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High-risk cytogenetic abnormalities in multiple myeloma: PETHEMA-GEM experience 多发性骨髓瘤的高危细胞遗传学异常:PETHEMA-GEM经验
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-12-10 DOI: 10.1002/hem3.70031
Veronica González-Calle, Paula Rodriguez-Otero, Maria J. Calasanz, Manuela Guijarro, Joaquin Martínez-López, Laura Rosiñol, Miguel T. Hernández, Ana I. Teruel, Mercedes Gironella, Albert Oriol, Javier de la Rubia, Ana P. González-Rodríguez, Joan Bargay, Felipe de Arriba, Luis Palomera, Marta-Sonia González-Pérez, Anna Sureda, Enrique Ocio, Juan J. Lahuerta, Joan Bladé, Jesus F. San Miguel, Maria V. Mateos, Norma C. Gutiérrez
{"title":"High-risk cytogenetic abnormalities in multiple myeloma: PETHEMA-GEM experience","authors":"Veronica González-Calle,&nbsp;Paula Rodriguez-Otero,&nbsp;Maria J. Calasanz,&nbsp;Manuela Guijarro,&nbsp;Joaquin Martínez-López,&nbsp;Laura Rosiñol,&nbsp;Miguel T. Hernández,&nbsp;Ana I. Teruel,&nbsp;Mercedes Gironella,&nbsp;Albert Oriol,&nbsp;Javier de la Rubia,&nbsp;Ana P. González-Rodríguez,&nbsp;Joan Bargay,&nbsp;Felipe de Arriba,&nbsp;Luis Palomera,&nbsp;Marta-Sonia González-Pérez,&nbsp;Anna Sureda,&nbsp;Enrique Ocio,&nbsp;Juan J. Lahuerta,&nbsp;Joan Bladé,&nbsp;Jesus F. San Miguel,&nbsp;Maria V. Mateos,&nbsp;Norma C. Gutiérrez","doi":"10.1002/hem3.70031","DOIUrl":"10.1002/hem3.70031","url":null,"abstract":"<p>This study examines the impact of cytogenetic abnormalities and their co-segregation on the prognosis of newly diagnosed multiple myeloma patients. The analysis included 1304 patients from four different GEM-PETHEMA clinical trials. Genetic alterations, such as t(4;14), t(14;16), del(17p), +1q, and del(1p), were investigated using FISH on CD38 purified plasma cells. The frequency of genetic alterations detected were as follows: del(17p) in 8%, t(4;14) in 12%, t(14;16) in 3%, +1q in 43%, and del(1p) in 8%. The median follow-up was 61 months, and the median progression-free survival (PFS) and overall survival (OS) were 44 months and not reached, respectively. Consistent with previous reports, the presence of t(4;14) was associated with shorter PFS and OS. In our series, the presence of t(14;16) did not impact survival, maybe due to limitations in sample size. Del(17p) was linked to poor prognosis using a cut-off level of ≥20% positive cells, without any impact of higher cut-off in prognosis, except for patients with clonal fraction ≥80% who had a dismal outcome. Cosegregation of cytogenetic abnormalities patients worsened the prognosis in t(4;14) patients but not in patients with del(17p), which retained its adverse prognosis even as a solitary abnormality. Gain(1q) was associated with significantly shorter PFS and OS, while del(1p) affected PFS but not OS. Nevertheless, when co-segregation was eliminated, the detrimental effect of +1q or del(1p) was no longer observed. In conclusion, this study confirms the prognostic significance of high-risk cytogenetic abnormalities in MM and highlights the importance of considering co-occurrence for accurate prognosis assessment.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11632121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Models for the marrow: A comprehensive review of AI-based cell classification methods and malignancy detection in bone marrow aspirate smears 骨髓模型:基于人工智能的细胞分类方法和骨髓抽吸涂片恶性肿瘤检测的综合综述
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-12-03 DOI: 10.1002/hem3.70048
Tabita Ghete, Farina Kock, Martina Pontones, David Pfrang, Max Westphal, Henning Höfener, Markus Metzler
