Hyunyee Rosa Cho, Susanne Isfort, Kim Kricheldorf, Frank Stegelmann, Martine Klausmann, Florian H. Heidel, Martin Griesshammer, Holger Schulz, Andreas Hochhaus, Joachim Göthert, Rudolf Schlag, Wiebke Hollburg, Lino Teichmann, Katja Sockel, Stefan Wilop, Deniz Gezer, Martin Kirschner, Konstanze Döhner, Tim H. Brümmendorf, Steffen Koschmieder, for the German Study Group for Myeloproliferative Neoplasms (GSG-MPN)
{"title":"减轻骨髓增殖性肿瘤患者房颤相关并发症的抗血栓和细胞减少治疗:来自GSG-MPN生物登记的意义","authors":"Hyunyee Rosa Cho, Susanne Isfort, Kim Kricheldorf, Frank Stegelmann, Martine Klausmann, Florian H. Heidel, Martin Griesshammer, Holger Schulz, Andreas Hochhaus, Joachim Göthert, Rudolf Schlag, Wiebke Hollburg, Lino Teichmann, Katja Sockel, Stefan Wilop, Deniz Gezer, Martin Kirschner, Konstanze Döhner, Tim H. Brümmendorf, Steffen Koschmieder, for the German Study Group for Myeloproliferative Neoplasms (GSG-MPN)","doi":"10.1002/hem3.70090","DOIUrl":null,"url":null,"abstract":"<p>Vascular complications such as thromboembolic events (TEs) and severe bleeding events (BEs) are the major causes of morbidity and mortality in patients (pts) with Myeloproliferative Neoplasms (MPNs).<span><sup>1</sup></span> TEs are promoted by the hypercoagulable state in MPN, caused by elevated blood counts, activation of platelets, leukocytes, and endothelial cells, the presence of the JAK2V617F mutation, and increased circulating procoagulant microparticles and the occurrence of acquired activated protein C resistance. Disease-associated bleeding may occur via acquired von Willebrand syndrome, platelet dysfunction, antiplatelet agents (APAs), and thrombocytopenia.<span><sup>2</sup></span> In addition, hemostasis can be disturbed by anticoagulation therapy, acquired hemophilia,<span><sup>3</sup></span> or complications such as liver dysfunction or disseminated intravascular coagulopathies due to infection.<span><sup>2</sup></span></p><p>Atrial fibrillation (AF) is the most common sustained arrhythmia, with increasing prevalence with age.<span><sup>4, 5</sup></span> The incidence of AF has rarely been studied in MPN, but was suggested to be higher compared to the general population.<span><sup>6</sup></span> The same study found that MPN pts with AF had a higher frequency of cardiovascular risk factors (CVRFs) and thrombotic complications and a shorter thrombosis-free survival than MPN pts without AF.<span><sup>6</sup></span> However, in a separate study comparing 63 pts with polycythemia vera (PV) and AF to 124 control pts with AF only, no increased incidence of thrombosis was found.<span><sup>7</sup></span> Both studies found no increase in major BE. However, none of the two studies reported the use and effects of cytoreductive therapy (CRT) in their cohorts, a critical means to decrease the risk of both initial and recurrent thrombosis in high-risk MPN pts.</p><p>Therefore, we conducted this retrospective analysis of 2,780 MPN pts enrolled in the GSG-MPN bioregistry, in order to identify the characteristics of AF in MPN pts and to assess the benefit–risk profile of antithrombotic therapies (ATTs) alone or in combination with MPN-specific CRT. The German Study Group MPN bioregistry (GSG-MPN bioregistry) is an ambispective observational study of MPN pts, with over 70 centers participating. Recruitment started in August 2012, with a data cut-off date of January 2020.</p><p>As in the general population,<span><sup>6</sup></span> the median age of AF pts in our MPN cohort was higher than those without AF (Supporting Information S1: Table S3). The prevalence of AF in pts older than 80 years of age in our MPN cohort was higher than that in the general population (18.2% [Supporting Information S1: Figure S1] vs. 8.8% in the FRAMINGHAM study<span><sup>8</sup></span>).