Pub Date : 2024-07-25DOI: 10.3389/frhem.2024.1441070
Barbara Loteta, A. Pitino, Martina Pitea, C. Alati, Giovanni Tripepi, Maria Caterina Micó, Maria Pellicano', Francesca Cogliandro, Gaetana Porto, Giorgia Policastro, Giovanna Utano, Ilaria Maria Delfino, Annalisa Sgarlata, Anna Scopelliti, Aurora Idato, Giovanni Laenza, M. Altomonte, G. D’Arrigo, Mercedes Gori, Massimo Martino
To evaluate the efficacy of biosimilar (BIO) pegfilgrastim (PEG) in lymphoma patients after autologous stem cell transplantation (ASCT).86 consecutive lymphoma patients who received BIO/PEG after ASCT were assessed. The primary endpoints of this study were the incidence of febrile neutropenia (FN) and time to neutrophil engraftment.Most patients were males (67.4%) with a median age of 48 years. FN occurred in 66 patients (76.7%), and most of the fever was grade 1-2. The median time to neutrophil engraftment was 9 days. The incidence of FN differs based on lymphoma type (p-value <0.01) and was higher in non-Hodgkin lymphoma (NHL) than in Hodgkin Lymphoma (HL). No statistical difference was found between NHL and HL regarding the time to reach the neutrophil engraftment. Hospitalization lasted from a minimum of 9 to a maximum of 34 days. The restricted mean time to discharge was 15.9 days (95%CI 14-16), without differences based on lymphoma type.Although the study has the significant limitation of not being randomized and not having a control arm, it highlights the efficacy and safety of a BIO-PEG formulation in patients with Lymphoma and undergoing ASCT.
{"title":"Effectiveness of biosimilar pegfilgrastim in patients with lymphoma after high-dose chemotherapy and autologous stem cell transplantation: a real-life study","authors":"Barbara Loteta, A. Pitino, Martina Pitea, C. Alati, Giovanni Tripepi, Maria Caterina Micó, Maria Pellicano', Francesca Cogliandro, Gaetana Porto, Giorgia Policastro, Giovanna Utano, Ilaria Maria Delfino, Annalisa Sgarlata, Anna Scopelliti, Aurora Idato, Giovanni Laenza, M. Altomonte, G. D’Arrigo, Mercedes Gori, Massimo Martino","doi":"10.3389/frhem.2024.1441070","DOIUrl":"https://doi.org/10.3389/frhem.2024.1441070","url":null,"abstract":"To evaluate the efficacy of biosimilar (BIO) pegfilgrastim (PEG) in lymphoma patients after autologous stem cell transplantation (ASCT).86 consecutive lymphoma patients who received BIO/PEG after ASCT were assessed. The primary endpoints of this study were the incidence of febrile neutropenia (FN) and time to neutrophil engraftment.Most patients were males (67.4%) with a median age of 48 years. FN occurred in 66 patients (76.7%), and most of the fever was grade 1-2. The median time to neutrophil engraftment was 9 days. The incidence of FN differs based on lymphoma type (p-value <0.01) and was higher in non-Hodgkin lymphoma (NHL) than in Hodgkin Lymphoma (HL). No statistical difference was found between NHL and HL regarding the time to reach the neutrophil engraftment. Hospitalization lasted from a minimum of 9 to a maximum of 34 days. The restricted mean time to discharge was 15.9 days (95%CI 14-16), without differences based on lymphoma type.Although the study has the significant limitation of not being randomized and not having a control arm, it highlights the efficacy and safety of a BIO-PEG formulation in patients with Lymphoma and undergoing ASCT.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141803738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-22DOI: 10.3389/frhem.2024.1429916
Carla Semedo, Raquel Caroço, António Almeida, Bruno António Cardoso
Hematopoiesis is a complex and tightly regulated process that drives the formation of mature blood cells from a single hematopoietic stem cell. This complex process occurs within the bone marrow, which, once disrupted or deregulated, subverts normal hematopoietic development, allowing leukemic cells to emerge, proliferate, and thrive. Notably, several cellular populations and paracrine factors within the bone marrow fuel leukemia expansion and progression. This review presents an overview of the main microenvironmental components that promote myeloid leukemia progression, discussing the emerging therapeutical strategies that target both leukemic cells and the supportive bone marrow microenvironment – targeting both the seed and the soil.
