HemaSphere最新文献

{"title":"30-Minute infusion of isatuximab in patients with newly diagnosed multiple myeloma: Results of a Phase 1b study analysis","authors":"Enrique M. Ocio, Aurore Perrot, Philippe Moreau, Maria-Victoria Mateos, Sara Bringhen, Joaquín Martínez-López, Lionel Karlin, Song-Yau Wang, Corina Oprea, Yi Li, Ercem Kodas, Jesus San-Miguel","doi":"10.1002/hem3.70041","DOIUrl":"10.1002/hem3.70041","url":null,"abstract":"<p>The addition of an anti-CD38 antibody to standard treatment regimens, in combination with an immunomodulatory drug or a proteasome inhibitor and dexamethasone, provides benefit to multiple myeloma (MM) patients in the relapsed/refractory setting (RRMM), as well as at an earlier disease stage in quadruplet combinations for transplant-eligible or non-eligible patients with newly diagnosed MM (NDMM).<span><sup>1-3</sup></span> Isatuximab (Isa) is approved in various countries in combination with pomalidomide-dexamethasone or carfilzomib-dexamethasone for the treatment of RRMM patients.<span><sup>4-6</sup></span></p><p>Study findings in transplant-eligible NDMM patients demonstrated significant efficacy of Isa in quadruplet combinations with bortezomib-lenalidomide-dexamethasone (VRd) for induction therapy in the Phase 3 GMMG-HD7 trial (minimal residual disease [MRD] negativity: 50% with Isa-VRd vs 36% with VRd; <i>p</i> = 0.00017), and with carfilzomib-lenalidomide-dexamethasone (KRd) for induction/consolidation treatment in the Phase 3 IsKia/EMN24 trial (MRD negativity after consolidation: 77% with Isa-KRd vs 67% with KRd; <i>p</i> = 0.049), without new safety signals.<span><sup>7, 8</sup></span></p><p>In transplant-ineligible NDMM patients, significant PFS benefit (hazard ratio [HR], 0.60; 98.5% confidence interval [CI], 0.41–0.88; <i>p</i> < 0.001) and deep, sustained responses were reported with Isa in combination with VRd followed by Isa-Rd versus VRd followed by Rd, in a prespecified interim analysis of the Phase 3 IMROZ trial, with a manageable safety profile.<span><sup>9</sup></span> In the Phase 3 BENEFIT trial, the addition of weekly bortezomib to Isa-Rd (reduced-dose VRd) induced a significant improvement in MRD negativity at 18 months versus Isa-Rd (53% vs. 26%, <i>p</i> < 0.0001).<span><sup>10</sup></span></p><p>The evaluation of Isa with either bortezomib-cyclophosphamide-dexamethasone (VCd) or VRd has shown safety and efficacy of these quadruplet regimens in the Phase 1b trial TCD13983 (NCT02513186) in transplant-ineligible NDMM patients (all cohorts) or patients with no immediate intent for autologous stem cell transplantation included in Isa-VRd/Part-B, as previously reported.<span><sup>11, 12</sup></span></p><p>To enhance the convenience of long-term treatment with IV Isa for patients and healthcare providers, by improving the current duration of Isa infusion (75 min), we prospectively evaluated the feasibility, safety, and tolerability of a novel, fast, 30-min infusion method for Isa in patients who were on maintenance therapy in the TCD13983 study.</p><p>All patients on maintenance treatment, regardless of treatment cohort, were switched to 30-min infusion with Isa at 10 mg/kg (250-mL fixed-volume infusion). Details on study treatments before switching, premedications, and patient characteristics are provided in Supporting Information and Supporting Information S1: Figure S1. To accelerate the infusions to a target durat","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590294","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}

{"title":"How to diagnose acid sphingomyelinase deficiency (ASMD) and Niemann–Pick disease type C from bone marrow and peripheral blood smears","authors":"Sandrine Girard, Magali Pettazzoni, Roseline Froissart, Cécile Pagan, Thomas Boyer, Stephanie Dulucq, Valérie Gonçalves Monteiro, Nicolas Lechevalier, Marie Loosveld, Camille Lours, Caroline Mayeur-Rousse, Mélanie Pannetier, Caroline Peillon, Maria-Alessandra Rosenthal, Sonnthida Sep Hieng, Catherine Trichet, Lucile Baseggio, on behalf the French-Speaking Cellular Haematology Group (GFHC)","doi":"10.1002/hem3.70042","DOIUrl":"10.1002/hem3.70042","url":null,"abstract":"<p>Lysosomal storage diseases (LSD) are inborn errors of metabolism disorders characterized by a defect in a lysosomal enzyme, transporter, or cofactor. Niemann–Pick diseases are classified into two distinct disorders: acid sphingomyelinase deficiency (ASMD) historically known as Niemann–Pick disease types A, AB, and B, and Niemann-Pick disease type C (NPC).