{"title":"Models for the marrow: A comprehensive review of AI-based cell classification methods and malignancy detection in bone marrow aspirate smears","authors":"Tabita Ghete,&nbsp;Farina Kock,&nbsp;Martina Pontones,&nbsp;David Pfrang,&nbsp;Max Westphal,&nbsp;Henning Höfener,&nbsp;Markus Metzler","doi":"10.1002/hem3.70048","DOIUrl":"https://doi.org/10.1002/hem3.70048","url":null,"abstract":"<p>Given the high prevalence of artificial intelligence (AI) research in medicine, the development of deep learning (DL) algorithms based on image recognition, such as the analysis of bone marrow aspirate (BMA) smears, is rapidly increasing in the field of hematology and oncology. The models are trained to identify the optimal regions of the BMA smear for differential cell count and subsequently detect and classify a number of cell types, which can ultimately be utilized for diagnostic purposes. Moreover, AI is capable of identifying genetic mutations phenotypically. This pipeline has the potential to offer an accurate and rapid preliminary analysis of the bone marrow in the clinical routine. However, the intrinsic complexity of hematological diseases presents several challenges for the automatic morphological assessment. To ensure general applicability across multiple medical centers and to deliver high accuracy on prospective clinical data, AI models would require highly heterogeneous training datasets. This review presents a systematic analysis of models for cell classification and detection of hematological malignancies published in the last 5 years (2019–2024). It provides insight into the challenges and opportunities of these DL-assisted tasks.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70048","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142762548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cerebral hemodynamics and oxygen metabolism in patients with milder and severe forms of sickle cell disease and thalassemia 轻度和重度镰状细胞病和地中海贫血患者的脑血流动力学和氧代谢
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-12-02 DOI: 10.1002/hem3.70022
Liza Afzali-Hashemi, Koen P. A. Baas, Anouk Schrantee, Erfan Nur, Chau Vu, Soyoung Choi, Silvie Suriany, John C. Wood, Aart J. Nederveen, Bart J. Biemond
{"title":"Cerebral hemodynamics and oxygen metabolism in patients with milder and severe forms of sickle cell disease and thalassemia","authors":"Liza Afzali-Hashemi,&nbsp;Koen P. A. Baas,&nbsp;Anouk Schrantee,&nbsp;Erfan Nur,&nbsp;Chau Vu,&nbsp;Soyoung Choi,&nbsp;Silvie Suriany,&nbsp;John C. Wood,&nbsp;Aart J. Nederveen,&nbsp;Bart J. Biemond","doi":"10.1002/hem3.70022","DOIUrl":"https://doi.org/10.1002/hem3.70022","url":null,"abstract":"<p>Silent cerebral infarcts (SCIs) are present in patients with sickle cell disease (SCD) and thalassemia, but the pathophysiology of SCIs is not fully understood. Previous studies mainly focused on cerebral hemodynamics and oxygen metabolism in patients with severe SCD (HbSS/HbSβ°) but not in milder forms of SCD (HbSC/HbSβ<sup>+</sup>) and thalassemia despite the high prevalence of SCIs in these patients. In this work, we studied the cerebral hemodynamics and oxygen metabolism, and SCI lesion load in 75 severe and 26 mild adult SCD patients, 18 thalassemia patients (as anemic comparison group), and 30 healthy controls before and after a vasodilatory challenge with acetazolamide. Cerebral blood flow was significantly higher in patients with severe SCD and thalassemia compared to patients with mild SCD and controls (<i>p</i> &lt; 0.05). Conversely, oxygen extraction fraction and cerebral metabolic rate of oxygen (CMRO<sub>2</sub>) were significantly lower in patients with severe SCD and thalassemia compared to other groups (<i>p</i> &lt; 0.01). In contrast, no difference in SCI volumes was found between mild and severe SCD and thalassemia patients. After acetazolamide administration, oxygen delivery increased less in severe SCD and thalassemia patients compared to other groups (<i>p</i> &lt; 0.01) and CMRO<sub>2</sub> decreased only in severe SCD patients (<i>p</i> &lt; 0.01). Given the reduced CMRO<sub>2</sub> values in severe SCD and thalassemia patients, we conclude that reduced cerebral oxygen consumption in these patient groups is mostly related to anemia. Our data suggest that the pathophysiology of SCIs in patients with milder forms of SCD might be more related to prior episodes of anemia or other sickle cell-related factors.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142762105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Interferon gamma-mediated prevention of tumor progression in a mouse model of multiple myeloma 干扰素γ介导的多发性骨髓瘤小鼠模型中肿瘤进展的预防
