HemaSphere最新文献

What's wrong with drug development for sickle cell disease?

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2025-02-06 DOI: 10.1002/hem3.70082

Valentine Brousse, David Rees, Raffaella Colombatti

The repeated failure to bring new disease-modifying or curative therapies to individuals with sickle cell disease (SCD) has sadly been demonstrated yet again.Newly marketed drugs, which were much awaited by patients with SCD and provisionally approved for use in many countries, were withdrawn because of clinical trials showing a lack of benefit and/or possible harm. More specifically, crizanlizumab, an antiadhesive monoclonal antibody failed to demonstrate meaningful clinical benefit in a confirmatory phase 3 trial and had its approval withdrawn across Europe by the EMA and equivalent authorities.1 More recently, in September 2024, voxelotor, an anti-sickling agent, approved by the FDA and EMA, was abruptly withdrawn from the market and ongoing clinical trials by the manufacturer, following trial and registry data showing an unexpected excess of deaths and clinical complications in patients taking the drug.2 In the last 5 years, several other drugs have also been dropped after failing to show benefit in late-stage clinical trials in SCD, including rivipansel, sevuparin, ticagrelor, prasugrel, and poloxamer 188.3-7 To date, no drug targeting acute vaso-occlusive pain, the major debilitating and recurrent symptom of the disease, has been successfully developed. At the end of 2024, patients are left with hydroxyurea, a 150-year-old drug, which is effective but definitely not curative. Last but not least, effective curative treatments involving gene therapies are currently not available in Europe, despite highly promising results. So, what is wrong with drug development for SCD?At this stage, it is not entirely clear where the blame lies. It seems possible that useful drugs have been lost to individuals with SCD because of badly designed or executed clinical trials with inappropriate endpoints, complex socioeconomic issues, or other selection biases, possibly driven by the desire of pharmaceutical companies to complete trials and access the market rapidly for economic reasons. Equally, it is possible that ineffective and potentially harmful drugs were prematurely approved for use by many authorities across the world and promoted by healthcare providers and patient associations, eager to have an additional treatment. Clearly, it is important to learn from these experiences.First, it is vital to try and design more appropriate clinical trials. Important factors to consider include how outcomes in SCD vary very widely across different countries and continents, and that the effects of a drug in European countries, where more than 95% of children with sickle cell disease survive to adulthood, may be very different to the effects in some African countries, where fewer than 20%–50% affected children survive.8 Similarly, it is important to focus on appropriate endpoints, with the recent voxelotor experience perhaps illustrating that althoug

{"title":"What's wrong with drug development for sickle cell disease?","authors":"Valentine Brousse, David Rees, Raffaella Colombatti","doi":"10.1002/hem3.70082","DOIUrl":"https://doi.org/10.1002/hem3.70082","url":null,"abstract":"The repeated failure to bring new disease-modifying or curative therapies to individuals with sickle cell disease (SCD) has sadly been demonstrated yet again.Newly marketed drugs, which were much awaited by patients with SCD and provisionally approved for use in many countries, were withdrawn because of clinical trials showing a lack of benefit and/or possible harm. More specifically, crizanlizumab, an antiadhesive monoclonal antibody failed to demonstrate meaningful clinical benefit in a confirmatory phase 3 trial and had its approval withdrawn across Europe by the EMA and equivalent authorities.1 More recently, in September 2024, voxelotor, an anti-sickling agent, approved by the FDA and EMA, was abruptly withdrawn from the market and ongoing clinical trials by the manufacturer, following trial and registry data showing an unexpected excess of deaths and clinical complications in patients taking the drug.2 In the last 5 years, several other drugs have also been dropped after failing to show benefit in late-stage clinical trials in SCD, including rivipansel, sevuparin, ticagrelor, prasugrel, and poloxamer 188.3-7 To date, no drug targeting acute vaso-occlusive pain, the major debilitating and recurrent symptom of the disease, has been successfully developed. At the end of 2024, patients are left with hydroxyurea, a 150-year-old drug, which is effective but definitely not curative. Last but not least, effective curative treatments involving gene therapies are currently not available in Europe, despite highly promising results. So, what is wrong with drug development for SCD?At this stage, it is not entirely clear where the blame lies. It seems possible that useful drugs have been lost to individuals with SCD because of badly designed or executed clinical trials with inappropriate endpoints, complex socioeconomic issues, or other selection biases, possibly driven by the desire of pharmaceutical companies to complete trials and access the market rapidly for economic reasons. Equally, it is possible that ineffective and potentially harmful drugs were prematurely approved for use by many authorities across the world and promoted by healthcare providers and patient associations, eager to have an additional treatment. Clearly, it is important to learn from these experiences.First, it is vital to try and design more appropriate clinical trials. Important factors to consider include how outcomes in SCD vary very widely across different countries and continents, and that the effects of a drug in European countries, where more than 95% of children with sickle cell disease survive to adulthood, may be very different to the effects in some African countries, where fewer than 20%–50% affected children survive.8 Similarly, it is important to focus on appropriate endpoints, with the recent voxelotor experience perhaps illustrating that althoug","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70082","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143248898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Chimeric antigen receptor T-cell therapy outcomes in T cell/histiocyte-rich large B-cell lymphoma and subsequent treatment strategies after disease progression: A GELTAMO/GETH study

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2025-02-04 DOI: 10.1002/hem3.70077

Mariana Bastos-Oreiro, Gloria Iacoboni, Víctor N. Garcés, Ana C. Caballero, Nuria Martínez, Javier Delgado, Aitana Balaguer, Mi Kwon, Sonia Gonzalez de Villambrosia, Rafael Hernani, Ana Jimenez-Ubieto, Rebeca Bailen, Izaskun Zaberio, Alejandro Martín García-Sancho, Pere Barba