</p><p>Since the incidence and complication rate of MPN pts increase with age and since CRT is recommended in an age-adapted manner, we performed a case–control analysis following a 1:1 pattern, with age as a matching factor (Table 1, <i>n</i> = 134 with AF vs. <i>n</i> = 134 without AF). Here, unlike in non-age-matched analyses (Supporting Information S1: Table S3), which showed higher incidence of TEs and BEs in AF pts, no significant difference in the prevalence of TEs and BEs was observed after age-matching. Also, the higher percentage of arterial TE in AF pts was no longer observed after age-matching, suggesting that all pts (MPN pts as well as non-MPN pts) develop a preponderance of arterial over venous TE with increasing age, as has been described before.<span><sup>1, 9, 10</sup></span></p><p>While cardiovascular comorbidities are reported to be risk factors for the development of AF,<span><sup>8, 11</sup></span> in our age-matched cohort, it was revealed that AF pts had more cardiac comorbidities than non-AF pts. In addition, use of any type of ATT, including vitamin K antagonists (VKAs) and direct oral anticoagulant (DOAC), was more prominent in AF pts. Conversely, a higher percentage of non-AF pts were treated with APA.</p><p>When analyzing the entire cohort of MPN pts without age-matching, our Kaplan–Meier survival analyses showed significantly inferior OS in pts with coexisting AF (Supplemental Figure 4A). 5-year OS was 92% in pts without AF and 82% in pts with AF. When focusing on the time after diagnosis of MPN (as opposed to the lifetime of a patient), the incidence of events in AF pts was higher only for BEs but not for TEs when compared to non-AF pts (Supporting Information S1: Figure S4B,C). 10-year BEFS was 97% in pts without AF and 89% in pts with AF. In current guidelines on the management of pts with AF in the general population, anticoagulants are recommended for pts with AF and an elevated CHA2DS2-VASc score of ≥2 in men or ≥3 in women.<span><sup>12</sup></span> Thus, it is likely that the increased incidence of cardiovascular comorbidities in our MPN pts with AF led to higher CHA2DS2-VASc scores and to a higher rate of prophylactic ATTs, independently from the MPN management. The increased prevalence of bleeding after but rarely before the MPN diagnosis in this group of pts (Supporting Information S1: Figure 4C) may at least in part be explained by this increase in ATTs, as described earlier.<span><sup>9</sup></span> Importantly, the fact that no difference in thromboembolic event-free survival (TEFS) was observed between our MPN pts with AF vs. those without AF (Supporting Information S1: Figure 4B) suggests that management of AF pts in our cohort successfully prevented excess TEs in these pts. The definition of TEFS and bleeding event-free survival (BEFS) is provided in the methods section of the supplemental file.</p><p>We then performed survival analysis after age-matching of the cohort to reduce the influence of differences in the sample size and the age difference between the pts with vs without AF. The inferior survival outcomes were no longer observed in age-matched analyses. The presence of AF did not have a significant overall influence on the OS, TEFS, or BEFS in MPN pts (Figure 1A–C). We speculate that this was due to the success of the combined use of ATTs and CRT in an aging MPN population at high risk for TEs due to coexisting AF. The difference in BEFS was no longer significant in age-matched analysis, which may indicate that management of anticoagulation has become better tolerated during the past few years, possibly through the increased use of DOACs instead of VKAs, also shown in more recent MPN cohort analyses.