HemaSphere最新文献

{"title":"Impact of myelodysplasia-related and additional gene mutations in intensively treated patients with NPM1-mutated AML","authors":"Sibylle Cocciardi,&nbsp;Maral Saadati,&nbsp;Nina Weiß,&nbsp;Daniela Späth,&nbsp;Silke Kapp-Schwoerer,&nbsp;Isabelle Schneider,&nbsp;Annika Meid,&nbsp;Verena I. Gaidzik,&nbsp;Sabrina Skambraks,&nbsp;Walter Fiedler,&nbsp;Michael W. M. Kühn,&nbsp;Ulrich Germing,&nbsp;Karin T. Mayer,&nbsp;Michael Lübbert,&nbsp;Elli Papaemmanuil,&nbsp;Felicitas Thol,&nbsp;Michael Heuser,&nbsp;Arnold Ganser,&nbsp;Lars Bullinger,&nbsp;Axel Benner,&nbsp;Hartmut Döhner,&nbsp;Konstanze Döhner","doi":"10.1002/hem3.70060","DOIUrl":"10.1002/hem3.70060","url":null,"abstract":"<p>This study aimed to evaluate the impact of the myelodysplasia-related gene (MRG) as well as additional gene mutations on outcomes in intensively treated patients with <i>NPM1</i>-mutated (<i>NPM1</i>^mut) AML. Targeted DNA sequencing of 263 genes was performed in 568 <i>NPM1</i>^mut AML patients (median age: 59 years) entered into the prospective AMLSG 09-09 treatment trial. Most commonly co-mutated genes were <i>DNMT3A</i> (49.8%), <i>FLT3</i>-TKD (25.9%), <i>PTPN11</i> (24.8%), <i>NRAS</i> (22.7%), <i>TET2</i> (21.7%), <i>IDH2</i> (21.3%), <i>IDH1</i> (18%), and <i>FLT3</i>-ITD (17.3%). MRG mutations were identified in 18.1% of cases (18–60 years: 9.8%; &gt;60 years: 28.7%). When focusing on the 470 patients with 2022 ELN favorable-risk <i>NPM1</i>^mut AML, multivariable analysis for event-free survival (EFS) identified age (<i>p</i> &lt; 0.001), <i>DNMT3A</i>^R882 (<i>p</i> &lt; 0.001), <i>IDH1</i> (<i>p</i> = 0.007), and MRG mutations (<i>p</i> = 0.03) as unfavorable factors, cohesin gene co-mutations (<i>p</i> = 0.001) and treatment with gemtuzumab ozogamicin (<i>p</i> = 0.007) as favorable factors. Restricting the analysis to a subset of CR/CRi patients with available data on <i>NPM1</i>^mut measurable residual disease (MRD) status in blood post cycle 2 in the model, MRG mutations lost their significant effect, whereas <i>DNMT3A</i>^R882, <i>MYC</i>, and cohesin gene mutations retained the adverse and favorable effects. For OS, age (<i>p</i> &lt; 0.001), <i>DNMT3A</i>^R882 (<i>p</i> = 0.042), <i>IDH1</i> (<i>p</i> = 0.045), and <i>KRAS</i> (0.003) mutations were unfavorable factors, sole favorable factor was <i>IDH2</i> co-mutation (<i>p</i> = 0.037). In 2022 ELN favorable-risk <i>NPM1</i>^mut AML, MRG mutations are associated with inferior EFS; however, this effect is no longer present when considering <i>NPM1</i>^mut MRD status post cycle 2; <i>DNMT3A</i>^R882 and <i>MYC</i> mutations remained adverse, and cohesin gene mutations favorable prognostic factors independent of the <i>NPM1</i>^mut MRD status.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004524","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":"Postoperative stage 0 Hodgkin lymphoma. Is surgery alone a curative option?","authors":"Audrey Couturier,&nbsp;Alexandra Judet,&nbsp;Mohamed Touati,&nbsp;Thomas Nivet,&nbsp;Pierre Daufresne,&nbsp;Fabien Claves,&nbsp;Eric Durot,&nbsp;Rémy Duléry,&nbsp;Roch Houot,&nbsp;Guillaume Manson","doi":"10.1002/hem3.70076","DOIUrl":"10.1002/hem3.70076","url":null,"abstract":"&lt;p&gt;Classic Hodgkin lymphoma (HL) is a rare hematologic malignancy with high curative potential. Diagnosis is based on pathologic examination of an involved lymph node through microbiopsy or lymphadenectomy. The disease is then classified by PET/CT imaging as either early stage (Ann Arbor stage I or II) or advanced stage (Ann Arbor stage III or IV).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Standard treatment includes chemotherapy (CT), often combined with radiotherapy (combined modality treatment [CMT]), and is guided by established prognostic factors (i.e., patient age, presence of a large mediastinal mass, B symptoms, inflammation, or 4 or more involved sites). In addition, PET/CT is extensively used for prognostication,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; treatment guidance,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; and response assessment.