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Morath O, Rinke J, Walter A, Crodel C, Meggendorfer M, Baer C, Hochhaus A, Ernst T. Molecular predictors of venous and arterial thrombotic events in patients with myelofibrosis. Ann Hematol 2025:10.1007/s00277-025-06361-7. [PMID: 40287867 DOI: 10.1007/s00277-025-06361-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 04/07/2025] [Indexed: 04/29/2025]
Abstract
While patients with myelofibrosis (MF) face an elevated risk of thrombosis, no validated scoring system currently exists to effectively assess this specific risk. This study aimed to explore distinct molecular risk factors for arterial (ATE) and venous (VTE) thrombosis in a cohort of 141 MF patients. Mutation analysis was performed by next-generation sequencing for a panel of 30 target myeloid genes as previously described: 137 driver and 164 non-driver mutations were detected. JAK2-V617F was identified in 77 (55%) patients, CALR in 45 (32%) patients, and seven (5%) patients carried an MPL variant. Patients #58 and #60 harbored JAK2-V617F and MPL; and patient #67 was positive for all three driver genes. The JAK2-V617F variant allele frequency (VAF) was assessed in 66/80 patients, revealing a median of 34.0% (range, 5.0-96.0). ASXL1 (n = 34 patients) were the most common non-driver mutations, followed by TET2 (n = 26), U2AF1 (n = 12), and DNMT3A (n = 11). During a median follow up of 4.8 years, 24 (17%) patients experienced VTE, 15 (11%) ATE, and two patients experienced both. Among the 24 patients with VTE, 12 (50%) experienced splanchnic vein thrombosis. The JAK2-V617F mutation was associated with VTE (OR 2.6, 95% CI 1.01-7.16), while the DNMT3A mutation was an independent predictor of ATE (OR 5.40, 95% CI 1.30-22.42). High JAK2-V617F VAF (> 50%) was not related with an increased thrombotic risk. Results of this study demonstrate the significance of DNMT3A mutations as an independent molecular risk factor for ATE, highlighting the potential to include these somatic non-driver mutations in future thrombosis risk scores.
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Affiliation(s)
- Olga Morath
- Klinik für Innere Medizin II, Abteilung Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany.
| | - Jenny Rinke
- Klinik für Innere Medizin II, Abteilung Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany
| | - Annabell Walter
- Klinik für Innere Medizin II, Abteilung Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany
| | - Carl Crodel
- Klinik für Innere Medizin II, Abteilung Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany
| | | | | | - Andreas Hochhaus
- Klinik für Innere Medizin II, Abteilung Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany
| | - Thomas Ernst
- Klinik für Innere Medizin II, Abteilung Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany
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Guy A, Morange PE, James C. How I approach the treatment of thrombotic complications in patients with myeloproliferative neoplasms. Blood 2025; 145:1769-1779. [PMID: 39541574 DOI: 10.1182/blood.2024025627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 10/23/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
ABSTRACT Arterial and venous thromboses are the most significant complications in patients with myeloproliferative neoplasms (MPNs), with the primary treatment goal being thrombotic risk reduction. In MPN with no history of thrombosis, primary prevention mainly involves the use of aspirin, and cytoreduction is added in high-risk patients. However, thrombotic complications can unveil an MPN in ∼20% of cases, necessitating the initiation of both antithrombotic therapy for the thrombosis and cytoreductive treatment for the MPN. The duration of anticoagulant therapy after an initial venous thromboembolic event is subject to discussion. Furthermore, the occurrence of a thrombotic complication in patients with a known diagnosis of MPN prompts a reconsideration of both antithrombotic and hematologic management. This review uses case-based discussions to explore the management of thrombotic complications in patients with MPN. It addresses the nature and duration of antithrombotic treatments, as well as the approach to cytoreduction. Special attention is given to the place of direct oral anticoagulants and to the management of patients with MPN with splanchnic vein thrombosis, which is disproportionately common in this group.
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Affiliation(s)
- Alexandre Guy
- Laboratory of Hematology, University Hospital Bordeaux, Pessac, France
- Biologie des Maladies Cardiovasculaires, U-1034, University of Bordeaux, INSERM, Pessac, France
| | - Pierre-Emmanuel Morange
- Laboratory of Hematology, Assistance Publique-Hôpitaux de Marseille, Marseille, France
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Centre de Recherche en Cardiovasculaire et Nutrition, University of Aix-Marseille, INSERM, Marseille, France
| | - Chloé James
- Laboratory of Hematology, University Hospital Bordeaux, Pessac, France
- Biologie des Maladies Cardiovasculaires, U-1034, University of Bordeaux, INSERM, Pessac, France
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Pasquer H, Kiladjian JJ, Benajiba L. Current myeloproliferative neoplasm scoring systems for clinical practice. Blood 2025; 145:257-276. [PMID: 39476004 DOI: 10.1182/blood.2024025459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 10/12/2024] [Indexed: 01/18/2025] Open
Abstract
ABSTRACT BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies that are caused by the proliferation of myeloid cells that harbor a JAK-STAT pathway activating driver mutation. MPN management recommendations are based on the evaluation of different risks to prevent disease evolution-associated events while preserving patients' quality of life. Such risks can be common across all MPNs or specific to each subtype (polycythemia vera [PV], essential thrombocythemia [ET], prefibrotic myelofibrosis [MF], and primary MF). Patients with MF harbor the worse prognosis, and hematopoietic stem cell transplantation (HSCT) is the only curative treatment at the expense of a high rate of morbidity and mortality. Therefore, accurate scoring systems to estimate overall survival are crucial for the management of patients with MF and the selection for HSCT. In PV and ET, the prediction of vascular events is prioritized given their higher incidence and related morbidity and mortality. Finally, quality of life evaluation is important for all subtypes. To predict these risks and adapt MPN therapeutic strategies, clinical risk scores have been developed over the past decades and more recently have incorporated molecular risk factors for more accurate risk stratification. The large number of scoring systems available, combined with disease heterogeneity and the necessity to predict diverse outcomes, make it difficult for clinicians to choose the most appropriate score to evaluate their patients' risk in 2024. Here, we provide an overview of MPN disease evolution-associated event incidence and conduct an exhaustive comparative review of the scoring systems currently available for each risk. Finally, we propose an algorithm for the use of these scores in clinical practice in each MPN subtype.
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Affiliation(s)
- Hélène Pasquer
- Centre d'Investigations Cliniques, INSERM CIC 1427, Hôpital Saint-Louis, Université Paris Cité, Assistance Publique des Hôpitaux de Paris, Paris, France
- INSERM UMR 944, Institut de Recherche Saint-Louis, Paris, France
| | - Jean-Jacques Kiladjian
- Centre d'Investigations Cliniques, INSERM CIC 1427, Hôpital Saint-Louis, Université Paris Cité, Assistance Publique des Hôpitaux de Paris, Paris, France
- INSERM UMR 1131, Institut de Recherche Saint-Louis, Paris, France
| | - Lina Benajiba
- Centre d'Investigations Cliniques, INSERM CIC 1427, Hôpital Saint-Louis, Université Paris Cité, Assistance Publique des Hôpitaux de Paris, Paris, France
- INSERM UMR 944, Institut de Recherche Saint-Louis, Paris, France
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Griesshammer M, Al-Ali HK, Eckardt JN, Fiegl M, Göthert J, Jentsch-Ullrich K, Koschmieder S, Kvasnicka HM, Reiter A, Schmidt B, Heidel FH. How I diagnose and treat patients in the pre-fibrotic phase of primary myelofibrosis (pre-PMF) - practical approaches of a German expert panel discussion in 2024. Ann Hematol 2025; 104:295-306. [PMID: 39888352 PMCID: PMC11868337 DOI: 10.1007/s00277-025-06191-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 01/04/2025] [Indexed: 02/01/2025]
Abstract
The prefibrotic phase of primary myelofibrosis (pre-PMF) represents a distinct subentity within the spectrum of myeloproliferative neoplasms (MPNs), recognized by the World Health Organization (WHO) and the International Consensus Classification (ICC). Pre-PMF is characterized by unique morphological, clinical, and molecular features, distinguishing it from essential thrombocythemia (ET) and overt myelofibrosis (overt-PMF). The diagnostic process for pre-PMF relies on bone marrow histology, identification of molecular mutations and exclusion of other myeloid neoplasms. Misclassification remains a significant challenge due to overlapping phenotypes and the heterogeneity of clinical presentations, which range from asymptomatic cases to severe cytopenias and a high thrombotic risk. Management strategies for pre-PMF focus on mitigating symptom burden, reducing thromboembolic events, and preventing disease progression. Low-risk patients often benefit from observational approaches or low-dose aspirin, while cytoreductive therapies, such as hydroxyurea or interferon-alpha, are utilized in symptomatic or high-risk cases. JAK inhibitors like ruxolitinib have shown promise in addressing splenomegaly and systemic symptoms, although their role in pre-PMF requires further investigation. Advances in artificial intelligence are enhancing diagnostic precision by refining bone marrow histopathological analysis, paving the way for more accurate disease classification and tailored therapeutic strategies. This position paper integrates insights from a German expert panel discussion, underscoring the need for interdisciplinary collaboration, adherence to updated WHO/ICC diagnostic criteria, and personalized treatment approaches. By addressing diagnostic challenges and therapeutic nuances, it seeks to improve outcomes and quality of life for patients navigating the complexities of pre-PMF.
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Affiliation(s)
- Martin Griesshammer
- Oncology, Haemostaseology and Palliative Care, Johannes Wesling Medical Center Minden, University Clinic for Hematology, University of Bochum, Bochum, Germany
| | | | - Jan-Niklas Eckardt
- Department of Internal Medicine I, University Hospital Dresden, Dresden, Germany
- Else-Kröner-Fresenius- Center for Digital Health, Dresden University of Technology, Dresden, Germany
| | | | - Joachim Göthert
- Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany
| | | | - Steffen Koschmieder
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Hans Michael Kvasnicka
- Fakultät für Gesundheit (Department für Humanmedizin), Pathologie, Universität Witten/Herdecke, Herdecke, Germany
| | - Andreas Reiter
- Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany
| | - Burkhard Schmidt
- Hämatologie und Onkologie München Pasing MVZ GmbH, München, Germany
| | - Florian H Heidel
- Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School (MHH), Hannover, Germany.
- Cellular Therapy Center (CTC), Hannover Medical School (MHH), Hannover, Germany.
- Leibniz Institute on Aging, Fritz-Lipmann-Institute, Jena, Germany.
- Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School (MHH), Carl-Neuberg-Str. 1, D-30625, Hannover, Germany.
