HemaSphere最新文献

{"title":"Metabolic blood profile and response to treatment with the pyruvate kinase activator mitapivat in patients with sickle cell disease","authors":"Myrthe J. van Dijk,&nbsp;Titine J. J. Ruiter,&nbsp;Sigrid van der Veen,&nbsp;Minke A. E. Rab,&nbsp;Brigitte A. van Oirschot,&nbsp;Jennifer Bos,&nbsp;Cleo Derichs,&nbsp;Anita W. Rijneveld,&nbsp;Marjon H. Cnossen,&nbsp;Erfan Nur,&nbsp;Bart J. Biemond,&nbsp;Marije Bartels,&nbsp;Roger E. G. Schutgens,&nbsp;Wouter W. van Solinge,&nbsp;Judith J. M. Jans,&nbsp;Eduard J. van Beers,&nbsp;Richard van Wijk","doi":"10.1002/hem3.109","DOIUrl":"10.1002/hem3.109","url":null,"abstract":"<p>Mitapivat is an investigational, oral, small-molecule allosteric activator of pyruvate kinase (PK). PK is a regulatory glycolytic enzyme that is key in providing the red blood cell (RBC) with sufficient amounts of adenosine triphosphate (ATP). In sickle cell disease (SCD), decreased 2,3-DPG levels increase the oxygen affinity of hemoglobin, thereby preventing deoxygenation and polymerization of sickle hemoglobin. The PK activator mitapivat has been shown to decrease levels of 2,3-DPG and increase levels of ATP in RBCs in patients with SCD. In this phase 2, investigator-initiated, open-label study (https://www.clinicaltrialsregister.eu/ NL8517; EudraCT 2019-003438-18), untargeted metabolomics was used to explore the overall metabolic effects of 8-week treatment with mitapivat in the dose-finding period. In total, 1773 unique metabolites were identified in dried blood spots of whole blood from ten patients with SCD and 42 healthy controls (HCs). The metabolic phenotype of patients with SCD revealed alterations in 139/1773 (7.8%) metabolites at baseline when compared to HCs (false discovery rate-adjusted <i>p</i> &lt; 0.05), including increases of (derivatives of) polyamines, purines, and acyl carnitines. Eight-week treatment with mitapivat in nine patients with SCD altered 85/1773 (4.8%) of the total metabolites and 18/139 (12.9%) of the previously identified altered metabolites in SCD (unadjusted <i>p</i> &lt; 0.05). Effects were observed on a broad spectrum of metabolites and were not limited to glycolytic intermediates. Our results show the relevance of metabolic profiling in SCD, not only to unravel potential pathophysiological pathways and biomarkers in multisystem diseases but also to determine the effect of treatment.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 6","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11196954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450365","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":"The ETO2 transcriptional cofactor maintains acute leukemia by driving a MYB/EP300-dependent stemness program","authors":"Alexandre Fagnan,&nbsp;Zakia Aid,&nbsp;Marie Baille,&nbsp;Aneta Drakul,&nbsp;Elie Robert,&nbsp;Cécile K. Lopez,&nbsp;Cécile Thirant,&nbsp;Yann Lecluse,&nbsp;Julie Rivière,&nbsp;Cathy Ignacimouttou,&nbsp;Silvia Salmoiraghi,&nbsp;Eduardo Anguita,&nbsp;Audrey Naimo,&nbsp;Christophe Marzac,&nbsp;Françoise Pflumio,&nbsp;Sébastien Malinge,&nbsp;Christian Wichmann,&nbsp;Yun Huang,&nbsp;Camille Lobry,&nbsp;Julie Chaumeil,&nbsp;Eric Soler,&nbsp;Jean-Pierre Bourquin,&nbsp;Claus Nerlov,&nbsp;Olivier A. Bernard,&nbsp;Juerg Schwaller,&nbsp;Thomas Mercher","doi":"10.1002/hem3.90","DOIUrl":"https://doi.org/10.1002/hem3.90","url":null,"abstract":"<p>Transcriptional cofactors of the ETO family are recurrent fusion partners in acute leukemia. We characterized the ETO2 regulome by integrating transcriptomic and chromatin binding analyses in human erythroleukemia xenografts and controlled ETO2 depletion models. We demonstrate that beyond its well-established repressive activity, ETO2 directly activates transcription of MYB, among other genes. The ETO2-activated signature is associated with a poorer prognosis in erythroleukemia but also in other acute myeloid and lymphoid leukemia subtypes. Mechanistically, ETO2 colocalizes with EP300 and MYB at enhancers supporting the existence of an ETO2/MYB feedforward transcription activation loop (e.g., on MYB itself). Both small-molecule and PROTAC-mediated inhibition of EP300 acetyltransferases strongly reduced ETO2 protein, chromatin binding, and ETO2-activated transcripts. Taken together, our data show that ETO2 positively enforces a leukemia maintenance program that is mediated in part by the MYB transcription factor and that relies on acetyltransferase cofactors to stabilize ETO2 scaffolding activity.