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In some cases, patients undergo radical resection of affected lymph nodes or lesions and no further disease is found on PET/CT staging (i.e., “postoperative stage 0”). In 1965, Lacher reported the clinical outcomes of 11 patients with radical excision of Hodgkin's lymphoma.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Eight of these 11 patients received postoperative treatment (radiation, chemotherapy, or a combination of both). Of the three patients who received no further treatment, two patients experienced disease relapse. Neither relapse occurred at the primary disease site. These observations were made before the development of modern imaging techniques, thus limiting the assessment of initial disease extension. Long-term remissions induced by surgery alone have recently been reported in patients with heavily pretreated relapsed or refractory disease&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;; however, such outcomes have not been reported for newly diagnosed patients.&lt;/p&gt;&lt;p&gt;Patients with postoperative stage 0 HL may meet the criteria for early-stage favorable disease, whether these patients should be treated as such is unknown. This is a rare clinical scenario, and these patients were excluded from clinical studies due to the absence of measurable disease.&lt;/p&gt;&lt;p&gt;In this study, we describe the characteristics and outcomes of 13 patients with postoperative stage 0 HL.&lt;/p&gt;&lt;p&gt;We retrospectively analyzed adult patients with localized HL who underwent radical resection (i.e., adenectomy). Only patients with negative postoperative staging PET/CT were included. Patients with nodular lymphocyte-predominant Hodgkin lymphoma were excluded from the analysis.&lt;/p&gt;&lt;p&gt;We identified 13 patients from seven centers in France who underwent complete surgical tumor resection between 2008 and 2023. All resections were performed with negative surgical margins. Staging PET/CT was systematically conducted for all patients, and no evidence of persistent disease was detected after surgery. Outcomes for the entire cohort are summarized in Table 1 and Figure 1. After a median follow-up of 55 months (6–154) after surgical resection, only one patient relapsed, who had not received any","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004543","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":"Prognostic significance of immune reconstitution following CD19 CAR T-cell therapy for relapsed/refractory B-cell lymphoma","authors":"Sophia Stock,&nbsp;Veit L. Bücklein,&nbsp;Viktoria Blumenberg,&nbsp;Giulia Magno,&nbsp;Alica-Joana Emhardt,&nbsp;Alessandra M. E. Holzem,&nbsp;David M. Cordas dos Santos,&nbsp;Christian Schmidt,&nbsp;Stefanie Grießhammer,&nbsp;Lisa Frölich,&nbsp;Sebastian Kobold,&nbsp;Michael von Bergwelt-Baildon,&nbsp;Kai Rejeski,&nbsp;Marion Subklewe","doi":"10.1002/hem3.70062","DOIUrl":"10.1002/hem3.70062","url":null,"abstract":"<p>Immune deficits after CD19 chimeric antigen receptor (CAR) T-cell therapy can be long-lasting, predisposing patients to infections and non-relapse mortality. In B-cell non-Hodgkin lymphoma (B-NHL), the prognostic impact of immune reconstitution (IR) remains ill-defined, and detailed cross-product comparisons have not been performed to date. In this retrospective observational study, we longitudinally characterized lymphocyte subsets and immunoglobulin levels in 105 B-NHL patients to assess patterns of immune recovery arising after CD19 CAR-T. Three key IR criteria were defined as CD4⁺ T helper (T_H) cells &gt; 200/µL, any detectable B cells, and serum immunoglobulin G (IgG) levels &gt;4 g/L. After a median follow-up of 24.6 months, 