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-12-02 DOI: 10.1002/hem3.70047
Zoltán Kellermayer, Sabrin Tahri, Madelon M. E. de Jong, Natalie Papazian, Cathelijne Fokkema, Elodie C. G. Stoetman, Remco Hoogenboezem, Gregory van Beek, Mathijs A. Sanders, Louis Boon, Chelsea Den Hollander, Annemiek Broijl, Pieter Sonneveld, Tom Cupedo
{"title":"Interferon gamma-mediated prevention of tumor progression in a mouse model of multiple myeloma","authors":"Zoltán Kellermayer,&nbsp;Sabrin Tahri,&nbsp;Madelon M. E. de Jong,&nbsp;Natalie Papazian,&nbsp;Cathelijne Fokkema,&nbsp;Elodie C. G. Stoetman,&nbsp;Remco Hoogenboezem,&nbsp;Gregory van Beek,&nbsp;Mathijs A. Sanders,&nbsp;Louis Boon,&nbsp;Chelsea Den Hollander,&nbsp;Annemiek Broijl,&nbsp;Pieter Sonneveld,&nbsp;Tom Cupedo","doi":"10.1002/hem3.70047","DOIUrl":"https://doi.org/10.1002/hem3.70047","url":null,"abstract":"<p>Malignant plasma cells in multiple myeloma patients reside in the bone marrow and continuously interact with local immune cells. Progression and therapy response are influenced by this immune environment, highlighting the need for a detailed understanding of endogenous immune responses to malignant plasma cells. Here we used the 5TGM1 murine transfer model of multiple myeloma to dissect early immune responses to myeloma cells. We modeled stable and progressive disease by transferring 5TGM1 murine myeloma cells into C57Bl/6 mice and KaLwRij mice, respectively. We used flow cytometry and single-cell and bulk transcriptomic analyses to characterize differential immune responses in stable and progressive disease. Transfer of 5TGM1 cells in C57Bl/6 mice led to stable disease with low tumor burden in a subset of animals. Stable disease was associated with sustained activation and expansion of NK cells, ILC1, and CD8<sup>+</sup> T cells, a response that was lost upon disease progression. Single-cell RNA-sequencing of immune cells and bulk RNA sequencing of immune and mesenchymal stromal cells implicated the activation of interferon responses as a central immune pathway during stable disease. Experimentally, neutralization of IFNγ significantly increased myeloma development and progression in C57Bl/6 mice, testifying to the importance of this pathway in early disease control. In conclusion, we provide a framework for studying immune responses to multiple myeloma progression in immunocompetent and genetically modifiable mice and highlight the importance of bone marrow immunity in tumor control.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142762104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma 双特异性STAT3/5降解物有效阻断急性髓系白血病和自然杀伤/T细胞淋巴瘤
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-11-28 DOI: 10.1002/hem3.70001
Daniel Pölöske, Helena Sorger, Anna Schönbichler, Elvin D. de Araujo, Heidi A. Neubauer, Anna Orlova, Sanna H. Timonen, Diaaeldin I. Abdallah, Aleksandr Ianevski, Heikki Kuusanmäki, Marta Surbek, Elisabeth Heyes, Thomas Eder, Christina Wagner, Tobias Suske, Martin L. Metzelder, Michael Bergmann, Maik Dahlhoff, Florian Grebien, Roman Fleck, Christine Pirker, Walter Berger, Emir Hadzijusufovic, Wolfgang R. Sperr, Lukas Kenner, Peter Valent, Tero Aittokallio, Marco Herling, Satu Mustjoki, Patrick T. Gunning, Richard Moriggl
{"title":"Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma","authors":"Daniel Pölöske,&nbsp;Helena Sorger,&nbsp;Anna Schönbichler,&nbsp;Elvin D. de Araujo,&nbsp;Heidi A. Neubauer,&nbsp;Anna Orlova,&nbsp;Sanna H. Timonen,&nbsp;Diaaeldin I. Abdallah,&nbsp;Aleksandr Ianevski,&nbsp;Heikki Kuusanmäki,&nbsp;Marta Surbek,&nbsp;Elisabeth Heyes,&nbsp;Thomas Eder,&nbsp;Christina Wagner,&nbsp;Tobias Suske,&nbsp;Martin L. Metzelder,&nbsp;Michael Bergmann,&nbsp;Maik Dahlhoff,&nbsp;Florian Grebien,&nbsp;Roman Fleck,&nbsp;Christine Pirker,&nbsp;Walter Berger,&nbsp;Emir Hadzijusufovic,&nbsp;Wolfgang R. Sperr,&nbsp;Lukas Kenner,&nbsp;Peter Valent,&nbsp;Tero Aittokallio,&nbsp;Marco Herling,&nbsp;Satu Mustjoki,&nbsp;Patrick T. Gunning,&nbsp;Richard Moriggl","doi":"10.1002/hem3.70001","DOIUrl":"https://doi.org/10.1002/hem3.70001","url":null,"abstract":"<p>The transcription