Chimeric antigen receptor T-cell therapy (CAR-T) is an effective approach for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). However, some rare variants do not seem to respond as well to this T-cell redirecting strategy. T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is an infrequent subtype of LBCL which typically develops in young, male patients, characterized by an aggressive clinical course and chemo-refractory disease.1, 2 THRLBCL has unique biological characteristics and a inhibitory tumor immune microenvironment.3, 4 It is well-known that the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is a key driver of immune escape;5, 6 this lymphoma subtype has been associated with PD-L1 gene alterations, such as PD-L1 copy gains and high PD-L1 expression on malignant B cells (often surrounded by abundant PD-L1–expressing macrophages and PD-1 + T cells). This distinct clinical behavior, together with its low incidence, have led to an underrepresentation of THRLBCL patients in most clinical trials, including those evaluating CAR T-cell therapy. Therefore, real-world data with this entity is highly anticipated. Taking all of this into consideration, we aimed to assess the safety and efficacy outcomes of THRLBCL after CAR T-cell therapy, outside of the clinical trial setting, as well as the efficacy of postrelapse approaches.We carried out a retrospective, multicentre study including all adult patients with this diagnosis registered in the GELTAMO/GETH-TC database (Grupo Español de Linfomas y Trasplante Autólogo de Médula Ósea/Grupo Español de Trasplante Hematopoyético y Terapia Celular) from April 2019 to January 2024 who had received a CD19-targeted CAR T-cell infusion. The primary endpoint was overall survival (OS) and the secondary endpoints were response rate, progression-free survival (PFS), duration of response (DR), and subsequent therapy outcome. Twenty patients with R/R THRLBCL from 11 Spanish centers received CAR T-cell therapy from April 2019 to December 2023. If the patient had experienced disease progression after CAR-T, participating centers completed an additional database on subsequent treatments and their outcomes. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the ASTCT consensus criteria.7 Response assessment followed the Lugano recommendations.8 OS and PFS were determined from CAR-T cell infusion for CAR T-cell outcomes and since the start of the first subsequent treatment for the following approaches. These were calculated using the Kaplan–Meier method and the Cox model to obtain hazard ratios (HR) with 95% confidence intervals (CI) and p-values. All reported p-values were two-sided, and statistical significance was defined at p < 0.05

{"title":"Chimeric antigen receptor T-cell therapy outcomes in T cell/histiocyte-rich large B-cell lymphoma and subsequent treatment strategies after disease progression: A GELTAMO/GETH study","authors":"Mariana Bastos-Oreiro, Gloria Iacoboni, Víctor N. Garcés, Ana C. Caballero, Nuria Martínez, Javier Delgado, Aitana Balaguer, Mi Kwon, Sonia Gonzalez de Villambrosia, Rafael Hernani, Ana Jimenez-Ubieto, Rebeca Bailen, Izaskun Zaberio, Alejandro Martín García-Sancho, Pere Barba","doi":"10.1002/hem3.70077","DOIUrl":"https://doi.org/10.1002/hem3.70077","url":null,"abstract":"Chimeric antigen receptor T-cell therapy (CAR-T) is an effective approach for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). However, some rare variants do not seem to respond as well to this T-cell redirecting strategy. T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is an infrequent subtype of LBCL which typically develops in young, male patients, characterized by an aggressive clinical course and chemo-refractory disease.1, 2 THRLBCL has unique biological characteristics and a inhibitory tumor immune microenvironment.3, 4 It is well-known that the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is a key driver of immune escape;5, 6 this lymphoma subtype has been associated with PD-L1 gene alterations, such as PD-L1 copy gains and high PD-L1 expression on malignant B cells (often surrounded by abundant PD-L1–expressing macrophages and PD-1 + T cells). This distinct clinical behavior, together with its low incidence, have led to an underrepresentation of THRLBCL patients in most clinical trials, including those evaluating CAR T-cell therapy. Therefore, real-world data with this entity is highly anticipated. Taking all of this into consideration, we aimed to assess the safety and efficacy outcomes of THRLBCL after CAR T-cell therapy, outside of the clinical trial setting, as well as the efficacy of postrelapse approaches.We carried out a retrospective, multicentre study including all adult patients with this diagnosis registered in the GELTAMO/GETH-TC database (Grupo Español de Linfomas y Trasplante Autólogo de Médula Ósea/Grupo Español de Trasplante Hematopoyético y Terapia Celular) from April 2019 to January 2024 who had received a CD19-targeted CAR T-cell infusion. The primary endpoint was overall survival (OS) and the secondary endpoints were response rate, progression-free survival (PFS), duration of response (DR), and subsequent therapy outcome. Twenty patients with R/R THRLBCL from 11 Spanish centers received CAR T-cell therapy from April 2019 to December 2023. If the patient had experienced disease progression after CAR-T, participating centers completed an additional database on subsequent treatments and their outcomes. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the ASTCT consensus criteria.7 Response assessment followed the Lugano recommendations.8 OS and PFS were determined from CAR-T cell infusion for CAR T-cell outcomes and since the start of the first subsequent treatment for the following approaches. These were calculated using the Kaplan–Meier method and the Cox model to obtain hazard ratios (HR) with 95% confidence intervals (CI) and p-values. All reported p-values were two-sided, and statistical significance was defined at p < 0.05","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70077","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dynamic evolution of TCF3-PBX1 leukemias at the single-cell level under chemotherapy pressure

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2025-02-03 DOI: 10.1002/hem3.70071

Mira Kusterer, Mari Lahnalampi, Minna Voutilainen, Alexandra Brand, Sandra Pennisi, Johana Norona, Gaia Gentile, Heike Herzog, Gabriele Greve, Michael Lübbert, Mikko Sipola, Emma Kaartinen, Roman Sankowski, Marco Prinz, Saskia Killmer, Marilyn S. Lago, Bertram Bengsch, Stepan R. Cysar, Konrad Aumann, Martin Werner, Justus Duyster, Olli Lohi, Merja Heinäniemi, Jesús Duque-Afonso

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. The translocation t(1;19), encoding the TCF3-PBX1 fusion, is associated with intermediate risk and central nervous system (CNS) infiltration at relapse. Using our previously generated TCF3-PBX1 conditional knock-in mice, we established a model to study relapsed clones after in vivo chemotherapy treatment, CNS infiltration, and clonal dynamic evolution of phenotypic diversity at the single cell-level using next-generation sequencing technologies and mass cytometry. Mice transplanted with TCF3-PBX1⁺ leukemia cells and treated with vehicle succumbed to disease, whereas 40% of treated mice with prednisolone or daunorubicin survived. Bulk and single-cell RNA sequencing of FACS-sorted GFP+ cells from TCF3-PBX1⁺ leukemias arising after chemotherapy treatment revealed that apoptosis, interleukin-, and TGFβ-signaling pathways were regulated in CNS-infiltrating leukemic cells. Across tissues, upregulation of the MYC signaling pathway was detected in persisting leukemic cells and its downregulation by BRD3/4 inhibition increased sensitivity to chemotherapy. In TCF3-PBX1⁺ leukemia cells collected after chemotherapy treatment, mass cytometry identified increased phosphorylation of STAT3/5 upon preBCR stimulation, which was susceptible to inhibition by the proteasome inhibitor bortezomib. In summary, we developed a TCF3-PBX1⁺ ALL mouse model and characterized relapsed disease after in vivo chemotherapy and cell phenotype dependence on microenvironment. Transcriptomics and phospho-proteomics revealed distinct pathways that may underlie chemotherapy resistance and might be suitable for pharmacological interventions in human ALL.

