Pub Date : 2025-06-01DOI: 10.1053/j.seminhematol.2025.09.001
Carolin Seeling , Arnold Ganser , Hartmut Döhner , Michael W.M. Kühn
After decades of therapeutic inertia, the treatment of acute myeloid leukemia (AML) has seen remarkable improvements over the past ten years. Scientific discoveries have substantially enhanced the understanding of AML disease biology. The improved knowledge about leukemic transformation and disease mechanisms in this heterogeneous group of aggressive blood cancers has resulted in enhanced biologically defined risk prognostication and the development of novel targeted therapeutic agents. Many of these mechanism-based therapeutics have entered clinical development, with some getting approval for the treatment of specific genetically defined AML subgroups in patients fit or unfit for intensive chemotherapy-based treatment. As a result, the European LeukemiaNet (ELN) expert panel has established a distinct genetic risk stratification for AML patients undergoing less-intensive treatment, which incorporates targeted drugs (ELN 2024). The ELN 2022 risk categories, designed for predicting outcomes following intensive chemotherapy, did not adequately assess responses to these new regimens. In this review, we discuss the current state-of-the-art approaches in both intensive and less-intensive front-line treatments for AML, highlighting the most promising therapeutic innovations.
{"title":"Tailoring intensive and less-intensive treatment in acute myeloid leukemia","authors":"Carolin Seeling , Arnold Ganser , Hartmut Döhner , Michael W.M. Kühn","doi":"10.1053/j.seminhematol.2025.09.001","DOIUrl":"10.1053/j.seminhematol.2025.09.001","url":null,"abstract":"<div><div>After decades of therapeutic inertia, the treatment of acute myeloid leukemia (AML) has seen remarkable improvements over the past ten years. Scientific discoveries have substantially enhanced the understanding of AML disease biology. The improved knowledge about leukemic transformation and disease mechanisms in this heterogeneous group of aggressive blood cancers has resulted in enhanced biologically defined risk prognostication and the development of novel targeted therapeutic agents. Many of these mechanism-based therapeutics have entered clinical development, with some getting approval for the treatment of specific genetically defined AML subgroups in patients fit or unfit for intensive chemotherapy-based treatment. As a result, the European LeukemiaNet (ELN) expert panel has established a distinct genetic risk stratification for AML patients undergoing less-intensive treatment, which incorporates targeted drugs (ELN 2024). The ELN 2022 risk categories, designed for predicting outcomes following intensive chemotherapy, did not adequately assess responses to these new regimens. In this review, we discuss the current state-of-the-art approaches in both intensive and less-intensive front-line treatments for AML, highlighting the most promising therapeutic innovations.</div></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"62 3","pages":"Pages 196-208"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145303254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01DOI: 10.1053/j.seminhematol.2025.06.003
Jens Schrezenmeier , B.J.P. Huntly
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy defined by the clonal expansion of undifferentiated myeloid blasts with a block in differentiation and aberrant self-renewal. While recurrent genomic mutations are well-documented in AML, epigenetic dysregulation has emerged as an equally pivotal driver of leukemogenesis, a notion corroborated by the frequent recurrence of mutations in epigenetic regulators. Leukemic cells exhibit pervasive epigenetic alterations—including abnormal DNA methylation patterns, dysregulated histone modification, disrupted chromatin architecture and RNA-based regulatory mechanisms —which collectively rewire gene expression programs. These changes silence key differentiation genes and sustain self-renewal pathways, enforcing the developmental arrest and hyper-proliferation that are the hallmarks of AML. Importantly, epigenetic aberrations in AML are not merely downstream consequences of genetic lesions but actively contribute to the malignant phenotype. Somatic mutations frequently target epigenetic regulators (for example, DNA methyltransferases or histone modifiers), and these lesions cooperate with other genetic alterations to initiate and maintain the leukemic clone. Together, these insights highlight epigenetic dysregulation as a central mechanism in AML pathogenesis.