factors STAT3, STAT5A, and STAT5B steer hematopoiesis and immunity, but their enhanced expression and activation promote acute myeloid leukemia (AML) or natural killer/T cell lymphoma (NKCL). Current therapeutic strategies focus on blocking upstream tyrosine kinases to inhibit STAT3/5, but these kinase blockers are not selective against STAT3/5 activation and frequent resistance causes relapse, emphasizing the need for targeted drugs. We evaluated the efficacy of JPX-0700 and JPX-0750 as dual STAT3/5 binding inhibitors promoting protein degradation. JPX-0700/−0750 decreased the mRNA and protein levels of STAT3/5 targets involved in cancer survival, metabolism, and cell cycle progression, exhibiting nanomolar to low micromolar efficacy. They induced cell death and growth arrest in both AML/NKCL cell lines and primary AML patient blasts. We found that both AML/NKCL cells hijack STAT3/5 signaling through either upstream activating mutations in kinases, activating mutations in STAT3, mutational loss of negative STAT regulators, or genetic gains in anti-apoptotic, pro-proliferative, or epigenetic-modifying STAT3/5 targets. This emphasizes a vicious cycle for proliferation and survival through STAT3/5. Both JPX-0700/−0750 treatment reduced leukemic cell growth in human AML or NKCL xenograft mouse models significantly, being well tolerated by mice. Synergistic cell death was induced upon combinatorial use with approved chemotherapeutics in AML/NKCL cells.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Sevuparin strongly reduces hepcidin expression in cells, mice, and healthy human volunteers Sevuparin在细胞、小鼠和健康人类志愿者中显著降低hepcidin的表达
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-11-28 DOI: 10.1002/hem3.70035
Michela Asperti, Andrea Denardo, Magdalena Gryzik, Kristina E. M. Persson, Göran Westerberg, John Öhd, Maura Poli
{"title":"Sevuparin strongly reduces hepcidin expression in cells, mice, and healthy human volunteers","authors":"Michela Asperti,&nbsp;Andrea Denardo,&nbsp;Magdalena Gryzik,&nbsp;Kristina E. M. Persson,&nbsp;Göran Westerberg,&nbsp;John Öhd,&nbsp;Maura Poli","doi":"10.1002/hem3.70035","DOIUrl":"https://doi.org/10.1002/hem3.70035","url":null,"abstract":"<p>Hepcidin is an essential regulator of systemic iron availability mediating both iron uptake from the diet and its release from body stores. Abnormally high hepcidin levels resulting from inflammation in chronic diseases cause iron restriction with the onset of anemia. Restoring physiological levels of hepcidin could contribute to ameliorating anemia in these patients. Heparin derivatives are known to suppress hepcidin expression acting on the BMP/SMAD pathway. The novel heparin derivative sevuparin, modified to markedly reduce its anticoagulant activity, is proposed as a promising hepcidin antagonizing strategy. Sevuparin was tested for its anti-hepcidin properties <i>in vitro</i> in HepG2 cells, <i>in vivo</i> in mice, and in healthy volunteers. Sevuparin strongly suppressed basal, BMP6-, and IL6-dependent hepcidin expression in HepG2 cells in a dose- and time-dependent manner, modulating the essential BMP6/SMAD cascade. These effects were evident in C57BL/6J mice after intravenous injection of a single dose of sevuparin (20 mg/kg) with a 70% reduction of hepcidin mRNA. Remarkably, similar effects were observed in healthy volunteers following single subcutaneous doses at 3, 6, and 9 mg/kg with 40%–50% suppression at 3 and 6 mg/kg and 72% at 9 mg/kg. Moreover, sevuparin was able to reduce hepcidin upregulation in a mouse model of acute inflammation induced by LPS, also showing an amelioration of the inflammatory markers. Combined with its excellent safety profile, these data suggest a role for sevuparin in treating high-hepcidin disorders.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142748883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Prospective phase II study of allogeneic hematopoietic stem cell transplantation with targeted busulfan, fludarabine, and etoposide conditioning in pediatric acute lymphoblastic leukemia 靶向布苏凡、氟达拉滨和依托泊苷治疗小儿急性淋巴细胞白血病的异基因造血干细胞移植前瞻性II期研究