<span><sup>1</sup></span> ASMD is a rare autosomal recessive LSD, caused by pathogenic variants in the ASM-encoding <i>SMPD1</i> gene (OMIM#607608).<span><sup>2</sup></span> It results in the accumulation of sphingomyelin and other lipids, primarily in the liver, spleen, lung, bone marrow, lymph nodes, and central nervous system.<span><sup>3</sup></span> Depending on their clinical phenotype, three different subtypes have been reported: A (severe infantile neurovisceral form), AB (chronic neurovisceral form), and B (chronic visceral form), with a continuum spectrum.<span><sup>1-4</sup></span> NPC is an autosomal recessive LSD caused by the defective function of one of two proteins, NPC1 or NPC2. It results from mutations in the corresponding genes (OMIM#257220 and OMIM#607625). These two proteins act in sequence to regulate the egress of endocytosed nonesterified cholesterol from the late endosomal/lysosomal compartment. NPC manifests as a neurovisceral disease with a highly heterogeneous clinical spectrum.<span><sup>5</sup></span> The prognosis of NPC is correlated with the age of onset of neurological symptoms, with four neurological forms defined: early infantile, late infantile, juvenile, and adolescent-adult. The diagnosis of ASMD and NPC is difficult because these diseases are heterogeneous and may share clinical features with other LSD such as Gaucher disease, especially when splenomegaly is present.<span><sup>5</sup></span> Some cytological abnormalities have been reported in bone marrow (BM) and peripheral blood (PB) smears from ASMD and NPC patients, which could help to guide the more specific analysis such as enzymatic activity, biomarkers measurement, and genetic testing.<span><sup>6</sup></span> However, the cytological data available in the literature are rather limited, often described in single case reports, and do not distinguish the different forms of ASMD and NPC. This work aims to report the cytological features of BM and PB in a retrospective study of 30 French cases from 28 families with ASMD types A [<i>n</i> = 5], AB [<i>n</i> = 3], B [<i>n</i> = 16], and NPC [<i>n</i> = 6], to improve knowledge and define recommendations to assist in diagnosis.</p><p>The diagnosis of cases was based on biochemical analysis, specifically either a deficiency in acid sphingomyelinase activity in blood and/or an abnormal plasma biomarkers profile (i.e., lysosphingomyelin, lysosphingomyelin509/<i>N</i>-palmitoyl-O-phosphocholineserine, and oxysterols), confirmed by specific gene analysis, except for two suspected NPC patients for whom the genetic study was inconclusive and identified a vari","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590301","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}

{"title":"GPRASP protein deficiency triggers lymphoproliferative disease by affecting B-cell differentiation","authors":"Antonio Morales-Hernández,&nbsp;Emilia Kooienga,&nbsp;Heather Sheppard,&nbsp;Gabriela Gheorghe,&nbsp;Claire Caprio,&nbsp;Ashley Chabot,&nbsp;Shannon McKinney-Freeman","doi":"10.1002/hem3.70037","DOIUrl":"10.1002/hem3.70037","url":null,"abstract":"<p><i>Gprasp1</i> and <i>Gprasp2</i> encode proteins that control the stability and cellular trafficking of CXCR4, a master regulator of hematopoiesis whose dynamic regulation is required for appropriate trafficking of B-cells in the germinal center (GC). Here, we report that <i>Gprasp1</i> and <i>Gprasp2</i>-deficient B-cells accumulate in the GC and show transcriptional abnormalities, affecting the mechanisms controlling <i>Aicda</i> expression and exposing them to excessive somatic hypermutation. Consequently, about 30% of mice transplanted with <i>Gprasp</i>-deficient hematopoietic stem and progenitor cells developed a biologically aggressive and fatal B-cell hyperproliferative disease by 20–50 weeks