{"title":"Epigenetic dysregulation in acute myeloid leukemia","authors":"Jens Schrezenmeier , B.J.P. Huntly","doi":"10.1053/j.seminhematol.2025.06.003","DOIUrl":"10.1053/j.seminhematol.2025.06.003","url":null,"abstract":"<div><div>Acute myeloid leukemia (AML) is an aggressive hematologic malignancy defined by the clonal expansion of undifferentiated myeloid blasts with a block in differentiation and aberrant self-renewal. While recurrent genomic mutations are well-documented in AML, epigenetic dysregulation has emerged as an equally pivotal driver of leukemogenesis, a notion corroborated by the frequent recurrence of mutations in epigenetic regulators. Leukemic cells exhibit pervasive epigenetic alterations—including abnormal DNA methylation patterns, dysregulated histone modification, disrupted chromatin architecture and RNA-based regulatory mechanisms —which collectively rewire gene expression programs. These changes silence key differentiation genes and sustain self-renewal pathways, enforcing the developmental arrest and hyper-proliferation that are the hallmarks of AML. Importantly, epigenetic aberrations in AML are not merely downstream consequences of genetic lesions but actively contribute to the malignant phenotype. Somatic mutations frequently target epigenetic regulators (for example, DNA methyltransferases or histone modifiers), and these lesions cooperate with other genetic alterations to initiate and maintain the leukemic clone. Together, these insights highlight epigenetic dysregulation as a central mechanism in AML pathogenesis.</div></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"62 3","pages":"Pages 177-186"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01DOI: 10.1053/j.seminhematol.2025.08.001
Daniela V. Wenge, Scott A. Armstrong
Menin inhibitors are emerging as targeted therapies for acute leukemias with high HOXA gene expression. These leukemias harbor mutations including KMT2A-rearrangements, NPM1c mutations, NUP98-fusions, UBTF tandem duplications and potentially others. Mechanistically, each of these oncoproteins depend on the KMT2A:Menin interaction to maintain critical gene expression. Several Menin inhibitors have entered clinical trials and have shown impressive efficacy in heavily pretreated patients with acute myeloid leukemia (AML). Revumenib received FDA approval for patients with relapsed or refractory acute myeloid leukemia with KMT2A-rearrangements in November 2024. Despite the success of Menin inhibitors, leukemia progression due to therapeutic resistance is a common occurrence with monotherapy. Hence, current clinical trials focus on Menin inhibition in combination with chemotherapy and/or standard-of-care targeted therapies to potentially overcome or prevent resistance. Menin inhibitors are also being investigated in patients with newly diagnosed acute leukemia or as a maintenance therapy post allogeneic stem cell transplantation. This review provides an overview of the mechanism of action of Menin inhibitors and the disease subsets that show sensitivity. We explain the current understanding of genetic resistance, mediated by Menin mutations that reduce drug binding affinity, and the emerging understanding of other types of resistance. Ongoing clinical trials are summarized, and we discuss the future role of Menin inhibition as a potentially practice-changing treatment for up to 50% of patients with AML.
{"title":"Menin inhibition for the treatment of acute leukemia","authors":"Daniela V. Wenge, Scott A. Armstrong","doi":"10.1053/j.seminhematol.2025.08.001","DOIUrl":"10.1053/j.seminhematol.2025.08.001","url":null,"abstract":"<div><div>Menin inhibitors are emerging as targeted therapies for acute leukemias with high <em>HOXA</em> gene expression. These leukemias harbor mutations including <em>KMT2A</em>-rearrangements, <em>NPM1c</em> mutations, <em>NUP98</em>-fusions, <em>UBTF</em> tandem duplications and potentially others. Mechanistically, each of these oncoproteins depend on the KMT2A:Menin interaction to maintain critical gene expression. Several Menin inhibitors have entered clinical trials and have shown impressive efficacy in heavily pretreated patients with acute myeloid leukemia (AML). Revumenib received FDA approval for patients with relapsed or refractory acute myeloid leukemia with <em>KMT2A</em>-rearrangements in November 2024. Despite the success of Menin inhibitors, leukemia progression due to therapeutic resistance is a common occurrence with monotherapy. Hence, current clinical trials focus on Menin inhibition in combination with chemotherapy and/or standard-of-care targeted therapies to potentially overcome or prevent resistance. Menin inhibitors are also being investigated in patients with newly diagnosed acute leukemia or as a maintenance therapy post allogeneic stem cell transplantation. This review provides an overview of the mechanism of action of Menin inhibitors and the disease subsets that show sensitivity. We explain the current understanding of genetic resistance, mediated by Menin mutations that reduce drug binding affinity, and the emerging understanding of other types of resistance. Ongoing clinical trials are summarized, and we discuss the future role of Menin inhibition as a potentially practice-changing treatment for up to 50% of patients with AML.