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-11-28 DOI: 10.1002/hem3.70051
Kyung Taek Hong, Hyun Jin Park, Bo Kyung Kim, Jung Yoon Choi, Sang Hoon Song, SeungHwan Lee, Kyung-Sang Yu, In-Jin Jang, Hyoung Jin Kang
{"title":"Prospective phase II study of allogeneic hematopoietic stem cell transplantation with targeted busulfan, fludarabine, and etoposide conditioning in pediatric acute lymphoblastic leukemia","authors":"Kyung Taek Hong,&nbsp;Hyun Jin Park,&nbsp;Bo Kyung Kim,&nbsp;Jung Yoon Choi,&nbsp;Sang Hoon Song,&nbsp;SeungHwan Lee,&nbsp;Kyung-Sang Yu,&nbsp;In-Jin Jang,&nbsp;Hyoung Jin Kang","doi":"10.1002/hem3.70051","DOIUrl":"https://doi.org/10.1002/hem3.70051","url":null,"abstract":"&lt;p&gt;Allogeneic hematopoietic stem cell transplantation (HSCT) is an important treatment option for high-risk hematologic malignancies that harnesses the graft-versus-leukemia effect and employs a conditioning regimen to eradicate residual leukemic cells.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; High-risk acute lymphoblastic leukemia (ALL), including relapsed or refractory cases, remains a major indication for allogeneic HSCT in the pediatric population.&lt;span&gt;&lt;sup&gt;1-5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Myeloablative conditioning regimens using total body irradiation (TBI) have demonstrated better outcomes than those of chemoconditioning in various pivotal prospective trials.&lt;span&gt;&lt;sup&gt;6-8&lt;/sup&gt;&lt;/span&gt; Most notably, the recently published FORUM trial demonstrated a superior overall survival (OS) rate and lower cumulative incidence (CI) of relapse and treatment-related mortality with 12 Gy TBI plus etoposide compared with those of chemoconditioning with fludarabine, thiotepa, and either busulfan or treosulfan in high-risk pediatric patients with ALL above 4 years of age.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; However, there remains an unmet need for chemoconditioning regimens for pediatric patients below 4 years of age. Additionally, concerns persist regarding the long-term complications of TBI with myeloablative dosing, particularly in the pediatric population, such as secondary malignancy and endocrinologic problems.&lt;span&gt;&lt;sup&gt;9-11&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Busulfan is a key chemotherapeutic drug for chemoconditioning; however, it exhibits variable pharmacokinetic profiles.&lt;span&gt;&lt;sup&gt;12&lt;/sup&gt;&lt;/span&gt; To optimize busulfan dosing and reduce unexpected toxicity or underdosing, our institution has implemented intensive pharmacokinetic monitoring of busulfan for chemoconditioning yielding favorable outcomes in HSCT for pediatric leukemia.&lt;span&gt;&lt;sup&gt;13, 14&lt;/sup&gt;&lt;/span&gt; In particular, our previous report on a chemoconditioning regimen utilizing targeted busulfan, fludarabine, and etoposide in high-risk pediatric patients with ALL showed promising outcomes.&lt;span&gt;&lt;sup&gt;15&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Herein, we present the findings of a prospective phase II trial (ClinicalTrials.gov: NCT02047578) evaluating the efficacy of targeted busulfan (the target busulfan area under the curve [AUC] between 74 and 76 mg × h/L), fludarabine (40 mg/m², once daily, 5 days), and etoposide (20 mg/kg, once daily, 3 days) conditioning regimens for allogeneic HSCT using matched sibling or unrelated donors in pediatric patients with high-risk ALL. The primary outcome of this study was the 1-year event-free survival (EFS) rate after HSCT, which was anticipated to exceed 80%. We estimated the sample size as a 20% increase in the 1-year EFS rate (to 80%) compared to historical data, with a type I error of 5% and a power of 80%. This study began in February 2014, and the final patient was enrolled in August 2021. The Institutional Review Board of our institution approved the study protocol (H-1210-066-434), and written informed consent was ob","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70051","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142748884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Kinetics of lymphocytosis in naïve chronic lymphocytic leukemia patients treated with covalent Bruton's tyrosine kinase inhibitors: An Italian multicenter real-life experience 用共价布鲁顿酪氨酸激酶抑制剂治疗naïve慢性淋巴细胞白血病患者的淋巴细胞增多动力学:意大利多中心现实生活经验