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Morath O, Crodel C, Rinke J, Sander I, Tekbas A, Meggendorfer M, Baer C, Hochhaus A, Ernst T. Molecular and Clinical Risk Factors Associated with Thrombosis and Bleeding in Myelofibrosis Patients. Hamostaseologie 2024. [PMID: 39708833 DOI: 10.1055/a-2410-8530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND The risk of thrombosis and bleeding in myelofibrosis (MF) has been historically underappreciated. We sought to investigate potential molecular and clinical risk factors for venous (VTE) and arterial (ATE) thrombotic events as well as bleeding episodes. METHODS Data from 246 consecutive MF patients were analyzed. Driver mutations were tested in 191 patients. RESULTS In total, 181 mutations were found in 177 MF patients: 118 (61.8%) patients showed JAK2-V617F, 50 patients (26.2%) showed CALR, and 6 patients (3.1%) showed MPL mutations. Two patients were JAK2-V617F and MPL positive and one patient was positive for all three genes. Fourteen (7.3%) patients were triple negative. The JAK2-V617F allele burden was assessed in 63 JAK2-V617F-mutated patients, revealing a median of 35.6% (range: 5.0-96.0). At the time of MF diagnosis and during follow-up, 84 thrombotic events (52 VTEs and 32 ATEs) were observed, corresponding to 6.6% of patients per year. A significant association was found between JAK2-V617F mutation (OR: 2.5, 95% CI: 1.1-5.6) and prior VTE (OR: 7.6, 95% CI: 2.1-27.1) with an increased risk of VTE. Patients with prefibrotic MF had a higher rate of ATE than patients with overt MF. Hemorrhagic events occurred in 34 (13.8%) patients, corresponding to 3.8% of patients per year. Fibrosis grade 3 was associated with bleeding risk (OR: 3.4, 95% CI: 1.2-9.2, p = 0.02). CONCLUSIONS The presence of the JAK2-V617F mutation, regardless of allele burden, and prior thrombosis were strongly associated with an increased risk of VTE. Patients with prefibrotic MF might be considered at high risk for developing ATE.
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Affiliation(s)
- Olga Morath
- Klinik für Innere Medizin II, Abteilung Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany
| | - Carl Crodel
- Klinik für Innere Medizin II, Abteilung Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany
| | - Jenny Rinke
- Klinik für Innere Medizin II, Abteilung Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany
| | - Inken Sander
- Klinik für Innere Medizin II, Abteilung Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany
| | - Aysun Tekbas
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Jena, Germany
| | | | | | - Andreas Hochhaus
- Klinik für Innere Medizin II, Abteilung Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany
| | - Thomas Ernst
- Klinik für Innere Medizin II, Abteilung Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany
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Breccia M, Palandri F, Polverelli N, Caira M, Berluti M, Palumbo GA, De Stefano V. Epidemiology and disease characteristics of myelofibrosis: a comparative analysis between Italy and global perspectives. Front Oncol 2024; 14:1382872. [PMID: 39114304 PMCID: PMC11303153 DOI: 10.3389/fonc.2024.1382872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 07/02/2024] [Indexed: 08/10/2024] Open
Abstract
Myelofibrosis (MF) is a clonal disorder of hematopoietic stem cells characterized by altered bone marrow function and fibrosis. The aim of this narrative review is to report on the most recent epidemiologic data and to discuss features of MF and current strategies for the management of this condition in clinical practice. MF features covered by our review will include: characteristics of patients with MF; myeloproliferative and myelodepletive phenotypes; MF-associated thrombosis and bleeding; risk of infections; prefibrotic and overt PMF; secondary MF. Finally, we will discuss a few aspects of MF management in clinical practice and suggest strategies for its optimization and standardization. The focus of our paper is on Italy, but relevant data from other countries will also be reviewed.
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Affiliation(s)
- Massimo Breccia
- Dipartimento di Medicina Traslazionale e di Precisione, Sapienza Università, Roma, Italy
| | - Francesca Palandri
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia Seragnoli, Bologna, Italy
| | - Nicola Polverelli
- Unit of Blood Diseases and stem cell transplantation, ASST Spedali Civili di Brescia, University of Brescia, Brescia, Italy
| | | | | | - Giuseppe A. Palumbo
- Dipartimento di Scienze Mediche Chirurgiche e Tecnologie Avanzate “G. F. Ingrassia”, Università di Catania, Catania, Italy
| | - Valerio De Stefano
- Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
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Vachhani P, Loghavi S, Bose P. SOHO State of the Art Updates and Next Questions | Diagnosis, Outcomes, and Management of Prefibrotic Myelofibrosis. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2024; 24:413-426. [PMID: 38341324 DOI: 10.1016/j.clml.2024.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/15/2024] [Accepted: 01/16/2024] [Indexed: 02/12/2024]
Abstract
Prefibrotic primary myelofibrosis (prefibrotic PMF) is a myeloproliferative neoplasm with distinct characteristics comprising histopathological and clinico-biological parameters. It is classified as a subtype of primary myelofibrosis. In clinical practice, it is essential to correctly distinguish prefibrotic PMF from essential thrombocythemia especially but also overt PMF besides other myeloid neoplasms. Risk stratification and survival outcomes for prefibrotic PMF are worse than that of ET but better than that of overt PMF. Rates of progression to overt PMF and blast phase disease are also higher for prefibrotic PMF than ET. In this review we first discuss the historical context to the evolution of prefibrotic PMF as an entity, its presenting features and diagnostic criteria. We emphasize the differences between prefibrotic PMF, ET, and overt PMF with regards to presenting features and disease outcomes including thrombohemorrhagic events and progression to fibrotic and blast phase disease. Next, we discuss the risk stratification models and contextualize these in the setting of clinical management. We share our view of personalizing treatment to address unique patient needs in the context of currently available management options. Lastly, we discuss areas of critical need in clinical research and speculate on the possibility of future disease course modifying therapies in prefibrotic PMF.
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Affiliation(s)
- Pankit Vachhani
- Department of Medicine, Division of Hematology and Oncology, The University of Alabama at Birmingham, Birmingham, AL
| | - Sanam Loghavi
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Prithviraj Bose
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
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Găman MA, Srichawla BS, Chen YF, Roy P, Dhali A, Nahian A, Manan MR, Kipkorir V, Suteja RC, Simhachalam Kutikuppala LV, Găman AM, Diaconu CC. Overview of dyslipidemia and metabolic syndrome in myeloproliferative neoplasms. World J Clin Oncol 2024; 15:717-729. [PMID: 38946827 PMCID: PMC11212607 DOI: 10.5306/wjco.v15.i6.717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 05/05/2024] [Accepted: 05/28/2024] [Indexed: 06/24/2024] Open
Abstract
Myeloproliferative neoplasms (MPNs) occur due to the abnormal proliferation of one or more terminal myeloid cell lines in peripheral blood. Subjects suffering from MPNs display a high burden of cardiovascular risk factors, and thrombotic events are often the cause of death in this population of patients. Herein, we provide a brief overview of dyslipidemia and metabolic syndrome and their epidemiology in MPNs and examine the common molecular mechanisms between dyslipidemia, metabolic syndrome, and MPNs, with a special focus on cardiovascular risk, atherosclerosis, and thrombotic events. Furthermore, we investigate the impact of dyslipidemia and metabolic syndrome on the occurrence and survival of thrombosis in MPN patients, as well as the management of dyslipidemia in MPNs, and the impact of MPN treatment on serum lipid concentrations, particularly as side/adverse effects reported in the context of clinical trials.
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Affiliation(s)
- Mihnea-Alexandru Găman
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest 050474, Romania
- Department of Hematology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, Bucharest 022328, Romania
- Department of Cellular and Molecular Pathology, Stefan S Nicolau Institute of Virology, Romanian Academy, Bucharest 030304, Romania
| | - Bahadar Singh Srichawla
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01655, United States
| | - Yong-Feng Chen
- Department of Basic Medical Sciences, School of Medicine of Taizhou University, Taizhou University, Taizhou 318000, Zhejiang Province, China
| | - Poulami Roy
- Department of Medicine, North Bengal Medical College and Hospital, West Bengal 734012, India
| | - Arkadeep Dhali
- Academic Department of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S5 7AU, United Kingdom
| | - Ahmed Nahian
- Lecom at Seton Hill, Greensburg, PA 15601, United States
| | | | - Vincent Kipkorir
- Department of Human Anatomy and Physiology, University of Nairobi, Nairobi 00100, Kenya
| | | | | | - Amelia Maria Găman
- Department of Pathophysiology, University of Medicine and Pharmacy of Craiova, Craiova 200349, Romania
- Clinic of Hematology, Filantropia City Hospital, Craiova 200143, Romania
| | - Camelia Cristina Diaconu
- Department of Internal Medicine, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest 050474, Romania
- Internal Medicine Clinic, Clinical Emergency Hospital of Bucharest, Bucharest 105402, Romania
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9
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Huang K, Mo Q, Liao C, Feng S, Liu G, Jiang D, Lei P. The clinical significance of TAT, PIC, TM, and t-PAIC in vascular events of BCR/ABL-negative myeloproliferative neoplasms. Clin Exp Med 2024; 24:107. [PMID: 38776019 PMCID: PMC11111525 DOI: 10.1007/s10238-024-01371-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 05/04/2024] [Indexed: 05/25/2024]
Abstract
Predicting the likelihood vascular events in patients with BCR/ABL1-negative myeloproliferative neoplasms (MPN) is essential for the treatment of the disease. However, effective assessment methods are lacking. Thrombin-antithrombin complex (TAT), plasmin-α2- plasmininhibitor complex (PIC), thrombomodulin (TM), and tissue plasminogen activator-inhibitor complex (t-PAIC) are the new direct indicators for coagulation and fibrinolysis. The aim of this study was to investigate the changes of these four new indicators in thrombotic and hemorrhagic events in BCR/ABL1-negative MPN. The study cohort of 74 patients with BCR/ABL negative myeloproliferative disorders included essential thrombocythemia, polycythemia vera, and primary myelofibrosis (PMF). A panel of 4 biomarkers, including TAT, PIC, TM, and t-PAIC were determined using Sysmex HISCL5000 automated analyzers, whereas fibrin/fibrinogen degradation products (FDP), D-dimer and Antithrombin III (ATIII) were analyzed using Sysmex CS5100 coagulation analyzer. A total of 24 (32.4%) patients experienced thrombotic events and hemorrhagic events occurred in 8 patients (10.8%). Compared to patients without hemorrhagic-thrombotic events, patients with thrombotic events had higher fibrinogen (FIB) level, FDP level and lower ATIII activity, while patients with hemorrhagic events had lower white blood cell count and hemoglobin level, higher FDP level (P < 0.05). Patients with a JAK2V617F mutation were more likely to experience thrombotic events (P < 0.05). In addtion, patients with thrombotic events had higher TAT, PIC, TM, and t-PAIC levels than patients without hemorrhagic-thrombotic events (P < 0.05), whereas patients with hemorrhagic events had a lower median value in TAT and TM (no statistical difference, P > 0.05). Patients with higher TAT, TM and t-PAIC were more likely to experience thrombotic events (P < 0.05), and only TAT was positively correlated with thrombotic events (Spearman r =0.287, P = 0.019). TAT, PIC, TM, and t-PAIC combined with ATIII and FDP have a certain value for predicting thrombosis in patients with BCR/ABL1-negative MPN. These 6 parameters are worth further exploration as predictive factors and prognostic markers for early thrombotic events.