</div></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"62 3","pages":"Pages 187-195"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145055678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01DOI: 10.1053/S0037-1963(25)00019-8
{"title":"outside front cover, PMS 8883 metallic AND 4/C","authors":"","doi":"10.1053/S0037-1963(25)00019-8","DOIUrl":"10.1053/S0037-1963(25)00019-8","url":null,"abstract":"","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"62 2","pages":"Page CO1"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144470361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01DOI: 10.1053/j.seminhematol.2025.04.004
Jorge J. Castillo , Francesco Autore , Neil L. Berinstein , Andrew R. Branagan , Meletios A. Dimopoulos , Carlos Fernandez de Larrea , Simone Ferrero , Prashant Kapoor , Efstathios Kastritis , Jahanzaib Khwaja , Monique C. Minnema , Lugui Qiu , John F. Seymour , Josephine M.I. Vos , Christopher J. Patterson , Christian Buske , Jeffrey V. Matous , Steven P. Treon , M. Lia Palomba
Over the last decade, covalent Bruton tyrosine kinase (BTK) inhibitors have become a standard option for treating patients with symptomatic Waldenström Macroglobulinemia (WM) in the frontline or relapsed settings. However, the definition of intolerance and resistance to covalent BTK inhibitors has not been established. Understanding the best approaches to managing such patients is crucial to avoiding premature abandonment of effective therapy or pursuing futile therapies unlikely to be effective in controlling symptomatic disease progression. With the advent of noncovalent BTK inhibitors and BCL2 antagonists, in addition to clinical trials evaluating phospholipid-drug conjugates, antibody-drug conjugates, and bispecific antibodies, the present Consensus Panel 5 aims to establish working definitions for intolerance and resistance to covalent BTK inhibitors, as well as provide strategies to identify and manage these issues not infrequently encountered in clinical practice.
{"title":"Report of Consensus Panel 5 from the 12th International Workshop on Waldenstrom's Macroglobulinemia on the management of patients with intolerance or resistance to covalent BTK inhibitors","authors":"Jorge J. Castillo , Francesco Autore , Neil L. Berinstein , Andrew R. Branagan , Meletios A. Dimopoulos , Carlos Fernandez de Larrea , Simone Ferrero , Prashant Kapoor , Efstathios Kastritis , Jahanzaib Khwaja , Monique C. Minnema , Lugui Qiu , John F. Seymour , Josephine M.I. Vos , Christopher J. Patterson , Christian Buske , Jeffrey V. Matous , Steven P. Treon , M. Lia Palomba","doi":"10.1053/j.seminhematol.2025.04.004","DOIUrl":"10.1053/j.seminhematol.2025.04.004","url":null,"abstract":"<div><div>Over the last decade, covalent Bruton tyrosine kinase (BTK) inhibitors have become a standard option for treating patients with symptomatic Waldenström Macroglobulinemia (WM) in the frontline or relapsed settings. However, the definition of intolerance and resistance to covalent BTK inhibitors has not been established. Understanding the best approaches to managing such patients is crucial to avoiding premature abandonment of effective therapy or pursuing futile therapies unlikely to be effective in controlling symptomatic disease progression. With the advent of noncovalent BTK inhibitors and BCL2 antagonists, in addition to clinical trials evaluating phospholipid-drug conjugates, antibody-drug conjugates, and bispecific antibodies, the present Consensus Panel 5 aims to establish working definitions for intolerance and resistance to covalent BTK inhibitors, as well as provide strategies to identify and manage these issues not infrequently encountered in clinical practice.</div></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"62 2","pages":"Pages 113-119"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01DOI: 10.1053/j.seminhematol.2025.04.001
Prashant Kapoor , Meletios A. Dimopoulos , Stephen M. Ansell , Efstathios Kastritis , Ranjana Advani , Eric Durot , Pierre Morel , Charalampia Kyriakou , Roman Hajek , Daniela Drandi , Jithma P. Abeykoon , Signy Chow , Xinxin Cao , Christopher J. Patterson , Jeffrey V. Matous , Christian Buske , Steven P. Treon , Marie J. Kersten