38% of patients displayed T_H cells, 11% showed any B cells, and 41% had IgG recovery. Notable product-specific differences emerged, including deeper T_H cell aplasia with CD28z- versus longer B-cell aplasia with 41BBz-based products. Patients with any IR recovery experienced extended progression-free survival (PFS) (median 20.8 vs. 1.7 months, <i>p</i> &lt; 0.0001) and overall survival (OS) (34.9 vs. 4.0 months, <i>p</i> &lt; 0.0001). While landmark analysis at 90 days confirmed improved PFS in patients with any recovery (34.9 vs. 8.6 months, <i>p</i> = 0.005), no significant OS difference was noted. Notably, 72% of patients with refractory disease never displayed recovery of any IR criteria. Early progressors showed diminished IR at the time of progression/relapse compared to patients with late progression/recurrence (after Day 90). Our results highlight the profound immune deficits observed after CD19 CAR-T and shed light on the intersection of IR and efficacy in B-NHL. Importantly, IR was impaired considerably postprogression, carrying significant implications for subsequent T-cell-engaging therapies and treatment sequencing.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978319","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":"“Low-risk” myelodysplastic neoplasm (MDS): Time for a name change?","authors":"Shoshana Burke,&nbsp;Stephen P. Hibbs","doi":"10.1002/hem3.70066","DOIUrl":"10.1002/hem3.70066","url":null,"abstract":"&lt;p&gt;Disease names matter. Consider these historical changes in labelling: “gay-related immune deficiency” (GRID) renamed as HIV/AIDS or “juvenile diabetes” renamed as type 1 diabetes. These name changes partially reflect better understanding of aetiology but such labels also shape the way diseases are perceived.&lt;/p&gt;&lt;p&gt;Here, we revisit the language used to describe myelodysplastic neoplasia (MDS). We review the rationale and consequences of renaming myelodysplastic &lt;i&gt;syndrome&lt;/i&gt; as &lt;i&gt;neoplasia&lt;/i&gt;. We then focus on the “low-risk” designation of the majority of cases of MDS, arguing that this label is misleading and has real-world consequences for patients, clinicians, and research funders.&lt;/p&gt;&lt;p&gt;The importance of nomenclature and perception of MDS was the subject of a recent World Health Organization (WHO) consortium.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Historically, classification of MDS as neoplasms was controversial. However, MDS fulfils contemporary medical and biological criteria of cancer, and the recent WHO's proposal to rename MDS as “myelodysplastic neoplasms” aimed to “underscore their neoplastic nature and harmonise terminology.”&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; A similar trend is seen for myeloproliferative neoplasms (MPN), where clinical discussions increasingly emphasise their status as blood cancers.&lt;/p&gt;&lt;p&gt;For MDS, the confusing compromise was to keep the acronym but change the name to myelodysplastic neoplasm.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Importantly, the decision to change the name was well received by some patient support groups, who saw it as a clarification of the condition's status as cancer, rather than a change. Furthermore, designating MDS as a type of cancer provided access to cancer support groups and services within charitable blood cancer organisations.&lt;/p&gt;&lt;p&gt;However, renaming as myelodysplastic &lt;i&gt;neoplasm&lt;/i&gt; risks causing unnecessarily distress for some patients.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; The psychological impact of the word cancer remains significant, freighted with ideas of toxic chemotherapy, hair loss, vomiting, and social isolation. It is biologically correct to classify MDS (and MPN) as neoplasms, but how this label plays out in the lives of individual patients is complex and highly variable.