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-11-28 DOI: 10.1002/hem3.144
Idanna Innocenti, Antonio Mosca, Annamaria Tomasso, Andrea Galitzia, Lydia Scarfò, Francesca Morelli, Eugenio Galli, Francesca Martini, Eugenio Sangiorgi, Roberta Laureana, Giulia Benintende, Veronica Mattiello, Sabrina Chiriu, Maria I. Del Principe, Giulia Zamprogna, Massimo Gentile, Enrica A. Martino, Emilia Cappello, Maria C. Montalbano, Giuliana Farina, Vanessa Innao, Luca Stirparo, Caterina Patti, Paolo Sportoletti, Alberto Fresa, Gioacchino Catania, Marta Coscia, Silvia Bellesi, Alessandra Tedeschi, Alessandro Sanna, Andrea Visentin, Francesco Autore, Raffaella Pasquale, Livio Trentin, Marzia Varettoni, Paolo Ghia, Roberta Murru, Luca Laurenti
{"title":"Kinetics of lymphocytosis in naïve chronic lymphocytic leukemia patients treated with covalent Bruton's tyrosine kinase inhibitors: An Italian multicenter real-life experience","authors":"Idanna Innocenti,&nbsp;Antonio Mosca,&nbsp;Annamaria Tomasso,&nbsp;Andrea Galitzia,&nbsp;Lydia Scarfò,&nbsp;Francesca Morelli,&nbsp;Eugenio Galli,&nbsp;Francesca Martini,&nbsp;Eugenio Sangiorgi,&nbsp;Roberta Laureana,&nbsp;Giulia Benintende,&nbsp;Veronica Mattiello,&nbsp;Sabrina Chiriu,&nbsp;Maria I. Del Principe,&nbsp;Giulia Zamprogna,&nbsp;Massimo Gentile,&nbsp;Enrica A. Martino,&nbsp;Emilia Cappello,&nbsp;Maria C. Montalbano,&nbsp;Giuliana Farina,&nbsp;Vanessa Innao,&nbsp;Luca Stirparo,&nbsp;Caterina Patti,&nbsp;Paolo Sportoletti,&nbsp;Alberto Fresa,&nbsp;Gioacchino Catania,&nbsp;Marta Coscia,&nbsp;Silvia Bellesi,&nbsp;Alessandra Tedeschi,&nbsp;Alessandro Sanna,&nbsp;Andrea Visentin,&nbsp;Francesco Autore,&nbsp;Raffaella Pasquale,&nbsp;Livio Trentin,&nbsp;Marzia Varettoni,&nbsp;Paolo Ghia,&nbsp;Roberta Murru,&nbsp;Luca Laurenti","doi":"10.1002/hem3.144","DOIUrl":"https://doi.org/10.1002/hem3.144","url":null,"abstract":"&lt;p&gt;Chronic lymphocytic leukemia (CLL) therapy has recently undergone a revolution with the introduction of a new class of drugs: covalent Bruton's tyrosine kinase inhibitors (cBTKi), paving the way for a chemotherapy-free approach.&lt;span&gt;&lt;sup&gt;1-4&lt;/sup&gt;&lt;/span&gt; Presently, cBTKi can be utilized in the first line of CLL management, thanks to the results of phase III clinical trials such as RESONATE-2 and ELEVATE-TN, which demonstrated the superiority of Ibrutinib over chemotherapy with chlorambucil&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; and acalabrutinib over chemoimmunotherapy with chlorambucil + obinutuzumab,&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; in terms of progression-free survival (PFS) in both cases. Ibrutinib exhibited better PFS, overall survival (OS), and overall response rate than the monoclonal anti-CD20 antibody ofatumumab in previously treated patients with CLL.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Additionally, the ASCEND study, another phase III randomized clinical trial, demonstrated that acalabrutinib significantly improved PFS compared to a physician's choice of Idelalisib + rituximab or bendamustine + rituximab, in patients with relapsed/refractory CLL.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;BTK plays a pivotal role in B-cell receptor (BCR) signal transduction,&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; stimulating important pathways such as NFKB&lt;span&gt;&lt;sup&gt;10, 11&lt;/sup&gt;&lt;/span&gt; and CXCR4.&lt;span&gt;&lt;sup&gt;12&lt;/sup&gt;&lt;/span&gt; Consequently, BTK is involved in B-cell survival, proliferation, and adhesion, while its activation promotes B-cell proliferation.&lt;span&gt;&lt;sup&gt;13&lt;/sup&gt;&lt;/span&gt; Paradoxically, ibrutinib has shown to increase absolute lymphocyte count (ALC) in the initial phase of treatment, regardless of previous lines of therapy. Ibrutinib-induced lymphocytosis may be explained by the redistribution of lymphocytes from neoplastic nodal compartments into the peripheral blood.