HemaSpherePub Date : 2024-10-19DOI: 10.1002/hem3.70033
Frédéric B. Piel, Roshan Colah, Dipty L. Jain
{"title":"Casting light on the national mission to eliminate sickle cell disease in India","authors":"Frédéric B. Piel, Roshan Colah, Dipty L. Jain","doi":"10.1002/hem3.70033","DOIUrl":"https://doi.org/10.1002/hem3.70033","url":null,"abstract":"<p>Sickle cell disease (SCD) is a neglected global public health burden.<span><sup>1</sup></span> Although it primarily affects populations from sub-Saharan Africa,<span><sup>2</sup></span> SCD is also prevalent across the Indian subcontinent, particularly among tribal (or scheduled) populations.<span><sup>3</sup></span> India is the most populated country in the world. According to the latest population estimates of the United Nations World Population Prospects,<span><sup>4</sup></span> 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.<span><sup>2</sup></span> 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.<span><sup>5</sup></span> 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.<span><sup>6</sup></span></p><p>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,<span><sup>7</sup></span> United Kingdom,<span><sup>8</sup></span> Jamaica,<span><sup>9</sup></span> and Brazil.<span><sup>10</sup></span> Pilot studies of these interventions have been conducted in numerous low-income countries.<span><sup>11</sup></span> Cost-benefit analyses conducted in sub-Saharan Africa<span><sup>12</sup></span> and India<span><sup>13</sup></span> 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,<span><sup>14</sup></span> 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.<span><sup>11</sup></span></p><p>In July 2023, the Government of India launched the “National Sickle Cell Anaemia Elimination Mission.”<span><sup>15</sup></span> 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}
HemaSpherePub Date : 2024-10-17DOI: 10.1002/hem3.70028
Roch Houot, Emmanuel Gyan
{"title":"Promoting and supporting leadership in hematology departments","authors":"Roch Houot, Emmanuel Gyan","doi":"10.1002/hem3.70028","DOIUrl":"https://doi.org/10.1002/hem3.70028","url":null,"abstract":"<p>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.<span><sup>1</sup></span> 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.</p><p>Challenges with medical staff retention have also exacerbated the workload of healthcare professionals.<span><sup>2</sup></span> The shortage of healthcare workers in Europe is projected to reach 4.1 million by 2030, including 0.6 million physicians.<span><sup>3</sup></span> Workforce shortages contribute to burnout among physicians and other healthcare workers, which renders the tasks of heads of departments extremely challenging.<span><sup>4, 5</sup></span></p><p>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.<span><sup>2, 6</sup></span> The number of hematologic specialists and the competence of their training have become a concern in European countries.<span><sup>6</sup></span></p><p>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.<span><sup>6</sup></span> 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.<span><sup>2</sup></span> 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.</p><p>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.<span><sup>4</sup></span> The factors associated with the unfavorable experiences included heavy work overload, work-life imbalance, and perceived lack of support from the institution.<span><sup>4, 7</sup></span> 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.<span><","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}
HemaSpherePub Date : 2024-10-13DOI: 10.1002/hem3.70027
Yizhou Huang, Charles E. de Bock
{"title":"Overcoming a T-ALL order: A comprehensive study linking genomics to clinical outcomes","authors":"Yizhou Huang, Charles E. de Bock","doi":"10.1002/hem3.70027","DOIUrl":"https://doi.org/10.1002/hem3.70027","url":null,"abstract":"<p>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.<span><sup>1</sup></span> In an effort to include genomics into the risk stratification for T-ALL, a new study led by Charles Mullighan and David Teachey<span><sup>2</sup></span> 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.</p><p>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 <i>KMT2A</i> fusions present in the ETP-like subtype being mostly <i>KMT2A::AFDN</i> fusion, while the non-ETP subtypes exclusively have <i>KMT2A::MLLT1</i> 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).</p><p>It will come as no surprise that this study confirms the high frequency of recurrent <i>NOTCH1</i> mutations (69% of cases) in T-ALL, second only to <i>CDKN2A</i> 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 <i>NOTCH1</i> 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}