{"title":"Dynamic evolution of TCF3-PBX1 leukemias at the single-cell level under chemotherapy pressure","authors":"Mira Kusterer, Mari Lahnalampi, Minna Voutilainen, Alexandra Brand, Sandra Pennisi, Johana Norona, Gaia Gentile, Heike Herzog, Gabriele Greve, Michael Lübbert, Mikko Sipola, Emma Kaartinen, Roman Sankowski, Marco Prinz, Saskia Killmer, Marilyn S. Lago, Bertram Bengsch, Stepan R. Cysar, Konrad Aumann, Martin Werner, Justus Duyster, Olli Lohi, Merja Heinäniemi, Jesús Duque-Afonso","doi":"10.1002/hem3.70071","DOIUrl":"https://doi.org/10.1002/hem3.70071","url":null,"abstract":"Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. The translocation t(1;19), encoding the TCF3-PBX1 fusion, is associated with intermediate risk and central nervous system (CNS) infiltration at relapse. Using our previously generated TCF3-PBX1 conditional knock-in mice, we established a model to study relapsed clones after in vivo chemotherapy treatment, CNS infiltration, and clonal dynamic evolution of phenotypic diversity at the single cell-level using next-generation sequencing technologies and mass cytometry. Mice transplanted with TCF3-PBX1+ leukemia cells and treated with vehicle succumbed to disease, whereas 40% of treated mice with prednisolone or daunorubicin survived. Bulk and single-cell RNA sequencing of FACS-sorted GFP+ cells from TCF3-PBX1+ leukemias arising after chemotherapy treatment revealed that apoptosis, interleukin-, and TGFβ-signaling pathways were regulated in CNS-infiltrating leukemic cells. Across tissues, upregulation of the MYC signaling pathway was detected in persisting leukemic cells and its downregulation by BRD3/4 inhibition increased sensitivity to chemotherapy. In TCF3-PBX1+ leukemia cells collected after chemotherapy treatment, mass cytometry identified increased phosphorylation of STAT3/5 upon preBCR stimulation, which was susceptible to inhibition by the proteasome inhibitor bortezomib. In summary, we developed a TCF3-PBX1+ ALL mouse model and characterized relapsed disease after in vivo chemotherapy and cell phenotype dependence on microenvironment. Transcriptomics and phospho-proteomics revealed distinct pathways that may underlie chemotherapy resistance and might be suitable for pharmacological interventions in human ALL.","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70071","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Waiting and seeing: The importance of long-term system-wide monitoring of mouse models of disease

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2025-01-31 DOI: 10.1002/hem3.70087

David G. Kent

Researchers undertaking complex in vivo research ranging from assessing hematopoietic stem cell (HSC) function to complex disease modeling are all too familiar with the pressures to find a phenotype and publish the resulting data as soon as possible. Moreover, the vagaries of the academic system are such that the individual driving the project is also often under pressure to deliver the first story and move on to the next project, making it doubly difficult to delve deeper into the biology of a specific mouse model. Therefore, the field has many exciting mouse models where only the surface has been scratched with respect to the biological function of a particular mutation. Running counter to this is a recent paper in HemaSphere1 from the McKinney-Freeman lab that explores a mouse model of G-protein-coupled receptor-associated sorting proteins (GPRASPs) longitudinally for its wider effects on the hematopoietic system. The paper “GPRASP protein deficiency triggers lymphoproliferative disease by affecting B-cell differentiation”1 is a direct follow-up on the exciting story detailing GPRASP functional consequences in HSCs that appeared several years ago in Blood.2 This new study in HemaSphere shows the power of undertaking detailed biological assessments of a mouse model beyond the initial findings in the area of research that a specific lab has expertise and is a great example of the power of fully characterizing and monitoring mouse models.GPRASPs were identified as candidate molecules for altering HSC function due to their expression in long-term HSCs and evidence in other tissues of influencing and mediating microenvironmental changes. With previous functions highlighted in development and the maintenance of homeostasis, they represented strong targets for functional validation. The McKinney-Freeman lab took the first steps by individually silencing GPRASP family members in the setting of HSC transplantation to test whether GPRASP loss of function would enhance homing and function of HSCs. They showed increased survival, quiescence, migration, and homing and further went on to detail that GPRASPs were involved in the degradation of CXCR4, which meant that their removal increased the stability of CXCR4, a known regulator of HSC lodgement and homing in the adult bone marrow.2 Notably, CXCR4 is the main chemokine receptor for stromal-derived factor 1 (SDF1), the key driver of the HSC chemotaxis that allows bone marrow homing to occur and is highly expressed on HSCs. That said, CXCR4 is also expressed in a range of other cells, and this is where the story gets interesting in this study.Many researchers would have stopped the study here and moved on to a new model, but as shown in the recent issue of HemaSphere, Morales-Hernández has now followed up the mouse model and discovered another exciting role for GPRASPs