&lt;/p&gt;&lt;p&gt;The nomenclature of “low-risk” MDS is widely used in treatment guidelines,&lt;span&gt;&lt;sup&gt;1, 5-7&lt;/sup&gt;&lt;/span&gt; scientific discussion, and clinical encounters. For pathologists concerned exclusively with the risk of progression to acute myeloid leukemia (AML), “low-risk” is an apt designation. But progression to AML is not the only risk conferred by MDS, and the suffering of most MDS patients does not relate to progression. Despite a low risk of progression, “low-risk” MDS has an average survival of just over 5 years.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Furthermore, over 80% of patients suffer the life-changing sequelae of anaemia, including fatigue, dizziness, and heart failure.&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Treatment options for “low-risk” MDS are limit","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948036","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":"Replacement therapy in pregnant women with von Willebrand disease during delivery: Factor levels and pharmacokinetics","authors":"Wala Al Arashi,&nbsp;Michael E. Cloesmeijer,&nbsp;Frank W. G. Leebeek,&nbsp;Johannes J. Duvekot,&nbsp;Marieke J. H. A. Kruip,&nbsp;Ron A. A. Mathôt,&nbsp;Marjon H. Cnossen,&nbsp;the OPTI-CLOT/To WiN study group and SYMPHONY consortium","doi":"10.1002/hem3.70061","DOIUrl":"10.1002/hem3.70061","url":null,"abstract":"<p>Limited data are available on VWF activity (VWF:Act) and factor VIII (FVIII:C) levels during delivery after VWF/FVIII concentrate administration in women with von Willebrand disease (VWD). We aimed to evaluate treatment with a specific VWF/FVIII concentrate on factor levels in women with VWD during delivery and the postpartum period. A retrospective single-center study was conducted between January 1, 2008, and August 1, 2022. Pregnant women treated with Haemate®P during delivery were included if they had ≥2 consecutive VWF:Act and FVIII:C measurements post-infusion. VWF:Act/FVIII:C levels were compared to predefined target levels. A population pharmacokinetic (PopPK) model was developed, estimating VWF and FVIII pharmacokinetics after Haemate®P administration. Nineteen women were included. Targeted VWF:Act/FVIII:C peak levels were achieved after the first infusion (≥1.00 IU/mL, <i>n</i> = 12; ≥1.50 IU/mL, <i>n</i> = 5), and all VWF:Act/FVIII:C trough levels remained ≥0.50 IU/mL during first 72 h of treatment. All women had pretreatment FVIII:C levels ≥1.00 IU/mL, except one woman with type 2N, which was significantly higher than FVIII:C levels during the third trimester (median increase: 0.42 IU/mL, interquartile range: [0.12–0.92]). FVIII:C trough levels increased during treatment, median 2.05 IU/mL [1.65–2.71]. Nine women (47%) experienced postpartum hemorrhage and no thrombosis occurred. A one-compartment PopPK model adequately described VWF:Act/FVIII:C levels. Targeted VWF:Act/FVIII:C peak levels were achieved with the prescribed dosing regimens. VWF clearance was similar to that in nonpregnant individuals. Both pretreatment and FVIIIC trough levels during treatment were high with reduced FVIII clearance. Monitoring VWF:Act/FVIII:C levels is recommended for optimizing target levels and enriching the current PopPK model, improving VWF:Act/FVIII:C level predictions, and achieving more effective dosing.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931626","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":"High levels of global hydroxymethylation predict worse overall survival in MDS patients treated with azacitidine","authors":"Francesca Tiso,&nbsp;Florentien E. M. in 't Hout,&nbsp;Ruth Knops,&nbsp;Leonie I. Kroeze,&nbsp;Arno van Rooij,&nbsp;Arjan A. van de Loosdrecht,&nbsp;Theresia M. Westers,&nbsp;Saskia M. C. Langemeijer,&nbsp;Claude Preudhomme,&nbsp;Nicolas Duployez,&nbsp;Pierre Fenaux,&nbsp;Olivier Kosmider,&nbsp;Didier Bouscary,&nbsp;Aniek O. de Graaf,&nbsp;Joost H. A. Martens,&nbsp;Bert A. van der Reijden,&nbsp;Lionel Adès,&nbsp;Michaela Fontenay,&nbsp;Joop H. Jansen","doi":"10.1002/hem3.70034","DOIUrl":"10.1002/hem3.70034","url":null,"abstract":"&lt;p&gt;Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by cytopenia, dysplasia, and a risk of progressing to acute myeloid leukemia (AML).