<span><sup>13, 14</sup></span></p><p>The importance of ATTs and CRTs was evident from our study, particularly in pts with coexisting AF. OS was worse when AF pts received neither of the therapies, or when they were treated only with CRTs (Figure 1D). Compared to patients who received both therapies, patients who received neither therapy or only CRTs had significantly inferior OS (5-year OS for neither: not obtainable, for only CRTs: 31.3%, for Both: 86.7%). These significant differences were observed only in the AF group (<i>P</i> = 0.003). The result of the analysis of the non-AF group is shown in Supporting Information S1: Figure S5A.</p><p>An additional OS analysis was conducted using a 1:1 matched data set with a larger number of matching factors, including age, congestive heart failure, diabetes mellitus, arterial hypertension, abnormal renal function, and a history of thromboembolic and vascular events. This analysis yielded a similar result as the matching analysis using age alone (Supporting Information S1: Figure S9).</p><p>Similarly, the worst TEFS and BEFS was observed in pts with AF who were treated only with ATT (Figure 1E,F) compared to pts treated with combined therapy with ATT and CRT.</p><p>Through age-matched OS, TEFS, and BEFS analyses, we observed that MPN pts with AF treated with combined ATT and CRTs have better prognoses than those with ATT or CRT alone. We would like to emphasize that all age-matched survival analyses stratified by ATT and CRT were significant only in AF patients. In non-AF patients, OS, TEFS, and BEFS stratified by ATT and CRT showed no significance, as shown in Supporting Information S1: Figure S5. OS, TEFS, and BEFS analyses, separate for ATT and CRT, can be found in Supporting Information S1: Figures S6–S8.</p><p>Our data demonstrate the beneficial effects of MPN-specific CRT in addition to ATT for the prevention of TEs and BEs in MPN pts with coexisting AF. As outlined in current management guidelines for MPN, the risks of thromboembolism and bleeding have to be carefully balanced.<span><sup>2, 15</sup></span> One of the limitations of our study is that the prevalence of newly developed AF along with MPN over time could not be assessed in our study. AF was recorded at the time of registration, and it is hence unclear if the AF occurred before or after the MPN diagnosis. Moreover, while we observed a higher prevalence of AF in the MPN population compared to the non-MPN population, due to the observational nature of our study, we cannot prove a causal relationship, but can only suggest this interesting association. Finally, whether the ATTs were discontinued after the initiation of CRT was not consistently documented in this study. In future studies, such data could enable more nuanced analyses and offer deeper insights into the interplay between AF and MPN.</p><p>However, one of the strengths of our study is the large number of pts and the inclusion of all major MPN subtypes. It adds significant data on the management of AF in MPN pts, which are urgently needed in the absence of controlled clinical trials on this topic.</p><p>In conclusion, our study provides evidence for beneficial effects of CRT as additional treatment for MPN pts with coexisting AF, including not only elderly pts older than 60 years of age but also younger pts. Prospective studies are needed to validate these findings and determine whether pts with different MPN subtypes need to be managed differently.</p><p>The authors confirm their individual contributions to the manuscript as follows: Hyunyee Rosa Cho (Submitting author): Conceptualized and designed the study, collected the data, performed the statistical analyses, performed most of the data interpretation, drafted the original manuscript, and contributed to the critical review and revision of the manuscript. Steffen Koschmieder (Corresponding Author): Contributed to the collection of bioregistry data, contributed to interpretation of data evaluation, secured funding, provided supervision throughout the project, and participated in the review and revision of the manuscript. Susanne Isfort, Kim Kricheldorf, Frank Stegelmann, Martine Klausmann, Florian Heidel, Martin Griesshammer, Holger Schulz, Andreas Hochhaus, Joachim Göthert, Rudolf Schlag, Wiebke Hollburg, Lino Teichmann, Katja Sockel, Stefan Wilop, Deniz Gezer, Martin Kirschner, Konstanze Döhner, and Tim H. Brümmendorf contributed to the collection of bioregistry data, contributed to interpretation of data evaluation, and participated in the review of the manuscript. Each author reviewed the manuscript, believes it represents valid work, and approves it for submission.