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 6","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.90","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430255","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":"EHA2024 Hybrid Congress","authors":"","doi":"10.1002/hem3.104","DOIUrl":"https://doi.org/10.1002/hem3.104","url":null,"abstract":"","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 S1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.104","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141326621","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":"Quantitative analysis of bone marrow fibrosis highlights heterogeneity in myelofibrosis and augments histological assessment: An Insight from a phase II clinical study of zinpentraxin alfa","authors":"Hosuk Ryou,&nbsp;Korsuk Sirinukunwattana,&nbsp;Ruby Wood,&nbsp;Alan Aberdeen,&nbsp;Jens Rittscher,&nbsp;Olga K. Weinberg,&nbsp;Robert Hasserjian,&nbsp;Olga Pozdnyakova,&nbsp;Frank Peale,&nbsp;Brian Higgins,&nbsp;Pontus Lundberg,&nbsp;Kerstin Trunzer,&nbsp;Claire N. Harrison,&nbsp;Daniel Royston","doi":"10.1002/hem3.105","DOIUrl":"https://doi.org/10.1002/hem3.105","url":null,"abstract":"&lt;p&gt;Accurate assessment of bone marrow fibrosis is central to the diagnosis and assessment of patients with myeloproliferative neoplasms (MPNs).&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; However, European consensus criteria for fibrosis are subjective, only semiquantitative, and cannot fully capture sample fibrosis heterogeneity.&lt;span&gt;&lt;sup&gt;4-6&lt;/sup&gt;&lt;/span&gt; In response, we have recently demonstrated the potential of machine learning to improve the detection and quantitation of marrow fibrosis in MPN using routinely prepared bone marrow trephine (BMT) samples.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Such approaches can support accurate MPN classification/risk stratification and provide quantitative analysis of fibrosis heterogeneity, with the potential to support clinical trial teams in the evaluation of current and novel antifibrotic therapies.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Here, we report evidence of such utility in the context of stage 2 of a phase II study of zinpentraxin alfa in patients diagnosed with primary or secondary myelofibrosis (MF) [ClinicalTrials.gov identifier: NCT01981850]. The primary trial endpoint was bone marrow response (≥1 grade reduction from baseline fibrosis at any timepoint). Secondary endpoints included effects on disease-related anemia, thrombocytopenia, and constitutional symptoms.&lt;/p&gt;&lt;p&gt;Zinpentraxin alfa (ZPN; previously PRM-151) is a recombinant form of human pentraxin-2 (PTX2; also known as serum amyloid P component or SAP), a circulating endogenous regulator of the inflammatory response to tissue damage and a natural inhibitor of fibrosis.&lt;span&gt;&lt;sup&gt;8-10&lt;/sup&gt;&lt;/span&gt; In the open-label stage 1 of this phase 2 study, ZPN showed evidence of clinical activity and tolerable safety as monotherapy or in combination with ruxolitinib in patients with primary MF, post-polycythemia vera (PV) MF, or post-essential thrombocythemia (ET) MF.&lt;span&gt;&lt;sup&gt;11&lt;/sup&gt;&lt;/span&gt; A subsequent randomized dose-ranging study (stage 2) evaluated the efficacy and safety of three different doses of ZPN as monotherapy in patients with IPSS intermediate-1, intermediate-2, and high-risk primary MF, post-PV MF, or post-ET MF who were anemic or thrombocytopenic and ineligible for, intolerant of, or had an inadequate prior response to ruxolitinib.