&lt;span&gt;&lt;sup&gt;14&lt;/sup&gt;&lt;/span&gt; Furthermore, it was noted that Ibrutinib-induced lymphocytosis is transient in most patients, resolving within 8 months, but may rarely persist for over 12 months without impacting survival.&lt;span&gt;&lt;sup&gt;14&lt;/sup&gt;&lt;/span&gt; This evidence led to the introduction of a new criterion in the assessment of CLL therapy response: partial response with lymphocytosis (PR-L).&lt;span&gt;&lt;sup&gt;15&lt;/sup&gt;&lt;/span&gt; Subsequently, the kinetics of lymphocytosis in CLL treated with ibrutinib monotherapy showed that lymphocytosis occurred in the majority of patients treated in first line was higher in immunoglobulin variable heavy chain (IGHV) mutated settings and resolved in 95% of patients after a median of 18.4 months.&lt;span&gt;&lt;sup&gt;16&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Little is known about frequency and duration of lymphocytosis in patients treated with the second-generation cBTKi acalabrutinib. Therefore, the aim of this study is to outline the kinetics of lymphocytosis in CLL patients treated with acalabrutinib compared to ibrutinib.&lt;/p&gt;&lt;p&gt;We conducted a multicenter retrospective real-life study involving 17 Italian centers. The study was carried out according ","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.144","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inflammatory pathways and anti-inflammatory therapies in sickle cell disease 镰状细胞病的炎症途径和抗炎治疗
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-11-28 DOI: 10.1002/hem3.70032
Karina Tozatto-Maio, Felipe A. Rós, Ricardo Weinlich, Vanderson Rocha
{"title":"Inflammatory pathways and anti-inflammatory therapies in sickle cell disease","authors":"Karina Tozatto-Maio,&nbsp;Felipe A. Rós,&nbsp;Ricardo Weinlich,&nbsp;Vanderson Rocha","doi":"10.1002/hem3.70032","DOIUrl":"https://doi.org/10.1002/hem3.70032","url":null,"abstract":"<p>Sickle cell disease (SCD) is a monogenic disease, resulting from a single-point mutation, that presents a complex pathophysiology and high clinical heterogeneity. Inflammation stands as a prominent characteristic of SCD. Over the past few decades, the role of different cells and molecules in the regulation of the inflammatory process has been elucidated. In conjunction with the polymerization of hemoglobin S (HbS), intravascular hemolysis, which releases free heme, HbS, and hemoglobin-related damage-associated molecular patterns, initiates multiple inflammatory pathways that are not yet fully comprehended. These complex phenomena lead to a vicious cycle that perpetuates vaso-occlusion, hemolysis, and inflammation. To date, few inflammatory biomarkers can predict disease complications; conversely, there is a plethora of therapies that reduce inflammation in SCD, although clinical outcomes vary widely. Importantly, whether the clinical heterogeneity and complications are related to the degree of inflammation is not known. This review aims to further our understanding of the roles of main immune cells, and other inflammatory factors, as potential prognostic biomarkers for predicting clinical outcomes or identifying novel treatments for SCD.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Bortezomib before and after high-dose therapy in transplant-eligible patients with newly diagnosed multiple myeloma: Long-term overall survival after more than 10 years of follow-up from the phase III HOVON-65/GMMG-HD4 trial 对符合移植条件的新诊断多发性骨髓瘤患者进行大剂量治疗前后的硼替佐米治疗:HOVON-65/GMMG-HD4 III期试验10多年随访后的长期总生存率
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-11-20 DOI: 10.1002/hem3.70052
Elias K. Mai, Axel Nogai, Henk M. Lokhorst, Bronno van der Holt, Sonja Zweegman, Katja C. Weisel, Sandra Croockewit, Anna Jauch, Jens Hillengass, Marian Stevens-Kroef, Marc S. Raab, Annemiek Broijl, Gerard M. J. Bos, Peter Brossart, Paula Ypma, Christine Hanoun, Uta Bertsch, Thomas Hielscher, Hans J. Salwender, Christoph Scheid, Hartmut Goldschmidt, Pieter Sonneveld