The Consensus Panel 3 (CP3) of the 12th International Workshop on Waldenström macroglobulinemia (IWWM-12) has reviewed and incorporated current data to make recommendations for the management of patients with high-risk WM (HR-WM). Recognizing the considerable heterogeneity in survival outcomes and identifying a subgroup of patients with a very poor prognosis, the key recommendations from CP3 include: (1) Risk stratifying patients with smoldering WM (SWM) and active (symptomatic) WM at diagnosis (2) Using the degree of i) bone marrow lymphoplasmacytosis, ii) serum beta-2 microglobulin (β2M) elevation, iii) IgM increase, iv) serum albumin decrease and the presence of wild-type MYD88 status markers that adversely dictate the time-to-progression from smoldering to active WM to the define HR-SWM. (3) Among patients with active WM, the presenting parameters: advanced chronological age, low serum albumin, elevated serum lactate dehydrogenase, elevated β2M and the presence of TP53 alterations (TP53 mutation or deletion 17p) unfavorably impact the prognosis and should be utilized to risk-stratify patients into the HR category. (4) The panel encourages screening for genetic alterations at diagnosis, prior to initiating therapy and also with rapidly advancing disease or refractoriness to ongoing therapy, which might result from clonal evolution. Although limited data directing the selection and sequencing of therapies exist, a risk-adapted approach and clinical trial participation for patients with HR-WM are highly encouraged.
{"title":"Report of Consensus Panel 3 from the 12th International Workshop on Waldenstrom's Macroglobulinemia on the management of patients with high-risk disease","authors":"Prashant Kapoor , Meletios A. Dimopoulos , Stephen M. Ansell , Efstathios Kastritis , Ranjana Advani , Eric Durot , Pierre Morel , Charalampia Kyriakou , Roman Hajek , Daniela Drandi , Jithma P. Abeykoon , Signy Chow , Xinxin Cao , Christopher J. Patterson , Jeffrey V. Matous , Christian Buske , Steven P. Treon , Marie J. Kersten","doi":"10.1053/j.seminhematol.2025.04.001","DOIUrl":"10.1053/j.seminhematol.2025.04.001","url":null,"abstract":"<div><div>The Consensus Panel 3 (CP3) of the 12th International Workshop on Waldenström macroglobulinemia (IWWM-12) has reviewed and incorporated current data to make recommendations for the management of patients with high-risk WM (HR-WM). Recognizing the considerable heterogeneity in survival outcomes and identifying a subgroup of patients with a very poor prognosis, the key recommendations from CP3 include: (1) Risk stratifying patients with smoldering WM (SWM) and active (symptomatic) WM at diagnosis (2) Using the degree of i) bone marrow lymphoplasmacytosis, ii) serum beta-2 microglobulin (β2M) elevation, iii) IgM increase, iv) serum albumin decrease and the presence of wild-type <em>MYD88</em> status markers that adversely dictate the time-to-progression from smoldering to active WM to the define HR-SWM. (3) Among patients with active WM, the presenting parameters: advanced chronological age, low serum albumin, elevated serum lactate dehydrogenase, elevated β2M and the presence of <em>TP53</em> alterations <em>(TP53</em> mutation or deletion 17p) unfavorably impact the prognosis and should be utilized to risk-stratify patients into the HR category. (4) The panel encourages screening for genetic alterations at diagnosis, prior to initiating therapy and also with rapidly advancing disease or refractoriness to ongoing therapy, which might result from clonal evolution. Although limited data directing the selection and sequencing of therapies exist, a risk-adapted approach and clinical trial participation for patients with HR-WM are highly encouraged.</div></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"62 2","pages":"Pages 90-105"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144182113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01DOI: 10.1053/j.seminhematol.2025.04.002
Alessandra Tedeschi , Rebecca Auer , Francesco Autore , Jorge J. Castillo , Moshe E. Gatt , Eva Kimby , David F. Moreno , Roger G. Owen , Lugui Qiu , Aldo M. Roccaro , Shayna Sarosiek , Naohiro Sekiguchi , John F. Seymour , Marzia Varettoni , Christopher J. Patterson , Jeffrey V. Matous , Christian Buske , Steven P. Treon , Ramon Garcia Sanz