{"title":"Targeting the bone marrow niche, moving towards leukemia eradication","authors":"Carla Semedo, Raquel Caroço, António Almeida, Bruno António Cardoso","doi":"10.3389/frhem.2024.1429916","DOIUrl":"https://doi.org/10.3389/frhem.2024.1429916","url":null,"abstract":"Hematopoiesis is a complex and tightly regulated process that drives the formation of mature blood cells from a single hematopoietic stem cell. This complex process occurs within the bone marrow, which, once disrupted or deregulated, subverts normal hematopoietic development, allowing leukemic cells to emerge, proliferate, and thrive. Notably, several cellular populations and paracrine factors within the bone marrow fuel leukemia expansion and progression. This review presents an overview of the main microenvironmental components that promote myeloid leukemia progression, discussing the emerging therapeutical strategies that target both leukemic cells and the supportive bone marrow microenvironment – targeting both the seed and the soil.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141816344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-13DOI: 10.3389/frhem.2024.1335161
T. Leitner, Cyrus Khandanpour, K. Wendelin, F. Oduncu, Christoph Kimmich, Ralph Naumann, Miriam Kull, Hartmut Goldschmidt, Martin Ehmer, C. Kiewitz, Hans-Jürgen Salwender
Therapy for relapsed and refractory multiple myeloma (RRMM) remains challenging. While monoclonal antibodies against CD38 combined with pomalidomide have demonstrated efficacy in clinical trials, real-world data remain sparse. We present real-world data from a compassionate use program (CUP) of isatuximab given in combination with pomalidomide and dexamethasone according to the German Compassionate Use Directive ahead of commercial availability for adult patients with RRMM. Patients had received at least two prior lines of therapy, including lenalidomide and a proteasome inhibitor (PI), and had demonstrated disease progression on the last therapy. Isatuximab was administered as part of the clinical routine. In total, 18 patients were included in the CUP before the official market availability of isatuximab. The data reflect a heterogeneous population in terms of age, risk factors, previous diseases, and treatments. Most of the patients had received two full isatuximab cycles. The analysis showed no new safety signals, supporting the manageable toxicity profile of isatuximab and highlighting its potential in real-world settings.
{"title":"First clinical experience of isatuximab safety and tolerability in relapsed and refractory multiple myeloma: real-world data from a compassionate use program in Germany","authors":"T. Leitner, Cyrus Khandanpour, K. Wendelin, F. Oduncu, Christoph Kimmich, Ralph Naumann, Miriam Kull, Hartmut Goldschmidt, Martin Ehmer, C. Kiewitz, Hans-Jürgen Salwender","doi":"10.3389/frhem.2024.1335161","DOIUrl":"https://doi.org/10.3389/frhem.2024.1335161","url":null,"abstract":"Therapy for relapsed and refractory multiple myeloma (RRMM) remains challenging. While monoclonal antibodies against CD38 combined with pomalidomide have demonstrated efficacy in clinical trials, real-world data remain sparse. We present real-world data from a compassionate use program (CUP) of isatuximab given in combination with pomalidomide and dexamethasone according to the German Compassionate Use Directive ahead of commercial availability for adult patients with RRMM. Patients had received at least two prior lines of therapy, including lenalidomide and a proteasome inhibitor (PI), and had demonstrated disease progression on the last therapy. Isatuximab was administered as part of the clinical routine. In total, 18 patients were included in the CUP before the official market availability of isatuximab. The data reflect a heterogeneous population in terms of age, risk factors, previous diseases, and treatments. Most of the patients had received two full isatuximab cycles. The analysis showed no new safety signals, supporting the manageable toxicity profile of isatuximab and highlighting its potential in real-world settings.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141347088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-18DOI: 10.3389/frhem.2024.1356561
Laura Pelagatti, Giulia Pozzi, Samuele Cortellazzi, Cristina Mancini, Eugenia Martella, L. Pagliaro, Mariateresa Giaimo, Giovanni Roti, M. Vitale, C. Carubbi, E. Masselli
Polycythemia vera (PV) is a JAK2-mutated myeloproliferative neoplasm (MPN) characterized by clonal erythrocytosis and an intrinsic risk of transformation into acute myeloid leukemia (AML), known as blast-phase (BP) disease, a condition typified by dismal prognosis. In PV, the evolution to BP generally occurs through an overt fibrotic progression, represented by the post-PV myelofibrotic (MF) stage. However, direct leukemic transformation from PV may also occur in up to ~50% of patients. In this study, we sought to shed light on the morphological, clinical, and molecular features that may differentiate BP arising from a direct transition from the PV stage (post-PV-BP) from those evolving through a diagnosis of post-PV myelofibrosis (post-PV-MF-BP). We retrospectively analyzed a cohort of post-PV-BP (n=5) and post-PV-MF-BP (n=5). We found that BP arising from PV directly displayed significantly lower leukocyte count (median 2.93 × 109/L, range: 2.30–39.40 vs. median 41.05 × 109/L, range: 5.46–58.01; P=0.03), and spleen diameter (14.0 cm, range: 11.5–20.0 vs. 25.5 cm, range: 18–26; P=0.03) as compared to those experiencing an overt fibrotic stage. The most striking differences emerged from bone marrow (BM) morphological analysis: all post-PV-BP were characterized by significantly higher cellularity (median 70%, range: 60%–98% vs. 28%, range: 2%–41%, P=0.0245), lower degree of fibrosis (fibrosis grade 1 vs. fibrosis grade 3 in all cases, P=0.008) and dysplastic features involving all three lineages, most prominently the erythroid and megakaryocytic compartment. Next-generation sequencing (NGS) analysis revealed that post-PV-BP cases were enriched in mutations located in genes involved in DNA methylation such as DNMT3A, IDH1/2, and TET2 (45% vs. 15%, P=0.038). With all the limits of the small number of patients for each cohort, our data suggest that BPs that arise directly from PV present a peculiar phenotype, consistent with the molecular signature of the disease, typified by mutations of genes occurring with a high frequency in Myelodysplastic Syndromes (MDS) and MDS/MPN. Further studies in larger cohorts are warranted to translate these observations into robust evidence that may advise therapeutic choices.