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Affiliation(s)
- Kangle Huang
- Department of Hematology, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Jiefang West Road, No. 61, Changsha, 410005, China
| | - Qiuyu Mo
- Department of Oncology, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, 545007, Guangxi, China
| | - Chushu Liao
- Department of Hematology, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Jiefang West Road, No. 61, Changsha, 410005, China
| | - Shan Feng
- Department of Hematology, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Jiefang West Road, No. 61, Changsha, 410005, China
| | - Guanghua Liu
- Department of Hematology, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Jiefang West Road, No. 61, Changsha, 410005, China
| | - Duanfeng Jiang
- Department of Hematology, The Fourth Affiliated Hospital of Guangxi Medical University, Heping Road, No. 156, Liuzhou, 545007, Guangxi, China.
- Department of Hematology, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570311, China.
| | - Ping Lei
- Department of Hematology, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Jiefang West Road, No. 61, Changsha, 410005, China.
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10
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Krecak I, Verstovsek S, Lucijanic M. Optimization of cardiovascular risk factor management in patients with BCR::ABL1 negative chronic myeloproliferative neoplasms, current knowledge, and perspectives. Ann Hematol 2024; 103:1513-1523. [PMID: 37665349 DOI: 10.1007/s00277-023-05426-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 08/24/2023] [Indexed: 09/05/2023]
Abstract
The exact prognostic role of cardiovascular (CV) risk factors in patients with BCR::ABL1 negative chronic myeloproliferative neoplasms (MPNs) remains unknown as it is often masked by other MPN-related features that bear strong prognostic impact on thrombotic risk. Therefore, current MPN treatment is not primarily guided by presence of CV risk factors. Treatment of CV risk factors in MPN patients usually mirrors that from the general population, despite the fact that CV risk factors in MPNs have their own specificities. Moreover, the optimal target levels for different metabolic deflections in MPNs (i.e., low-density lipoprotein, serum uric acid, or glycated hemoglobin levels) have not been defined. In the current review, we separately discuss the most important aspects of every individual CV risk factor (arterial hypertension, hyperlipidemia, chronic kidney disease, smoking, diabetes mellitus, hyperuricemia, and obesity and cachexia) in MPNs, summarize recent advances in the field, and propose future directions and research areas which may be needed to appropriately manage CV risk factors in MPNs.
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Affiliation(s)
- Ivan Krecak
- Department of Internal Medicine, General Hospital of Sibenik-Knin County, Stjepana Radića 83, 22000, Sibenik, Croatia.
- Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
- University of Applied Sciences, Sibenik, Croatia.
| | | | - Marko Lucijanic
- Department of Hematology, University Hospital Dubrava, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
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Lucijanic M, Krecak I, Soric E, Sabljic A, Galusic D, Holik H, Perisa V, Moric Peric M, Zekanovic I, Budimir J, Kusec R. Evaluation of Absolute Neutrophil, Lymphocyte and Platelet Count and Their Ratios as Predictors of Thrombotic Risk in Patients with Prefibrotic and Overt Myelofibrosis. Life (Basel) 2024; 14:523. [PMID: 38672793 PMCID: PMC11051164 DOI: 10.3390/life14040523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 04/09/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
AIM To investigate the prognostic contribution of absolute neutrophil (ANC), lymphocyte (ALC), platelet count and their ratios, neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), to thrombotic risk in patients with prefibrotic and overt fibrotic myelofibrosis (MF). METHODS We retrospectively analyzed a cohort of 256 patients with prefibrotic (85 patients) and overt fibrotic MF (171 patients) treated in six Croatian hematological centers. RESULTS Prefibrotic compared to overt fibrotic MF patients presented with significantly higher ALC, platelet count and PLR, and experienced longer time to thrombosis (TTT). Among prefibrotic patients, ANC > 8.33 × 109/L (HR 13.08, p = 0.036), ALC > 2.58 × 109/L (HR 20.63, p = 0.049) and platelet count > 752 × 109/L (HR 10.5, p = 0.043) remained independently associated with shorter TTT. Among overt fibrotic patients, ANC > 8.8 × 109/L (HR 4.49, p = 0.004), ALC ≤ 1.43 × 109/L (HR 4.15, p = 0.003), platelet count ≤ 385 × 109/L (HR 4.68, p = 0.004) and chronic kidney disease (HR 9.07, p < 0.001) remained independently associated with shorter TTT. CONCLUSIONS Prognostic properties of ANC, ALC and platelet count are mutually independent and exceed those of NLR and PLR regarding thrombotic risk stratification. ALC and platelet count associate in opposite directions with thrombotic risk in prefibrotic and overt fibrotic MF patients.
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Affiliation(s)
- Marko Lucijanic
- Hematology Department, University Hospital Dubrava, Av. Gojka Suska 6, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, Ul. Salata 3, 10000 Zagreb, Croatia
| | - Ivan Krecak
- Department of Internal Medicine, General Hospital Sibenik, Ul. Stjepana Radica 83, 22000 Sibenik, Croatia
- School of Medicine, University of Rijeka, Ul. Brace Branchetta 20/1, 51000 Rijeka, Croatia
- Sibenik University of Applied Science, Trg Andrije Hebranga 11, 22000 Sibenik, Croatia
| | - Ena Soric
- Hematology Department, University Hospital Dubrava, Av. Gojka Suska 6, 10000 Zagreb, Croatia
| | - Anica Sabljic
- Hematology Department, University Hospital Dubrava, Av. Gojka Suska 6, 10000 Zagreb, Croatia
| | - Davor Galusic
- Department of Hematology, University Hospital of Split, Soltanska ul. 1, 21000 Split, Croatia
- School of Medicine, University of Split, Soltanska ul. 2, 21000 Split, Croatia
| | - Hrvoje Holik
- Department of Internal Medicine, “Dr. Josip Bencevic” General Hospital, Ul. Andrije Stampara, 35000 Slavonski Brod, Croatia
- Faculty of Medicine, University of Osijek, Ul. Josipa Huttlera 4, 31000 Osijek, Croatia
| | - Vlatka Perisa
- Faculty of Medicine, University of Osijek, Ul. Josipa Huttlera 4, 31000 Osijek, Croatia
- Department of Hematology, Osijek University Hospital, Ul. Josipa Huttlera 4, 31000 Osijek, Croatia
| | - Martina Moric Peric
- Department of Internal Medicine, General Hospital Zadar, Ul. Boze Pericica 5, 23000 Zadar, Croatia
| | - Ivan Zekanovic
- Department of Internal Medicine, General Hospital Zadar, Ul. Boze Pericica 5, 23000 Zadar, Croatia
| | - Josipa Budimir
- Department of Internal Medicine, General Hospital Sibenik, Ul. Stjepana Radica 83, 22000 Sibenik, Croatia
| | - Rajko Kusec
- Hematology Department, University Hospital Dubrava, Av. Gojka Suska 6, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, Ul. Salata 3, 10000 Zagreb, Croatia
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12
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Kappenstein M, von Bubnoff N. Real-World Electronic Medical Records Data Identify Risk Factors for Myelofibrosis and Can Be Used to Validate Established Prognostic Scores. Cancers (Basel) 2024; 16:1416. [PMID: 38611094 PMCID: PMC11011132 DOI: 10.3390/cancers16071416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 04/01/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024] Open
Abstract
Myelofibrosis (MF) is a myeloproliferative neoplasia arising de novo as primary myelofibrosis (PMF) or secondary to polycythemia vera or essential thrombocythemia. Patients experience a high symptom burden and a marked reduction in life expectancy. Despite progress in molecular understanding and treatment, the clinical and prognostic heterogeneity of MF complicates treatment decisions. The International Prognostic Scoring System (IPSS) integrates clinical factors for risk stratification in MF. This study leverages the TriNetX database with more than 64,000 MF patients to assess the impact of accessible parameters on survival and complicating events, including AML transformation, cachexia, increased systemic inflammation, thrombosis and hemorrhage. Age over 65 years correlated with increased risks of death, AML transformation, thrombosis and hemorrhage. Anemia (Hb < 10 g/dL), leukocytosis (>25 × 103/µL) and thrombocytopenia (<150 × 103/µL) reduced survival and increased risks across all assessed events. Monocytosis is associated with decreased survival, whereas eosinophilia and basophilia were linked to improved survival. Further, as proof of concept for the applicability of TriNetX for clinical scores, we devised a simplified IPSS, and confirmed its value in predicting outcomes. This comprehensive study underscores the importance of age, anemia, leukocytosis and thrombocytopenia in predicting disease trajectory and contributes to refining prognostic models, addressing the challenges posed by the disease's heterogeneity.