</p><p>Susanne Isfort reports advisory board honoraria from GSK, Pfizer, Incyte, and Novartis, honoraria from Novartis, BMS, Pfizer, Incyte, AOP Orphan; and other financial support (e.g., travel support) from Alexion, Novartis, Pfizer, Mundipharma, Roche, Hexal, and AOP Orphan. Frank Stegelmann reports consulting fees from BMS/Celgene, Incyte, MorphoSys, Novartis and received honoraria from AbbVie, AOP Orphan, Incyte, Novartis, and Pfizer. Florian H. Heidel has received research funding from Novartis, Celgene/BMS, and CTI BioPharma and has served as a consultant for Novartis, BMS, AOP, Janssen, Abbvie, GSK, and Kartos. Martin Griesshammer received consulting fees from AOP Orphan, Novartis, BMS, AbbVie, Pfizer, Roche, Janssen, Gilead, AstraZeneca, Sierra, Lilly, GSK and reports honoraria from AOP Orphan, Novartis, BMS, AbbVie, Pfizer, Roche, Janssen, Gilead, AstraZeneca, Sierra, Lilly, and GSK. Andreas Hochhaus reports Research support by Novartis, BMS, Pfizer, Incyte, Enliven, TERNS. Lino Teichmann reports honoraria from AOP Pharma, BMS, Jazz. Pharmaceuticals, Novartis, and Sobi and consultancy for Astellas, Blueprint. Medicines, BMS, GSK, Pfizer, and Sobi. Katja Sockel received lecture fees from BMS, Novartis, GSK, AbbVie, Jazz, advisory fees from BMS, Novartis, GSK, Blueprint, and SOBI R, and reports research support from Active Biotech. Stefan Wilop reports advisory board honoraria and presentation fees from BMS. Deniz Gezer reports advisory board activity for AMGEN, Takeda and Celgene and travel money from AMGEN, Celgene, and Bristol-Myers Squibb. Konstanze Döhner received research support from Novartis, Celgene/BMS, Astellas and Agios, received honoraria from Novartis, Janssen, Celgene/BMS, Daiichi Sankyo, JAZZ, Rosche and GSK. Reports advisory board honoraria from Novartis, Janssen, Celgene/BMS, Daiichi Sankyo, JAZZ, Rosche, AbbVie, and GSK. Tim H. Brümmendorf reports COI from Novartis, Pfiyer, Synlab, Incyte, Merck, and Rosche. Steffen Koschmieder received research funding from Geron, Janssen, AOP Pharma, and Novartis; received consulting fees from Pfizer, Incyte, Ariad, Novartis, AOP Pharma, Bristol Myers Squibb, Celgene, Geron, Janssen, CTI BioPharma, Roche, Bayer, GSK, Sierra Oncology, and PharmaEssentia; received payment or honoraria from Novartis, BMS/Celgene, and Pfizer; received travel/accommodation support from Alexion, Novartis, Bristol Myers Squibb, Incyte, AOP Pharma, CTI BioPharma, Pfizer, Celgene, Janssen, Geron, Roche, AbbVie, GSK, Sierra Oncology, and Kartos; had a patent issued for a BET inhibitor at RWTH Aachen University; participated on advisory boards for Pfizer, Incyte, Ariad, Novartis, AOP Pharma, BMS, Celgene, Geron, Janssen, CTI BioPharma, Roche, Bayer, GSK, Sierra Oncology, and PharmaEssentia, and is an Editor of <i>HemaSphere</i>. The remaining authors declare no conflict of interest.</p><p>This work was supported by the German Research Foundation (DFG) within the Clinical Research Unit CRU344 to S.K. (KO 2155/9-2, project number 417911533) and T.B. (BR 1782/5-2 and BR 1782/6-1, project number 428857858) and Center for Integrated Oncology, CIO-Aachen.