多发性红细胞增多症（PV）是一种 JAK2 基因突变的骨髓增殖性肿瘤（MPN），其特征是克隆性红细胞增多症和转化为急性髓性白血病（AML）的内在风险，即所谓的爆炸期（BP）疾病，这种疾病的典型特征是预后不良。在骨髓增生性白血病中，向骨髓增生性白血病的演变一般是通过明显的纤维化进展进行的，即骨髓纤维化（MF）后阶段。然而，多达约 50% 的患者也可能会从骨髓增生性白血病直接转变为白血病。在本研究中，我们试图揭示可将从 PV 阶段直接转变而来的 BP（PV-BP 后）与通过诊断 PV 后骨髓纤维化而演变而来的 BP（PV-MF-BP 后）区分开来的形态学、临床和分子特征。我们回顾性地分析了一组后PV-BP（5人）和后PV-MF-BP（5人）。我们发现，由 PV 直接引起的 BP 的白细胞计数明显较低（中位数为 2.93 × 109/L，范围：2.30-39.40；中位数为 41.05 × 109/L，范围：5.46-58.01；中位数为 2.93 × 109/L，范围：2.30-39.40）：5.46-58.01；P=0.03）和脾脏直径（14.0 厘米，范围：11.5-20.0 vs. 25.5 厘米，范围：18-26；P=0.03）。骨髓（BM）形态学分析显示了最显著的差异：所有PV-BP后患者的特点都是细胞率显著增高（中位数70%，范围：60%-98% vs. 28%，范围：2%-41%，P=0.0245），纤维化程度较低（所有病例中纤维化1级 vs. 纤维化3级，P=0.008），以及涉及所有三个系的发育不良特征，其中最突出的是红系和巨核细胞系。下一代测序（NGS）分析显示，PV-BP 后病例富含 DNA 甲基化相关基因的突变，如 DNMT3A、IDH1/2 和 TET2（45% 对 15%，P=0.038）。尽管每个队列中的患者人数较少，但我们的数据表明，由 PV 直接引起的 BPs 表现出一种特殊的表型，与该疾病的分子特征一致，骨髓增生异常综合征（MDS）和 MDS/MPN 中出现频率较高的基因突变是其典型特征。要将这些观察结果转化为可靠的证据，为治疗选择提供建议，还需要在更大的群体中开展进一步的研究。
{"title":"Morphological, clinical, and molecular profiling of post-polycythemia vera accelerated/blast phase occurring with and without antecedent secondary myelofibrosis","authors":"Laura Pelagatti, Giulia Pozzi, Samuele Cortellazzi, Cristina Mancini, Eugenia Martella, L. Pagliaro, Mariateresa Giaimo, Giovanni Roti, M. Vitale, C. Carubbi, E. Masselli","doi":"10.3389/frhem.2024.1356561","DOIUrl":"https://doi.org/10.3389/frhem.2024.1356561","url":null,"abstract":"Polycythemia vera (PV) is a JAK2-mutated myeloproliferative neoplasm (MPN) characterized by clonal erythrocytosis and an intrinsic risk of transformation into acute myeloid leukemia (AML), known as blast-phase (BP) disease, a condition typified by dismal prognosis. In PV, the evolution to BP generally occurs through an overt fibrotic progression, represented by the post-PV myelofibrotic (MF) stage. However, direct leukemic transformation from PV may also occur in up to ~50% of patients. In this study, we sought to shed light on the morphological, clinical, and molecular features that may differentiate BP arising from a direct transition from the PV stage (post-PV-BP) from those evolving through a diagnosis of post-PV myelofibrosis (post-PV-MF-BP). We retrospectively analyzed a cohort of post-PV-BP (n=5) and post-PV-MF-BP (n=5). We found that BP arising from PV directly displayed significantly lower leukocyte count (median 2.93 × 109/L, range: 2.30–39.40 vs. median 41.05 × 109/L, range: 5.46–58.01; P=0.03), and spleen diameter (14.0 cm, range: 11.5–20.0 vs. 25.5 cm, range: 18–26; P=0.03) as compared to those experiencing an overt fibrotic stage. The most striking differences emerged from bone marrow (BM) morphological analysis: all post-PV-BP were characterized by significantly higher cellularity (median 70%, range: 60%–98% vs. 28%, range: 2%–41%, P=0.0245), lower degree of fibrosis (fibrosis grade 1 vs. fibrosis grade 3 in all cases, P=0.008) and dysplastic features involving all three lineages, most prominently the erythroid and megakaryocytic compartment. Next-generation sequencing (NGS) analysis revealed that post-PV-BP cases were enriched in mutations located in genes involved in DNA methylation such as DNMT3A, IDH1/2, and TET2 (45% vs. 15%, P=0.038). With all the limits of the small number of patients for each cohort, our data suggest that BPs that arise directly from PV present a peculiar phenotype, consistent with the molecular signature of the disease, typified by mutations of genes occurring with a high frequency in Myelodysplastic Syndromes (MDS) and MDS/MPN. Further studies in larger cohorts are warranted to translate these observations into robust evidence that may advise therapeutic choices.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140689422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-09DOI: 10.3389/frhem.2024.1365268
Kim Abbegail Tan Aldecoa, C. S. Macaraeg, Camelia Arsene, G. Krishnamoorthy, Tiffany Chng, Garrett Cherry, Nabila Chowdhury, Ryan Clark, Dana Deeb, Lisa Deptula, Grey Dietz, Ewomamobuho Eto, Victoria Golston, Landon Lawson, Chioma Mbionwu, Obiefuna Okponyia, Jennifer Orejuela, Thomaidha Qipo, Sumit Raut, Judie Goodman
The Omicron variant, one of the variants causing the coronavirus disease of 2019 (COVID-19), was first identified in November 2021 and became the predominant variant in 2022. Although causing less severe disease, this variant and its subvariants have been associated with increased transmissibility and limited protection despite vaccination and prior infection. Individuals with sickle cell disease (SCD) are particularly at greater risk of severe illness and death, and studies regarding the effectiveness of COVID-19 vaccination have been limited in this population. The study aims to determine the effectiveness of COVID-19 vaccination during this period among individuals with SCD and to examine various factors that can influence the likelihood of COVID-19 infection