{"title":"Waiting and seeing: The importance of long-term system-wide monitoring of mouse models of disease","authors":"David G. Kent","doi":"10.1002/hem3.70087","DOIUrl":"10.1002/hem3.70087","url":null,"abstract":"Researchers undertaking complex in vivo research ranging from assessing hematopoietic stem cell (HSC) function to complex disease modeling are all too familiar with the pressures to find a phenotype and publish the resulting data as soon as possible. Moreover, the vagaries of the academic system are such that the individual driving the project is also often under pressure to deliver the first story and move on to the next project, making it doubly difficult to delve deeper into the biology of a specific mouse model. Therefore, the field has many exciting mouse models where only the surface has been scratched with respect to the biological function of a particular mutation. Running counter to this is a recent paper in HemaSphere1 from the McKinney-Freeman lab that explores a mouse model of G-protein-coupled receptor-associated sorting proteins (GPRASPs) longitudinally for its wider effects on the hematopoietic system. The paper “GPRASP protein deficiency triggers lymphoproliferative disease by affecting B-cell differentiation”1 is a direct follow-up on the exciting story detailing GPRASP functional consequences in HSCs that appeared several years ago in Blood.2 This new study in HemaSphere shows the power of undertaking detailed biological assessments of a mouse model beyond the initial findings in the area of research that a specific lab has expertise and is a great example of the power of fully characterizing and monitoring mouse models.GPRASPs were identified as candidate molecules for altering HSC function due to their expression in long-term HSCs and evidence in other tissues of influencing and mediating microenvironmental changes. With previous functions highlighted in development and the maintenance of homeostasis, they represented strong targets for functional validation. The McKinney-Freeman lab took the first steps by individually silencing GPRASP family members in the setting of HSC transplantation to test whether GPRASP loss of function would enhance homing and function of HSCs. They showed increased survival, quiescence, migration, and homing and further went on to detail that GPRASPs were involved in the degradation of CXCR4, which meant that their removal increased the stability of CXCR4, a known regulator of HSC lodgement and homing in the adult bone marrow.2 Notably, CXCR4 is the main chemokine receptor for stromal-derived factor 1 (SDF1), the key driver of the HSC chemotaxis that allows bone marrow homing to occur and is highly expressed on HSCs. That said, CXCR4 is also expressed in a range of other cells, and this is where the story gets interesting in this study.Many researchers would have stopped the study here and moved on to a new model, but as shown in the recent issue of HemaSphere, Morales-Hernández has now followed up the mouse model and discovered another exciting role for GPRASPs","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11783231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cytopenic overt primary myelofibrosis at presentation: Analysis of outcomes in the prospective, real-world ERNEST-2 registry

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2025-01-31 DOI: 10.1002/hem3.70072

Paola Guglielmelli, Arianna Ghirardi, Alessandra Carobbio, Arianna Masciulli, Lucrezia Morrone, Barbara Mora, Elisa Rumi, Ana Triguero, Maria C. Finazzi, Helna Pettersson, Valentina Boldrini, Daniele Vanni, Alessandro Rambaldi, Francesco Passamonti, Alberto Alvarez-Larràn, Bjorn Andreasson, Alessandro M. Vannucchi, Tiziano Barbui

Unlike polycythemia vera (PV), essential thrombocythemia (ET), and prefibrotic primary myelofibrosis (pre-PMF), which show variable expansion of myeloid cell lineages at diagnosis, overt primary myelofibrosis (PMF) may present with uni- or multi-lineage cytosis and isolated or multiple cytopenias, the latter feature configuring a “cytopenic” phenotype (CyP).1 Among 1000 patients with PMF seen at Mayo Clinic, anemia and thrombocytopenia at diagnosis were found in 38%, including 24% requiring transfusions and 18%, respectively; those figures increased to 58%, 46%, and 28% for patients within 1 year from diagnosis.2 Furthermore, cytopenias are exacerbated by treatments, including JAK inhibitors.3, 4 Cytopenic MF is associated with a poorer prognosis compared to the “myeloproliferative” (MyP) counterpart and poses therapeutic challenges because of limited treatment options.5 In the aforementioned study, overall survival (OS) was 7.9 years for patients without anemia compared to 4.9, 3.4, and 2.1 years, respectively, for patients with mild, moderate, and severe anemia. These findings were confirmed in other retrospective studies.6 Also, isolated thrombocytopenia is prognostically adverse.7-9 Anemia, especially if transfusion dependent, and thrombocytopenia, are individually enlisted in conventional risk scores for survival prediction,10-12 including MIPSS70/v2.0 score,13-15 and are associated with increased risk of blast phase (BP).16We report herein the analysis of data derived from the European multicenter collaborative ERNEST registry, specifically focusing on clinical characteristics and outcomes of MF patients with CyP. The ERNEST project prospectively enrolled patients with primary and secondary MF across tertiary European centers, with the aim of assuring reliability, representativeness, and comparability of real-world data. The project, promoted by the European LeukemiaNet (ELN) and coordinated by FROM (Research Foundation at Papa Giovanni XXIII Hospital in Bergamo), was supported by Novartis through a research collaboration. From February 2013 to May 2014, 1292 patients with WHO diagnosis of MF were included (ERNEST-1); for a subset of 584 overt PMF patients, enrolled in three countries (Italy, Spain, Sweden), extended follow-up data were available until the latest cutoff of December 2020 (ERNEST-2). The Institutional Review Board and Ethical Committee of each Centre approved the study, which was conducted in accordance with the Declaration of Helsinki. After the exclusion of 25 patients with incomplete data at diagnosis, a total of 559 patients constituted the current study population. A CyP was defined by the presence of at least one cytopenia at diagnosis: (i) sex-adjusted anemia (An), that is, hemoglobin (Hb) < 11

{"title":"Cytopenic overt primary myelofibrosis at presentation: Analysis of outcomes in the prospective, real-world ERNEST-2 registry","authors":"Paola Guglielmelli, Arianna Ghirardi, Alessandra Carobbio, Arianna Masciulli, Lucrezia Morrone, Barbara Mora, Elisa Rumi, Ana Triguero, Maria C. Finazzi, Helna Pettersson, Valentina Boldrini, Daniele Vanni, Alessandro Rambaldi, Francesco Passamonti, Alberto Alvarez-Larràn, Bjorn Andreasson, Alessandro M. Vannucchi, Tiziano Barbui","doi":"10.1002/hem3.70072","DOIUrl":"10.1002/hem3.70072","url":null,"abstract":"Unlike polycythemia vera (PV), essential thrombocythemia (ET), and prefibrotic primary myelofibrosis (pre-PMF), which show variable expansion of myeloid cell lineages at diagnosis, overt primary myelofibrosis (PMF) may present with uni- or multi-lineage cytosis and isolated or multiple cytopenias, the latter feature configuring a “cytopenic” phenotype (CyP).1 Among 1000 patients with PMF seen at Mayo Clinic, anemia and thrombocytopenia at diagnosis were found in 38%, including 24% requiring transfusions and 18%, respectively; those figures increased to 58%, 46%, and 28% for patients within 1 year from diagnosis.2 Furthermore, cytopenias are exacerbated by treatments, including JAK inhibitors.3, 4 Cytopenic MF is associated with a poorer prognosis compared to the “myeloproliferative” (MyP) counterpart and poses therapeutic challenges because of limited treatment options.5 In the aforementioned study, overall survival (OS) was 7.9 years for patients without anemia compared to 4.9, 3.4, and 2.1 years, respectively, for patients with mild, moderate, and severe anemia. These findings were confirmed in other retrospective studies.6 Also, isolated thrombocytopenia is prognostically adverse.7-9 Anemia, especially if transfusion dependent, and thrombocytopenia, are individually enlisted in conventional risk scores for survival prediction,10-12 including MIPSS70/v2.0 score,13-15 and are associated with increased risk of blast phase (BP).16We report herein the analysis of data derived from the European multicenter collaborative ERNEST registry, specifically focusing on clinical characteristics and outcomes of MF patients with CyP. The ERNEST project prospectively enrolled patients with primary and secondary MF across tertiary European centers, with the aim of assuring reliability, representativeness, and comparability of real-world data. The project, promoted by the European LeukemiaNet (ELN) and coordinated by FROM (Research Foundation at Papa Giovanni XXIII Hospital in Bergamo), was supported by Novartis through a research collaboration. From February 2013 to May 2014, 1292 patients with WHO diagnosis of MF were included (ERNEST-1); for a subset of 584 overt PMF patients, enrolled in three countries (Italy, Spain, Sweden), extended follow-up data were available until the latest cutoff of December 2020 (ERNEST-2). The Institutional Review Board and Ethical Committee of each Centre approved the study, which was conducted in accordance with the Declaration of Helsinki. After the exclusion of 25 patients with incomplete data at diagnosis, a total of 559 patients constituted the current study population. A CyP was defined by the presence of at least one cytopenia at diagnosis: (i) sex-adjusted anemia (An), that is, hemoglobin (Hb) < 11","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11783225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Diagnosis and treatment of AML in the context of WHO and ICC 2022 classifications: Divergent nomenclature converges on common therapies