HemaSpherePub Date : 2024-10-08DOI: 10.1002/hem3.70017
Gian Matteo Rigolin, Pier Paolo Olimpieri, Valentina Summa, Simone Celant, Lydia Scarfò, Maria Pia Ballardini, Antonio Urso, Silvia Gambara, Francesco Cavazzini, Paolo Ghia, Antonio Cuneo, Pierluigi Russo
{"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, Pier Paolo Olimpieri, Valentina Summa, Simone Celant, Lydia Scarfò, Maria Pia Ballardini, Antonio Urso, Silvia Gambara, Francesco Cavazzini, Paolo Ghia, Antonio Cuneo, 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}
HemaSpherePub Date : 2024-10-08DOI: 10.1002/hem3.70016
Romane Durand, Céline Bellanger, Géraldine Descamps, Christelle Dousset, Sophie Maïga, Jennifer Derrien, Laura Thirouard, Louise Bouard, Hélène Asnagli, Philip Beer, Andrew Parker, Patricia Gomez-Bougie, Marie-Claire Devilder, Philippe Moreau, Cyrille Touzeau, Agnès Moreau-Aubry, David Chiron, Catherine Pellat-Deceunynck
{"title":"Combined inhibition of CTPS1 and ATR is a metabolic vulnerability in p53-deficient myeloma cells","authors":"Romane Durand, Céline Bellanger, Géraldine Descamps, Christelle Dousset, Sophie Maïga, Jennifer Derrien, Laura Thirouard, Louise Bouard, Hélène Asnagli, Philip Beer, Andrew Parker, Patricia Gomez-Bougie, Marie-Claire Devilder, Philippe Moreau, Cyrille Touzeau, Agnès Moreau-Aubry, David Chiron, Catherine Pellat-Deceunynck","doi":"10.1002/hem3.70016","DOIUrl":"10.1002/hem3.70016","url":null,"abstract":"<p>In multiple myeloma, as in B-cell malignancies, mono- and especially bi-allelic <i>TP53</i> gene inactivation is a high-risk factor for treatment resistance, and there are currently no therapies specifically targeting p53 deficiency. In this study, we evaluated if the loss of cell cycle control in p53-deficient myeloma cells would confer a metabolically actionable vulnerability. We show that CTP synthase 1 (<i>CTPS1</i>), which encodes a CTP synthesis rate-limiting enzyme essential for DNA and RNA synthesis in lymphoid cells, is overexpressed in samples from myeloma patients displaying a high proliferation rate (high <i>MKI67</i> expression) or a low p53 score (synonymous with <i>TP53</i> deletion and/or mutation). This overexpression of <i>CTPS1</i> was associated with reduced survival in two cohorts. Using scRNA-seq analysis in 24 patient samples, we further demonstrate that myeloma cells in the S or G2/M phase display high <i>CTPS1</i> expression. Pharmacological inhibition of CTPS1 by STP-B induced cell cycle arrest in early S phase in isogenic NCI-H929 or XG7 <i>TP53</i><sup>+/+</sup>, <i>TP53</i><sup>−/−</sup>, and <i>TP53</i><sup>R175H/R175H</sup> cells and in a <i>TP53</i><sup>−/R123STOP</sup> patient sample. The functional annotation of transcriptional changes in 10 STP-B-treated myeloma cell lines revealed a decrease in protein translation and confirmed the blockade of cells into the S phase. The pharmacological inhibition of ATR, which governs the intrinsic S/G2 checkpoint, in STP-B-induced S-phase arrested cells synergistically induced cell death in <i>TP53</i><sup>+/+</sup>, <i>TP53</i><sup>−/−</sup>, and <i>TP53</i><sup>R175H/R175H</sup> isogenic cell lines (Bliss score >15). This combination induced replicative stress and caspase-mediated cell death and was highly effective in resistant/refractory patient samples with <i>TP53</i> deletion and/or mutation and in <i>TP53</i><sup>−/−</sup> NCI-H929 xenografted NOD-scid IL2Rgamma mice. Our in vitro, ex vivo, and in vivo data provide the rationale for combined CTPS1 and ATR inhibition for the treatment of p53-deficient patients.</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/PMC11460984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390133","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}
HemaSpherePub Date : 2024-10-08DOI: 10.1002/hem3.70011
Susanne Ghandili, Judith Dierlamm, Carsten Bokemeyer, Henrik Kusche, Frederik Peters