and severity among SCD individuals.This is a retrospective analysis of adult patients (≥18 years) with SCD who had emergency and inpatient encounters between January 1 and December 31, 2022. Multivariable regression analysis was performed to determine the effectiveness of the COVID-19 vaccine among this population.The study found that COVID-19 vaccination lowered the infection risk among SCD individuals by over 70% if they have received at least one dose of the vaccine. The study also found that individuals with SCD and a history of acute chest syndrome were over 3 times more likely to have a COVID-19 infection diagnosis than those without a history of acute chest syndrome.The study confirms the effectiveness of the COVID-19 vaccine among individuals with SCD during the Omicron period of the COVID-19 pandemic.
{"title":"Evaluating the effectiveness of COVID-19 vaccines in adults with sickle cell disease during the Omicron period of COVID-19 pandemic","authors":"Kim Abbegail Tan Aldecoa, C. S. Macaraeg, Camelia Arsene, G. Krishnamoorthy, Tiffany Chng, Garrett Cherry, Nabila Chowdhury, Ryan Clark, Dana Deeb, Lisa Deptula, Grey Dietz, Ewomamobuho Eto, Victoria Golston, Landon Lawson, Chioma Mbionwu, Obiefuna Okponyia, Jennifer Orejuela, Thomaidha Qipo, Sumit Raut, Judie Goodman","doi":"10.3389/frhem.2024.1365268","DOIUrl":"https://doi.org/10.3389/frhem.2024.1365268","url":null,"abstract":"The Omicron variant, one of the variants causing the coronavirus disease of 2019 (COVID-19), was first identified in November 2021 and became the predominant variant in 2022. Although causing less severe disease, this variant and its subvariants have been associated with increased transmissibility and limited protection despite vaccination and prior infection. Individuals with sickle cell disease (SCD) are particularly at greater risk of severe illness and death, and studies regarding the effectiveness of COVID-19 vaccination have been limited in this population. The study aims to determine the effectiveness of COVID-19 vaccination during this period among individuals with SCD and to examine various factors that can influence the likelihood of COVID-19 infection and severity among SCD individuals.This is a retrospective analysis of adult patients (≥18 years) with SCD who had emergency and inpatient encounters between January 1 and December 31, 2022. Multivariable regression analysis was performed to determine the effectiveness of the COVID-19 vaccine among this population.The study found that COVID-19 vaccination lowered the infection risk among SCD individuals by over 70% if they have received at least one dose of the vaccine. The study also found that individuals with SCD and a history of acute chest syndrome were over 3 times more likely to have a COVID-19 infection diagnosis than those without a history of acute chest syndrome.The study confirms the effectiveness of the COVID-19 vaccine among individuals with SCD during the Omicron period of the COVID-19 pandemic.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140723647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-04DOI: 10.3389/frhem.2024.1341225
Yaoshui Long, Wenxue Bai
Thalassemia is one of the inherited hemoglobin disorders worldwide, resulting in ineffective erythropoiesis, chronic hemolytic anemia, compensatory hemopoietic expansion, hypercoagulability, etc., and when a mother carries the thalassemia gene, the child is more likely to have severe thalassemia. Furthermore, the economic and time costs of genetic testing for thalassemia prevent many thalassemia patients from being diagnosed in time. To solve this problem, we performed least absolute shrinkage and selection operator (LASSO) regression to analyze the correlation between thalassemia and blood routine indicators containing mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red blood cell (RBC). We then built a nomogram to predict the occurrence of thalassemia, and receiver operating characteristic (ROC) curve was used to verify the prediction efficiency of this model. In total, we obtained 7,621 cases, including 847 thalassemia patients and 6,774 non-thalassemia. Among the 847 thalassemia patients, with a positivity rate of 67.2%, 569 cases were positive for α-thalassemia, and with a rate of 31.5%, 267 cases were positive for β-thalassemia. The remaining 11 cases were positive for both α- and β-thalassemia. Based on machine learning algorithm, we screened four optimal indicators, namely, MCV, MCH, RBC, and MCHC. The AUC value of MCV, MCH, RBC, and MCHC were 0.907, 0.906, 0.796, and 0.795, respectively. Moreover, the AUC value of the prediction model was 0.911. In summary, a novel and effective machine learning model was built to predict thalassemia, which functioned accurately, and may provide new insights for the early screening of thalassemia in the future.