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2025-01-31 DOI: 10.1002/hem3.70083

Uwe Platzbecker, Richard A. Larson, Sandeep Gurbuxani

As a consequence of rapidly developing genetic technologies and advances in the understanding of the pathogenesis of acute myeloid leukemia (AML), the classification of AML has moved gradually from a morphologic and cytochemical-based system to one that is genetically defined. Recent molecular and genetic developments have been integrated into the diagnostic criteria for AML in the fifth edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours and the 2022 International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias, expanding the list of genetically defined entities. In this review article, we use a case-based format describing the diagnostic workup, risk stratification, and possible treatment options to highlight the impact of the 2022 WHO and ICC classifications on clinical practice. We show that despite much commentary and anguish, there is a significant overlap between the two classifications. We further highlight the fact that even for entities with divergent nomenclature, such as TP53-mutated AML, the actual genetic lesion leads to convergent therapy.

{"title":"Diagnosis and treatment of AML in the context of WHO and ICC 2022 classifications: Divergent nomenclature converges on common therapies","authors":"Uwe Platzbecker, Richard A. Larson, Sandeep Gurbuxani","doi":"10.1002/hem3.70083","DOIUrl":"10.1002/hem3.70083","url":null,"abstract":"As a consequence of rapidly developing genetic technologies and advances in the understanding of the pathogenesis of acute myeloid leukemia (AML), the classification of AML has moved gradually from a morphologic and cytochemical-based system to one that is genetically defined. Recent molecular and genetic developments have been integrated into the diagnostic criteria for AML in the fifth edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours and the 2022 International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias, expanding the list of genetically defined entities. In this review article, we use a case-based format describing the diagnostic workup, risk stratification, and possible treatment options to highlight the impact of the 2022 WHO and ICC classifications on clinical practice. We show that despite much commentary and anguish, there is a significant overlap between the two classifications. We further highlight the fact that even for entities with divergent nomenclature, such as TP53-mutated AML, the actual genetic lesion leads to convergent therapy.","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11783223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Limited stage mantle cell lymphoma: A real-world study of primary treatment and prognosis in Sweden 2006–2018

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2025-01-27 DOI: 10.1002/hem3.70080

Alexandra Albertsson-Lindblad, Sara Ekberg, Ingrid Glimelius, Fredrik Ellin, Kristina Sonnevi, Catharina Lewerin, Lena Brandefors, Karin E. Smedby, Mats Jerkeman

Radiotherapy (RT) is an alternative to chemoimmunotherapy (CIT) in early-stage mantle cell lymphoma (MCL) as associated with activity and lower toxicity compared to CIT.1-3 However, little is known how to stratify patients in relation to prognostic factors such as MCL International Prognostic Index (MIPI) and high-risk biology.4-7 Here, we present overall (OS) and progression-free survival (PFS) in relation to prognostic factors and given treatment in a population-based cohort of patients diagnosed with stage I–II MCL in Sweden 2006–2018.The study included all patients diagnosed with MCL 2006–2018 in the Swedish Lymphoma Register (SLR).8 Early-stage MCL was defined as nodal or extra-nodal stage I or II disease, based on radiology with computer or positron emission tomography (PET) scan, peripheral blood count, and bone marrow examination. Patients were followed up to April 20, 2022. Patient characteristics, treatment, response, and data on documented relapse or progression proved by either radiology and/or biopsy were retrieved from SLR and supplementary medical records review. Data for calculation of Charlson comorbidity index (CCI) and survival data were retrieved from the National Patient Register and the Swedish Population Register respectively.9 Treatment was categorized as CIT, curative (≥24 Gy) or non-curative (<24 Gy) RT, watch and wait, or as other/missing. CIT followed by RT was grouped with CIT. High-risk biology was defined as blastoid histology, Ki67 ≥ 30%, or p53 overexpression (OE). Comparison of variables between subgroups was performed by Student's t-test, Mann–Whitney's test, or chi-square test. The Kaplan–Meier estimator was used for calculation of PFS and OS from end of first treatment if not otherwise specified until date of relapse or progression (PD) (PFS) or end of FU (OS + PFS). Hazard ratios (HRs) were estimated with Cox regression in univariable models by age, sex, ECOG, MIPI, stage, elevated lactate dehydrogenase (LDH), and RT ≥ 24 Gy and by multivariable models including variables with significant HRs (p < 0.05) in univariable analysis. Stata SE 16.1 was used for all analysis. The study was approved by the Regional Board of the Ethical Committee in Lund, Sweden (2018/739).In total, 1412 MCL patients were identified, of which 173 (13%) fulfilled criteria for stage I–II disease. Out of stage I-II, PET-scan was used for staging in 8% and 22 (13%) patients had extra-nodal disease. Data on high-risk biology was available in 66 (64%) patients, of whom 30 (45%) had at least one high-risk biology marker. Stage I–II patients had lower MIPI, less frequently B symptoms, and elevated LDH compared to stage III–IV (Supporting Information S1: Table 1). Stage I (n = 72) patients were of lower age and blastoid MCL was less frequent compared to stage II (n = 101), but similar in B symptoms,