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Using the international prognostic scoring systems (IPSS, IPSS-R, and recently IPSS-M), patients can be categorized into different risk groups for overall and leukemia-free survival.&lt;span&gt;&lt;sup&gt;2-4&lt;/sup&gt;&lt;/span&gt; In combination with fitness and individual preferences, the therapeutic strategy for each patient is determined.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Currently, the strategies most commonly used are best supportive care (BSC) with or without EPO/G-CSF in lower-risk MDS, lenalidomide (LEN) in patients with a del(5q), or luspatercept in patients with ring sideroblasts/&lt;i&gt;SF3B1&lt;/i&gt; mutations. In higher-risk MDS, hypomethylating agents (HMAs), chemotherapy, and/or stem cell transplantation can be considered. MDS patients carry mutations in genes involved in DNA methylation including &lt;i&gt;TET2&lt;/i&gt; (20%–30%), &lt;i&gt;DNMT3A&lt;/i&gt; (10%), and &lt;i&gt;IDH1/2&lt;/i&gt; (5%–10%).&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; DNMT3A is a DNA methyltransferase that converts cytosine (C) into 5-methylcytosine (5mC). Methylated DNA can in turn be actively demethylated by TET enzymes (including TET2), converting 5mC into 5-hydroxymethylcytosine (5hmC) which is further converted into cytosine by subsequent actions of TET proteins, thymidine DNA glycosylase (TDG), and the base excision repair (BER) pathway. Mutations in &lt;i&gt;TET2&lt;/i&gt; result in defective enzymatic activity and significantly decreased levels of 5hmC. TET proteins need vitamin C, Fe&lt;sup&gt;2+,&lt;/sup&gt; and alpha-ketoglutarate (α-KG) as cofactors for proper enzymatic activity. The latter is produced by IDH1/2 enzymes. Mutations in &lt;i&gt;IDH1&lt;/i&gt; and &lt;i&gt;IDH2&lt;/i&gt; result in the aberrant production of 2-hydroxyglutarate instead of α-KG, which inhibits TET activity. Therefore, also in &lt;i&gt;IDH1/2&lt;/i&gt; mutated cells, decreased 5hmC levels can be observed.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Cancer cells often show hypermethylation, which may result in silencing of tumor suppressor genes.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; The methylation process is reversible and can be influenced by the administration of HMAs like azacitidine (AZA) and decitabine. Both compounds have shown important activity in MDS and AML.&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; HMAs are analogs of the nucleoside cytidine and they are incorporated into the DNA during DNA replication, inhibiting the DNA methylation process and causing hypomethylation. In addition, 80%–90% of azacitidine is incorporated into the RNA. As not all patients respond to HMAs and the response may take several courses of therapy before an effect becomes apparent,&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; the identification of markers that predict response is warranted. Recently, a set of 39 methylation sites was found significantly different in MDS patients responding to AZA, compared to nonresponders.&lt;span&gt;&lt;sup&gt;11&lt;/sup&gt;&lt;/span&gt; We previously demonstrated that ","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931623","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":"Annual Sickle Cell & Thalassaemia Conference (ASCAT) - October 2024","authors":"","doi":"10.1002/hem3.70009","DOIUrl":"https://doi.org/10.1002/hem3.70009","url":null,"abstract":"&lt;p&gt;&lt;b&gt;Topic:&lt;/b&gt; 001–Basic and translational&lt;/p&gt;&lt;p&gt;A. Ejaz&lt;sup&gt;1&lt;/sup&gt;, S. Liu&lt;sup&gt;1&lt;/sup&gt;, S. Holliman&lt;sup&gt;1&lt;/sup&gt;, C. Scott&lt;sup&gt;1&lt;/sup&gt;, D. Songdej&lt;sup&gt;2&lt;/sup&gt;, V. Viprakasit&lt;sup&gt;3&lt;/sup&gt;, J. Davies&lt;sup&gt;1&lt;/sup&gt;, C. Babbs&lt;sup&gt;1&lt;/sup&gt;, D.R. Higgs&lt;sup&gt;1&lt;/sup&gt;&lt;/p&gt;&lt;p&gt;University of Oxford&lt;sup&gt;1&lt;/sup&gt;, Ramathibodi Hospital&lt;sup&gt;2&lt;/sup&gt;, Siriraj Hospital&lt;sup&gt;3&lt;/sup&gt;&lt;/p&gt;&lt;p&gt;Zeta globin, an embryonic alpha-like globin, is repressed from 8 weeks gestation in humans.