{"title":"Constructing a novel clinical indicator model to predict the occurrence of thalassemia in pregnancy through machine learning algorithm","authors":"Yaoshui Long, Wenxue Bai","doi":"10.3389/frhem.2024.1341225","DOIUrl":"https://doi.org/10.3389/frhem.2024.1341225","url":null,"abstract":"Thalassemia is one of the inherited hemoglobin disorders worldwide, resulting in ineffective erythropoiesis, chronic hemolytic anemia, compensatory hemopoietic expansion, hypercoagulability, etc., and when a mother carries the thalassemia gene, the child is more likely to have severe thalassemia. Furthermore, the economic and time costs of genetic testing for thalassemia prevent many thalassemia patients from being diagnosed in time. To solve this problem, we performed least absolute shrinkage and selection operator (LASSO) regression to analyze the correlation between thalassemia and blood routine indicators containing mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red blood cell (RBC). We then built a nomogram to predict the occurrence of thalassemia, and receiver operating characteristic (ROC) curve was used to verify the prediction efficiency of this model. In total, we obtained 7,621 cases, including 847 thalassemia patients and 6,774 non-thalassemia. Among the 847 thalassemia patients, with a positivity rate of 67.2%, 569 cases were positive for α-thalassemia, and with a rate of 31.5%, 267 cases were positive for β-thalassemia. The remaining 11 cases were positive for both α- and β-thalassemia. Based on machine learning algorithm, we screened four optimal indicators, namely, MCV, MCH, RBC, and MCHC. The AUC value of MCV, MCH, RBC, and MCHC were 0.907, 0.906, 0.796, and 0.795, respectively. Moreover, the AUC value of the prediction model was 0.911. In summary, a novel and effective machine learning model was built to predict thalassemia, which functioned accurately, and may provide new insights for the early screening of thalassemia in the future.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140742651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-28DOI: 10.3389/frhem.2024.1373408
Hammad Hassan, Sheerien Rajput
Transfusion Medicine is facing mounting challenges, including but not limited to donor availability, blood supply shortages, and transfusion-associated complications, such as immunogenicity and transmission of viral infections. ‘Blood Pharming’, for in vitro Red Blood Cells (RBC) synthesis, offers a potentially effective approach to addressing the challenges and risks associated with the transfusion of blood and related products. This innovative approach employs cells from variable sources such as Hematopoietic stem cells (HSCs), induced pluripotent stem cells (iPSCs), or immortalized progenitor cell lines, directing their differentiation towards erythropoiesis in an in-vitro environment that mimics the normal bone marrow niche required for erythropoiesis. This review article provides a comprehensive analysis of the progress and hurdles in blood pharming, emphasizing in vitro RBC synthesis for clinical application. In-vitro large-scale production of RBCs offers cutting-edge advantages, such as consistent scalability, the capacity to acquire desired blood phenotypes, and a significant reduction in transfusion-related infections, however, substantial molecular and methodological challenges still need to be addressed before the transfer of this approach from bench to bedside. The review discusses the challenges in ensuring scalability that matches demand and supply, the structural and functional integrity of in-vitro synthesized RBCs compared to their in-vivo counterparts, and the cost-effective methods of RBC synthesis in vitro. It also highlights the importance of implementing thorough characterization and testing protocols to comply with regulatory standards. Additionally, it delves into the ethical concerns associated with commercializing such products. In summary, this review examines the progress and obstacles in the field of in-vitro blood pharming. Through a comprehensive analysis of the present state of the discipline, ongoing scholarly investigations, and prospective avenues of inquiry, our objective is to contribute to a more profound comprehension of the potential impact of synthetic RBCs on the transformation of transfusion medicine.