{"title":"Limited stage mantle cell lymphoma: A real-world study of primary treatment and prognosis in Sweden 2006–2018","authors":"Alexandra Albertsson-Lindblad, Sara Ekberg, Ingrid Glimelius, Fredrik Ellin, Kristina Sonnevi, Catharina Lewerin, Lena Brandefors, Karin E. Smedby, Mats Jerkeman","doi":"10.1002/hem3.70080","DOIUrl":"10.1002/hem3.70080","url":null,"abstract":"Radiotherapy (RT) is an alternative to chemoimmunotherapy (CIT) in early-stage mantle cell lymphoma (MCL) as associated with activity and lower toxicity compared to CIT.1-3 However, little is known how to stratify patients in relation to prognostic factors such as MCL International Prognostic Index (MIPI) and high-risk biology.4-7 Here, we present overall (OS) and progression-free survival (PFS) in relation to prognostic factors and given treatment in a population-based cohort of patients diagnosed with stage I–II MCL in Sweden 2006–2018.The study included all patients diagnosed with MCL 2006–2018 in the Swedish Lymphoma Register (SLR).8 Early-stage MCL was defined as nodal or extra-nodal stage I or II disease, based on radiology with computer or positron emission tomography (PET) scan, peripheral blood count, and bone marrow examination. Patients were followed up to April 20, 2022. Patient characteristics, treatment, response, and data on documented relapse or progression proved by either radiology and/or biopsy were retrieved from SLR and supplementary medical records review. Data for calculation of Charlson comorbidity index (CCI) and survival data were retrieved from the National Patient Register and the Swedish Population Register respectively.9 Treatment was categorized as CIT, curative (≥24 Gy) or non-curative (<24 Gy) RT, watch and wait, or as other/missing. CIT followed by RT was grouped with CIT. High-risk biology was defined as blastoid histology, Ki67 ≥ 30%, or p53 overexpression (OE). Comparison of variables between subgroups was performed by Student's t-test, Mann–Whitney's test, or chi-square test. The Kaplan–Meier estimator was used for calculation of PFS and OS from end of first treatment if not otherwise specified until date of relapse or progression (PD) (PFS) or end of FU (OS + PFS). Hazard ratios (HRs) were estimated with Cox regression in univariable models by age, sex, ECOG, MIPI, stage, elevated lactate dehydrogenase (LDH), and RT ≥ 24 Gy and by multivariable models including variables with significant HRs (p < 0.05) in univariable analysis. Stata SE 16.1 was used for all analysis. The study was approved by the Regional Board of the Ethical Committee in Lund, Sweden (2018/739).In total, 1412 MCL patients were identified, of which 173 (13%) fulfilled criteria for stage I–II disease. Out of stage I-II, PET-scan was used for staging in 8% and 22 (13%) patients had extra-nodal disease. Data on high-risk biology was available in 66 (64%) patients, of whom 30 (45%) had at least one high-risk biology marker. Stage I–II patients had lower MIPI, less frequently B symptoms, and elevated LDH compared to stage III–IV (Supporting Information S1: Table 1). Stage I (n = 72) patients were of lower age and blastoid MCL was less frequent compared to stage II (n = 101), but similar in B symptoms, ","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

sMAdCAM-1 is decreased after allo-HCT, along with gut microbiota dysbiosis, and is associated with hematopoietic recovery

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2025-01-27 DOI: 10.1002/hem3.70074

Karen Fadel, Lama Siblany, Razan Mohty, Nicolas Stocker, Ludovic Suner, Eolia Brissot, Anne Banet, Simona Sestili, Rémy Duléry, Zoé Van de Wyngaert, Laure Ricard, Ramdane Belhocine, Agnès Bonnin, Antoine Capes, Tounes Ledraa, Frederic De Vassoigne, Harry Sokol, Mohamad Mohty, Béatrice Gaugler, Florent Malard

Chemotherapy and total-body irradiation-based conditioning regimens, together with the use of broad-spectrum antibiotics during allogeneic hematopoietic cell transplantation (allo-HCT), induce gut microbiota dysbiosis,1, 2 which is associated with poor patient outcomes.1 Furthermore, it has been reported that the intestinal microbiome and the hematopoietic system interplay.3, 4Fidelle et al. showed recently in a cohort of non-small cell lung cancer patients that antibiotic-induced dysbiosis led to the loss of MAdCAM-1 tissular expression and decreased soluble MadCAM-1 (sMAdCAM-1).5 MAdCAM-1, expressed on endothelial cells, interacts with the α4β7 integrin to direct hematopoietic stem cell (HSC) homing and engraftment6 and the trafficking of lymphocytes into Peyer's patches and the intestinal lamina propria.7 It is established that the MAdCAM-1/α4β7 axis is implicated in the recruitment of effector donor CD8 T cells to the recipient intestine and that blocking this axis prevents graft-versus-host disease (GvHD).8, 9 Altogether, this suggests that the interplay between the MAdCAM-1/α4β7 axis, the microbiota, and the use of antibiotics warrants investigation in the setting of allo-HCT. We, therefore, aimed to investigate the impact of sMAdCAM-1 level on patients' outcomes after allo-HCT, particularly GvHD and hematopoietic recovery.This retrospective study comprised a cohort of 279 consecutive adult patients with a hematological malignancy who underwent allo-HCT between October 2012 and June 2018. Patient and disease characteristics are detailed in Table 1. Written informed consent was obtained from each patient in accordance with the principles of the Declaration of Helsinki. Sera were collected prior to allo-HCT (baseline timepoint), the day of allo-HCT (D0), and at D20, 90, and 360 after allo-HCT, and sMAdCAM-1 was quantified using the Human MAdCAM-1 DuoSet ELISA kit (Bio-Techne/R&D Systems). Patients' supportive care (including infection prophylaxis), serum preparation and sMAdCAM-1 quantification, stool collection, DNA extraction and 16S sequencing, and analysis and statistical methods are listed in the Supporting Information File.Because tissue biopsies are difficult to obtain and sMAdCAM-1 originates from cleavage of tissular MAdCAM-1, we evaluated sMAdCAM-1 concentrations in the blood using ELISA as a surrogate marker for tissular MadCAM-1 expression. sMAdCAM-1 levels significantly decreased following conditioning, reaching 4234 pg/mL at D0 versus 8815 pg/mL at baseline (p < 0.0001), and continued to decline to 3277 pg/mL by D20 (p < 0.0001). At D90 (n = 221), while sMAdCAM-1 levels increased compared to D20, being 4275 pg/mL (p < 0.0001), it remained significantly lower compared to baseline samples (p <