Approximately 95% of lymphoplasmacytic lymphomas (LPL) are IgM secreting and are characterized as Waldenstrom Macroglobulinemia (WM). Conversely, non-IgM secreting LPL are rare. As part of the 12th International Workshop on WM (IWWM-12), a consensus panel of experts was tasked to develop recommendations for the management and response assessment of non-IgM LPL. The panel considered that in view of available molecular, pathological and clinical data, non-IgM LPL should be considered as a separate sub-entity of LPL. The panel further recommended that the IWWM-2 consensus criteria used for IgM LPL (WM) treatment initiation, should also be used for non-IgM LPL and be independent of IgG or IgA paraprotein level unless symptomatic hyperviscosity is present. The panel agreed that based on current evidence, there is insufficient data to support a different clinical management for non-IgM vs IgM (WM) LPL. Moreover, the panel advised that patients with non-IgM LPL should be treated in a similar manner to patients with IgM LPL independent of MYD88 mutation status until more is known about its impact on treatment outcomes for non-IgM LPL patients. The panel therefore recommends the use of the IWWM-11 IgM LPL (WM) response criteria for cases of non-IgM LPL with a monoclonal IgA or IgG paraprotein component, but creating a specific panel to develop formal response criteria for this LPL subset was also recommended.
{"title":"Report of Consensus Panel 4 from the 12th International Workshop on Waldenstrom's Macroglobulinemia on the management of patients with non-IgM lymphoplasmacytic lymphoma","authors":"Alessandra Tedeschi , Rebecca Auer , Francesco Autore , Jorge J. Castillo , Moshe E. Gatt , Eva Kimby , David F. Moreno , Roger G. Owen , Lugui Qiu , Aldo M. Roccaro , Shayna Sarosiek , Naohiro Sekiguchi , John F. Seymour , Marzia Varettoni , Christopher J. Patterson , Jeffrey V. Matous , Christian Buske , Steven P. Treon , Ramon Garcia Sanz","doi":"10.1053/j.seminhematol.2025.04.002","DOIUrl":"10.1053/j.seminhematol.2025.04.002","url":null,"abstract":"<div><div>Approximately 95% of lymphoplasmacytic lymphomas (LPL) are IgM secreting and are characterized as Waldenstrom Macroglobulinemia (WM). Conversely, non-IgM secreting LPL are rare. As part of the 12th International Workshop on WM (IWWM-12), a consensus panel of experts was tasked to develop recommendations for the management and response assessment of non-IgM LPL. The panel considered that in view of available molecular, pathological and clinical data, non-IgM LPL should be considered as a separate sub-entity of LPL. The panel further recommended that the IWWM-2 consensus criteria used for IgM LPL (WM) treatment initiation, should also be used for non-IgM LPL and be independent of IgG or IgA paraprotein level unless symptomatic hyperviscosity is present. The panel agreed that based on current evidence, there is insufficient data to support a different clinical management for non-IgM vs IgM (WM) LPL. Moreover, the panel advised that patients with non-IgM LPL should be treated in a similar manner to patients with IgM LPL independent of MYD88 mutation status until more is known about its impact on treatment outcomes for non-IgM LPL patients. The panel therefore recommends the use of the IWWM-11 IgM LPL (WM) response criteria for cases of non-IgM LPL with a monoclonal IgA or IgG paraprotein component, but creating a specific panel to develop formal response criteria for this LPL subset was also recommended.</div></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"62 2","pages":"Pages 106-112"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01DOI: 10.1053/j.seminhematol.2025.04.006
Shirley D'Sa , Jahanzaib Khwaja , Signy Chow , Meletios A. Dimopoulos , Irene Dogliotti , Moshe E. Gatt , Roman Hajek , Jindriska Lindsay , Giampaolo Merlini , Pierre Morel , Alessandra Tedeschi , Claudio Cerchione , Merav Leiba , Christopher J. Patterson , Steven P. Treon , Christian Buske , Jeffrey V. Matous , Marzia Varettoni , Josephine M.I. Vos , Filip Eftimov , Efstathios Kastritis
The IgM-related peripheral neuropathies (IgM-PN) are a group of chronic disorders characterized by the presence of monoclonal IgM that may be associated with one of several diseases affecting the peripheral nerves. In many cases, there is a monoclonal IgM associated with activity against neural targets, leading to progressive peripheral nerve demyelination. Neurological symptoms in this setting can also result from direct invasion of the peripheral or central nervous system by lymphoplasmacytic cells (neurolymphomatosis and Bing-Neel syndrome respectively) or via other mechanisms (for example AL amyloid deposition or cryoglobulinemic vasculitis). There is an expanding array of treatment options, but high-quality data are sparse. Diagnostic accuracy is important and needs collaboration between hematologists and neuromuscular specialists to determine the sequence and intensity of investigations. Appropriate causal attribution to the IgM disorder is essential to enable the correct therapeutic intervention. The aims of treatment intervention should be clear and realistic. Consistent and clinically meaningful measures are needed to capture treatment success. Despite therapeutic advances, many patients experience persistent disability, highlighting the need for further research.