{"title":"Blood pharming: exploring the progress and hurdles in producing in-vitro red blood cells for therapeutic applications","authors":"Hammad Hassan, Sheerien Rajput","doi":"10.3389/frhem.2024.1373408","DOIUrl":"https://doi.org/10.3389/frhem.2024.1373408","url":null,"abstract":"Transfusion Medicine is facing mounting challenges, including but not limited to donor availability, blood supply shortages, and transfusion-associated complications, such as immunogenicity and transmission of viral infections. ‘Blood Pharming’, for in vitro Red Blood Cells (RBC) synthesis, offers a potentially effective approach to addressing the challenges and risks associated with the transfusion of blood and related products. This innovative approach employs cells from variable sources such as Hematopoietic stem cells (HSCs), induced pluripotent stem cells (iPSCs), or immortalized progenitor cell lines, directing their differentiation towards erythropoiesis in an in-vitro environment that mimics the normal bone marrow niche required for erythropoiesis. This review article provides a comprehensive analysis of the progress and hurdles in blood pharming, emphasizing in vitro RBC synthesis for clinical application. In-vitro large-scale production of RBCs offers cutting-edge advantages, such as consistent scalability, the capacity to acquire desired blood phenotypes, and a significant reduction in transfusion-related infections, however, substantial molecular and methodological challenges still need to be addressed before the transfer of this approach from bench to bedside. The review discusses the challenges in ensuring scalability that matches demand and supply, the structural and functional integrity of in-vitro synthesized RBCs compared to their in-vivo counterparts, and the cost-effective methods of RBC synthesis in vitro. It also highlights the importance of implementing thorough characterization and testing protocols to comply with regulatory standards. Additionally, it delves into the ethical concerns associated with commercializing such products. In summary, this review examines the progress and obstacles in the field of in-vitro blood pharming. Through a comprehensive analysis of the present state of the discipline, ongoing scholarly investigations, and prospective avenues of inquiry, our objective is to contribute to a more profound comprehension of the potential impact of synthetic RBCs on the transformation of transfusion medicine.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140373039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-28DOI: 10.3389/frhem.2024.1331008
Ulrich Jaeger, Ingrid Simonitsch-Klupp, Patrick Klammer, A. Egle, S. Heibl, Peter Neumeister, E. Willenbacher, Florian Erlsbacher, J. Larcher-Senn, Philipp B. Staber, E. Porpaczy, C. Skrabs, M. Mayerhoefer, Marcus Hacker, T. Melchardt, Michael A. Fridrik, R. Greil
Patients with diffuse large B-cell lymphoma (DLBCL) relapsing early (within 12 months) or primary refractory to induction therapy with rituximab (R) and CHOP have a poor prognosis. We therefore initiated a study with obinutuzumab and venetoclax.Twenty-one patients with DLBCL (relapsed within 12 months or primary refractory), detectable Bcl-2 protein expression, and CD20 positivity were included in this prospective single-arm study between 2016 and 2021. Obinutuzumab was administered i.v. at a dose of 1,000 mg on days 1, 8, and 15 in cycle 1 and on day 1 of each of the following 21-day cycles. Venetoclax was given at 800 mg daily p.o. continuously. Treatment was repeated for up to three cycles. Eligible patients were planned to either proceed to cellular therapies or receive up to nine cycles of maintenance. The primary endpoint was objective response rate (ORR) after three cycles (Eudract Nr. 2016-001760-10 and NCT02987400).Twenty-one patients (median age, 64 years) with refractory or early relapsed DLBCL after one (N = 11) to four previous lines of therapy were included. The majority of patients received three cycles of obinutuzumab/venetoclax (range, 1–8). The regimen was well tolerated with manageable cytopenias and infections. Severe adverse events related to treatment were observed in 9.5%. The ORR was 38.1% (8/21 patients) with a best response of five complete remissions (CRs; 23.8%) and three partial remissions (PRs; 14.2%). The primary endpoint (45% ORR) was not met. Response duration was 83.3% at 84 days, with a progression-free survival of 38.8% at 84 days and 25.9% at 168 days and a median overall survival of 169.1 weeks. All deaths were due to underlying disease. Seven patients became eligible for autologous transplant. Overall, nine patients (42.8%) received 11 cellular therapies (5 ASCT and 6 CAR-T). Three patients went directly from obinutuzumab/venetoclax to CAR-T therapy. All patients had successful peripheral stem cell or T-cell harvests. Characteristics of responders include relapsed disease (response rate, 6 of 11 = 54%), very good or good R-IPI (7 of 8), and low number of previous therapies (median = 1).Obinutuzumab/venetoclax represents an effective chemo-free relapse regimen with low toxicity that can be followed by cellular therapies, particularly CAR-T cells.