{"title":"The changing influence of neighborhood socioeconomic status on long-term survival in diffuse large B-cell lymphoma patients: A German metropolitan case-control study spanning over three decades","authors":"Susanne Ghandili, Judith Dierlamm, Carsten Bokemeyer, Henrik Kusche, Frederik Peters","doi":"10.1002/hem3.70011","DOIUrl":"10.1002/hem3.70011","url":null,"abstract":"<p>An increasing body of evidence suggests that area-based socioeconomic status (SES) in addition to patient and disease characteristics might be viewed as a relevant prognostic factor for long-term survival in diffuse large B-cell lymphoma (DLBCL) patients.<span><sup>1-6</sup></span> Possible explanations focused on barriers to care due to lack of adequate health insurance resulting in delayed or inadequate care<span><sup>1, 6</sup></span> while there is also evidence that large-scale implementation of CD20-directed immunochemotherapy in the standard of care considerably affected DLBCL-specific survival at the population level.<span><sup>7</sup></span> Here, we investigate the extent to which the introduction of rituximab-based immunochemotherapy has affected socioeconomic status (SES) disparities in all-cause overall survival (OS). This retrospective, case-control study conducts a population-based analysis in a German metropolitan area over a period of 32 years, encompassing the time before and after the introduction of up-front CD20-directed immunochemotherapy within a universal healthcare system.</p><p>DLBCL cases were reported to the Hamburg Cancer Registry between January 1, 1990 and December 31, 2022, as the first occurrence of a primary diagnosis “C83.3” according to the International Statistical Classification of Diseases, German Modification (ICD-10-GM in combination with morphology “9680” or “9684” of the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3). Patients under 18 years, without a residency in Hamburg, with an incomplete record (e.g., information only from pathology report or death certificate), with a DLBCL location at the central nervous system (ICD-O-3 “C70,” “C71,” or “C72”), a follow-up duration of less than 3 months, or incomplete information regarding sex or SES were excluded. For assessing the impact of the introduction of modern immunochemotherapy in 2003, the sample was divided into two sub-cohorts (controls diagnosed between 1990 and 2003 and thus defining the pre-rituximab era and cases diagnosed between 2004 and 2022 defining the rituximab era). Patients with a primary diagnosis of T-cell lymphoma (ICD-10-GM coding “C84.4,” “C84.6,” “C84.7,” “C86.5”) in 1990–2022 were used as negative controls, as these patients did not benefit from the breakthrough in modern immunochemotherapy as DLBCL patient did. The SES index, hereinafter “SES,” refers to the deprivation score “Sozialindex” for the City of Hamburg, which is defined for each of the 103 urban districts in Hamburg by the Social Welfare Authority of the Free and Hanseatic City of Hamburg and calculated in 2011 and 2020. The index is based on statistics related to household income, social housing, house/apartment sizes per head, and welfare reception as an indirect proxy of income.<span><sup>8</sup></span> Based on the quintiles of the index score the SES was grouped into low, middle, and high and thereafter assigned to patients based on ","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/PMC11459230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390138","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}
HemaSpherePub Date : 2024-10-07DOI: 10.1002/hem3.70023
{"title":"Correction to “Single-cell RNA sequencing of pediatric Hodgkin lymphoma to study the inhibition of T cell subtypes”","authors":"","doi":"10.1002/hem3.70023","DOIUrl":"10.1002/hem3.70023","url":null,"abstract":"<p>de Kanter J, Steemers A, González D, et al. Single-cell RNA sequencing of pediatric Hodgkin lymphoma to study the inhibition of T cell subtypes. <i>HemaSphere</i>. 2024;8:e149.</p><p>In the author listing of the manuscript, the first name of an author was incorrectly listed as Daniel Montiel Gonzalez. The correct name is Diego Montiel González.</p><p>The original publication has been corrected. We apologize for this error.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390134","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}