&lt;sup&gt;1&lt;/sup&gt; Its de-repression is of clinical interest as transgenic mouse models have shown that it can substitute for alpha globin&lt;sup&gt;2&lt;/sup&gt;—making it an attractive target for de-repressive gene editing strategies as a therapy for alpha thalassemia. Work from our lab examining &lt;i&gt;cis&lt;/i&gt; regulatory factors has found that a discrete region of chromatin overlying zeta globin is deacetylated in mouse definitive erythropoiesis; while it is acetylated in primitive erythropoiesis when the gene is active.&lt;sup&gt;3&lt;/sup&gt; Previous work has also identified two &lt;i&gt;trans&lt;/i&gt; regulatory factors—BCL11A and LRF. Knockout models of these factors show de-repression of zeta-globin to 15% of all alpha-like globin expression, less than that seen in primitive erythropoiesis when zeta globin is expressed maximally at 40% of all alpha-like globin.&lt;sup&gt;3&lt;/sup&gt; There are likely to be additional, as yet unidentified, factors involved in zeta globin regulation.&lt;/p&gt;&lt;p&gt;Human models of persistence of zeta globin expression are key to uncovering these factors. Studies in patients with compound heterozygous &lt;i&gt;KLF1&lt;/i&gt; mutations have found increased embryonic globin levels, likely due to KLF1's role in activating BCL11A and LRF (4). Some survivors of alpha thalassemia major (Barts hydrops fetalis syndrome) express high quantities of zeta globin, more than would be expected purely from deletions of the alpha globin genes. We have undertaken transcriptomic and chromatin analyses in these patients to characterize novel factors that may be involved in zeta globin regulation. We have identified several candidate genes, which have been intersected with results from CRISPR/Cas9 knockout screens of epigenetic modulators and transcription factors, to further refine our results. We are now undertaking exploratory studies of these factors to uncover the mechanisms by which they interact with the zeta globin locus, and plan ultimately to develop strategies for de-repressing zeta globin.&lt;/p&gt;&lt;p&gt;1. FB Piel, DJ Weatherall. &lt;i&gt;The New England Journal of Medicine&lt;/i&gt;, 2014; 371(20), 1908–1916.&lt;/p&gt;&lt;p&gt;2. JE Russell, SA Liebhaber. &lt;i&gt;Blood&lt;/i&gt;, 1998; 92(9), 3057–3063.&lt;/p&gt;&lt;p&gt;3. AJ King et al. &lt;i&gt;Nature Communications&lt;/i&gt;, 2021; 12(1), 4439.&lt;/p&gt;&lt;p&gt;4. V Viprakasit et al. &lt;i&gt;Blood&lt;/i&gt;. 2014; 123(10), 1586–1595.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Topic:&lt;/b&gt; 001–Basic and translational&lt;/p&gt;&lt;p&gt;M.J.M. Traets&lt;sup&gt;1&lt;/sup&gt;, J.F. Bos&lt;sup&gt;1&lt;/sup&gt;, S. Van der Veen&lt;sup&gt;2&lt;/sup&gt;, A. Kidane Gebremeskel&lt;sup&gt;3&lt;/sup&gt;, B.A. van Oirschot&lt;sup&gt;1&lt;/sup&gt;, S.E.M. Schols&lt;sup&gt;4&lt;/sup&gt;, M.N. Lauw&lt;sup&gt;5&lt;/sup","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 S4","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187085","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":"Annual Sickle Cell & Thalassaemia Conference (ASCAT) - October 2023","authors":"","doi":"10.1002/hem3.70021","DOIUrl":"https://doi.org/10.1002/hem3.70021","url":null,"abstract":"&lt;p&gt;&lt;b&gt;Topics 002&lt;/b&gt;–Novel therapies, gene therapies and bone marrow transplant&lt;/p&gt;&lt;p&gt;F. Locatelli&lt;sup&gt;1&lt;/sup&gt;, P. Lang&lt;sup&gt;2&lt;/sup&gt;, S. Corbacioglu&lt;sup&gt;3&lt;/sup&gt;, A. Li&lt;sup&gt;4&lt;/sup&gt;, J. de