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Affiliation(s)
| | - Nikolas von Bubnoff
- Medical Center, Department of Hematology and Oncology, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
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13
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Tefferi A, Vannucchi AM, Barbui T. Essential thrombocythemia: 2024 update on diagnosis, risk stratification, and management. Am J Hematol 2024; 99:697-718. [PMID: 38269572 DOI: 10.1002/ajh.27216] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 01/08/2024] [Indexed: 01/26/2024]
Abstract
OVERVIEW Essential thrombocythemia is a Janus kinase 2 (JAK2) mutation-prevalent myeloproliferative neoplasm characterized by clonal thrombocytosis; clinical course is often indolent but might be interrupted by thrombotic or hemorrhagic complications, microcirculatory symptoms (e.g., headaches, lightheadedness, and acral paresthesias), and, less frequently, by disease transformation into myelofibrosis (MF) or acute myeloid leukemia. DIAGNOSIS In addition to thrombocytosis (platelets ≥450 × 109 /L), formal diagnosis requires the exclusion of other myeloid neoplasms, including prefibrotic MF, polycythemia vera, chronic myeloid leukemia, and myelodysplastic syndromes with ring sideroblasts and thrombocytosis. Bone marrow morphology typically shows increased number of mature-appearing megakaryocytes distributed in loose clusters. GENETICS Approximately 80% of patients express myeloproliferative neoplasm driver mutations (JAK2, CALR, MPL), in a mutually exclusive manner; in addition, about 50% harbor other mutations, the most frequent being TET2 (9%-11%), ASXL1 (7%-20%), DNMT3A (7%), and SF3B1 (5%). Abnormal karyotype is seen in <10% of patients and includes +9/20q-/13q-. SURVIVAL AND PROGNOSIS Life expectancy is less than that of the control population. Median survival is approximately 18 years but exceeds >35 years in younger patients. The triple A survival risk model, based on Age, Absolute neutrophil count, and Absolute lymphocyte count, effectively delineates high-, intermediate-1-, intermediate-2-, and low-risk disease with corresponding median survivals of 8, 14, 21, and 47 years. RISK FACTORS FOR THROMBOSIS Four risk categories are considered: very low (age ≤60 years, no thrombosis history, JAK2 wild-type), low (same as very low but JAK2 mutation present), intermediate (same as low but age >60 years), and high (thrombosis history or age >60 years with JAK2 mutation). MUTATIONS AND PROGNOSIS MPL and CALR-1 mutations have been associated with increased risk of MF transformation; spliceosome with inferior overall and MF-free survival; TP53 with leukemic transformation, and JAK2V617F with thrombosis. Leukemic transformation rate at 10 years is <1% but might be higher in JAK2-mutated patients with extreme thrombocytosis and those with abnormal karyotype. TREATMENT The main goal of therapy is to prevent thrombosis. In this regard, once-daily low-dose aspirin is advised for all patients and twice daily for low-risk disease. Cytoreductive therapy is advised for high-risk and optional for intermediate-risk disease. First-line cytoreductive drugs of choice are hydroxyurea and pegylated interferon-α and second-line busulfan. ADDITIONAL CONTENT The current review includes specific treatment strategies in the context of extreme thrombocytosis, pregnancy, splanchnic vein thrombosis, perioperative care, and post-essential thrombocythemia MF, as well as new investigational drugs.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Alessandro Maria Vannucchi
- CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, University of Florence, AOU Careggi, Florence, Italy
| | - Tiziano Barbui
- Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy
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14
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Andreescu M, Andreescu B. A Review About the Assessment of the Bleeding and Thrombosis Risk for Patients With Myeloproliferative Neoplasms Scheduled for Surgery. Cureus 2024; 16:e56008. [PMID: 38606222 PMCID: PMC11007487 DOI: 10.7759/cureus.56008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/12/2024] [Indexed: 04/13/2024] Open
Abstract
Myeloproliferative neoplasms (MPNs) present a unique challenge in surgical management due to their inherent predisposition to both bleeding and thrombosis. MPNs are a heterogenous group of acquired clonal conditions. The three classic MPNs are essential thrombocythemia (ET), myelofibrosis (PMF), and polycythemia vera (PV). All subtypes of MPN are associated with both thrombotic and bleeding complications. There are four risk categories for thrombosis in MPN patients: age, thrombosis history, and JAK-2 mutation. They are further classified as very low, low, intermediate, and high risk. The genetic landscape of MPN is fascinating and complex like all myeloid disorders. Bleeding risk can be assessed through leukocytosis, thrombocytosis, acquired von Willebrand syndrome (AVWS), and a previous history of bleeding in a patient. Risk assessment and perioperative management are important aspects of improving the quality of life and preventing complications in surgeries. Preoperative management includes a risk assessment of venous thromboembolism, use of appropriate pharmacological treatment, platelet count control, and correction and cardiovascular risk factors. This review summarizes the assessment of bleeding and thrombosis risk for patients with MPNs scheduled for surgery. Furthermore, this review discusses various tools that can be used to identify MPN patients at risk of thrombosis prior to surgery.
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Affiliation(s)
- Mihaela Andreescu
- Faculty of Medicine, Titu Maiorescu University, Bucharest, ROU
- Hematology, Colentina Clinical Hospital, Bucharest, ROU
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15
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Mehta D, Alimam S, McLornan DP, Henry JA, Ahmed S, Ghosh AK, Tyebally S, Walker JM, Patel R, Amerikanou R, O'Nions J, Wilson AJ, Lambert J, Sekhar M, Chen D. Cardiovascular risk in a contemporary cohort of patients with myeloproliferative neoplasms'. Curr Res Transl Med 2024; 72:103420. [PMID: 38262189 DOI: 10.1016/j.retram.2023.103420] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 10/06/2023] [Accepted: 10/12/2023] [Indexed: 01/25/2024]
Abstract
BACKGROUND Myeloproliferative neoplasms (MPNs) are a group of disorders of clonal haemopoiesis associated with an inherent risk of arterial and venous thrombotic complications. The prevalence of thrombotic complications and the impact of cardiovascular risk factors (CVRFs) in contemporary patient cohorts within the current era of MPN treatments have not been completely defined. OBJECTIVES We aim to characterise the cardiovascular risk of patients with MPN by identifying the prevalence of CVRFs and describing the pattern of thrombotic events. We also aim to utilise the QRISK3 algorithm, which is a validated model used to estimate an individual's risk of developing cardiovascular disease, to further phenotype this cohort of patients. METHODS We perform a retrospective analysis on a single-centre cohort of 438 patients with MPN. RESULTS MPN patients continue to carry a high burden of vascular morbidity with a prevalence of arterial thrombotic events in 15.8 % (69/438) and venous thrombotic events in 13.2 % (58/438) of the cohort. The novel use of the QRISK3 algorithm, which showed a mean score of 13.7 % across the MPN population, provides further evidence to suggest an increased cardiovascular risk in MPN patients. CONCLUSION With an increased risk of cardiovascular disease in patients with MPN, we propose an integrated approach between primary and specialised healthcare services using risk stratification tools such as QRISK3, which will allow aggressive optimisation of CVRFs to prevent thrombosis and reduce the overall morbidity and mortality in patients with MPN.
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Affiliation(s)
- Dipal Mehta
- University College Hospital, University College of London Hospitals NHS Foundation Trust, London NW1 2BU, UK
| | - Samah Alimam
- University College Hospital, University College of London Hospitals NHS Foundation Trust, London NW1 2BU, UK
| | - Donal P McLornan
- University College Hospital, University College of London Hospitals NHS Foundation Trust, London NW1 2BU, UK
| | - John A Henry
- John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK
| | - Syeda Ahmed
- University College Hospital, University College of London Hospitals NHS Foundation Trust, London NW1 2BU, UK
| | - Arjun K Ghosh
- University College Hospital, University College of London Hospitals NHS Foundation Trust, London NW1 2BU, UK; Hatter Cardiovascular Institute, University College of London, London WC1E 6HX, UK; Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London EC1A 7BE, UK
| | - Sara Tyebally
- University College Hospital, University College of London Hospitals NHS Foundation Trust, London NW1 2BU, UK; Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London EC1A 7BE, UK
| | - John M Walker
- University College Hospital, University College of London Hospitals NHS Foundation Trust, London NW1 2BU, UK; Hatter Cardiovascular Institute, University College of London, London WC1E 6HX, UK
| | - Riyaz Patel
- University College Hospital, University College of London Hospitals NHS Foundation Trust, London NW1 2BU, UK
| | - Rodothea Amerikanou
- University College Hospital, University College of London Hospitals NHS Foundation Trust, London NW1 2BU, UK
| | - Jenny O'Nions
- University College Hospital, University College of London Hospitals NHS Foundation Trust, London NW1 2BU, UK
| | - Andrew J Wilson
- University College Hospital, University College of London Hospitals NHS Foundation Trust, London NW1 2BU, UK
| | - Jon Lambert
- University College Hospital, University College of London Hospitals NHS Foundation Trust, London NW1 2BU, UK
| | - Mallika Sekhar
- University College Hospital, University College of London Hospitals NHS Foundation Trust, London NW1 2BU, UK
| | - Daniel Chen
- University College Hospital, University College of London Hospitals NHS Foundation Trust, London NW1 2BU, UK; Hatter Cardiovascular Institute, University College of London, London WC1E 6HX, UK; Prince of Wales & St George Hospitals, South East Sydney Local Health District, Sydney NSW, Australia.
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16
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McLornan DP, Godfrey AL, Green A, Frewin R, Arami S, Brady J, Butt NM, Cargo C, Ewing J, Francis S, Garg M, Harrison C, Innes A, Khan A, Knapper S, Lambert J, Mead A, McGregor A, Neelakantan P, Psaila B, Somervaille TCP, Woodley C, Nangalia J, Cross NCP, McMullin MF. Diagnosis and evaluation of prognosis of myelofibrosis: A British Society for Haematology Guideline. Br J Haematol 2024; 204:127-135. [PMID: 37932932 DOI: 10.1111/bjh.19164] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 10/02/2023] [Accepted: 10/08/2023] [Indexed: 11/08/2023]
Affiliation(s)
- Donal P McLornan
- Department of Haematology, University College London Hospitals, London, UK
| | - Anna L Godfrey
- Haematopathology and Oncology Diagnostics Service, Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Anna Green
- Department of Histopathology, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Rebecca Frewin
- Department of Haematology, Gloucestershire Hospitals NHS Foundation Trust, Gloucester, UK
| | - Siamak Arami
- Department of Haematology, London Northwest Healthcare University NHS Trust, London, UK
| | - Jessica Brady
- Department of Clinical Oncology, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Nauman M Butt
- Department of Haematology, The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK
| | - Catherine Cargo
- Department of Haematology, Leeds Teaching Hospitals NHS Foundation Trust, Leeds, UK
| | - Joanne Ewing
- Department of Haematology, University Hospitals Birmingham Trust, Birmingham, UK
| | - Sebastian Francis
- Department of Haematology, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK
| | - Mamta Garg
- Department of Haematology, University Hospitals Leicester NHS Trust, Leicester, UK
| | - Claire Harrison
- Department of Haematology, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Andrew Innes
- Department of Haematology, Imperial College, London, UK
| | - Alesia Khan
- Department of Haematology, Leeds Teaching Hospitals NHS Foundation Trust, Leeds, UK
| | - Steve Knapper
- Department of Haematology, Cardiff University, Cardiff, UK
| | - Jonathan Lambert
- Department of Haematology, University College London Hospitals, London, UK
| | - Adam Mead
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Haematology, Churchill Hospital, Oxford University NHS Trust, Oxford, UK
| | - Andrew McGregor
- Department of Haematology, Freeman Hospital, Newcastle upon Tyne, UK
| | - Pratap Neelakantan
- Department of Haematology, Royal Berkshire NHS Foundation Trust, Berkshire, UK
| | - Bethan Psaila
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Haematology, Churchill Hospital, Oxford University NHS Trust, Oxford, UK
| | - Tim C P Somervaille
- Cancer Research UK Manchester Institute and The Christie NHS Foundation Trust, Manchester, UK
| | - Claire Woodley
- Department of Haematology, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Jyoti Nangalia
- Wellcome Sanger Institute, University of Cambridge, Cambridge, UK
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Beleva EA. Splanchnic Vein Thrombosis in Myelofibrosis-An Underappreciated Hallmark of Disease Phenotype. Int J Mol Sci 2023; 24:15717. [PMID: 37958701 PMCID: PMC10649007 DOI: 10.3390/ijms242115717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 10/21/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Splanchnic vein thrombosis (SVT) encompasses thrombosis in the vessels of the splanchnic basin and has a relatively rare occurrence with a reported frequency in the general population of 1-2%. An episode of seemingly unprovoked SVT almost always triggers a diagnostic work-up for a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN), since atypical site thrombosis is a hallmark of MPN-associated thrombophilia. Primary myelofibrosis (PMF) is a rare MPN with an estimated incidence between 0.1 and 1/100,000 per year. Although prothrombotic tendency in PMF is not envisioned as a subject of specific therapeutic management, unlike other MPNs, such as polycythemia vera (PV) and essential thrombocythemia (ET), thrombotic risk and SVT prevalence in PMF may be comparably high. Additionally, unlike PV and ET, SVT development in PMF may depend more on procoagulant mechanisms involving endothelium than on blood cell activation. Emerging results from registry data also suggest that PMF patients with SVT may exhibit lower risk and better prognosis, thus highlighting the need for better thrombotic risk stratification and identifying a subset of patients with potential benefit from antithrombotic prophylaxis. This review highlights specific epidemiological, pathogenetic, and clinical features pertinent to SVT in myelofibrosis.