HemaSpherePub Date : 2024-10-07DOI: 10.1002/hem3.70024
Alfredo Rivas-Delgado, Cristina López, Guillem Clot, Ferran Nadeu, Marta Grau, Gerard Frigola, Jan Bosch-Schips, Josefine Radke, Naveed Ishaque, Miguel Alcoceba, Gustavo Tapia, Luis Luizaga, Carmen Barcena, Nicholas Kelleher, Neus Villamor, Tycho Baumann, Ana Muntañola, Juan M. Sancho-Cia, Alejandro M. García-Sancho, Eva Gonzalez-Barca, Estella Matutes, Jordi A. Brito, Kennosuke Karube, Itziar Salaverria, Anna Enjuanes, Stefan Wiemann, Frank L. Heppner, Reiner Siebert, Fina Climent, Elías Campo, Eva Giné, Armando López-Guillermo, Silvia Beà
{"title":"Testicular large B-cell lymphoma is genetically similar to PCNSL and distinct from nodal DLBCL","authors":"Alfredo Rivas-Delgado, Cristina López, Guillem Clot, Ferran Nadeu, Marta Grau, Gerard Frigola, Jan Bosch-Schips, Josefine Radke, Naveed Ishaque, Miguel Alcoceba, Gustavo Tapia, Luis Luizaga, Carmen Barcena, Nicholas Kelleher, Neus Villamor, Tycho Baumann, Ana Muntañola, Juan M. Sancho-Cia, Alejandro M. García-Sancho, Eva Gonzalez-Barca, Estella Matutes, Jordi A. Brito, Kennosuke Karube, Itziar Salaverria, Anna Enjuanes, Stefan Wiemann, Frank L. Heppner, Reiner Siebert, Fina Climent, Elías Campo, Eva Giné, Armando López-Guillermo, Silvia Beà","doi":"10.1002/hem3.70024","DOIUrl":"10.1002/hem3.70024","url":null,"abstract":"<p>Testicular large B-cell lymphoma (TLBCL) is an infrequent and aggressive lymphoma arising in an immune-privileged site and has recently been recognized as a distinct entity from diffuse large B-cell lymphoma (DLBCL). We describe the genetic features of TLBCL and compare them with published series of nodal DLBCL and primary large B-cell lymphomas of the CNS (PCNSL). We collected 61 patients with TLBCL. We performed targeted next-generation sequencing, copy number arrays, and fluorescent <i>in situ</i> hybridization to assess chromosomal rearrangements in 40 cases with available material. Seventy percent of the cases showed localized stages. <i>BCL6</i> rearrangements were detected in 36% of cases, and no concomitant <i>BCL2</i> and <i>MYC</i> rearrangements were found. TLBCL had fewer copy number alterations (<i>p </i>< 0.04) but more somatic variants (<i>p </i>< 0.02) than nodal DLBCL and had more frequent 18q21.32-q23 (<i>BCL2</i>) gains and 6q and 9p21.3 (<i>CDKN2A/B</i>) deletions. <i>PIM1</i>, <i>MYD88</i><sup><i>L265P</i></sup>, <i>CD79B</i>, <i>TBL1XR1</i>, <i>MEF2B</i>, <i>CIITA</i>, <i>EP300,</i> and <i>ETV6</i> mutations were more frequent in TLBCL, and <i>BCL10</i> mutations in nodal DLBCL. There were no major genetic differences between TLBCL and PCNSL. Localized or disseminated TLBCL displayed similar genomic profiles. Using LymphGen, the majority of cases were classified as MCD. However, we observed a subgroup of patients classified as BN2, both in localized and disseminated TLBCL, suggesting a degree of genetic heterogeneity in the TLBCL genetic profile. TLBCL has a distinctive genetic profile similar to PCNSL, supporting its recognition as a separate entity from DLBCL and might provide information to devise targeted therapeutic approaches.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390137","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":"Safe and potent anti-CD19 CAR T-cells with shRNA-IL-6 gene silencing element in patients with refractory or relapsed B-cell acute lymphoblastic leukemia","authors":"Jin-Feng Ma, Jia-Wei Yan, Mei-Jing Liu, Chun-Long Yan, Xiao-Wen Tang, Hui-Ying Qiu, Miao Miao, Yue Han, Li-Min Li, Li-Qing Kang, Nan Xu, Zhou Yu, Jing-Wen Tan, Hong-Jia Zhu, Xu Jia, Zhi-Zhi Zhang, Miao Wang, Hai-Ping Dai, Lei Yu, Sheng-Li Xue, De-Pei Wu, Wen-Jie Gong","doi":"10.1002/hem3.70007","DOIUrl":"10.1002/hem3.70007","url":null,"abstract":"<p>Severe cytokine release syndrome (sCRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) have limited the widespread use of chimeric antigen receptor T (CAR T)-cell therapy. We designed a novel anti-CD19 CAR (ssCART-19) with a small hairpin RNA (shRNA) element to silence the interleukin-6 (IL-6) gene, hypothesizing it could reduce sCRS and ICANS by alleviating monocyte activation and proinflammatory cytokine release. In a post hoc analysis of two clinical trials, we compared