la Fuente&lt;sup&gt;5&lt;/sup&gt;, D. Wall&lt;sup&gt;6&lt;/sup&gt;, R. Meisel&lt;sup&gt;7&lt;/sup&gt;, A. Shah&lt;sup&gt;8&lt;/sup&gt;, R. Liem&lt;sup&gt;9&lt;/sup&gt;, M. Mapara&lt;sup&gt;10&lt;/sup&gt;, B. Carpenter&lt;sup&gt;11&lt;/sup&gt;, J. Kwiatkowski&lt;sup&gt;12&lt;/sup&gt;, M.D. Cappellini&lt;sup&gt;13&lt;/sup&gt;, A. Kattamis&lt;sup&gt;14&lt;/sup&gt;, S. Sheth&lt;sup&gt;15&lt;/sup&gt;, S. Grupp&lt;sup&gt;16&lt;/sup&gt;, P. Kohli&lt;sup&gt;17&lt;/sup&gt;, D. Shi&lt;sup&gt;17&lt;/sup&gt;, L. Ross&lt;sup&gt;17&lt;/sup&gt;, Y. Bobruff&lt;sup&gt;17&lt;/sup&gt;, C. Simard&lt;sup&gt;17&lt;/sup&gt;, L. Zhang&lt;sup&gt;17&lt;/sup&gt;, P.K. Morrow&lt;sup&gt;18&lt;/sup&gt;, B. Hobbs&lt;sup&gt;17&lt;/sup&gt;, H. Frangoul&lt;sup&gt;19&lt;/sup&gt;&lt;/p&gt;&lt;p&gt;IRCCS, Ospedale Pediatrico Bambino Gesù Rome, Catholic University of the Sacred Heart&lt;sup&gt;1&lt;/sup&gt;, University of Tübingen&lt;sup&gt;2&lt;/sup&gt;, University of Regensburg&lt;sup&gt;3&lt;/sup&gt;, BC Children's Hospital, University of British Columbia&lt;sup&gt;4&lt;/sup&gt;, Imperial College Healthcare NHS Trust, St Mary's Hosp ital&lt;sup&gt;5&lt;/sup&gt;, The Hospital for Sick Children/University of Toronto&lt;sup&gt;6&lt;/sup&gt;, Heinrich-Heine-University&lt;sup&gt;7&lt;/sup&gt;, Stanford University&lt;sup&gt;8&lt;/sup&gt;, Ann &amp; Robert H. Lurie Children's Hospital of Chicago&lt;sup&gt;9&lt;/sup&gt;, Herbert Irving Comprehensive Cancer Center, Columbia University&lt;sup&gt;10&lt;/sup&gt;, University College Hospital NHS Trust&lt;sup&gt;11&lt;/sup&gt;, Children's Hospital of Philadelphia&lt;sup&gt;12&lt;/sup&gt;, University of Milan&lt;sup&gt;13&lt;/sup&gt;, University of Athens&lt;sup&gt;14&lt;/sup&gt;, Joan and Sanford I Weill Medical College of Cornell University&lt;sup&gt;15&lt;/sup&gt;, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania&lt;sup&gt;16&lt;/sup&gt;, Vertex Pharmaceuticals&lt;sup&gt;17&lt;/sup&gt;, CRISPR Therapeutics&lt;sup&gt;18&lt;/sup&gt;, Sarah Cannon Center for Blood Cancer at The Children's Hospital at TriStar Centennial&lt;sup&gt;19&lt;/sup&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; Exagamglogene autotemcel (exa-cel) is a one-time non-viral cell therapy designed to reactivate fetal hemoglobin (HbF) via ex vivo CRISPR/Cas9 gene-editing at the erythroid enhancer region of &lt;i&gt;BCL11A&lt;/i&gt; in autologous CD34+ hematopoietic stem and progenitor cells.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Aims:&lt;/b&gt; Evaluate efficacy and safety of exa-cel in patients (pts) with transfusion-dependent β-thalassemia (TDT) in a pre-specified interim analysis of the CLIMB THAL-111 trial.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Methods:&lt;/b&gt; CLIMB THAL-111 is an ongoing phase 3 trial of exa-cel in pts age 12–35 y with TDT and a history of ≥100 mL/kg/y or ≥10 U/y of packed red blood cell (RBC) transfusions 2 y before screening. Primary and key secondary efficacy endpoints are proportion of pts who maintain a weighted average hemoglobin (Hb) ≥9g/dL without RBC transfusion for ≥12 mos (TI12; primary) and ≥6 mos (TI6; key secondary). Evaluable pts were followed for ≥16 mos after exa‑cel infusion. Evaluation of TI12 and TI6 started 60 days after last RBC transfusion for post-transplant support or TDT management. Pts completing trial enrolled in long-term follow-up Study 131.