaltrials.gov/study/NCT04170023). Consequently, these patients, despite achieving a very good hematological response associated with a large population of PNH erythrocytes, were compelled to discontinue this effective treatment, and to be switched to standard-of-care anti-C5 treatment (single 2700 mg","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 1","pages":"163-167"},"PeriodicalIF":10.1,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27502","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142430486","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}
Yiannis Petros Dimopoulos, Wei Wang, Sa A. Wang, Sanam Loghavi, Courtney D. DiNardo, Yoheved Gerstein, Shimin Hu, Zhenya Tang, Charmaine Joyce Lim Ilagan, Beenu Thakral, Siba El Hussein, Jie Xu, Shaoying Li, Pei Lin, Keyur P. Patel, Chi Young Ok, L. Jeffrey Medeiros, Hong Fang
<p>Li-Fraumeni syndrome (LFS) is a rare inherited disorder associated with germline pathogenic <i>TP53</i> variants. The absence of the functional gene product, p53 protein, results in failure to activate programmed cell death in the appropriate context and leads to uncontrolled cell proliferation. LFS patients present with a high incidence of various malignancies, often at young ages. In contrast to the high occurrence rate of solid tumors, hematologic neoplasms in LFS patients are relatively rare and not systemically described. A few previous studies showed that leukemias developed in about 2%–4% of LFS patients, whereas lymphomas are less frequent, seen in approximately 2% of LFS patients.<span><sup>1-3</sup></span></p><p>This study explored the clinicopathologic spectrum of hematologic neoplasms in LFS patients. Eighteen patients with a well-established clinical diagnosis of LFS and confirmatory <i>TP53</i> genetic testing as well as a hematologic neoplasm were included, spanning the time interval from 1/1/2000 through 8/5/2023. Their LFS diagnosis was further confirmed by our LFS Progeny Database and/or Clinical Cancer Genetics (CCG) team that runs the LFS program in our institution. Four previously reported patients (cases #1, 2, 6, 7 in that cohort)<span><sup>4</sup></span> were included in this study. To the best of our knowledge, this is the largest cohort described to date.</p><p>The cohort included 12 (67%) women and 6 (33%) men. Their clinical history and hematologic diagnoses are presented in Table 1. All patients had a confirmed germline pathogenic variant of <i>TP53</i> at MD Anderson Cancer Center and/or an outside institution, although the detailed nomenclature of <i>TP53</i> germline mutation in 4 patients (cases #1, 8, 14, 18) tested at an outside institution was not available. All 18 patients had an extensive family history of malignancies (Supplementary Table 1). Seventeen (94%) patients had other malignant or pre-malignant neoplasms in additional to hematologic malignancy; 7 (39%) patients had one neoplasm and 10 (56%) patients had ≥2 neoplasms. The most common non-hematologic malignancies were breast cancer (9/18, 50%), sarcoma (8/18, 44%), and gastrointestinal tumors (5/18, 28%). The only patient without any other neoplasm (case #18) was diagnosed with B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) at the age of 11 years and died 4 years later.</p><p>The median age at diagnosis of the first malignancy was 32 years (range, 1–54 years) and the median age at diagnosis of hematologic neoplasm was 41 years (range, 11–73 years). The initial presenting hematologic neoplasms included myelodysplastic syndrome (MDS) (<i>n</i> = 10, 56%), “de novo” acute myeloid leukemia (AML) developing in patients without a prior history of MDS or other hematologic neoplasms (<i>n</i> = 2, 11%), B-ALL/LBL (<i>n</i> = 2, 11%), plasma cell neoplasms (PCN) (<i>n</i> = 2, 11%), T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) (<i>n</i> = 1, 6%), and myelop
{"title":"The spectrum of hematologic neoplasms in patients with Li-Fraumeni syndrome","authors":"Yiannis Petros Dimopoulos, Wei Wang, Sa A. Wang, Sanam Loghavi, Courtney D. DiNardo, Yoheved Gerstein, Shimin Hu, Zhenya Tang, Charmaine Joyce Lim Ilagan, Beenu Thakral, Siba El Hussein, Jie Xu, Shaoying Li, Pei Lin, Keyur P. Patel, Chi Young Ok, L. Jeffrey Medeiros, Hong Fang","doi":"10.1002/ajh.27497","DOIUrl":"10.1002/ajh.27497","url":null,"abstract":"<p>Li-Fraumeni syndrome (LFS) is a rare inherited disorder associated with germline pathogenic <i>TP53</i> variants. The absence of the functional gene product, p53 protein, results in failure to activate programmed cell death in the appropriate context and leads to uncontrolled cell proliferation. LFS patients present with a high incidence of various malignancies, often at young ages. In contrast to the high occurrence rate of solid tumors, hematologic neoplasms in LFS patients are relatively rare and not systemically described. A few previous studies showed that leukemias developed in about 2%–4% of LFS patients, whereas lymphomas are less frequent, seen in approximately 2% of LFS patients.<span><sup>1-3</sup></span></p><p>This study explored the clinicopathologic spectrum of hematologic neoplasms in LFS patients. Eighteen patients with a well-established clinical diagnosis of LFS and confirmatory <i>TP53</i> genetic testing as well as a hematologic neoplasm were included, spanning the time interval from 1/1/2000 through 8/5/2023. Their LFS diagnosis was further confirmed by our LFS Progeny Database and/or Clinical Cancer Genetics (CCG) team that runs the LFS program in our institution. Four previously reported patients (cases #1, 2, 6, 7 in that cohort)<span><sup>4</sup></span> were included in this study. To the best of our knowledge, this is the largest cohort described to date.</p><p>The cohort included 12 (67%) women and 6 (33%) men. Their clinical history and hematologic diagnoses are presented in Table 1. All patients had a confirmed germline pathogenic variant of <i>TP53</i> at MD Anderson Cancer Center and/or an outside institution, although the detailed nomenclature of <i>TP53</i> germline mutation in 4 patients (cases #1, 8, 14, 18) tested at an outside institution was not available. All 18 patients had an extensive family history of malignancies (Supplementary Table 1). Seventeen (94%) patients had other malignant or pre-malignant neoplasms in additional to hematologic malignancy; 7 (39%) patients had one neoplasm and 10 (56%) patients had ≥2 neoplasms. The most common non-hematologic malignancies were breast cancer (9/18, 50%), sarcoma (8/18, 44%), and gastrointestinal tumors (5/18, 28%). The only patient without any other neoplasm (case #18) was diagnosed with B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) at the age of 11 years and died 4 years later.</p><p>The median age at diagnosis of the first malignancy was 32 years (range, 1–54 years) and the median age at diagnosis of hematologic neoplasm was 41 years (range, 11–73 years). The initial presenting hematologic neoplasms included myelodysplastic syndrome (MDS) (<i>n</i> = 10, 56%), “de novo” acute myeloid leukemia (AML) developing in patients without a prior history of MDS or other hematologic neoplasms (<i>n</i> = 2, 11%), B-ALL/LBL (<i>n</i> = 2, 11%), plasma cell neoplasms (PCN) (<i>n</i> = 2, 11%), T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) (<i>n</i> = 1, 6%), and myelop","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"99 12","pages":"2416-2419"},"PeriodicalIF":10.1,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27497","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399153","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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