posttransplant. Histological and molecular profiling reveal that <i>Gprasp1-</i> and <i>Gprasp2-</i>deficient neoplasms morphologically resemble human high-grade B-cell lymphomas of germinal center origin with shared morphologic features of both Burkitt Lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), and molecular features consistent with DLBCL, as well as elevated mutational burden and heterogenous transcriptional and mutational signature. Thus, reduced <i>Gprasp1</i> and <i>Gprasp2</i> gene expression perturbs B-cell maturation and increases the risk of B-cell neoplasms of germinal center origin. As this model recapitulates the essential features of the heterogenous group of human hematopoietic malignancies, it could be a powerful tool to interrogate the mechanisms of lymphomagenesis for these cancers.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545088","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}

{"title":"Mitochondrial retention in mature red blood cells from patients with sickle cell disease is associated with stress erythropoiesis but not with proinflammatory state","authors":"Marc Romana,&nbsp;Sandrine Laurance,&nbsp;Marie-Dominique Hardy-Dessources,&nbsp;Laetitia Claer,&nbsp;Sylvie Ravion,&nbsp;Karim Dorgham,&nbsp;Yohann Garnier,&nbsp;Lea Kuznicki,&nbsp;Vanessa Tarer,&nbsp;Benoit Tressières,&nbsp;Sophie D. Lefevre,&nbsp;Veronique Baccini,&nbsp;Mariano A. Ostuni,&nbsp;Caroline Le Van Kim,&nbsp;Maryse Etienne-Julan","doi":"10.1002/hem3.70030","DOIUrl":"https://doi.org/10.1002/hem3.70030","url":null,"abstract":"&lt;p&gt;Sickle cell disease (SCD) is a hemoglobinopathy characterized by the occurrence of vaso-occlusive events, severe chronic hemolytic anemia, and ultimately chronic complications and end-organ damages.&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; SCD pathophysiology has been shown to be extremely complex, resulting from microcirculatory dysfunctions associated with altered vaso-regulation and activation of inflammation cascades responsible of sterile inflammatory state, endothelial and neutrophil activation, and release of neutrophil extracellular trap (NET).&lt;span&gt;&lt;sup&gt;1, 4-6&lt;/sup&gt;&lt;/span&gt; More recently, a dysfunctional erythropoiesis has been described in SS patients characterized by high level of reticulocytes, increased apoptosis at the later stage of erythropoiesis, and abnormal retention of mitochondria in red blood cells (RBCs).&lt;span&gt;&lt;sup&gt;7-13&lt;/sup&gt;&lt;/span&gt; It is noteworthy that the functionality of these mitochondria in mature sickle RBCs remains controversial&lt;span&gt;&lt;sup&gt;11, 12&lt;/sup&gt;&lt;/span&gt; and mechanisms responsible for the mitochondrial retention during erythropoiesis have not been identified. Besides these unanswered points, several groups reported &lt;i&gt;in vitro&lt;/i&gt; evidence that plasma mitochondrial DNA released by hemolysis of these abnormal RBCs could trigger type I interferon production&lt;span&gt;&lt;sup&gt;12&lt;/sup&gt;&lt;/span&gt; and NET release in SCD patients.&lt;span&gt;&lt;sup&gt;13&lt;/sup&gt;&lt;/span&gt; Altogether, these studies suggested that mitochondrial DNA from sickle mature RBCs could play a key role in the proinflammatory state associated with the disease.&lt;/p&gt;&lt;p&gt;In the present study, we characterized mature RBCs retaining mitochondria in a large cohort of the two main SCD genotypes, that is, SS and SC adult patients (71 and 40 patients, respectively) compared to 21 AA control individuals. We analyzed associations between mitochondria retention and hemolysis as well as inflammation markers (see patients and methods in Supporting Information and Supporting Information S1: Table 1 for the biological and demographic parameters).