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 3","pages":""},"PeriodicalIF":14.6000,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70090","citationCount":"0","resultStr":"{\"title\":\"Mitigation of atrial fibrillation-related complications with antithrombotic and cytoreductive therapy in patients with Myeloproliferative Neoplasms: Implications from the GSG-MPN bioregistry\",\"authors\":\"Hyunyee Rosa Cho, Susanne Isfort, Kim Kricheldorf, Frank Stegelmann, Martine Klausmann, Florian H. Heidel, Martin Griesshammer, Holger Schulz, Andreas Hochhaus, Joachim Göthert, Rudolf Schlag, Wiebke Hollburg, Lino Teichmann, Katja Sockel, Stefan Wilop, Deniz Gezer, Martin Kirschner, Konstanze Döhner, Tim H. Brümmendorf, Steffen Koschmieder, for the German Study Group for Myeloproliferative Neoplasms (GSG-MPN)\",\"doi\":\"10.1002/hem3.70090\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Vascular complications such as thromboembolic events (TEs) and severe bleeding events (BEs) are the major causes of morbidity and mortality in patients (pts) with Myeloproliferative Neoplasms (MPNs).<span><sup>1</sup></span> TEs are promoted by the hypercoagulable state in MPN, caused by elevated blood counts, activation of platelets, leukocytes, and endothelial cells, the presence of the JAK2V617F mutation, and increased circulating procoagulant microparticles and the occurrence of acquired activated protein C resistance. Disease-associated bleeding may occur via acquired von Willebrand syndrome, platelet dysfunction, antiplatelet agents (APAs), and thrombocytopenia.<span><sup>2</sup></span> In addition, hemostasis can be disturbed by anticoagulation therapy, acquired hemophilia,<span><sup>3</sup></span> or complications such as liver dysfunction or disseminated intravascular coagulopathies due to infection.<span><sup>2</sup></span></p><p>Atrial fibrillation (AF) is the most common sustained arrhythmia, with increasing prevalence with age.<span><sup>4, 5</sup></span> The incidence of AF has rarely been studied in MPN, but was suggested to be higher compared to the general population.<span><sup>6</sup></span> The same study found that MPN pts with AF had a higher frequency of cardiovascular risk factors (CVRFs) and thrombotic complications and a shorter thrombosis-free survival than MPN pts without AF.<span><sup>6</sup></span> However, in a separate study comparing 63 pts with polycythemia vera (PV) and AF to 124 control pts with AF only, no increased incidence of thrombosis was found.<span><sup>7</sup></span> Both studies found no increase in major BE. However, none of the two studies reported the use and effects of cytoreductive therapy (CRT) in their cohorts, a critical means to decrease the risk of both initial and recurrent thrombosis in high-risk MPN pts.</p><p>Therefore, we conducted this retrospective analysis of 2,780 MPN pts enrolled in the GSG-MPN bioregistry, in order to identify the characteristics of AF in MPN pts and to assess the benefit–risk profile of antithrombotic therapies (ATTs) alone or in combination with MPN-specific CRT. The German Study Group MPN bioregistry (GSG-MPN bioregistry) is an ambispective observational study of MPN pts, with over 70 centers participating. Recruitment started in August 2012, with a data cut-off date of January 2020.</p><p>As in the general population,<span><sup>6</sup></span> the median age of AF pts in our MPN cohort was higher than those without AF (Supporting Information S1: Table S3). The prevalence of AF in pts older than 80 years of age in our MPN cohort was higher than that in the general population (18.2% [Supporting Information S1: Figure S1] vs. 8.8% in the FRAMINGHAM study<span><sup>8</sup></span>).