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Affiliation(s)
- Elina A. Beleva
- Clinic of Hematology, Military Medical Academy, 1606 Sofia, Bulgaria;
- QSAR and Molecular Modelling, Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
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18
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Lim HY, Ho P. Thrombosis Risk Assessment in Myeloproliferative Neoplasm-Is There a Role for Viscoelastic Testing? Semin Thromb Hemost 2023; 49:173-181. [PMID: 36055269 DOI: 10.1055/s-0042-1753483] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Philadelphia chromosome-negative myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia, and myelofibrosis. They are associated with increased thrombotic events, and the primary goal of therapy, in particular those with polycythemia vera and essential thrombocythemia, is the prevention of thrombotic complications typically with antiplatelet therapy and/or cytoreduction. While several patient-, disease-, and genomic-related factors have been identified to influence thrombotic risks, there are no routine laboratory investigations to date that are sufficiently accurate to assess the underlying procoagulant state and predict the thrombotic risks. Conventional coagulation testing only measures time to clot formation and cannot reliably predict bleeding and thrombotic risks. Global coagulation assays such as thromboelastography, thrombin, and fibrin generation may provide a more thorough assessment of hemostatic function. Thromboelastography and thromboelastometry are viscoelastic tests which measure the mechanical properties of the hemostatic process, including the global dynamics of clot formation, stabilization, and dissolution. While viscoelastic testing is gaining traction in the investigations of coagulopathies and goal-directed blood product replacement in trauma and massive transfusion settings, the role of these assays in thrombosis is less well defined. Here, we provide a review of the current evidence of the role of viscoelastic testing in myeloproliferative neoplasm, particularly in the thrombotic risk assessment.
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Affiliation(s)
- Hui Yin Lim
- Department of Hematology, Northern Pathology Victoria, Northern Hospital, Epping VIC, Australia.,Australian Centre for Blood Diseases, Monash University, Melbourne VIC, Australia.,Department of Medicine, Northern Health, University of Melbourne, Heidelberg, VIC, Australia
| | - Prahlad Ho
- Department of Hematology, Northern Pathology Victoria, Northern Hospital, Epping VIC, Australia.,Australian Centre for Blood Diseases, Monash University, Melbourne VIC, Australia.,Department of Medicine, Northern Health, University of Melbourne, Heidelberg, VIC, Australia
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19
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Thiele J, Kvasnicka HM, Orazi A, Gianelli U, Gangat N, Vannucchi AM, Barbui T, Arber DA, Tefferi A. The international consensus classification of myeloid neoplasms and acute Leukemias: myeloproliferative neoplasms. Am J Hematol 2023; 98:166-179. [PMID: 36200127 DOI: 10.1002/ajh.26751] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/30/2022] [Accepted: 10/02/2022] [Indexed: 02/04/2023]
Abstract
A group of international experts, including hematopathologists, oncologists, and geneticists were recently summoned (September 2021, Chicago, IL, USA) to update the 2016/17 World Health Organization classification system for hematopoietic tumors. After careful deliberation, the group introduced the new International Consensus Classification (ICC) for Myeloid Neoplasms and Acute Leukemias. This current in-depth review focuses on the ICC-2022 category of JAK2 mutation-prevalent myeloproliferative neoplasms (MPNs): essential thrombocythemia, polycythemia vera, primary myelofibrosis, and MPN, unclassifiable. The ICC MPN subcommittee chose to preserve the primary role of bone marrow morphology in disease classification and diagnostics, while also acknowledging the complementary role of genetic markers for establishing clonality, facilitating MPN subtype designation, and disease prognostication.
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Affiliation(s)
- Jürgen Thiele
- Institute of Pathology, University of Cologne, Cologne, Germany
| | | | - Attilio Orazi
- Department of Pathology, Texas Tech University Health Sciences Center, El Paso, Texas, USA
| | - Umberto Gianelli
- Department of Health Sciences and S.C. Anatomia Patologica, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - Naseema Gangat
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Alessandro M Vannucchi
- CRIMM-Centro Ricerca e Innovazione delle Malattie Mieloproliferative, Azienda Ospedaliera-Universitaria Careggi, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Tiziano Barbui
- FROM Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Daniel A Arber
- Department of Pathology, University of Chicago, Chicago, Illinois, USA
| | - Ayalew Tefferi
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
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20
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Vannucchi AM. Molecular prognostication in Ph-negative MPNs in 2022. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2022; 2022:225-234. [PMID: 36485130 PMCID: PMC9820187 DOI: 10.1182/hematology.2022000339] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The application of genomic techniques, including cytogenetics and DNA sequencing, to decipher the molecular landscape of patients with myeloproliferative neoplasms (MPNs) has radically modified diagnostic approach and management through improved risk stratification. Three driver mutated genes (JAK2, MPL, CALR) are variably harbored by >80% of patients and associated with clinical characteristics, as well as major disease-related complications and different survival outcomes. Therefore, JAK2 V617F mutation is included in the revised International Prognosis Score of Thrombosis for Essential Thrombocythemia score for prediction of thrombosis in patients with essential thrombocythemia and prefibrotic primary myelofibrosis, while a CALR type 1 mutated genotype constitutes a favorable variable for survival in patients with myelofibrosis (MF). Novel, integrated clinical and cytogenetic/mutation scores (Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients with Primary Myelofibrosis [MIPSS70/v2], genetically inspired prognostic scoring system [GIPSS], Myelofibrosis Secondary to PV and ET- Prognostic Model [MYSEC-PM]) have been devised that guide selection of stem cell transplantation candidates with MF or help predict the risk associated with the transplant procedure (Myelofibrosis Transplant Scoring System), with greater performance compared with conventional scores based on hematologic and clinical variables only. On the other hand, several clinical needs remain unmet despite the great amount of molecular information available nowadays. These include the prediction of evolution to acute leukemia in a clinically actionable time frame, the identification of patients most likely to derive durable benefits from target agents, in primis JAK inhibitors, and, conversely, the significance of molecular responses that develop in patients receiving interferon or some novel agents. Here, we discuss briefly the significance and the role of genomic analysis for prognostication in patients with MPNs from a clinician's point of view, with the intent to provide how-to-use hints.
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Affiliation(s)
- Alessandro Maria Vannucchi
- CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
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EXABS-161-MPN Management of Pre-Fibrotic Primary Myelofibrosis. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2022; 22 Suppl 2:S65-S66. [PMID: 36164235 DOI: 10.1016/s2152-2650(22)00665-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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22
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Hernández-Boluda JC, Pastor-Galán I, Arellano-Rodrigo E, Raya JM, Pérez-Encinas M, Ayala R, Ferrer-Marín F, Velez P, Mora E, Fox ML, Hernández-Rivas JM, Xicoy B, Mata-Vázquez MI, García-Fortes M, Pérez-López R, Angona A, Cuevas B, Senín A, Ramírez MJ, Ramírez-Payer A, Gómez-Casares MT, Martínez-Valverde C, Magro E, Steegmann JL, Durán MA, García-Hernández C, Gasior M, de Villambrosia SG, Alvarez-Larrán A, Pereira A. Predictors of thrombosis and bleeding in 1613 myelofibrosis patients from the Spanish Registry of Myelofibrosis. Br J Haematol 2022; 199:529-538. [PMID: 36089912 DOI: 10.1111/bjh.18440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/14/2022] [Accepted: 08/18/2022] [Indexed: 12/01/2022]
Abstract
Available data have proved insufficient to develop consensus recommendations on the prevention of thrombosis and bleeding in myelofibrosis (MF). We evaluated the incidence and risk factors of vascular complications in 1613 patients from the Spanish Myelofibrosis Registry. Over a total of 6981 patient-years at risk, 6.4% of the study population had at least one thrombotic event after MF diagnosis, amounting to an incidence rate of 1.65 per 100 patient-years. Prior history of thrombosis, the JAK2 mutation, and the intermediate-2/high-risk International Prognostic Scoring System (IPSS) categories conferred an increased thrombotic risk after adjustment for the risk-modifying effect of anti-thrombotic and cytoreductive treatments. History of thrombosis and the JAK2 mutation allowed us to pinpoint a group of patients at higher risk of early thrombosis. No decreased incidence of thrombosis was observed while patients were on anti-thrombotic or cytoreductive treatment. An increased risk of venous thrombosis was found during treatment with immunomodulatory agents. A total of 5.3% of patients had at least one episode of major bleeding, resulting in an incidence rate of 1.5 events per 100 patient-years. Patients in the intermediate-2/high-risk IPSS categories treated with anti-coagulants had an almost sevenfold increased risk of major bleeding. These findings should prove useful for guiding decision-making in clinical practice.
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Affiliation(s)
| | - Irene Pastor-Galán
- Hematology Department, Hospital Clínico Universitario-INCLIVA, Valencia, Spain
| | | | - José-María Raya
- Hematology Department, Hospital Universitario de Canarias, Tenerife, Spain
| | - Manuel Pérez-Encinas
- Hematology Department, Hospital Clínico Universitario, Santiago de Compostela, Spain
| | - Rosa Ayala
- Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Francisca Ferrer-Marín
- Hematology Department, Hospital Morales Meseguer, Universidad Católica San Antonio de Murcia, Centro de Investigación Biomédica en Red de Enfermedades Raras, Murcia, Spain
| | - Patricia Velez
- Hematology Department, Hospital del Mar, Barcelona, Spain
| | - Elvira Mora
- Hematology Department, Hospital Universitario La Fe, Valencia, Spain
| | - María-Laura Fox
- Hematology Department, Vall d'Hebron Hospital Universitari, Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | | | - Blanca Xicoy
- Hematology Department, Hospital Germans Trias i Pujol, Institut Català d'Oncologia, Josep Carreras Leukemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain
| | | | - María García-Fortes
- Hematology Department, Hospital Universitario Virgen de la Victoria, Málaga, Spain
| | - Raúl Pérez-López
- Hematology Department, Hospital Virgen de la Arrixaca, Murcia, Spain
| | - Anna Angona
- Hematology Department, Hospital Josep Trueta, Institut Català d'Oncologia, Girona, Spain
| | - Beatriz Cuevas
- Hematology Department, Hospital Universitario de Burgos, Burgos, Spain
| | - Alicia Senín
- Hematology Department, Hospital Duran i Reynals, Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain
| | - María-José Ramírez
- Hematology Department, Hospital General Jerez de la Frontera, Cádiz, Spain
| | | | | | | | - Elena Magro
- Hematology Department, Hospital Príncipe de Asturias, Alcalá de Henares, Spain
| | | | | | | | | | | | - Alberto Alvarez-Larrán
- Hematology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Arturo Pereira
- Department of Hemotherapy and Hemostasis, Hospital Clínic, Barcelona, Spain
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Prediction of thrombosis in post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a study on 1258 patients. Leukemia 2022; 36:2453-2460. [PMID: 36042316 DOI: 10.1038/s41375-022-01673-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 07/25/2022] [Accepted: 07/27/2022] [Indexed: 11/08/2022]
Abstract
Patients with Philadelphia-negative myeloproliferative neoplasms are at high risk of thrombotic events (TEs). Predisposing factors have been identified in essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (primary MF, PMF), while yet not recognized in post PV/ET-MF (known as secondary MF, SMF). Within the 1258 SMF of the MYSEC (MYelofibrosis SECondary to PV and ET) dataset, 135 (10.7%) developed a TE at a median follow-up of 3.5 years (range, 1-21.4), with an incidence of 2.3% patients per year. Venous events accounted for two-thirds of the total. Cox multivariable analysis, supported by Fine-Gray models with death as competitive risk, showed that being on cytoreductive therapy at time of SMF evolution is associated with an absolute risk reduction of thrombosis equal to 3.3% within 3 years. Considering individually cytoreductive therapies, univariate regression model found that both conventional cytoreduction, mainly hydroxyurea, (HR 0.41, 95% CI: 0.26-0.65, p = 0.0001) and JAK inhibitors, mostly ruxolitinib, (HR 0.50, 95% CI: 0.24-1.02, p = 0.05) were associated with fewer thrombosis. Our study informs treating physicians of a non-low incidence of TEs in post PV/ET-MF and of the potential protective role of cytoreductive therapy in terms of thrombotic events.