{"title":"sMAdCAM-1 is decreased after allo-HCT, along with gut microbiota dysbiosis, and is associated with hematopoietic recovery","authors":"Karen Fadel, Lama Siblany, Razan Mohty, Nicolas Stocker, Ludovic Suner, Eolia Brissot, Anne Banet, Simona Sestili, Rémy Duléry, Zoé Van de Wyngaert, Laure Ricard, Ramdane Belhocine, Agnès Bonnin, Antoine Capes, Tounes Ledraa, Frederic De Vassoigne, Harry Sokol, Mohamad Mohty, Béatrice Gaugler, Florent Malard","doi":"10.1002/hem3.70074","DOIUrl":"10.1002/hem3.70074","url":null,"abstract":"Chemotherapy and total-body irradiation-based conditioning regimens, together with the use of broad-spectrum antibiotics during allogeneic hematopoietic cell transplantation (allo-HCT), induce gut microbiota dysbiosis,1, 2 which is associated with poor patient outcomes.1 Furthermore, it has been reported that the intestinal microbiome and the hematopoietic system interplay.3, 4Fidelle et al. showed recently in a cohort of non-small cell lung cancer patients that antibiotic-induced dysbiosis led to the loss of MAdCAM-1 tissular expression and decreased soluble MadCAM-1 (sMAdCAM-1).5 MAdCAM-1, expressed on endothelial cells, interacts with the α4β7 integrin to direct hematopoietic stem cell (HSC) homing and engraftment6 and the trafficking of lymphocytes into Peyer's patches and the intestinal lamina propria.7 It is established that the MAdCAM-1/α4β7 axis is implicated in the recruitment of effector donor CD8 T cells to the recipient intestine and that blocking this axis prevents graft-versus-host disease (GvHD).8, 9 Altogether, this suggests that the interplay between the MAdCAM-1/α4β7 axis, the microbiota, and the use of antibiotics warrants investigation in the setting of allo-HCT. We, therefore, aimed to investigate the impact of sMAdCAM-1 level on patients' outcomes after allo-HCT, particularly GvHD and hematopoietic recovery.This retrospective study comprised a cohort of 279 consecutive adult patients with a hematological malignancy who underwent allo-HCT between October 2012 and June 2018. Patient and disease characteristics are detailed in Table 1. Written informed consent was obtained from each patient in accordance with the principles of the Declaration of Helsinki. Sera were collected prior to allo-HCT (baseline timepoint), the day of allo-HCT (D0), and at D20, 90, and 360 after allo-HCT, and sMAdCAM-1 was quantified using the Human MAdCAM-1 DuoSet ELISA kit (Bio-Techne/R&D Systems). Patients' supportive care (including infection prophylaxis), serum preparation and sMAdCAM-1 quantification, stool collection, DNA extraction and 16S sequencing, and analysis and statistical methods are listed in the Supporting Information File.Because tissue biopsies are difficult to obtain and sMAdCAM-1 originates from cleavage of tissular MAdCAM-1, we evaluated sMAdCAM-1 concentrations in the blood using ELISA as a surrogate marker for tissular MadCAM-1 expression. sMAdCAM-1 levels significantly decreased following conditioning, reaching 4234 pg/mL at D0 versus 8815 pg/mL at baseline (p < 0.0001), and continued to decline to 3277 pg/mL by D20 (p < 0.0001). At D90 (n = 221), while sMAdCAM-1 levels increased compared to D20, being 4275 pg/mL (p < 0.0001), it remained significantly lower compared to baseline samples (p &lt","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Combining SKY92 gene expression profiling and FISH (according to R2-ISS) defines ultra-high-risk Multiple Myeloma

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2025-01-23 DOI: 10.1002/hem3.70078

Xiang Zhou, Annika Hofmann, Benedict Engel, Cornelia Vogt, Silvia Nerreter, Yoko Tamamushi, Friederike Schmitt, Maria leberzammer, Emilia Stanojkovska, Marietta Truger, Xianghui Xiao, Christine Riedhammer, Maximilian J. Steinhardt, Mara John, Julia Mersi, Seungbin Han, Umair Munawar, Johannes M. Waldschmidt, Claudia Haferlach, Hermann Einsele, Leo Rasche, K. Martin Kortüm

The definition of high-risk (HR) multiple myeloma (MM) is still a matter of debate. We prospectively evaluated the HR detection using FISH in combination with SKY92 gene expression profiling in 258 MM patients (newly diagnosed [ND] MM: n = 109; relapsed/refractory [RR] MM: n = 149). HR SKY92 was significantly enriched in RRMM (57/121, 47.1%) compared with NDMM (17/95, 17.9%) (p < 0.0001). RRMM patients with HR SKY92 showed significantly shorter progression-free survival (PFS) (p < 0.0001) and overall survival (OS) (p < 0.0001) than SKY92 standard-risk (SR). In NDMM, HR SKY92 also indicated a significantly inferior PFS (p < 0.0001) in comparison with SR. We combined SKY92 with FISH (HR: t(4;14), del17p, +1q21 according to R2-ISS) in 181 patients (NDMM: n = 79; RRMM: n = 102). We found a discrepancy between both risk stratification systems, with only 49 (27.1%) patients being defined as HR by both SKY92 and FISH (“double HR”). In terms of survival outcomes, “double HR” presented a negative prognostic factor for PFS in both NDMM (p < 0.0001) and RRMM (p < 0.0001). Furthermore, “double-HR” patients showed the worst OS (p = 0.000 13) in RRMM. Additionally, whole genome sequencing (WGS) revealed CRBN mutation (n = 3) and bi-allelic events (mutation and/or deletion) in TP53 (n = 7) and TNFRSF17 (n = 1). Altogether, we provide the first prospective real-world evidence that the combination SKY92 and FISH (according to R2-ISS) identifies a subset of patients with ultra-HR MM, and WGS complements SKY92 and FISH in MM risk stratification.