弥漫大B细胞淋巴瘤（DLBCL）早期（12个月内）复发或对利妥昔单抗（R）和CHOP诱导疗法初治难治的患者预后较差。这项前瞻性单臂研究在2016年至2021年间纳入了21例DLBCL（12个月内复发或初治难治）、可检测到Bcl-2蛋白表达和CD20阳性的患者。在第一周期的第1、8和15天以及随后每个21天周期的第1天，以1000毫克的剂量静脉注射奥比奴珠单抗。Venetoclax每天800毫克，连续口服。治疗最多重复三个周期。符合条件的患者计划接受细胞疗法或最多九个周期的维持治疗。主要终点是三个周期后的客观反应率（ORR）（Eudract Nr. 2016-001760-10 和 NCT02987400）。21例患者（中位年龄64岁）是既往接受过1（N = 11）至4种疗法的难治性或早期复发DLBCL患者。大多数患者接受了三个周期的obinutuzumab/venetoclax治疗（范围为1-8个周期）。该方案耐受性良好，细胞减少和感染可控。9.5%的患者出现了与治疗相关的严重不良反应。ORR为38.1%（8/21例患者），最佳反应为5例完全缓解（CR；23.8%）和3例部分缓解（PR；14.2%）。未达到主要终点（45% ORR）。84天的应答持续时间为83.3%，84天的无进展生存期为38.8%，168天的无进展生存期为25.9%，中位总生存期为169.1周。所有患者均因潜在疾病死亡。七名患者符合自体移植条件。总体而言，9名患者（42.8%）接受了11种细胞疗法（5种ASCT和6种CAR-T）。3名患者直接从奥比妥珠单抗/韦尼妥珠单抗转为CAR-T疗法。所有患者都成功收获了外周干细胞或T细胞。应答者的特征包括疾病复发（应答率，11人中有6人=54%）、R-IPI非常好或好（8人中有7人）以及既往治疗次数少（中位数=1）。
{"title":"Phase II single-arm study of a combination of obinutuzumab and venetoclax in early relapsed or refractory diffuse large B-cell lymphoma—final results of the AGMT NHL15B study","authors":"Ulrich Jaeger, Ingrid Simonitsch-Klupp, Patrick Klammer, A. Egle, S. Heibl, Peter Neumeister, E. Willenbacher, Florian Erlsbacher, J. Larcher-Senn, Philipp B. Staber, E. Porpaczy, C. Skrabs, M. Mayerhoefer, Marcus Hacker, T. Melchardt, Michael A. Fridrik, R. Greil","doi":"10.3389/frhem.2024.1331008","DOIUrl":"https://doi.org/10.3389/frhem.2024.1331008","url":null,"abstract":"Patients with diffuse large B-cell lymphoma (DLBCL) relapsing early (within 12 months) or primary refractory to induction therapy with rituximab (R) and CHOP have a poor prognosis. We therefore initiated a study with obinutuzumab and venetoclax.Twenty-one patients with DLBCL (relapsed within 12 months or primary refractory), detectable Bcl-2 protein expression, and CD20 positivity were included in this prospective single-arm study between 2016 and 2021. Obinutuzumab was administered i.v. at a dose of 1,000 mg on days 1, 8, and 15 in cycle 1 and on day 1 of each of the following 21-day cycles. Venetoclax was given at 800 mg daily p.o. continuously. Treatment was repeated for up to three cycles. Eligible patients were planned to either proceed to cellular therapies or receive up to nine cycles of maintenance. The primary endpoint was objective response rate (ORR) after three cycles (Eudract Nr. 2016-001760-10 and NCT02987400).Twenty-one patients (median age, 64 years) with refractory or early relapsed DLBCL after one (N = 11) to four previous lines of therapy were included. The majority of patients received three cycles of obinutuzumab/venetoclax (range, 1–8). The regimen was well tolerated with manageable cytopenias and infections. Severe adverse events related to treatment were observed in 9.5%. The ORR was 38.1% (8/21 patients) with a best response of five complete remissions (CRs; 23.8%) and three partial remissions (PRs; 14.2%). The primary endpoint (45% ORR) was not met. Response duration was 83.3% at 84 days, with a progression-free survival of 38.8% at 84 days and 25.9% at 168 days and a median overall survival of 169.1 weeks. All deaths were due to underlying disease. Seven patients became eligible for autologous transplant. Overall, nine patients (42.8%) received 11 cellular therapies (5 ASCT and 6 CAR-T). Three patients went directly from obinutuzumab/venetoclax to CAR-T therapy. All patients had successful peripheral stem cell or T-cell harvests. Characteristics of responders include relapsed disease (response rate, 6 of 11 = 54%), very good or good R-IPI (7 of 8), and low number of previous therapies (median = 1).Obinutuzumab/venetoclax represents an effective chemo-free relapse regimen with low toxicity that can be followed by cellular therapies, particularly CAR-T cells.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140371441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-26DOI: 10.3389/frhem.2024.1373554
Jessica Nunes, Dirk Loeffler
Hematopoietic stem cells (HSCs) can self-renew and differentiate for the entire life of an organism to produce new blood cells when needed. This process is regulated by asymmetric cell division (ACD), an evolutionarily conserved mechanism whereby cell fate determinants are unequally segregated into the daughter cells during division to instruct different cell fates. After many years of controversy, recent technical advances in microscopy, imaging, and bioinformatics make it now possible to visualize and quantify how factors segregate asymmetrically in dividing HSCs and lead to predictable changes in daughter cell fates many days later. While the molecular processes behind ACD in HSCs are still poorly understood, accumulating evidence suggests that lysosomes and other organelles, including mitochondria, autophagosomes, mitophagosomes, and recycling endosomes can segregate asymmetrically and act as cell fate determinants during divisions. Asymmetric segregation of lysosomes and mitochondria has been shown to predict mitochondrial activity, translation, and differentiation of HSC daughter cells and their offspring. This discovery and recent seminal findings show that lysosomes, once considered to be merely the trash bin of the cell, regulate many aspects of HSC biology and are crucial for the maintenance of quiescence and stem cell function. Here we provide a historical perspective and discuss the recent advances in our understanding of ACD and the role of lysosomes in HSC function. We discuss the limitations of past studies, talk about emerging concepts, and suggest critical next steps required to move the field forward.