&lt;span&gt;&lt;sup&gt;12&lt;/sup&gt;&lt;/span&gt; Patients were randomized to receive 0.3, 3.0, or 10.0 mg/kg ZPN on Days 1, 3, and 5 of cycle 1 and every 4 weeks thereafter for up to nine cycles. Reticulin-stained BMTs from three timepoints (screening, cycle 4 [C4D1], and cycle 9 [C9D29]) were analyzed for a subset of patients enrolled in the stage 2 study for whom digital scanned images were available at all three timepoints (50/97) (Figure 1A,B). Prior manual assessment of marrow fibrosis had been performed as part of a blinded, independent central review by three expert hematopathologists. Quantitative assessment of fibrosis using Continuous Indexing of Fibrosis (CIF) was performed by automated analyses as previously described.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Briefly, CIF","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 6","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.105","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141326447","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":"Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in the United Kingdom: A real-world intention-to-treat analysis","authors":"Maeve A. O'Reilly,&nbsp;William Wilson,&nbsp;David Burns,&nbsp;Andrea Kuhnl,&nbsp;Frances Seymour,&nbsp;Ben Uttenthal,&nbsp;Caroline Besley,&nbsp;Rajesh Alajangi,&nbsp;Thomas Creasey,&nbsp;Shankara Paneesha,&nbsp;Johnathon Elliot,&nbsp;Carlos Gonzalez Arias,&nbsp;Sunil Iyengar,&nbsp;Matthew R. Wilson,&nbsp;Alison Delaney,&nbsp;Lourdes Rubio,&nbsp;Jonathan Lambert,&nbsp;Khalil Begg,&nbsp;Stephen Boyle,&nbsp;Kathleen P. L. Cheok,&nbsp;Graham P. Collins,&nbsp;Claire Roddie,&nbsp;Rod Johnson,&nbsp;Robin Sanderson","doi":"10.1002/hem3.87","DOIUrl":"https://doi.org/10.1002/hem3.87","url":null,"abstract":"<p>Brexucabtagene autoleucel (brexu-cel) is an autologous CD19 CAR T-cell product, approved for relapsed/refractory (r/r) mantle cell lymphoma (MCL). In ZUMA-2, brexu-cel demonstrated impressive responses in patients failing ≥2 lines, including a bruton's tyrosine kinase inhibitor, with an overall and complete response rate of 93% and 67%, respectively. Here, we report our real-world intention-to-treat (ITT) outcomes for brexu-cel in consecutive, prospectively approved patients, from 12 institutions in the United Kingdom between February 2021 and June 2023, with a focus on feasibility, efficacy, and tolerability. Of 119 approved, 104 underwent leukapheresis and 83 received a brexu-cel infusion. Progressive disease (PD) and/or manufacturing (MF) were the most common reasons for failure to reach harvest and/or infusion. For infused patients, best overall and complete response rates were 87% and 81%, respectively. At a median follow-up of 13.3 months, median progression-free survival (PFS) for infused patients was 21 months (10.1–NA) with a 6- and 12-month PFS of 82% (95% confidence interval [CI], 71–89) and 62% (95% CI, 49–73), respectively. ≥Grade 3 cytokine release syndrome and neurotoxicity occurred in 12% and 22%, respectively. On multivariate analysis, inferior PFS was associated with male sex, bulky disease, ECOG PS &gt; 1 and previous MF. Cumulative incidence of non-relapse mortality (NRM) was 6%, 15%, and 25% at 6, 12, and 24 months, respectively, and mostly attributable to infection. Outcomes for infused patients in the UK are comparable to ZUMA-2 and other real-world reports. However, ITT analysis highlights a significant dropout due to PD and/or MF. NRM events warrant further attention.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 6","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.87","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141315481","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":"Results from UKALL60+, a phase 2 study in older patients with untreated acute lymphoblastic leukemia","authors":"Bela Patel,&nbsp;Amy A. Kirkwood,&nbsp;Clare J. Rowntree,&nbsp;Krisztina Z. Alapi,&nbsp;Emilio Barretta,&nbsp;Laura Clifton-Hadley,&nbsp;Tom Creasey,&nbsp;SooWah Lee,&nbsp;David I. Marks,&nbsp;Anthony V. Moorman,&nbsp;Nicholas Morley,&nbsp;Pip Patrick,&nbsp;Zaynab Rana,&nbsp;Anita Rijneveld,&nbsp;John A. Snowden,&nbsp;Adele K. Fielding","doi":"10.1002/hem3.88","DOIUrl":"https://doi.org/10.1002/hem3.88","url":null,"abstract":"&lt;p&gt;Poor outcome for older patients with ALL has multiple attributions, including a higher incidence of high-risk genetic features,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; and comorbidities as well as treatment intolerance.