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Krecak I, Lucijanic M, Verstovsek S. Advances in Risk Stratification and Treatment of Polycythemia Vera and Essential Thrombocythemia. Curr Hematol Malig Rep 2022; 17:155-169. [PMID: 35932395 DOI: 10.1007/s11899-022-00670-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/22/2022] [Indexed: 11/30/2022]
Abstract
PURPOSE OF REVIEW Estimating and modifying thrombotic risk is currently the mainstay of care for patients with polycythemia vera (PV) and essential thrombocythemia (ET). In recent years, however, increased attention has shifted towards quality of life and disease modification. In this review, we discuss recent advances in risk stratification, present updated results for ruxolitinib and interferon randomized clinical trials, discuss new approaches in antiplatelet and anticoagulant treatment, and summarize early phase trials of novel agents and emerging therapeutic concepts for the treatment of PV and ET. RECENT FINDINGS International collaborations and novel technologies, i.e., next-generation sequencing and machine learning techniques, have demonstrated excellent abilities to improve thrombotic risk stratification in PV and ET. Updated results from ruxolitinib and interferon randomized clinical trials have confirmed excellent efficacy and safety of these agents, both as first- and second-line treatments. Early trials of novel agents (histone deacetylase inhibitors, telomerase inhibitors, lysine-specific demethylase-1 inhibitors, human double-minute 2 inhibitors, and hepcidin mimetics) have shown encouraging efficacy and safety in blood count control, reduction of splenomegaly, and alleviation of disease-related symptoms. Finally, accumulating evidence suggested that direct oral anticoagulants may be a valid therapeutic alternative to warfarin for prolonged thromboprophylaxis. International collaborations ("big data") with the help of new technologies represent an exciting new approach to analyze rare outcomes in rare diseases, especially for identifying novel prognostic biomarkers in PV and ET. Randomized clinical trials are also needed to fully elucidate whether novel agents may establish new standards of care.
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Affiliation(s)
- Ivan Krecak
- Department of Internal Medicine, General Hospital of Sibenik-Knin County, Stjepana Radića 83, 22000, Sibenik, Croatia. .,School of Medicine, University of Rijeka, Rijeka, Croatia.
| | - Marko Lucijanic
- Division of Hematology, University Hospital Dubrava, Zagreb, Croatia.,School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Srdan Verstovsek
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA
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Pastor-Galán I, Martín I, Ferrer B, Hernández-Boluda JC. Impact of molecular profiling on the management of patients with myelofibrosis. Cancer Treat Rev 2022; 109:102435. [PMID: 35839532 DOI: 10.1016/j.ctrv.2022.102435] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/30/2022] [Accepted: 07/04/2022] [Indexed: 11/02/2022]
Abstract
Myelofibrosis (MF) is a chronic myeloproliferative neoplasm (MPN) characterized by a highly heterogeneous clinical course, which can be complicated by severe constitutional symptoms, massive splenomegaly, progressive bone marrow failure, cardiovascular events, and development of acute leukemia. Constitutive signaling through the JAK-STAT pathway plays a fundamental role in its pathogenesis, generally due to activating mutations of JAK2, CALR and MPL genes (i.e., the MPN driver mutations), present in most MF patients. Next Generation Sequencing (NGS) panel testing has shown that additional somatic mutations can already be detected at the time of diagnosis in more than half of patients, and that they accumulate along the disease course. These mutations, mostly affecting epigenetic modifiers or spliceosome components, may cooperate with MPN drivers to favor clonal dominance or influence the clinical phenotype, and some, such as high molecular risk mutations, correlate with a more aggressive clinical course with poor treatment response. The current main role of molecular profiling in clinical practice is prognostication, principally for selecting high-risk patients who may be candidates for transplantation, the only curative treatment for MF to date. To this end, contemporary prognostic models incorporating molecular data are useful tools to discriminate different risk categories. Aside from certain clinical situations, decisions regarding medical treatment are not based on patient molecular profiling, yet this approach may become more relevant in novel treatment strategies, such as the use of vaccines against the mutant forms of JAK2 or CALR, or drugs directed against actionable molecular targets.
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Affiliation(s)
| | - Iván Martín
- Hospital Clínico Universitario-INCLIVA, Valencia, Spain
| | - Blanca Ferrer
- Hospital Clínico Universitario-INCLIVA, Valencia, Spain
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Lindgren M, Andréasson B, Samuelsson J, Pettersson H, Enblom-Larsson A, Ravn-Landtblom A, Scheding S, Bentham C, Ahlstrand E. Survival and risk of vascular complications in myelofibrosis-A population-based study from the Swedish MPN group. Eur J Haematol 2022; 109:336-342. [PMID: 35696444 DOI: 10.1111/ejh.13813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 05/30/2022] [Indexed: 11/30/2022]
Abstract
OBJECTIVE To gain knowledge of underlying risk factors for vascular complications and their impact on life expectancy in myelofibrosis. METHODS From a cohort of 392 myelofibrosis patients registered in the Swedish MPN registry 58 patients with vascular complications during follow-up were identified. Patients with vascular complications were compared with both 1:1 matched controls and the entire myelofibrosis cohort to explore potential risk factors for vascular complications and their impact on survival. RESULTS Incidence of vascular complications was 2.8 events per 100 patient-years and the majority of complications were thrombotic. Patients with complications were significantly older and had lower hemoglobin when compared to the entire cohort. In the case-control analysis, no significant risk factor differences were observed. The major cause of death was vascular complications and median survival was significantly impaired in patients with vascular complications (48 months) compared to controls (92 months). Inferior survival in patients with vascular complications was found to be dependent on IPSS risk category in a Cox regression model. CONCLUSION Vascular complications have a considerable impact on survival in MF. At diagnosis, risk assessment by IPSS does not only predict survival but is also associated with the risk of vascular complications.
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Affiliation(s)
- Marie Lindgren
- Department of Medicine, Kalmar County Hospital, Kalmar, Sweden.,Faculty of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Björn Andréasson
- Division of Hematology, Department of Medicine, NU Hospital Group, Uddevalla, Sweden
| | - Jan Samuelsson
- Department of Hematology, University Hospital Linköping, Linköping, Sweden
| | - Helna Pettersson
- Division of Hematology, Department of Medicine, NU Hospital Group, Uddevalla, Sweden
| | - Anneli Enblom-Larsson
- Department of Public Health and Clinical Medicine, Luleå Research Unit, Umeå University, Umeå, Sweden
| | - Anna Ravn-Landtblom
- Department of Medicine, Karolinska Institute and Department of Medicine, Division of Hematology, Stockholm South Hospital, Stockholm, Sweden
| | - Stefan Scheding
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Lund University, Lund, Sweden.,Department of Hematology, Skåne University Hospital, Lund, Sweden
| | | | - Erik Ahlstrand
- Department of Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
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De Marchi F, Okuda M, Morishita S, Imai M, Baba T, Horino M, Mori Y, Furuya C, Ogata S, Yang Y, Ando J, Ando M, Araki M, Komatsu N. Clinical and biological relevance of CREB3L1 in Philadelphia chromosome-negative myeloproliferative neoplasms. Leuk Res 2022; 119:106883. [DOI: 10.1016/j.leukres.2022.106883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 05/23/2022] [Accepted: 05/30/2022] [Indexed: 10/18/2022]
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Diabetes and Second Neoplasia Impact on Prognosis in Pre-Fibrotic Primary Myelofibrosis. Cancers (Basel) 2022; 14:cancers14071799. [PMID: 35406571 PMCID: PMC8997979 DOI: 10.3390/cancers14071799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/26/2022] [Accepted: 03/29/2022] [Indexed: 01/27/2023] Open
Abstract
Simple Summary The 2016 WHO-revised classification of MPNs recognized pre-fibrotic PMF (pre-PMF) as a distinct clinical entity from both overt fibrotic PMF (overt PMF) and essential thrombocythemia (ET). In fact, while the initial presentation of pre-PMF is often an isolated thrombocytosis, thus mimicking ET, its course may be symptomatic in a non-negligible number of cases. Conversely, overt PMF patients are enriched in higher-risk categories, thus suggesting a greater propensity for disease progression than pre-PMF. Importantly, median survival is significantly reduced in overt PMF vs. pre-PMF, thereby reinforcing the appropriateness of making this distinction in clinical practice. Nevertheless, a specific prognostic model for pre-PMF is still lacking, except for thrombotic risk. The aim of the present study was therefore to identify covariates other than those commonly related to PMF, which can better define prognosis in pre-PMF patients in the real-world setting, thus resulting in more personalized and efficient therapeutic approaches. Abstract The 2016 WHO classification recognized pre-fibrotic primary myelofibrosis (pre-PMF) as a distinct entity. Nevertheless, a prognostic model specific for pre-PMF is still lacking. Our aim was to identify the most relevant clinical, histological, and driver mutation information at diagnosis to evaluate outcomes in pre-PMF patients in the real-world setting. We firstly assessed the association between IPSS or DIPSS at diagnosis and response variables in 378 pre-PMF patients. A strict association was observed between IPSS and DIPSS and occurrence of death. Other analyzed endpoints were not associated with IPSS or DIPSS as thrombo-hemorrhagic events at diagnosis or during follow-up, or did not show a clinical plausibility, as transformation into acute leukemia or overt PMF. The only covariates which were significantly associated with death were diabetes and second neoplasia, and were therefore included in two different prognostic settings: the first based on IPSS at diagnosis [class 1 vs. 0, OR (95%CIs): 3.34 (1.85–6.04); class 2 vs. 0, OR (95%CIs): 12.55 (5.04–31.24)], diabetes [OR (95%CIs): 2.95 (1.41–6.18)], and second neoplasia [OR (95%CIs): 2.88 (1.63–5.07)]; the second with DIPSS at diagnosis [class 1 vs. 0, OR (95%CIs): 3.40 (1.89–6.10); class 2 vs. 0, OR (95%CIs): 25.65 (7.62–86.42)], diabetes [OR (95%CIs): 2.89 (1.37–6.09)], and second neoplasia [OR (95%CIs): 2.97 (1.69–5.24)]. In conclusion, our study underlines the importance of other additional risk factors, such as diabetes and second neoplasia, to be evaluated, together with IPSS and DIPSS, to better define prognosis in pre-PMF patients.