{"title":"Asymmetric cell division of hematopoietic stem cells: recent advances, emerging concepts, and future perspectives","authors":"Jessica Nunes, Dirk Loeffler","doi":"10.3389/frhem.2024.1373554","DOIUrl":"https://doi.org/10.3389/frhem.2024.1373554","url":null,"abstract":"Hematopoietic stem cells (HSCs) can self-renew and differentiate for the entire life of an organism to produce new blood cells when needed. This process is regulated by asymmetric cell division (ACD), an evolutionarily conserved mechanism whereby cell fate determinants are unequally segregated into the daughter cells during division to instruct different cell fates. After many years of controversy, recent technical advances in microscopy, imaging, and bioinformatics make it now possible to visualize and quantify how factors segregate asymmetrically in dividing HSCs and lead to predictable changes in daughter cell fates many days later. While the molecular processes behind ACD in HSCs are still poorly understood, accumulating evidence suggests that lysosomes and other organelles, including mitochondria, autophagosomes, mitophagosomes, and recycling endosomes can segregate asymmetrically and act as cell fate determinants during divisions. Asymmetric segregation of lysosomes and mitochondria has been shown to predict mitochondrial activity, translation, and differentiation of HSC daughter cells and their offspring. This discovery and recent seminal findings show that lysosomes, once considered to be merely the trash bin of the cell, regulate many aspects of HSC biology and are crucial for the maintenance of quiescence and stem cell function. Here we provide a historical perspective and discuss the recent advances in our understanding of ACD and the role of lysosomes in HSC function. We discuss the limitations of past studies, talk about emerging concepts, and suggest critical next steps required to move the field forward.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140381226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-15DOI: 10.3389/frhem.2024.1339870
Guillermo Garcia-Manero, Uwe Platzbecker, Kian-Huat Lim, Grzegorz Nowakowski, Omar Abdel-Wahab, Hagop Kantarjian, Amit Verma, D. Starczynowski
The intracellular serine/threonine interleukin 1 receptor-associated kinase 4 (IRAK4) is necessary for most signaling by activated Toll-like receptors (TLRs). Activation of IRAK4 drives activation of nuclear factor kappa B (NF-κB) and so promotes cell survival, inflammation, and other aspects of the adaptive immune response. However, the IRAK4 pathway can be coopted by cancers and lead to the survival and proliferation of malignant cells. Inappropriate IRAK4 activity has been linked with the progression of myelodysplastic syndrome (MDS), other hematologic malignancies, and some solid tumors, and preclinical cancer models indicate that IRAK4 inhibition has anti-tumor effects. As such, inhibition of IRAK4 is an emerging and attractive target for tumor suppression. The growing interest in IRAK4 motivated the 1st Symposium on IRAK4 in Cancer held in October 2022 to bring together IRAK4 researchers and clinicians to discuss new insights into the biology of IRAK4 and development of IRAK4 inhibitors. Presentations and discussions at the meeting provided updates on the biology of IRAK4 and its links with mutations in the spliceosome, new outcomes from preclinical models that indicate synergy between inhibitors of IRAK4 and FLT3 and BTK inhibitors, and an update on the clinical development of the investigational IRAK4 inhibitor emavusertib, currently being assessed in ongoing phase 1/2 clinical studies in hematologic cancers and several solid tumors.
{"title":"Research and clinical updates on IRAK4 and its roles in inflammation and malignancy: themes and highlights from the 1st symposium on IRAK4 in cancer","authors":"Guillermo Garcia-Manero, Uwe Platzbecker, Kian-Huat Lim, Grzegorz Nowakowski, Omar Abdel-Wahab, Hagop Kantarjian, Amit Verma, D. Starczynowski","doi":"10.3389/frhem.2024.1339870","DOIUrl":"https://doi.org/10.3389/frhem.2024.1339870","url":null,"abstract":"The intracellular serine/threonine interleukin 1 receptor-associated kinase 4 (IRAK4) is necessary for most signaling by activated Toll-like receptors (TLRs). Activation of IRAK4 drives activation of nuclear factor kappa B (NF-κB) and so promotes cell survival, inflammation, and other aspects of the adaptive immune response. However, the IRAK4 pathway can be coopted by cancers and lead to the survival and proliferation of malignant cells. Inappropriate IRAK4 activity has been linked with the progression of myelodysplastic syndrome (MDS), other hematologic malignancies, and some solid tumors, and preclinical cancer models indicate that IRAK4 inhibition has anti-tumor effects. As such, inhibition of IRAK4 is an emerging and attractive target for tumor suppression. The growing interest in IRAK4 motivated the 1st Symposium on IRAK4 in Cancer held in October 2022 to bring together IRAK4 researchers and clinicians to discuss new insights into the biology of IRAK4 and development of IRAK4 inhibitors. Presentations and discussions at the meeting provided updates on the biology of IRAK4 and its links with mutations in the spliceosome, new outcomes from preclinical models that indicate synergy between inhibitors of IRAK4 and FLT3 and BTK inhibitors, and an update on the clinical development of the investigational IRAK4 inhibitor emavusertib, currently being assessed in ongoing phase 1/2 clinical studies in hematologic cancers and several solid tumors.","PeriodicalId":101407,"journal":{"name":"Frontiers in hematology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139775587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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