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; The phase 2 clinical trial UKALL60+ (NCT01616238) was a collaboration between the UK National Cancer Research Institute Adult ALL Group and the Haemato-Oncology Foundation for Adults in the Netherlands (HOVON) to study treatment choices, quality of life (QoL) and outcomes in older patients with ALL. UKALL60+ offered four treatment “pathways”: pathway A for &lt;i&gt;BCR::ABL1&lt;/i&gt;+ ALL and pathways B, C, and D offering three choices of intensity for &lt;i&gt;BCR::ABL1&lt;/i&gt; negative ALL (Intensive, Intensive-plus and Non-Intensive, respectively), to be selected by investigator and patients. A registration-only choice (Pathway E) was also available. Details of treatment regimens are given in Figure S1. There were no exclusions for any comorbidities. The primary endpoint was complete remission (CR) after a 2-phase induction. Secondary endpoints included event-free survival (EFS) and overall survival (OS), the predictive value of MRD (Ig/TCR quantification, EuroMRD criteria),&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; patient-reported outcomes, and the relationship between the baseline characteristics (Charlson index. ECOG, Karnofsky and Chemotherapy Risk Assessment Scale for High-Age Patients [CRASH] scores) and treatment option chosen.&lt;/p&gt;&lt;p&gt;Between January 2013 and November 2018, 121 eligible patients, median age 69 (interquartile range [IQR]: 65–73, range: 55–83), of whom 107 had B-ALL and 14 T-ALL, were recruited at 34 sites (Table S1). Baseline characteristics are shown in Table 1 alongside the characteristics of the 65 patients aged over 60 years that were recruited to the contemporaneous UKALL14 trial, age 25–65 years. A consort diagram is shown in Figure S2.&lt;/p&gt;&lt;p&gt;Fifty-one of 81 (63%) patients with &lt;i&gt;BCR::ABL1&lt;/i&gt; negative disease were allocated to pathway B, 11% (9/81) to pathway C, and the remaining 26% (21/81) to pathway D. At a median follow-up: 65.9 months (IQR: 38.1–80.9), CR rate after two phases of induction, was achieved by 92% (70% confidence interval [CI]: 82.1–97.2) on pathway A, 70.6% (70% CI: 62.6–77.6) on pathway B, 55.6% (70% CI: 33.6–75.9) on pathway C and 47.6% (70% CI: 34.5%–61%) of those on pathway D. No participant achieved CR on study later than end of induction. Molecular remission occurred in 5/25 (20%; A), 13/51 (25.5%; B), 2/9 (22.2%; C), and 1/21 (4.8%; D) with data available. Only 26/121 (21.5%) patients achieved molecular remission at any point. The relationship between MRD and outcome at the three study timepoints is given in Table S2.&lt;/p&gt;&lt;p&gt;Ninety-six deaths were reported; 32 patients died without achieving CR (22/32, primary cause, ALL). Fifty-six patients died after relapse and eight died in CR (four from infection, three from second malignancies [small cell lung cancer, AML, and CMML] and one unknown). Surv","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 6","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.88","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141264659","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":"Primary central nervous system lymphomas: EHA–ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","authors":"Andreas J. M. Ferreri,&nbsp;Gerald Illerhaus,&nbsp;Jeanette K. Doorduijn,&nbsp;Dorothee P. Auer,&nbsp;Jacoline E. C. Bromberg,&nbsp;Teresa Calimeri,&nbsp;Kate Cwynarski,&nbsp;Christopher P. Fox,&nbsp;Khê Hoang-Xuan,&nbsp;Denis Malaise,&nbsp;Maurilio Ponzoni,&nbsp;Elisabeth Schorb,&nbsp;Carole Soussain,&nbsp;Lena Specht,&nbsp;Emanuele Zucca,&nbsp;Christian Buske,&nbsp;Mats Jerkeman,&nbsp;Martin Dreyling,&nbsp;EHA and ESMO Guidelines Committees","doi":"10.1002/hem3.89","DOIUrl":"https://doi.org/10.1002/hem3.89","url":null,"abstract":"&lt;p&gt;Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS), termed primary CNS lymphoma (PCNSL), is an aggressive neoplasm presenting with disease limited to the CNS. PCNSL was recognised as a distinct entity by the 2017 World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; In the 2022 edition of the WHO classification,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; this neoplasm is classified in the ‘Large B-cell lymphomas of immune-privileged sites' group, whereas it is considered a specific entity in the International Consensus Classification of Mature Lymphoid Neoplasms.