</p><p>Since the incidence and complication rate of MPN pts increase with age and since CRT is recommended in an age-adapted manner, we performed a case–control analysis following a 1:1 pattern, with age as a matching factor (Table 1, <i>n</i> = 134 with AF vs. <i>n</i> = 134 without AF). Here, unlike in non-age-matched analyses (Supporting Information S1: Table S3), which showed higher incidence of TEs and BEs in AF pts, no significant difference in the prevalence of TEs and BEs was observed after age-matching. Also, the higher percentage of arterial TE in AF pts was no longer observed after age-matching, suggesting that all pts (MPN pts as well as non-MPN pts) develop a preponderance of arterial over venous TE with increasing age, as has been described before.<span><sup>1, 9, 10</sup></span></p><p>While cardiovascular comorbidities are reported to be risk factors for the development of AF,<span><sup>8, 11</sup></span> in our age-matched cohort, it was revealed that AF pts had more cardiac comorbidities than non-AF pts. In addition, use of any type of ATT, including vitamin K antagonists (VKAs) and direct oral anticoagulant (DOAC), was more prominent in AF pts. Conversely, a higher percentage of non-AF pts were treated with APA.</p><p>When analyzing the entire cohort of MPN pts without age-matching, our Kaplan–Meier survival analyses showed significantly inferior OS in pts with coexisting AF (Supplemental Figure 4A). 5-year OS was 92% in pts without AF and 82% in pts with AF. When focusing on the time after diagnosis of MPN (as opposed to the lifetime of a patient), the incidence of events in AF pts was higher only for BEs but not for TEs when compared to non-AF pts (Supporting Information S1: Figure S4B,C). 10-year BEFS was 97% in pts without AF and 89% in pts with AF. In current guidelines on the management of pts with AF in the general population, anticoagulants are recommended for pts with AF and an elevated CHA2DS2-VASc score of ≥2 in men or ≥3 in women.<span><sup>12</sup></span> Thus, it is likely that the increased incidence of cardiovascular comorbidities in our MPN pts with AF led to higher CHA2DS2-VASc scores and to a higher rate of prophylactic ATTs, independently from the MPN management. The increased prevalence of bleeding after but rarely before the MPN diagnosis in this group of pts (Supporting Information S1: Figure 4C) may at least in part be explained by this increase in ATTs, as described earlier.<span><sup>9</sup></span> Importantly, the fact that no difference in thromboembolic event-free survival (TEFS) was observed between our MPN pts with AF vs. those without AF (Supporting Information S1: Figure 4B) suggests that management of AF pts in our cohort successfully prevented excess TEs in these pts. The definition of TEFS and bleeding event-free survival (BEFS) is provided in the methods section of the supplemental file.</p><p>We then performed survival analysis after age-matching of the cohort to reduce the influence of differences in the sample size and the age difference between the pts with vs without AF. The inferior survival outcomes were no longer observed in age-matched analyses. The presence of AF did not have a significant overall influence on the OS, TEFS, or BEFS in MPN pts (Figure 1A–C). We speculate that this was due to the success of the combined use of ATTs and CRT in an aging MPN population at high risk for TEs due to coexisting AF. The difference in BEFS was no longer significant in age-matched analysis, which may indicate that management of anticoagulation has become better tolerated during the past few years, possibly through the increased use of DOACs instead of VKAs, also shown in more recent MPN cohort analyses.<span><sup>13, 14</sup></span></p><p>The importance of ATTs and CRTs was evident from our study, particularly in pts with coexisting AF. OS was worse when AF pts received neither of the therapies, or when they were treated only with CRTs (Figure 1D). Compared to patients who received both therapies, patients who received neither therapy or only CRTs had significantly inferior OS (5-year OS for neither: not obtainable, for only CRTs: 31.3%, for Both: 86.7%). These significant differences were observed only in the AF group (<i>P</i> = 0.003). The result of the analysis of the non-AF group is shown in Supporting Information S1: Figure S5A.