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; As of 6 Se","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 S3","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143253115","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":"Proliferating CLL cells express high levels of CXCR4 and CD5","authors":"Daniel Friedman,&nbsp;Drshika P. Mehtani,&nbsp;Jennifer B. Vidler,&nbsp;Piers E. M. Patten,&nbsp;Robbert Hoogeboom","doi":"10.1002/hem3.70064","DOIUrl":"10.1002/hem3.70064","url":null,"abstract":"<p>Chronic lymphocytic leukemia (CLL) is an incurable progressive malignancy of CD5⁺ B cells with a birth rate between 0.1% and 1% of the entire clone per day. However, the phenotype and functional characteristics of proliferating CLL cells remain incompletely understood. Here, we stained peripheral blood CLL cells for ki67 and DNA content and found that CLL cells in G1-phase have a CXCR4^loCD5^hi phenotype, while CLL cells in S/G2/M-phase express high levels of both CXCR4 and CD5. Induction of proliferation in vitro using CD40L stimulation results in high ki67 levels in CXCR4^loCD5^hi cells with CXCR4 expression increasing as CLL cells progress through S and G2/M-phases, while CXCR4^hiCD5^lo CLL cells remained quiescent. Dye dilution experiments revealed an accumulation of Ki67^hi-divided cells in the CXCR4^hiCD5^hi fraction. In Eµ-TCL1 transgenic mice, the CXCR4^hiCD5^hi fraction expressed high levels of ki67 and was expanded in enlarged spleens of diseased animals. Human peripheral blood CXCR4^hiCD5^hi CLL cells express increased levels of IgM and the chemokine receptors CCR7 and CXCR5 and migrate efficiently toward CCL21. We found higher levels of CXCR4 in patients with progressive disease and the CXCR4^hiCD5^hi fraction was expanded upon clinical relapse. Thus, this study defines the phenotype and functional characteristics of dividing CLL cells identifying a novel subclonal population that underlies CLL pathogenesis and may drive clinical outcomes.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11651208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846552","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":"Definitions matter: Multicenter investigation of incidence and outcome of poor graft function after hematopoietic cell transplantation","authors":"Konradin F. Müskens,&nbsp;Winny N. R. Collot-d'Escury,&nbsp;Rana Dandis,&nbsp;Saskia Haitjema,&nbsp;Jürgen Kuball,&nbsp;Moniek A. de Witte,&nbsp;Marc Bierings,&nbsp;Caroline A. Lindemans,&nbsp;Stefan Nierkens,&nbsp;Mirjam E. Belderbos","doi":"10.1002/hem3.70059","DOIUrl":"10.1002/hem3.70059","url":null,"abstract":"<p>Despite advances in allogeneic hematopoietic cell transplantation (HCT), poor graft function (PGF) remains an important complication with substantial morbidity and mortality. The investigation of preventive and therapeutic PGF treatments is hindered by inconsistencies in reported incidence and outcomes across studies, which may be explained by heterogeneity in PGF definition. To assess the impact of definition heterogeneity, we conducted a multicenter study, analyzing over 35.000 longitudinal blood counts from 427 pediatric and 405 adult HCT recipients. We compared the incidence, risk factors, and outcome of PGF, based on the three most common definitions. We identified 97 pediatric and 75 adult HCT recipients fulfilling at least one PGF definition. The 2-year cumulative incidence of PGF varied significantly depending on the definition used, ranging from 6.8% to 20% in children and 4.9% to 18% in adults. Two-year mortality for PGF patients ranged from 33% to 40% in children and 46% to 65% in adults. Notably, PGF patients identified solely by lenient definitions had similar mortality to HCT recipients with good graft function. Risk factors for PGF also varied by definition in both cohorts, and included older recipient age and cord blood transplantation. In conclusion, our study demonstrates that differences in PGF definition significantly impact the reported incidence, risk factors, and outcome. This underscores the need to harmonize PGF definitions across scientific studies, clinical practice, and transplant registries. Future studies, using standardized, quantitative thresholds for PGF, are required to determine optimal treatment strategies for both mild and severe forms of PGF.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846537","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}