&lt;/p&gt;&lt;p&gt;Mitochondria presence in mature RBCs, total, and stress reticulocytes was assessed using flow cytometry (CD71/TO and/or MitoTracker Deep Red (MTKDR) staining) (Figure 1A). SS patients exhibited significant higher percentage of total circulating reticulocytes (5.0% ± 2.2%) compared to AA healthy donors (1.1% ± 0.4%), with a significant intermediate phenotype for SC patients (3.6% ± 1.7%) (Figure 1Bi). SS patients presented significant high levels of stress reticulocytes (2.6% ± 1.2%) compared to very low level observed in AA healthy donors (0.14 ± 0.09) while SC patients exhibited significant intermediate level (1.8% ± 1.0%) (Figure 1Bii). We did not observe significant difference of total and stress reticulocyte percentages between hydroxyurea (HU)-treated and nontreated SS patients (Figure 1Biii,iv). Percentage of mitochondria&lt;sup&gt;+&lt;/sup&gt;-total reticulocytes was significantly higher in SS patients (25.0% ± 13.2%) compared to AA healthy donors (11.9% ± 8.","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142525355","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}

{"title":"Abstract Book","authors":"","doi":"10.1002/hem3.70012","DOIUrl":"https://doi.org/10.1002/hem3.70012","url":null,"abstract":"&lt;p&gt;Alex F. Herrera&lt;sup&gt;1&lt;/sup&gt;, Michael Leblanc&lt;sup&gt;2&lt;/sup&gt;, Sharon M. Castellino&lt;sup&gt;3&lt;/sup&gt;, Hongli Li&lt;sup&gt;2&lt;/sup&gt;, Sarah Rutherford&lt;sup&gt;4&lt;/sup&gt;, Andrew Evens&lt;sup&gt;5&lt;/sup&gt;, Kelly Davison&lt;sup&gt;6&lt;/sup&gt;, Angela Punnett&lt;sup&gt;7&lt;/sup&gt;, Susan K. Parsons&lt;sup&gt;8&lt;/sup&gt;, Sairah Ahmed&lt;sup&gt;9&lt;/sup&gt;, Carla Casulo&lt;sup&gt;10&lt;/sup&gt;, Nancy L. Bartlett&lt;sup&gt;11&lt;/sup&gt;, Joseph Tuscano&lt;sup&gt;12&lt;/sup&gt;, Matthew Mei&lt;sup&gt;1&lt;/sup&gt;, Brian Hess&lt;sup&gt;13&lt;/sup&gt;, Ryan Jacobs&lt;sup&gt;14&lt;/sup&gt;, Hayder Saeed&lt;sup&gt;15&lt;/sup&gt;, Pallawi Torka&lt;sup&gt;16&lt;/sup&gt;, Boyu Hu&lt;sup&gt;17&lt;/sup&gt;, Craig H. Moskowitz&lt;sup&gt;18&lt;/sup&gt;, Supreet Kaur&lt;sup&gt;19&lt;/sup&gt;, Gaurav Goyal&lt;sup&gt;20&lt;/sup&gt;, Christopher Forlenza&lt;sup&gt;16&lt;/sup&gt;, Andrew Doan&lt;sup&gt;21&lt;/sup&gt;, Adam Lamble&lt;sup&gt;22&lt;/sup&gt;, Pankaj Kumar&lt;sup&gt;23&lt;/sup&gt;, Saeeda Chowdury&lt;sup&gt;24&lt;/sup&gt;, Brett Brinker&lt;sup&gt;25&lt;/sup&gt;, Namita Sharma&lt;sup&gt;26&lt;/sup&gt;, Avina Singh&lt;sup&gt;27&lt;/sup&gt;, Kristie Blum&lt;sup&gt;28&lt;/sup&gt;, Anamarija Perry&lt;sup&gt;29&lt;/sup&gt;, Alexandra Kovach&lt;sup&gt;21&lt;/sup&gt;, David Hodgson&lt;sup&gt;30&lt;/sup&gt;, Louis Constine&lt;sup&gt;10&lt;/sup&gt;, Lale Kostakoglu&lt;sup&gt;31&lt;/sup&gt;, Anca Prica&lt;sup&gt;30&lt;/sup&gt;, Hildy Dillon&lt;sup&gt;32&lt;/sup&gt;, Richard F. Little&lt;sup&gt;33&lt;/sup&gt;, Margaret A. Shipp&lt;sup&gt;34&lt;/sup&gt;, Michael Crump&lt;sup&gt;30&lt;/sup&gt;, Brad S. Kahl&lt;sup&gt;11&lt;/sup&gt;, John Leonard&lt;sup&gt;4&lt;/sup&gt;, Sonali Smith&lt;sup&gt;35&lt;/sup&gt;, Kara M. Kelly&lt;sup&gt;36&lt;/sup&gt;, Jonathan W. Friedberg&lt;sup&gt;10&lt;/sup&gt;&lt;/p&gt;&lt;p&gt;&lt;sup&gt;1&lt;/sup&gt;City of Hope, &lt;sup&gt;2&lt;/sup&gt;SWOG Statistics and Data Management Center, &lt;sup&gt;3&lt;/sup&gt;Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, &lt;sup&gt;4&lt;/sup&gt;Weill Cornell Medicine, &lt;sup&gt;5&lt;/sup&gt;Rutgers Cancer Institute of New Jersey, &lt;sup&gt;6&lt;/sup&gt;McGill University Health Center, &lt;sup&gt;7&lt;/sup&gt;SickKids Hospital, &lt;sup&gt;8&lt;/sup&gt;Tufts Medical Center, &lt;sup&gt;9&lt;/sup&gt;MD Anderson Cancer Center, &lt;sup&gt;10&lt;/sup&gt;University of Rochester, &lt;sup&gt;11&lt;/sup&gt;Washington University in St. Louis, &lt;sup&gt;12&lt;/sup&gt;UC Davis, &lt;sup&gt;13&lt;/sup&gt;Medical University of South Carolina, &lt;sup&gt;14&lt;/sup&gt;Levine Cancer Institute, &lt;sup&gt;15&lt;/sup&gt;Moffitt Cancer Center, &lt;sup&gt;16&lt;/sup&gt;Memorial Sloan Kettering Cancer Center, &lt;sup&gt;17&lt;/sup&gt;Huntsman Cancer Institute, University of Utah, &lt;sup&gt;18&lt;/sup&gt;University of Miami, &lt;sup&gt;19&lt;/sup&gt;University of Texas at San Antonio, &lt;sup&gt;20&lt;/sup&gt;University of Alabama at Birmingham, &lt;sup&gt;21&lt;/sup&gt;Children's Hospital of Los Angeles, &lt;sup&gt;22&lt;/sup&gt;Seattle Children's Hospital, &lt;sup&gt;23&lt;/sup&gt;Illinois Cancer Care, &lt;sup&gt;24&lt;/sup&gt;Prisma Health Cancer Institute, &lt;sup&gt;25&lt;/sup&gt;Cancer &amp; Hematology Center, &lt;sup&gt;26&lt;/sup&gt;Geisinger Community Medical Center, &lt;sup&gt;27&lt;/sup&gt;Fairview