{"title":"Report of Consensus Panel 1 from the 12th International Workshop on the management of patients with IgM and Waldenstrom's Macroglobulinemia related neuropathy","authors":"Shirley D'Sa , Jahanzaib Khwaja , Signy Chow , Meletios A. Dimopoulos , Irene Dogliotti , Moshe E. Gatt , Roman Hajek , Jindriska Lindsay , Giampaolo Merlini , Pierre Morel , Alessandra Tedeschi , Claudio Cerchione , Merav Leiba , Christopher J. Patterson , Steven P. Treon , Christian Buske , Jeffrey V. Matous , Marzia Varettoni , Josephine M.I. Vos , Filip Eftimov , Efstathios Kastritis","doi":"10.1053/j.seminhematol.2025.04.006","DOIUrl":"10.1053/j.seminhematol.2025.04.006","url":null,"abstract":"<div><div>The IgM-related peripheral neuropathies (IgM-PN) are a group of chronic disorders characterized by the presence of monoclonal IgM that may be associated with one of several diseases affecting the peripheral nerves. In many cases, there is a monoclonal IgM associated with activity against neural targets, leading to progressive peripheral nerve demyelination. Neurological symptoms in this setting can also result from direct invasion of the peripheral or central nervous system by lymphoplasmacytic cells (neurolymphomatosis and Bing-Neel syndrome respectively) or via other mechanisms (for example AL amyloid deposition or cryoglobulinemic vasculitis). There is an expanding array of treatment options, but high-quality data are sparse. Diagnostic accuracy is important and needs collaboration between hematologists and neuromuscular specialists to determine the sequence and intensity of investigations. Appropriate causal attribution to the IgM disorder is essential to enable the correct therapeutic intervention. The aims of treatment intervention should be clear and realistic. Consistent and clinically meaningful measures are needed to capture treatment success. Despite therapeutic advances, many patients experience persistent disability, highlighting the need for further research.</div></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"62 2","pages":"Pages 76-84"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01DOI: 10.1053/j.seminhematol.2025.05.001
Steven P. Treon MD, PhD , Christopher J. Patterson MS , Jeffrey Matous , Christian Buske
{"title":"Insights from the 12th International Workshop on Waldenstrom's Macroglobulinemia","authors":"Steven P. Treon MD, PhD , Christopher J. Patterson MS , Jeffrey Matous , Christian Buske","doi":"10.1053/j.seminhematol.2025.05.001","DOIUrl":"10.1053/j.seminhematol.2025.05.001","url":null,"abstract":"","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"62 2","pages":"Pages 71-75"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144470362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01DOI: 10.1053/j.seminhematol.2025.04.003
Eric Durot , Jithma P. Abeykoon , Damien Roos-Weil , M.J. Kersten , Charalampia Kyriakou , David F. Moreno , Stephen M. Ansell , Rebecca Auer , Xinxin Cao , Roger G. Owen , Shuhua Yi , Irene Dogliotti , Marek Trneny , Christopher J. Patterson , Jeffrey V. Matous , Christian Buske , Steven P. Treon , Ranjana Advani
Histological transformation (HT) in Waldenström’s macroglobulinemia (WM) is a rare complication and despite growing literature in the last years, no consensus recommendations exist. Consensus Panel 6 (CP6) of the 12th International Workshop on Waldenström’s Macroglobulinemia (IWWM-12) was convened to review the current data on transformed WM and make recommendations on its diagnosis and management. The key recommendations from IWWM-12 CP6 included: (1) in case of suspected HT, tissue biopsy is the gold standard for diagnosis; (2) the initial work-up should comprise 18FDG-PET/CT for the evaluation of disease extent and, for patients with clinical suspicion or for high-risk patients (CNS-IPI, multiple