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; This entity is also recognised by the WHO classification of CNS tumours.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; PCNSL can arise in both immunocompetent individuals and in those who are immunosuppressed (e.g. individuals living with human immunodeficiency virus and patients receiving immunosuppressive therapies following organ transplant). While no clear predisposing factors have been recognised in immunocompetent individuals, the nature, intensity and duration of immune suppression can influence the risk of PCNSL in those who are immunocompromised.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;This European Hematology Association (EHA)–European Society for Medical Oncology (ESMO) Clinical Practice Guideline (CPG) includes recommendations for the management of immunocompetent patients with PCNSL. In this population, PCNSL accounts for 2% of all primary CNS tumours and 4%-6% of extranodal lymphomas, with an incidence of 0.47/100 000 person-years.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; PCNSL is typically diagnosed in the sixth or seventh decade of life, with a median age at diagnosis of 68 years and a slightly higher frequency in males.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Notably, the recent increase in incidence is limited to patients of &gt;60 years. The incidence of PCNSL in African-American males of &lt;50 years is more than twofold higher than that in Caucasian males of the same age.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Among elderly patients, however, incidence in Caucasian males is twofold higher than that in African-American males. Similar patterns, but with a lesser magnitude, are evident among females.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;A comprehensive assessment of the extent of lymphoma involvement (see Supplementary Table S5, available at https://doi.org/10.1016/10.1016/j.annonc.2023.11.010) is mandatory to determine both the compartments involved within the CNS and the presence of concomitant systemic disease, as recommended by the IPCG guidelines.&lt;span&gt;&lt;sup&gt;13&lt;/sup&gt;&lt;/span&gt; Full neurological and oncohaematological evaluation is crucial before treatment planning. Gadolinium-enhanced MRI is the most relevant tool to define an extension of disease in the brain and spinal cord. Brain MRI should be repeated after biopsy and ideally within 14 days before starting treatment&lt;span&gt;&lt;sup&gt;12&lt;/sup&gt;&lt;/span&gt;; this is supported by extremely high prolifer","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 6","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.89","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141245916","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":"Human leukocyte antigen (HLA) class I expression on Hodgkin–Reed–Sternberg cells is an EBV-independent major determinant of microenvironment composition in classic Hodgkin lymphoma","authors":"Berit Müller-Meinhard,&nbsp;Nicole Seifert,&nbsp;Johanna Grund,&nbsp;Sarah Reinke,&nbsp;Fatih Yalcin,&nbsp;Helen Kaul,&nbsp;Sven Borchmann,&nbsp;Bastian von Tresckow,&nbsp;Peter Borchmann,&nbsp;Annette Plütschow,&nbsp;Julia Richter,&nbsp;Andreas Engert,&nbsp;Michael Altenbuchinger,&nbsp;Paul J. Bröckelmann,&nbsp;Wolfram Klapper","doi":"10.1002/hem3.84","DOIUrl":"https://doi.org/10.1002/hem3.84","url":null,"abstract":"<p>Hodgkin–Reed–Sternberg cells (HRSCs) in classic Hodgkin Lymphoma (HL) frequently lack expression of human leukocyte antigen class I (HLA-I), considered to hamper activation of cytotoxic T cells in the tumor microenvironment (TME). Here, we demonstrate HLA-I expression on