{"title":"Combining SKY92 gene expression profiling and FISH (according to R2-ISS) defines ultra-high-risk Multiple Myeloma","authors":"Xiang Zhou, Annika Hofmann, Benedict Engel, Cornelia Vogt, Silvia Nerreter, Yoko Tamamushi, Friederike Schmitt, Maria leberzammer, Emilia Stanojkovska, Marietta Truger, Xianghui Xiao, Christine Riedhammer, Maximilian J. Steinhardt, Mara John, Julia Mersi, Seungbin Han, Umair Munawar, Johannes M. Waldschmidt, Claudia Haferlach, Hermann Einsele, Leo Rasche, K. Martin Kortüm","doi":"10.1002/hem3.70078","DOIUrl":"10.1002/hem3.70078","url":null,"abstract":"The definition of high-risk (HR) multiple myeloma (MM) is still a matter of debate. We prospectively evaluated the HR detection using FISH in combination with SKY92 gene expression profiling in 258 MM patients (newly diagnosed [ND] MM: n = 109; relapsed/refractory [RR] MM: n = 149). HR SKY92 was significantly enriched in RRMM (57/121, 47.1%) compared with NDMM (17/95, 17.9%) (p < 0.0001). RRMM patients with HR SKY92 showed significantly shorter progression-free survival (PFS) (p < 0.0001) and overall survival (OS) (p < 0.0001) than SKY92 standard-risk (SR). In NDMM, HR SKY92 also indicated a significantly inferior PFS (p < 0.0001) in comparison with SR. We combined SKY92 with FISH (HR: t(4;14), del17p, +1q21 according to R2-ISS) in 181 patients (NDMM: n = 79; RRMM: n = 102). We found a discrepancy between both risk stratification systems, with only 49 (27.1%) patients being defined as HR by both SKY92 and FISH (“double HR”). In terms of survival outcomes, “double HR” presented a negative prognostic factor for PFS in both NDMM (p < 0.0001) and RRMM (p < 0.0001). Furthermore, “double-HR” patients showed the worst OS (p = 0.000 13) in RRMM. Additionally, whole genome sequencing (WGS) revealed CRBN mutation (n = 3) and bi-allelic events (mutation and/or deletion) in TP53 (n = 7) and TNFRSF17 (n = 1). Altogether, we provide the first prospective real-world evidence that the combination SKY92 and FISH (according to R2-ISS) identifies a subset of patients with ultra-HR MM, and WGS complements SKY92 and FISH in MM risk stratification.","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11754766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower-risk myelodysplastic syndromes

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2025-01-22 DOI: 10.1002/hem3.70073

David Rombaut, Sarah Sandmann, Tobias Tekath, Simon Crouch, Aniek O. de Graaf, Alexandra Smith, Daniel Painter, Olivier Kosmider, Magnus Tobiasson, Andreas Lennartsson, Bert A. van der Reijden, Sophie Park, Maud D'Aveni, Borhane Slama, Emmanuelle Clappier, Pierre Fenaux, Lionel Adès, Arjan van de Loosdrecht, Saskia Langemeijer, Argiris Symeonidis, Jaroslav Čermák, Claude Preudhomme, Aleksandar Savic, Ulrich Germing, Reinhard Stauder, David Bowen, Corine van Marrewijk, Elsa Bernard, Theo de Witte, Julian Varghese, Eva Hellström-Lindberg, Martin Dugas, Joost Martens, Luca Malcovati, Joop H. Jansen, Michaela Fontenay, MDS-RIGHT consortium

Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expression profiles. The integration of genomic, epigenomic, and transcriptomic profiling has the potential to spotlight distinct LR-MDS categories on the basis of pathophysiological mechanisms. We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well-annotated cohort of treatment-naive patients with LR-MDS at diagnosis from the EUMDS registry (ClinicalTrials.gov.NCT00600860). Unsupervised clustering analyses identified six clusters based on genetic profiling that concentrate into four clusters on the basis of genome-wide methylation profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct clinical and genetic features and distinct methylation landscape. All clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. By contrast, one cluster gathering patients with early leukemic evolution exhibited a specific pattern of hypermethylated promoters and, distinctly from other clusters, the upregulation of AP-1 complex members FOS/FOSL2 together with the absence of hypermethylation of their binding motif at target gene enhancers, which is of relevance for leukemic initiation. Among MDS patients with lower-risk IPSS-M, this cluster displayed a significantly inferior overall survival (p < 0.0001). Our study showed that genetic and DNA methylation features of LR-MDS at early stages may refine risk stratification, therefore offering the frame for a precocious therapeutic intervention.

{"title":"Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower-risk myelodysplastic syndromes","authors":"David Rombaut, Sarah Sandmann, Tobias Tekath, Simon Crouch, Aniek O. de Graaf, Alexandra Smith, Daniel Painter, Olivier Kosmider, Magnus Tobiasson, Andreas Lennartsson, Bert A. van der Reijden, Sophie Park, Maud D'Aveni, Borhane Slama, Emmanuelle Clappier, Pierre Fenaux, Lionel Adès, Arjan van de Loosdrecht, Saskia Langemeijer, Argiris Symeonidis, Jaroslav Čermák, Claude Preudhomme, Aleksandar Savic, Ulrich Germing, Reinhard Stauder, David Bowen, Corine van Marrewijk, Elsa Bernard, Theo de Witte, Julian Varghese, Eva Hellström-Lindberg, Martin Dugas, Joost Martens, Luca Malcovati, Joop H. Jansen, Michaela Fontenay, MDS-RIGHT consortium","doi":"10.1002/hem3.70073","DOIUrl":"10.1002/hem3.70073","url":null,"abstract":"Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expression profiles. The integration of genomic, epigenomic, and transcriptomic profiling has the potential to spotlight distinct LR-MDS categories on the basis of pathophysiological mechanisms. We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well-annotated cohort of treatment-naive patients with LR-MDS at diagnosis from the EUMDS registry (ClinicalTrials.gov.NCT00600860). Unsupervised clustering analyses identified six clusters based on genetic profiling that concentrate into four clusters on the basis of genome-wide methylation profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct clinical and genetic features and distinct methylation landscape. All clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. By contrast, one cluster gathering patients with early leukemic evolution exhibited a specific pattern of hypermethylated promoters and, distinctly from other clusters, the upregulation of AP-1 complex members FOS/FOSL2 together with the absence of hypermethylation of their binding motif at target gene enhancers, which is of relevance for leukemic initiation. Among MDS patients with lower-risk IPSS-M, this cluster displayed a significantly inferior overall survival (p < 0.0001). Our study showed that genetic and DNA methylation features of LR-MDS at early stages may refine risk stratification, therefore offering the frame for a precocious therapeutic intervention.","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11754767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0