</p><p>An additional OS analysis was conducted using a 1:1 matched data set with a larger number of matching factors, including age, congestive heart failure, diabetes mellitus, arterial hypertension, abnormal renal function, and a history of thromboembolic and vascular events. This analysis yielded a similar result as the matching analysis using age alone (Supporting Information S1: Figure S9).</p><p>Similarly, the worst TEFS and BEFS was observed in pts with AF who were treated only with ATT (Figure 1E,F) compared to pts treated with combined therapy with ATT and CRT.</p><p>Through age-matched OS, TEFS, and BEFS analyses, we observed that MPN pts with AF treated with combined ATT and CRTs have better prognoses than those with ATT or CRT alone. We would like to emphasize that all age-matched survival analyses stratified by ATT and CRT were significant only in AF patients. In non-AF patients, OS, TEFS, and BEFS stratified by ATT and CRT showed no significance, as shown in Supporting Information S1: Figure S5. OS, TEFS, and BEFS analyses, separate for ATT and CRT, can be found in Supporting Information S1: Figures S6–S8.</p><p>Our data demonstrate the beneficial effects of MPN-specific CRT in addition to ATT for the prevention of TEs and BEs in MPN pts with coexisting AF. As outlined in current management guidelines for MPN, the risks of thromboembolism and bleeding have to be carefully balanced.<span><sup>2, 15</sup></span> One of the limitations of our study is that the prevalence of newly developed AF along with MPN over time could not be assessed in our study. AF was recorded at the time of registration, and it is hence unclear if the AF occurred before or after the MPN diagnosis. Moreover, while we observed a higher prevalence of AF in the MPN population compared to the non-MPN population, due to the observational nature of our study, we cannot prove a causal relationship, but can only suggest this interesting association. Finally, whether the ATTs were discontinued after the initiation of CRT was not consistently documented in this study. In future studies, such data could enable more nuanced analyses and offer deeper insights into the interplay between AF and MPN.</p><p>However, one of the strengths of our study is the large number of pts and the inclusion of all major MPN subtypes. It adds significant data on the management of AF in MPN pts, which are urgently needed in the absence of controlled clinical trials on this topic.</p><p>In conclusion, our study provides evidence for beneficial effects of CRT as additional treatment for MPN pts with coexisting AF, including not only elderly pts older than 60 years of age but also younger pts. Prospective studies are needed to validate these findings and determine whether pts with different MPN subtypes need to be managed differently.</p><p>The authors confirm their individual contributions to the manuscript as follows: Hyunyee Rosa Cho (Submitting author): Conceptualized and designed the study, collected the data, performed the statistical analyses, performed most of the data interpretation, drafted the original manuscript, and contributed to the critical review and revision of the manuscript. Steffen Koschmieder (Corresponding Author): Contributed to the collection of bioregistry data, contributed to interpretation of data evaluation, secured funding, provided supervision throughout the project, and participated in the review and revision of the manuscript. Susanne Isfort, Kim Kricheldorf, Frank Stegelmann, Martine Klausmann, Florian Heidel, Martin Griesshammer, Holger Schulz, Andreas Hochhaus, Joachim Göthert, Rudolf Schlag, Wiebke Hollburg, Lino Teichmann, Katja Sockel, Stefan Wilop, Deniz Gezer, Martin Kirschner, Konstanze Döhner, and Tim H. Brümmendorf contributed to the collection of bioregistry data, contributed to interpretation of data evaluation, and participated in the review of the manuscript. Each author reviewed the manuscript, believes it represents valid work, and approves it for submission.