{"title":"Bortezomib before and after high-dose therapy in transplant-eligible patients with newly diagnosed multiple myeloma: Long-term overall survival after more than 10 years of follow-up from the phase III HOVON-65/GMMG-HD4 trial","authors":"Elias K. Mai,&nbsp;Axel Nogai,&nbsp;Henk M. Lokhorst,&nbsp;Bronno van der Holt,&nbsp;Sonja Zweegman,&nbsp;Katja C. Weisel,&nbsp;Sandra Croockewit,&nbsp;Anna Jauch,&nbsp;Jens Hillengass,&nbsp;Marian Stevens-Kroef,&nbsp;Marc S. Raab,&nbsp;Annemiek Broijl,&nbsp;Gerard M. J. Bos,&nbsp;Peter Brossart,&nbsp;Paula Ypma,&nbsp;Christine Hanoun,&nbsp;Uta Bertsch,&nbsp;Thomas Hielscher,&nbsp;Hans J. Salwender,&nbsp;Christoph Scheid,&nbsp;Hartmut Goldschmidt,&nbsp;Pieter Sonneveld","doi":"10.1002/hem3.70052","DOIUrl":"https://doi.org/10.1002/hem3.70052","url":null,"abstract":"&lt;p&gt;Life expectancy in patients with multiple myeloma (MM) has increased due to the availability of effective drugs such as proteasome inhibitors (PIs),&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; immunomodulatory drugs (IMiDs),&lt;span&gt;&lt;sup&gt;3-5&lt;/sup&gt;&lt;/span&gt; and more recently, monoclonal antibodies.&lt;span&gt;&lt;sup&gt;6-8&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;While the progression-free survival (PFS) rates and the depth of response increase with the use of modern multi-drug combinations, it is not clear whether these effects will translate into an improved long-term overall survival (OS). To draw such conclusions, long-term follow-up analyses from trials are needed as comparators for future trials. Here, we report on the long-term overall survival of the HOVON-65/GMMG-HD4 trial including the OS after more than 10 years, and the role of established prognostic factors.&lt;/p&gt;&lt;p&gt;The investigator-sponsored, open-label, randomized HOVON-65/GMMG-HD4 phase III trial was conducted by the Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON) and the German-speaking Myeloma Multicenter Group (GMMG) in 75 centers in the Netherlands, Belgium, and Germany from May 2005 to May 2008 and included 827 eligible patients. The trial was registered at www.trialregister.nl (until June 2022) and https://trialsearch.who.int/ as NTR213, at www.isrctn.com as ISRCTN64455289 and at www.clinicaltrialsregister.eu as EudraCT2004-000944-26. The ethics committees of the Erasmus University Medical Center, the University of Heidelberg, and all participating sites approved this trial. All patients gave written informed consent. The study was conducted in accordance with the European Clinical Trial Directive (2005) and the Declaration of Helsinki (1996).&lt;/p&gt;&lt;p&gt;Initial results of the trial have been published and include a detailed study protocol, inclusion and exclusion criteria, randomization procedures and toxicities,&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; and results after a median follow-up of 96 months.&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; After that, only OS data were collected on which we here report the final long-term survival data.&lt;/p&gt;&lt;p&gt;The aim of the trial was to investigate the use of bortezomib (BTZ) in induction and maintenance compared to treatment with classical cytotoxic agents as induction and thalidomide maintenance in transplant-eligible patients regarding the primary endpoint PFS, while OS was a secondary endpoint. Patients were randomized 1:1 to receive either vincristine, adriamycin, and dexamethasone (VAD) as induction therapy, followed by high-dose chemotherapy with melphalan and autologous stem-cell transplantation (ASCT), followed by maintenance therapy with thalidomide (VAD arm). In the PAD arm, BTZ, adriamycin, and dexamethasone were used in induction, followed by ASCT and maintenance with BTZ. Patients were stratified by center and International Staging System (ISS, I vs. II vs. III). A single ASCT was planned in the HOVON group, whereas in the GMMG, a tandem ASCT was planned. Patients with an HLA-identical sib","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70052","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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