Ridges Hospital, &lt;sup&gt;28&lt;/sup&gt;Emory University, Winship Cancer Institute, &lt;sup&gt;29&lt;/sup&gt;University of Michigan, &lt;sup&gt;30&lt;/sup&gt;Princess Margaret Cancer Centre, &lt;sup&gt;31&lt;/sup&gt;University of Virginia, &lt;sup&gt;32&lt;/sup&gt;SWOG Cancer Research Network, &lt;sup&gt;33&lt;/sup&gt;National Cancer Institute, &lt;sup&gt;34&lt;/sup&gt;Dana-Farber Cancer Institute, &lt;sup&gt;35&lt;/sup&gt;University of Chicago, &lt;sup&gt;36&lt;/sup&gt;Roswell Park Comprehensive Cancer Center&lt;/p&gt;&lt;p&gt;&lt;b&gt;Figure 1:&lt;/b&gt; Progression-Free Survival in in Modified Intent-to-treat Analysis Set.&lt;/p&gt;&lt;p&gt;&lt;/p&gt;&lt;p&gt;&lt;b","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 S2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142524543","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}

{"title":"Long-term outcome of 2-year survivors after allogeneic hematopoietic cell transplantation for acute leukemia","authors":"Marion Larue,&nbsp;Myriam Labopin,&nbsp;Thomas Schroeder,&nbsp;Xiao-jun Huang,&nbsp;Igor W. Blau,&nbsp;Johannes Schetelig,&nbsp;Arnold Ganser,&nbsp;Rose-Marie Hamladji,&nbsp;Wolfgang Bethge,&nbsp;Nicolaus Kröger,&nbsp;Gerard Socié,&nbsp;Urpu Salmenniemi,&nbsp;Henrik Sengeloev,&nbsp;Bhagirathbhai Dholaria,&nbsp;Bipin N. Savani,&nbsp;Arnon Nagler,&nbsp;Fabio Ciceri,&nbsp;Mohamad Mohty","doi":"10.1002/hem3.70026","DOIUrl":"10.1002/hem3.70026","url":null,"abstract":"<p>Information on late complications in patients with acute leukemia who have undergone allogeneic hematopoietic cell transplantation (HCT) is limited. We performed a left-truncated analysis of long-term survival in patients with acute leukemia who were alive and disease-free 2 years after HCT. We included 2701 patients with acute lymphoblastic leukemia (ALL) and 9027 patients with acute myeloid leukemia (AML) who underwent HCT between 2005 and 2012. The 10-year overall survival (OS) rate was 81.3% for ALL and 76.2% for AML, with the main causes of late mortality being relapse (ALL-33.9%, AML-44.9%) and chronic graft-versus-host disease (ALL-29%, AML-18%). At 10 years, HCT-related mortality was 16.8% and 20.4%, respectively. Older age and unrelated donor transplantation were associated with a worse prognosis for both types of leukemia. In addition, transplantation in the second or third complete remission and peripheral blood HSC for ALL are associated with worse outcomes. Similarly, adverse cytogenetics, female donor to male patient combination, and reduced intensity conditioning in AML contribute to poor prognosis. We conclude that 2-year survival in remission after HCT for acute leukemia is encouraging, with OS of nearly 80% at 10 years. However, the long-term mortality risk of HCT survivors remains significantly higher than that of the age-matched general population. These findings underscore the importance of tailoring transplantation strategies to improve long-term outcomes in patients with acute leukemia undergoing HCT.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499347","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}

{"title":"Casting light on the national mission to eliminate sickle cell disease in India","authors":"Frédéric B. Piel,&nbsp;Roshan Colah,&nbsp;Dipty L. Jain","doi":"10.1002/hem3.70033","DOIUrl":"https://doi.org/10.1002/hem3.70033","url":null,"abstract":"&lt;p&gt;Sickle cell disease (SCD) is a neglected global public health burden.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Although it primarily affects populations from sub-Saharan Africa,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; SCD is also prevalent across the Indian subcontinent, particularly among tribal (or scheduled) populations.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; India is the most populated country in the world. According to the latest population estimates of the United Nations World Population Prospects,&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; its population includes 1.441 billion people, and it is expected to further increase to reach 1.697 billion in 2063. India ranks as the country with the third highest number of annual births affected by SCD, after Nigeria and the Democratic Republic of the Congo.