ssCART-19 with common CAR T-cells (cCART-19) in relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Among 87 patients, 47 received ssCART-19 and 40 received cCART-19. Grade ≥3 CRS occurred in 14.89% (7/47) of the ssCART-19 group versus 37.5% (15/40) in the cCART-19 group (<i>p</i> = 0.036). ICANS occurred in 4.26% (2/47) of the ssCART-19 group (all grade 1) compared to 15% (2/40) of the cCART-19 group. Patients in the ssCART-19 group showed comparable rates of treatment response (calculated with rates of complete remission and incomplete hematological recovery) were 91.49% (43/47) for ssCART-19 and 85% (34/40) for cCART-19 (<i>p</i> = 0.999). With a median follow-up of 21.9 months, cumulative nonrelapse mortality was 10.4% for ssCART-19 and 13.6% for cCART-19 (<i>p</i> = 0.33). Median overall survival was 37.17 months for ssCART-19 and 32.93 months for cCART-19 (<i>p</i> = 0.40). Median progression-free survival was 24.17 months for ssCART-19 and 9.33 months for cCART-19 (<i>p</i> = 0.23). These data support the safety and efficacy of ssCART-19 for r/r B-ALL, suggesting its potential as a promising therapy.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390136","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}
HemaSpherePub Date : 2024-09-26DOI: 10.1002/hem3.70006
Qirui Zhang, Ton Falqués-Costa, Mattias Pilheden, Helena Sturesson, Tina Ovlund, Vendela Rissler, Anders Castor, Hanne V. H. Marquart, Birgitte Lausen, Thoas Fioretos, Axel Hyrenius-Wittsten, Anna K. Hagström-Andersson
{"title":"Activating mutations remodel the chromatin accessibility landscape to drive distinct regulatory networks in KMT2A-rearranged acute leukemia","authors":"Qirui Zhang, Ton Falqués-Costa, Mattias Pilheden, Helena Sturesson, Tina Ovlund, Vendela Rissler, Anders Castor, Hanne V. H. Marquart, Birgitte Lausen, Thoas Fioretos, Axel Hyrenius-Wittsten, Anna K. Hagström-Andersson","doi":"10.1002/hem3.70006","DOIUrl":"https://doi.org/10.1002/hem3.70006","url":null,"abstract":"<p>Activating <i>FLT3</i> and <i>RAS</i> mutations commonly occur in leukemia with <i>KMT2A</i>-gene rearrangements (<i>KMT2A</i>-r). However, how these mutations cooperate with the <i>KMT2A</i>-r to remodel the epigenetic landscape is unknown. Using a retroviral acute myeloid leukemia (AML) mouse model driven by <i>KMT2A::MLLT3</i>, we show that <i>FLT3</i><sup><i>ITD</i></sup>, <i>FLT3</i><sup><i>N676K</i></sup>, and <i>NRAS</i><sup><i>G12D</i></sup> remodeled the chromatin accessibility landscape and associated transcriptional networks. Although the activating mutations shared a common core of chromatin changes, each mutation exhibits unique profiles with most opened peaks associating with enhancers in intronic or intergenic regions. Specifically, <i>FLT3</i><sup><i>N676K</i></sup> and <i>NRAS</i><sup><i>G12D</i></sup> rewired similar chromatin and transcriptional networks, distinct from those mediated by <i>FLT3</i><sup><i>ITD</i></sup>. Motif analysis uncovered a role for the AP-1 family of transcription factors in <i>KMT2A::MLLT3</i> leukemia with <i>FLT3</i><sup><i>N676K</i></sup> and <i>NRAS</i><sup><i>G12D</i></sup>, whereas Runx1 and Stat5a/Stat5b were active in the presence of <i>FLT3</i><sup><i>ITD</i></sup>. Furthermore, transcriptional programs linked to immune cell regulation were activated in <i>KMT2A</i>-r AML expressing <i>NRAS</i><sup><i>G12D</i></sup> or <i>FLT3</i><sup><i>N676K</i></sup>, and the expression of NKG2D-ligands on <i>KMT2A</i>-r cells rendered them sensitive to CAR T cell-mediated killing. Human <i>KMT2A</i>-r AML cells could be pharmacologically sensitized to NKG2D-CAR T cells by treatment with the histone deacetylase inhibitor LBH589 (panobinostat) which caused upregulation of NKG2D-ligand levels. Co-treatment with LBH589 and NKG2D-CAR T cells enabled robust AML cell killing, and the strongest effect was observed for cells expressing <i>NRAS</i><sup><i>G12D</i></sup>. Finally, the results were validated and extended to acute leukemia in infancy. Combined, activating mutations induced mutation-specific changes in the epigenetic landscape, leading to changes in transcriptional programs orchestrated by specific transcription factor networks.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324559","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}