and/or specific extranodal involvements), cerebrospinal fluid examination and brain MRI; (3) standard dose chemoimmunotherapy (CIT) such as R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone) or R-CHP + polatuzumab vedotin are the preferred front-line regimen; (4) CNS prophylaxis and consolidation with autologous stem cell transplantation (SCT) can be considered according to de novo diffuse large B-cell lymphoma (DLBCL) guidelines; (5) T-cell-engaging therapies (CAR T-cells, bispecific antibodies) should be used in the relapse/refractory setting according to international guidelines for DLBCL and local access to these therapies. Key unanswered questions include the role of TP53 abnormalities and CXCR4 mutations on the risk of HT, the prognostic role of clonal relationship between WM and HT, the optimal front-line therapy (addition of novel agents to CIT, dose-intensive CIT, consolidation with autologous SCT), and the sequence of T-cell-engaging therapies. International collaboration and consideration of and inclusion in clinical trials is critical to address these issues in a rare patient population.
{"title":"Report of Consensus Panel 6 from the 12th International Workshop on Waldenstrom's Macroglobulinemia on Diagnosis and Management of Transformed Waldenstrom's Macroglobulinemia","authors":"Eric Durot , Jithma P. Abeykoon , Damien Roos-Weil , M.J. Kersten , Charalampia Kyriakou , David F. Moreno , Stephen M. Ansell , Rebecca Auer , Xinxin Cao , Roger G. Owen , Shuhua Yi , Irene Dogliotti , Marek Trneny , Christopher J. Patterson , Jeffrey V. Matous , Christian Buske , Steven P. Treon , Ranjana Advani","doi":"10.1053/j.seminhematol.2025.04.003","DOIUrl":"10.1053/j.seminhematol.2025.04.003","url":null,"abstract":"<div><div>Histological transformation (HT) in Waldenström’s macroglobulinemia (WM) is a rare complication and despite growing literature in the last years, no consensus recommendations exist. Consensus Panel 6 (CP6) of the 12th International Workshop on Waldenström’s Macroglobulinemia (IWWM-12) was convened to review the current data on transformed WM and make recommendations on its diagnosis and management. The key recommendations from IWWM-12 CP6 included: (1) in case of suspected HT, tissue biopsy is the gold standard for diagnosis; (2) the initial work-up should comprise <sup>18</sup>FDG-PET/CT for the evaluation of disease extent and, for patients with clinical suspicion or for high-risk patients (CNS-IPI, multiple and/or specific extranodal involvements), cerebrospinal fluid examination and brain MRI; (3) standard dose chemoimmunotherapy (CIT) such as R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone) or R-CHP + polatuzumab vedotin are the preferred front-line regimen; (4) CNS prophylaxis and consolidation with autologous stem cell transplantation (SCT) can be considered according to de novo diffuse large B-cell lymphoma (DLBCL) guidelines; (5) T-cell-engaging therapies (CAR T-cells, bispecific antibodies) should be used in the relapse/refractory setting according to international guidelines for DLBCL and local access to these therapies. Key unanswered questions include the role of <em>TP53</em> abnormalities and <em>CXCR4</em> mutations on the risk of HT, the prognostic role of clonal relationship between WM and HT, the optimal front-line therapy (addition of novel agents to CIT, dose-intensive CIT, consolidation with autologous SCT), and the sequence of T-cell-engaging therapies. International collaboration and consideration of and inclusion in clinical trials is critical to address these issues in a rare patient population.</div></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"62 2","pages":"Pages 120-125"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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