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Although SCD has long been considered to be mild across the Indian subcontinent, recent evidence has demonstrated that there was a much wider range of severity than previously thought.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Finally, tribal populations tend to be largely over-represented in the low socio-economic groups across India, making them a vulnerable group for many communicable and non-communicable diseases.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Interventions to reduce SCD morbidity and mortality, such as newborn screening, vaccinations, penicillin prophylaxis, and hydroxyurea, have proven to be effective in large-scale studies in high- and upper-middle-income countries, including the United States,&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; United Kingdom,&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Jamaica,&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; and Brazil.&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; Pilot studies of these interventions have been conducted in numerous low-income countries.&lt;span&gt;&lt;sup&gt;11&lt;/sup&gt;&lt;/span&gt; Cost-benefit analyses conducted in sub-Saharan Africa&lt;span&gt;&lt;sup&gt;12&lt;/sup&gt;&lt;/span&gt; and India&lt;span&gt;&lt;sup&gt;13&lt;/sup&gt;&lt;/span&gt; suggested that these interventions would also be effective in these settings. Nevertheless, due to a lack of political and financial commitments, no national program has so far been launched in a low- or lower-middle-income country of high prevalence for SCD. Despite the curative promises of gene therapies,&lt;span&gt;&lt;sup&gt;14&lt;/sup&gt;&lt;/span&gt; there is an urgent need to scale up interventions in the most affected countries to improve the quality of life of patients affected and reduce the global burden of SCD.&lt;span&gt;&lt;sup&gt;11&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In July 2023, the Government of India launched the “National Sickle Cell Anaemia Elimination Mission.”&lt;span&gt;&lt;sup&gt;15&lt;/sup&gt;&lt;/span&gt; Although this program was officially launched by Prime Minister Modi, it did not receive much attention internationally. The stated aims of the Mission are twofold: (i) to improve the care of all SCD patients for their better future and (ii) to lower the prevalence of the disease by 2047 through a multifaceted coordinated approach toward screening and awareness strategies. The ambitious plan at launch was to screen 70 million people across India over the first 3 years of the Missio","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70033","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451778","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}

{"title":"Promoting and supporting leadership in hematology departments","authors":"Roch Houot,&nbsp;Emmanuel Gyan","doi":"10.1002/hem3.70028","DOIUrl":"https://doi.org/10.1002/hem3.70028","url":null,"abstract":"&lt;p&gt;In recent years, the hospital system has faced tremendous pressure from economic and societal crises, which were further aggravated by the COVID-19 pandemic. Today, the European healthcare system is in a continuous crisis, primarily due to underinvestment and workforce shortages.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; In such a situation, management skills at all levels of hospital departments become critical, especially for heads of departments—a position historically driven in many countries, including France, by academic rather than managerial competencies.&lt;/p&gt;&lt;p&gt;Challenges with medical staff retention have also exacerbated the workload of healthcare professionals.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; The shortage of healthcare workers in Europe is projected to reach 4.1 million by 2030, including 0.6 million physicians.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Workforce shortages contribute to burnout among physicians and other healthcare workers, which renders the tasks of heads of departments extremely challenging.