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Dias E, Liberal R, Costa-Moreira P, Príncipe F, Fonseca E, Macedo G. Primary Myelofibrosis in the Prefibrotic Stage Presenting as Portal, Splenic, and Superior Mesenteric Vein Thrombosis: A Case Report and Review of the Literature. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2022; 29:125-131. [PMID: 35497670 PMCID: PMC8995663 DOI: 10.1159/000514658] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 12/29/2020] [Indexed: 08/30/2023]
Abstract
INTRODUCTION Myeloproliferative neoplasms are the most common cause of splanchnic vein thrombosis in the absence of cirrhosis or nearby malignancy. CASE PRESENTATION A 31-year-old male presented to the emergency department with epigastric pain associated with mild thrombocytosis and elevated levels of aminotransferases, lactate dehydrogenase, and C-reactive protein. Contrast-enhanced abdominal computed tomography revealed splanchnic venous thrombosis that involved the portal, splenic, and superior mesenteric veins, without signs of chronic liver disease. Anticoagulation with warfarin was immediately started. Diagnostic work-up was remarkable for the presence of the JAK2 V617T mutation and hypercellular bone marrow, with increased myeloid cells and atypical megakaryocytes, consistent with primary myelofibrosis in a prefibrotic stage. No other hypercoagulable conditions were identified. DISCUSSION We present a rare case of primary myelofibrosis in the prefibrotic stage presenting as portal-splenic-superior mesenteric vein thrombosis. This demonstrates that extensive splanchnic vein thrombosis may be the onset manifestation of myeloproliferative neoplasms, even in early stages and in the absence of concomitant hypercoagulable conditions. The presence of the JAK2 mutation is an important prothrombotic risk factor that can, per se, contribute to large venous thrombosis.
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Affiliation(s)
- Emanuel Dias
- Gastroenterology Department, Centro Hospitalar de São João, Porto, Portugal
| | - Rodrigo Liberal
- Gastroenterology Department, Centro Hospitalar de São João, Porto, Portugal
| | | | - Fernando Príncipe
- Hematology Department, Centro Hospitalar de São João, Porto, Portugal
| | - Elsa Fonseca
- Pathology Department, Centro Hospitalar de São João, Porto, Portugal
| | - Guilherme Macedo
- Gastroenterology Department, Centro Hospitalar de São João, Porto, Portugal
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JAK2 allele burden is correlated with a risk of venous but not arterial thrombosis. Thromb Res 2022; 211:1-5. [PMID: 35051830 DOI: 10.1016/j.thromres.2022.01.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/30/2021] [Accepted: 01/10/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND Thrombosis is the main complication in myeloproliferative neoplasms (MPN). A JAK2V617F mutation has been shown to be a risk factor for thrombosis. The implication of other risk factors alongside a mutation allele burden needs to be clarified (Trifa et al., 2018; Borowczyk et al., 2015). OBJECTIVE Our aim was to investigate the role of the JAK2 mutation allele burden in the risk of cardiovascular events (CVE) and/or venous thrombosis (VTE) in a cohort of patients with confirmed MPN, as well as in patients without confirmed MPN. METHODS We restrospectively included all consecutive patients who were positive for JAK2V617F seen by our unit between December 2008 and September 2016. Inclusion criteria were a positive test for the JAK2V617F mutation, with at least 1% allele burden, with or without confirmed MPN. RESULTS We included 239 patients of median age 71 years [60-81], followed-up for a median of 82.8 months [41.08-146.88]. For JAK2V617F positive patients having an allele burden superior to 50% the cumulative incidence of VTE was significantly higher than for those with an allele burden inferior to 50% (HR 3.11 95% CI [1.10-8.76] p = 0.031). The cumulative incidence of VTE was also higher in patients with obesity (HR 4.58 95% CI [1.33-15.8] p = 0.016). There was no significant association between a JAK2V617F allele burden and arterial thrombosis (manifesting as CVE). Previous VTE was also associated with a higher cumulative incidence of recurrence during follow-up HR 3.22 95% CI [1.17-8.81] p = 0.0231. CONCLUSION We show that a JAK2V617F allele burden is associated with risk of VTE but not with CVE.
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Barbui T, Carobbio A, De Stefano V. Thrombosis in myeloproliferative neoplasms during cytoreductive and antithrombotic drug treatment. Res Pract Thromb Haemost 2022; 6:e12657. [PMID: 35155976 PMCID: PMC8822262 DOI: 10.1002/rth2.12657] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 12/31/2021] [Accepted: 01/12/2022] [Indexed: 12/16/2022] Open
Abstract
A state-of-the-art lecture titled "Myeloproliferative Neoplasm-associated Thrombosis" was presented at the ISTH congress in 2021. We summarize here the main points of the lecture with two purposes: to report the incidence rates of major thrombosis in polycythemia vera and essential thrombocythemia and to discuss to what extent cytoreductive therapy and antithrombotic drugs have reduced the incidence of these events. Unfortunately, the incidence rate of thrombosis remains high, ranging between 2 and 5/100 person-years. It is likely that new drugs such as interferon and ruxolitinib can be more efficacious given their cytoreductive and anti-inflammatory activities. Despite prophylaxis with vitamin K antagonists and direct oral anticoagulants after venous thrombosis in either common sites or splanchnic or cerebral sites, the incidence rate is still elevated, as high as 4 to 5/100 person-years. Future studies with new drugs or new strategies should consider thrombosis as the primary endpoint or surrogate biomarkers only if previously validated.
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Affiliation(s)
- Tiziano Barbui
- FROM Research FoundationPapa Giovanni XXIII HospitalBergamoItaly
| | | | - Valerio De Stefano
- Section of HematologyDepartment of Radiological and Hematological SciencesCatholic UniversityFondazione Policlinico A. Gemelli IRCCSRomeItaly
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Covert Brain Infarcts in Patients with Philadelphia Chromosome-Negative Myeloproliferative Disorders. J Clin Med 2021; 11:jcm11010013. [PMID: 35011753 PMCID: PMC8745571 DOI: 10.3390/jcm11010013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/10/2021] [Accepted: 12/17/2021] [Indexed: 11/28/2022] Open
Abstract
Backgrounds and Purpose. Philadelphia chromosome-negative myeloproliferative disorders (Ph-negative MPD) are a rare group of hematological diseases, including three distinct pathologies: essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). They most often manifest with thrombotic complications, including cerebrovascular events. Covert brain infarcts (CBIs) are defin ed as predominantly small ischemic cerebral lesions that are detected using magnetic resonance imaging (MRI) in the absence of clinical stroke events. The relationship between MPD and CBIs remains unclear. Methods. Included in the study were 103 patients with the diagnosis of Ph-MPD (according to WHO 2016 criteria) (median age—47 (35; 54) years; 67% female). In total, 38 patients had ET, 42 had PV, and 23 had PMF. They underwent clinical examination, routine laboratory analyses (complete blood count), brain MRI, ultrasound carotid artery, flow-mediated dilatation (as a measure of endothelial dysfunction—FMD). Results. Overall, 23 patients experienced an ischemic stroke (as per MRI and/or clinical history), of which 16 (15.5%) could be classified as CBIs. The rate of CBIs per MPD subtype was statistically non-significant between groups (p = 0.35): ET–13.2%, PV–21.4%, and PMF–8.7%. The major vascular risk factors, including arterial hypertension, carotid atherosclerosis, and prior venous thrombosis, were not associated with CBIs (p > 0.05). Age was significantly higher in patients with CBIs compared to patients without MRI ischemic lesions: 50 (43; 57) years vs. 36 (29; 48) (p = 0.002). The frequency of headaches was comparable between the two groups. CBIs were associated with endothelial dysfunction (OR - 0.71 (95% CI: 0.49–0.90; p = 0.02)) and higher hemoglobin levels (OR—1.21 (95% CI: 1.06–1.55); p =0.03). Conclusions. CBIs are common in patients with Ph-negative MPD. Arterial hypertension and carotid atherosclerosis were not associated with CBIs in this group of patients. The most significant factors in the development of CBIs were endothelial dysfunction (as measured by FMD) and high hemoglobin levels. Patients with Ph-negative MPD and CBIs were older and had more prevalent endothelial dysfunction.
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Sant'Antonio E, Borsani O, Camerini C, Botta C, Santoro M, Allegra A, Siragusa S. Philadelphia chromosome-negative myeloproliferative neoplasms in younger adults: A critical discussion of unmet medical needs, with a focus on pregnancy. Blood Rev 2021; 52:100903. [PMID: 34742614 DOI: 10.1016/j.blre.2021.100903] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 10/23/2021] [Accepted: 10/27/2021] [Indexed: 11/02/2022]
Abstract
Myeloproliferative neoplasms (MPN) are traditionally regarded as a disease of older adults, though a not negligible fraction of cases occurs at a younger age, including women of childbearing potential. MPN in younger patients, indeed, offer several challenges for the clinical hematologist, that goes from difficulties in reaching a timely and accurate diagnosis to a peculiar thrombotic risk, with a relatively high incidence of thromboses in unusual sites (as the splanchnic veins or the cerebral ones). Moreover, the issue of pregnancy is recently gaining more attention as maternal age is rising and molecular screening are widely implemented, leading to a better recognition of these cases, both before and during pregnancy. In the present work we aim at discussing four clinical topic that we identified as areas of uncertainty or true unmet medical needs in the management of younger patients with MPN, with a particular focus on the topic of pregnancy. For each of these topics, we critically reviewed the available evidence that support treatment decisions, though acknowledging that recommendations in this field are mostly based on expert opinion or derived from guidelines of other clinical conditions that share with MPN a high vascular risk, as antiphospholipid syndrome. Taking into consideration both the lack of evidence-based data and the clinical heterogeneity of MPN, we support an individualized strategy of counseling and management for both young patients and for expectant mother with MPN.