HRSCs to be a strong determinant of TME composition whereas expression of HLA-II was associated with only minor differential gene expression in the TME. In HLA-I-positive HL the HRSC content and expression of CCL17/TARC in HRSCs are low, independent of the presence of Epstein–Barr virus in HRSCs. Additionally, HLA-I-positive HL shows a high content of CD8+ cytotoxic T cells. However, an increased expression of the inhibitory immune checkpoint LAG3 on CD8+ T cells in close proximity to HRSCs is observed. Suggesting interference with cytotoxic activity, we observed an absence of clonally expanded T cells in the TME. While HLA-I-positive HL is not associated with an unfavorable clinical course in our cohorts, they share features with the recently described H2 subtype of HL. Given the major differences in TME composition, immune checkpoint inhibitors may differ in their mechanism of action in HLA-I-positive compared to HLA-I-negative HL.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 6","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.84","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141245671","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 put a hex on HOX","authors":"Robert K. Slany","doi":"10.1002/hem3.83","DOIUrl":"https://doi.org/10.1002/hem3.83","url":null,"abstract":"&lt;p&gt;HOX-homeobox transcription factors are best known for their prominent role in embryogenesis where they control body segment identity. This regulatory principle has been “recycled” in adult tissues. HOX proteins frequently regulate the differentiation of tissue stem cells and aberrant HOX function can induce derailed maturation and tumorigenesis. A paradigm for this principle is hematopoiesis where HOXA9, a member of the so-called abdominal HOX proteins, has acquired a notorious reputation for its frequent involvement in leukemogenesis. A number of recurrent genomic aberrations in acute leukemia are associated with elevated HOXA9 expression. Examples are KMT2A (MLL) and NUP98 fusion proteins as well as the very common NPM mutations, which all induce HOXA9 overproduction. Besides, a sizable portion of acute myeloid leukemia with normal karyotype shows abnormally high levels of HOXA9. Overall, HOXA9 dysregulation can be observed in more than 50% of all cases of myeloid leukemia, and generally, this is associated with a negative prognosis (Figure 1).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;At a molecular level, HOXA9 acts as a so-called pioneer transcription factor that binds to a variety of AT-rich binding sites that mark prototypical enhancers and promoters important for hematopoietic precursor cells.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; On a subset of these sequences, HOXA9 assembles a trimeric complex with two other homeodomain transcription factors MEIS1 and PBX3, which contribute further DNA binding specificity. This stabilizes the trimer and in conjunction with other transcription factors leads to the establishment of specific enhancer/promoter sequences in a process that has been called enhancer sharpening.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; In consequence, genes necessary for the growth, proliferation, and survival of hematopoietic precursor cells are strongly activated. Prominent examples of HOXA9/MEIS1/PBX3 targets are &lt;i&gt;MYB&lt;/i&gt;, &lt;i&gt;MYC&lt;/i&gt;, &lt;i&gt;CDK6&lt;/i&gt;, &lt;i&gt;BCL2&lt;/i&gt;, and ribosomal genes to name just a few.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; This explains why the constitutive expression of HOXA9 is such a strong cancer driver. In normal cells, the production of HOXA9 and its binding partners is extinguished during differentiation.&lt;/p&gt;&lt;p&gt;These properties make HOXA9 an attractive target for pharmacological intervention. Unfortunately, transcription factors are notoriously hard to target with pharmaceutically applicable substances.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; The most advanced attempts to derail the HOX network relies on an indirect approach by blocking the function of menin.