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In the past two decades, the practice of hematology has experienced accelerated advancements in diagnostics and therapeutics, with notable prolongation of patient survival, albeit at the cost of intensified medical care due to the novel time-consuming therapeutic approaches. As such, the diversity of hematologic diagnoses and specialized treatments have created an expanding curriculum with ever more limited human resources.&lt;span&gt;&lt;sup&gt;2, 6&lt;/sup&gt;&lt;/span&gt; The number of hematologic specialists and the competence of their training have become a concern in European countries.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The European Hematology Association (EHA) has created solutions for training in hematology, including the European Hematology curriculum, developed through a “bottom-up” process, which has inspired national educational initiatives.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; The European Working Time Directive (EWTD), introduced in 2004, aims to reduce long working hours to enhance patient safety. In this context, the European Commission urged member states to adopt the EWTD for hospital physicians.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; However, these initiatives create challenges for department heads, who must manage increased workloads with limited staffing and heightened awareness of the adverse effects of inadequate organization on workers' health.&lt;/p&gt;&lt;p&gt;In a recent survey conducted with 2390 university hospital faculty members in France between October and December 2021, 40% of participants had severe burnout, 14% had suicidal ideation, and 12% had job strain.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; The factors associated with the unfavorable experiences included heavy work overload, work-life imbalance, and perceived lack of support from the institution.&lt;span&gt;&lt;sup&gt;4, 7&lt;/sup&gt;&lt;/span&gt; Although the impact of stressful events on the risk of burnout and suicide is undeniable, many personality traits, such as emotional stability, extraversion, and social integration, play a role.&lt;span&gt;&lt;","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449032","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}

{"title":"Overcoming a T-ALL order: A comprehensive study linking genomics to clinical outcomes","authors":"Yizhou Huang,&nbsp;Charles E. de Bock","doi":"10.1002/hem3.70027","DOIUrl":"https://doi.org/10.1002/hem3.70027","url":null,"abstract":"&lt;p&gt;Acute lymphoblastic leukemia (ALL) remains a leading success story of how modern therapies have improved patient outcomes from less than 10% survival rate in the 1950s to exceeding 90% today. This has been in part from the decades of research in the optimal use of chemotherapeutics, and, for B-cell ALL (B-ALL), the implementation of risk stratification based on clinical factors (e.g., age and peripheral blood cell counts), minimal/measurable residual disease (MRD), and cytogenetics (favorable, neutral, or unfavorable). However, for T-cell ALL (T-ALL), risk stratification is currently only based on MRD levels at the end of induction and again at the end of consolidation therapy with genomics and cytogenetics not considered prognostic factors in treatment decision-making.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; In an effort to include genomics into the risk stratification for T-ALL, a new study led by Charles Mullighan and David Teachey&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; has now been published as a landmark analysis of 1300 uniformly treated T-ALL cases that, for the first time, not only defines a total of 15 discrete genetic subtypes but also links them to clinical outcomes.