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Affiliation(s)
| | - Oscar Borsani
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Chiara Camerini
- Division of Hematology, Azienda USL Toscana Nord Ovest, Ospedale San Luca, Lucca, Italy
| | - Cirino Botta
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Marco Santoro
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Alessandro Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, Messina, Italy
| | - Sergio Siragusa
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
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Philadelphia-Negative Chronic Myeloproliferative Neoplasms during the COVID-19 Pandemic: Challenges and Future Scenarios. Cancers (Basel) 2021; 13:cancers13194750. [PMID: 34638236 PMCID: PMC8507529 DOI: 10.3390/cancers13194750] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/09/2021] [Accepted: 09/17/2021] [Indexed: 12/30/2022] Open
Abstract
An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) started in December 2019 in China and then become pandemic in February 2020. Several publications investigated the possible increased rate of COVID-19 infection in hematological malignancies. Based on the published data, strategies for the management of chronic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are provided. The risk of severe COVID-19 seems high in MPN, particularly in patients with essential thrombocythemia, but not negligible in myelofibrosis. MPN patients are at high risk of both thrombotic and hemorrhagic complications and this must be accounted in the case of COVID-19 deciding on a case-by-case basis. There are currently no data to suggest that hydroxyurea or interferon may influence the risk or severity of COVID-19 infection. Conversely, while the immunosuppressive activity of ruxolitinib might pose increased risk of infection, its abrupt discontinuation during COVID-19 syndrome is associated with worse outcome. All MPN patients should receive vaccine against COVID-19; reassuring data are available on efficacy of mRNA vaccines in MPNs.
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Yamade K, Yamaguchi T, Nagai Y, Kamisako T. Platelet count evaluation compared with the immunoplatelet reference method and performance evaluation of the hematology analyzer Celltac G. Int J Lab Hematol 2021; 43:927-938. [PMID: 33548102 DOI: 10.1111/ijlh.13481] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 12/14/2020] [Accepted: 01/11/2021] [Indexed: 12/25/2022]
Abstract
INTRODUCTION The hematology analyzer, Celltac G (Nihon Kohden), designed to improve platelet count (Plt) accuracy, is equipped with new sheath flow control technology. Clinical evaluation of the Celltac G was assessed by comparability with XN-9000 (Sysmex Corporation) and CELL-DYN Sapphire (Abbott Diagnostics). The accuracy of all three analyzers, which use different measuring principles, was compared with the immunoplatelet reference method (FCM-Ref). METHODS Repeatability and within-laboratory imprecision were assessed using 10 clinical fresh whole blood samples and three control materials with differing levels. Carryover was evaluated using 6 clinical fresh whole blood samples. For method comparison between the three analyzers, 388 samples were used. Plt accuracy among the three analyzers was evaluated using 54 blood samples, including 42 samples with a platelet count less than 50x109 /L. The International Council for Standardization in Haematology method for Plt was used as the FCM-Ref. RESULTS The Celltac G showed sufficient performance with regard to imprecision, carryover, and comparability. The Analytical Measurement Interval (AMI) and linearity for all parameters of Plt were validated within 4.6 to 809.1 (×109 /L). All hematology analyzers showed some disagreement in Plt when compared with the immunoplatelet reference method. CONCLUSION The Celltac G hematology analyzer is suitable for clinical use. Platelet count evaluation of the three analyzers suggests the need to determine a reportable measurement interval (RMI) in the clinical laboratory for adequate reporting of a Plt from multiple different values.
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Affiliation(s)
- Kenji Yamade
- Department of Central Clinical Laboratory, Kindai University Hospital, Osakasayama, Japan.,Kindai University Graduate School of Medical Sciences, Osakasayama, Japan
| | - Toshihiro Yamaguchi
- Department of Central Clinical Laboratory, Kindai University Hospital, Osakasayama, Japan
| | - Yutaka Nagai
- Faculty of Clinical Laboratory, Kansai University of Health Sciences, Kumatori, Japan.,IVD Business Operations, Nihon Kohden Corp., Tokyo, Japan
| | - Toshinori Kamisako
- Department of Central Clinical Laboratory, Kindai University Hospital, Osakasayama, Japan.,Kindai University Graduate School of Medical Sciences, Osakasayama, Japan
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Abstract
PURPOSE OF REVIEW Thrombocytosis is common to all myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis. Despite the traditionally held belief amongst many clinicians that thrombocytosis correlates with thrombosis risk, there is little evidence in the literature to support that claim. Herein we critically analyze the literature to better understand the relationship between thrombocytosis and risk of thrombosis in MPN. RECENT FINDINGS Both retrospective and prospective studies argue against associations between thrombocytosis and risk of thrombosis in patients with ET and PV. Rather, most studies suggest that the presence of extreme thrombocytosis is instead associated with an increased risk of hemorrhagic events, a paradoxical phenomenon with important clinical implications. Thrombosis risk has a multifactorial set of etiologies in MPNs. While qualitative abnormalities of the platelets may contribute, associations between platelet quantity and thrombosis risk are weak in MPN patients.
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Lucijanic M, Galusic D, Krecak I, Sedinic M, Holik H, Perisa V, Moric Peric M, Zekanovic I, Stoos-Veic T, Kusec R. Reduced renal function strongly affects survival and thrombosis in patients with myelofibrosis. Ann Hematol 2020; 99:2779-2785. [PMID: 32862283 DOI: 10.1007/s00277-020-04239-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 08/26/2020] [Indexed: 01/01/2023]
Abstract
We retrospectively investigated a cohort of 176 myelofibrosis patients (128 primary-PMF; 48 secondary-SMF) from five hematology centers. The presence of chronic kidney disease (CKD) was determined in addition to other clinical characteristics. CKD was present in 26.1% of MF patients and was significantly associated with older age (P < 0.001), higher WBC (P = 0.015), and its subsets (neutrophil, monocyte, and basophil counts), higher platelets (P = 0.001), lower albumin (P = 0.018), higher serum uric acid (P = 0.001), higher LDH (P = 0.022), and the presence of CV risk factors (P = 0.011). There was no significant association with driver mutations, degree of bone marrow fibrosis, PMF/SMF, or DIPSS risk categories (P > 0.05 for all analyses). The presence of CKD was significantly associated with shorter time to arterial (HR = 3.49; P = 0.041) and venous thrombosis (HR = 7.08; P = 0.030) as well as with shorter overall survival (HR 2.08; P = 0.009). In multivariate analyses, CKD (HR = 1.8; P = 0.014) was associated with shorter survival independently of the DIPSS (HR = 2.7; P < 0.001); its effect being more pronounced in lower (HR = 3.56; P = 0.036) than higher DIPSS categories (HR = 2.07; P = 0.023). MF patients with CKD should be candidates for active management aimed at the improvement of renal function. Prospective studies defining the optimal therapeutic approach are highly needed.
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Affiliation(s)
- Marko Lucijanic
- Hematology Department, University Hospital Dubrava, Av. Gojka Suska 6, 10000, Zagreb, Croatia.
| | - Davor Galusic
- Department of Hematology, University Hospital of Split, Soltanska ul. 1, 21000, Split, Croatia
| | - Ivan Krecak
- Hematology Department, General Hospital Sibenik, Ul. Stjepana Radića 83, 22000, Sibenik, Croatia
| | - Martina Sedinic
- Hematology Department, University Hospital Dubrava, Av. Gojka Suska 6, 10000, Zagreb, Croatia
| | - Hrvoje Holik
- Department of Internal Medicine, "Dr. Josip Bencevic" General Hospital, Ul. Andrije Štampara, 35000, Slavonski Brod, Croatia
| | - Vlatka Perisa
- Department of Hematology, Osijek University Hospital, Ul. Josipa Huttlera 4, 31000, Osijek, Croatia.,Faculty of Medicine, University of Osijek, Ul. Josipa Huttlera 4, 31000, Osijek, Croatia
| | - Martina Moric Peric
- Department of Internal Medicine, General Hospital Zadar, Ul. Boze Pericica 5, 23000, Zadar, Croatia
| | - Ivan Zekanovic
- Department of Internal Medicine, General Hospital Zadar, Ul. Boze Pericica 5, 23000, Zadar, Croatia
| | - Tajana Stoos-Veic
- Department of Clinical Cytology and Cytometry, University Hospital Dubrava, Av. Gojka Suska 6, 10000, Zagreb, Croatia.,School of Medicine, University of Zagreb, Ul. Salata 3, 10000, Zagreb, Croatia
| | - Rajko Kusec
- Hematology Department, University Hospital Dubrava, Av. Gojka Suska 6, 10000, Zagreb, Croatia.,School of Medicine, University of Zagreb, Ul. Salata 3, 10000, Zagreb, Croatia
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Skov V. Next Generation Sequencing in MPNs. Lessons from the Past and Prospects for Use as Predictors of Prognosis and Treatment Responses. Cancers (Basel) 2020; 12:E2194. [PMID: 32781570 PMCID: PMC7464861 DOI: 10.3390/cancers12082194] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/03/2020] [Accepted: 08/03/2020] [Indexed: 12/29/2022] Open
Abstract
The myeloproliferative neoplasms (MPNs) are acquired hematological stem cell neoplasms characterized by driver mutations in JAK2, CALR, or MPL. Additive mutations may appear in predominantly epigenetic regulator, RNA splicing and signaling pathway genes. These molecular mutations are a hallmark of diagnostic, prognostic, and therapeutic assessment in patients with MPNs. Over the past decade, next generation sequencing (NGS) has identified multiple somatic mutations in MPNs and has contributed substantially to our understanding of the disease pathogenesis highlighting the role of clonal evolution in disease progression. In addition, disease prognostication has expanded from encompassing only clinical decision making to include genomics in prognostic scoring systems. Taking into account the decreasing costs and increasing speed and availability of high throughput technologies, the integration of NGS into a diagnostic, prognostic and therapeutic pipeline is within reach. In this review, these aspects will be discussed highlighting their role regarding disease outcome and treatment modalities in patients with MPNs.
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Affiliation(s)
- Vibe Skov
- Department of Hematology, Zealand University Hospital, Vestermarksvej 7-9, 4000 Roskilde, Denmark
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Barbui T, Vannucchi AM, Guglielmelli P, De Stefano V, Rambaldi A. An agenda for future research projects in polycythemia vera and essential thrombocythemia. Haematologica 2020; 105:1999-2003. [PMID: 32467140 PMCID: PMC7395271 DOI: 10.3324/haematol.2019.246207] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 04/14/2020] [Indexed: 01/13/2023] Open
Affiliation(s)
- Tiziano Barbui
- FROM Research Foundation, Papa Giovanni XXIII Hospital, Bergamo
| | - Alessandro Maria Vannucchi
- Center of Research and Innovation of Myeloproliferative Neoplasms (CRIMM), Azienda Ospedaliera Universitaria Careggi and Department of Experimental and Clinical Medicine, University of Florence, Florence
| | - Paola Guglielmelli
- Center of Research and Innovation of Myeloproliferative Neoplasms (CRIMM), Azienda Ospedaliera Universitaria Careggi and Department of Experimental and Clinical Medicine, University of Florence, Florence
| | - Valerio De Stefano
- Section of Hematology, Department of Radiological and Hematological Sciences, Catholic University and Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome
| | - Alessandro Rambaldi
- Department of Oncology and Hematology, University of Milan, Milan and Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
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