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Menin is the product of the gene &lt;i&gt;multiple endocrine neoplasia&lt;/i&gt; and it physically binds to the histone methyltransferase KMT2A and its fusion derivatives. This association is necessary for the proper localization on chromatin. Menin inhibitors disrupt the menin KMT2A interaction and show early clinical promise in KMT2A-rearranged and NPM-mutated leukemia. For unknown reasons, ho","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 6","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.83","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141245670","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":"When to stop: Transfusions, difficult conversations and creativity","authors":"Sophie Evans,&nbsp;Stephen P. Hibbs","doi":"10.1002/hem3.79","DOIUrl":"10.1002/hem3.79","url":null,"abstract":"&lt;p&gt;When working within a haematology day unit I met patients receiving regular blood products as part of a ‘best supportive care’ approach. For some, this was because their disease had not responded to rounds of treatment; others had comorbidities or frailty that made chemotherapy inappropriate. I was often presented with a stack of blood product prescription charts to fill in for the following day. Often I had never met the patients in question, and sometimes there was no documentation about their transfusion regime, or most importantly about the aims of transfusion. For some patients having best supportive care for conditions like myelodysplastic syndrome, myelofibrosis, or aplastic anaemia, there are no prescribing guidelines, and the goal of treatment may never have been discussed. The easiest thing, especially when I was multitasking and under pressure to make quick decisions, was to repeat the previous prescription.&lt;/p&gt;&lt;p&gt;But as I got to know particular individuals, questions began to arise in my mind. An elderly patient called Bill* had been attending the day unit every 2 weeks for blood transfusions to relieve symptoms of anaemia, caused by myelodysplastic syndrome. Bill had tried oral chemotherapy but had suffered severe infections requiring hospitalisation as a result, and so his treatment had been stopped. Initially, his fatigue and breathlessness were managed well with transfusions every month, but within 6 months, he found the symptom relief would wane after just a week, leaving him lethargic. Accumulation of excess iron from blood transfusions added to his symptom burden. He went from walking into the day unit looking upbeat to being wheeled in looking withdrawn. I started to wonder whether his treatment made him feel better. How could we measure this? Was it right to keep giving him blood transfusions if they didn't help him feel better?&lt;/p&gt;&lt;p&gt;Since medical school, I have used art and comics to reflect. I have been drawn to patient stories in the realm of graphic medicine, using art and cartoons to explore illness and health narratives. These visual representations are unique reflections in that they allow me to view the artist's perspective in a way that prose does not. Creating something like a comic also allows me time to order my thoughts, to orient and contextualise experiences, and to assign meaning to them. Below is a depiction of an interaction I had with Bill**:&lt;/p&gt;&lt;p&gt;&lt;/p&gt;&lt;p&gt;&lt;/p&gt;&lt;p&gt;&lt;/p&gt;&lt;p&gt;When I revisit and reflect on this comic, I am clear that Bill needed the time and space to explore his feelings and motivations for treatment. My suggestion of a simple binary choice—to stop or to continue transfusions—looked immature and ill-considered when Bill opened up to me. Without knowing ‘the right thing' to say I chose to sit with him until my pager inevitably went off. I felt that I let him down by not giving him an answer or a plan. Bill had clearly expressed his misery in the hours spent at the day unit, but did I have the ri","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 5","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11130759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141160080","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}