&lt;/p&gt;&lt;p&gt;This new study integrates whole genome sequencing (WGS), whole exome sequencing (WES), and whole transcriptome sequencing data to expand the classification of T-ALL into a total of 15 different subtypes (Figure 1). The most significant variation from the current classification is the definition of two new subtypes, including a new early T-cell precursor (ETP)-like ALL subtype and an LMO2 γδ-like subtype—both of which have a diverse set of genetic alterations. Of the many genetic alterations, an interesting discriminator is the &lt;i&gt;KMT2A&lt;/i&gt; fusions present in the ETP-like subtype being mostly &lt;i&gt;KMT2A::AFDN&lt;/i&gt; fusion, while the non-ETP subtypes exclusively have &lt;i&gt;KMT2A::MLLT1&lt;/i&gt; fusion. The authors also compared the gene expression signatures of all 15 subtypes with normal hematopoietic and T-cell development cell stages. They found that the different T-ALL subtypes mapped across the entire continuum of T-cell development, supporting the hypothesis that each subtype represented a “frozen” stage of cellular differentiation. In the case of the ETP-like subtype, despite the heterogenous genetic drivers, the most likely cell of origin was found to be hematopoietic stem and progenitor cells (HSPC).&lt;/p&gt;&lt;p&gt;It will come as no surprise that this study confirms the high frequency of recurrent &lt;i&gt;NOTCH1&lt;/i&gt; mutations (69% of cases) in T-ALL, second only to &lt;i&gt;CDKN2A&lt;/i&gt; alterations (71% of cases), with the majority being coding sequence mutations that lead to activation of NOTCH1 signaling. However, this study also found rare single-nucleotide variants (SNV) within intron 28 of the &lt;i&gt;NOTCH1&lt;/i&gt; gene which generated a new splice acceptor site and resulted in a 43 amino acid insertion between the heterodimerization (HD) domain and the transmembrane (TM) domain of NOTCH1. Functionally, this new mutation","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435264","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}

{"title":"Outcomes and prognostic factors in 3306 patients with relapsed/refractory chronic lymphocytic leukemia treated with ibrutinib outside of clinical trials: A nationwide study","authors":"Gian Matteo Rigolin,&nbsp;Pier Paolo Olimpieri,&nbsp;Valentina Summa,&nbsp;Simone Celant,&nbsp;Lydia Scarfò,&nbsp;Maria Pia Ballardini,&nbsp;Antonio Urso,&nbsp;Silvia Gambara,&nbsp;Francesco Cavazzini,&nbsp;Paolo Ghia,&nbsp;Antonio Cuneo,&nbsp;Pierluigi Russo","doi":"10.1002/hem3.70017","DOIUrl":"10.1002/hem3.70017","url":null,"abstract":"<p>We performed a cohort study that included all patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) who received ibrutinib in the Italian National Health Service. With a median follow-up of 42.2 months (IQR 30.8–54.6 months), the study involved 3306 patients with a median age of 72.1 years, of whom 42.6% had received ≥2 previous lines of treatment. The estimated 24-month probabilities of being on treatment and alive were 57.9% (95% confidence interval [CI]: 59.6–56.2) and 76.6% (95% CI: 75.2–78.1), respectively. The median time to treatment discontinuation (TTD) was 31.3 months (95% CI: 29.5–33.5). Out of 3306 patients, 2015 (60.9%) discontinued treatment, with 993 cases attributed to death or disease progression (30.0% of all cases). Among the 1022 patients who discontinued treatment for reasons other than progression or death, 564 (17.1%) patients did so due to toxicity or medical decision, while 458 patients (13.8%) were lost to follow-up. Multivariable analysis revealed that age, Eastern Cooperative Oncology Group Performance Status, the number of previous lines of therapy, refractoriness to the last treatment, and reduced renal function were associated with shorter TTD and overall survival (OS). The coexistence of 17p− and <i>TP53</i> mutations had an independent unfavorable impact on TTD and OS. Nonstandard doses were associated with shorter TTD and advanced stage with shorter OS. The median OS postprogression and postdiscontinuation for other reasons were estimated at 12.9 (95% CI: 11.3–16.2) and 22.7 months (95% CI: 20.2–28.3), respectively. This large real-world study shows that ibrutinib is an effective treatment for R/R CLL. Baseline patient characteristics and double-hit <i>TP53</i> aberrations were associated with inferior prognosis, and discontinuation due to CLL progression portended a poor outcome.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11459203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390135","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}