</p><p>Susanne Isfort reports advisory board honoraria from GSK, Pfizer, Incyte, and Novartis, honoraria from Novartis, BMS, Pfizer, Incyte, AOP Orphan; and other financial support (e.g., travel support) from Alexion, Novartis, Pfizer, Mundipharma, Roche, Hexal, and AOP Orphan. Frank Stegelmann reports consulting fees from BMS/Celgene, Incyte, MorphoSys, Novartis and received honoraria from AbbVie, AOP Orphan, Incyte, Novartis, and Pfizer. Florian H. Heidel has received research funding from Novartis, Celgene/BMS, and CTI BioPharma and has served as a consultant for Novartis, BMS, AOP, Janssen, Abbvie, GSK, and Kartos. Martin Griesshammer received consulting fees from AOP Orphan, Novartis, BMS, AbbVie, Pfizer, Roche, Janssen, Gilead, AstraZeneca, Sierra, Lilly, GSK and reports honoraria from AOP Orphan, Novartis, BMS, AbbVie, Pfizer, Roche, Janssen, Gilead, AstraZeneca, Sierra, Lilly, and GSK. Andreas Hochhaus reports Research support by Novartis, BMS, Pfizer, Incyte, Enliven, TERNS. Lino Teichmann reports honoraria from AOP Pharma, BMS, Jazz. Pharmaceuticals, Novartis, and Sobi and consultancy for Astellas, Blueprint. Medicines, BMS, GSK, Pfizer, and Sobi. Katja Sockel received lecture fees from BMS, Novartis, GSK, AbbVie, Jazz, advisory fees from BMS, Novartis, GSK, Blueprint, and SOBI R, and reports research support from Active Biotech. Stefan Wilop reports advisory board honoraria and presentation fees from BMS. Deniz Gezer reports advisory board activity for AMGEN, Takeda and Celgene and travel money from AMGEN, Celgene, and Bristol-Myers Squibb. Konstanze Döhner received research support from Novartis, Celgene/BMS, Astellas and Agios, received honoraria from Novartis, Janssen, Celgene/BMS, Daiichi Sankyo, JAZZ, Rosche and GSK. Reports advisory board honoraria from Novartis, Janssen, Celgene/BMS, Daiichi Sankyo, JAZZ, Rosche, AbbVie, and GSK. Tim H. Brümmendorf reports COI from Novartis, Pfiyer, Synlab, Incyte, Merck, and Rosche. Steffen Koschmieder received research funding from Geron, Janssen, AOP Pharma, and Novartis; received consulting fees from Pfizer, Incyte, Ariad, Novartis, AOP Pharma, Bristol Myers Squibb, Celgene, Geron, Janssen, CTI BioPharma, Roche, Bayer, GSK, Sierra Oncology, and PharmaEssentia; received payment or honoraria from Novartis, BMS/Celgene, and Pfizer; received travel/accommodation support from Alexion, Novartis, Bristol Myers Squibb, Incyte, AOP Pharma, CTI BioPharma, Pfizer, Celgene, Janssen, Geron, Roche, AbbVie, GSK, Sierra Oncology, and Kartos; had a patent issued for a BET inhibitor at RWTH Aachen University; participated on advisory boards for Pfizer, Incyte, Ariad, Novartis, AOP Pharma, BMS, Celgene, Geron, Janssen, CTI BioPharma, Roche, Bayer, GSK, Sierra Oncology, and PharmaEssentia, and is an Editor of <i>HemaSphere</i>. The remaining authors declare no conflict of interest.</p><p>This work was supported by the German Research Foundation (DFG) within the Clinical Research Unit CRU344 to S.K. (KO 2155/9-2, project number 417911533) and T.B. 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引用次数: 0
摘要
重要的是,有房颤的MPN患者与没有房颤的MPN患者在血栓栓塞无事件生存(TEFS)方面没有观察到差异(支持信息S1:图4B),这表明在我们的队列中,房颤患者的管理成功地防止了这些患者的过量te。TEFS和无出血事件生存期(BEFS)的定义见补充文件的方法部分。然后,我们对队列进行年龄匹配后进行生存分析,以减少样本量差异和AF患者与非AF患者年龄差异的影响。在年龄匹配分析中不再观察到较差的生存结果。房颤的存在对MPN患者的OS、TEFS或BEFS没有显著的总体影响(图1A-C)。我们推测,这是由于ATTs和CRT联合使用在老年MPN人群中取得的成功,这些人群由于并发房颤而有较高的TEs风险。在年龄匹配分析中,BEFS的差异不再显著,这可能表明抗凝治疗在过去几年中变得更好耐受,可能是通过增加使用DOACs而不是vka,最近的MPN队列分析也显示了这一点。13,14从我们的研究中可以明显看出ats和crt的重要性,特别是对于合并房颤的患者。当房颤患者不接受这两种治疗或仅接受crt治疗时,OS更差(图1D)。与接受两种治疗的患者相比,不接受治疗或仅接受crt的患者的OS明显较差(两种治疗的5年OS均为:无法获得,仅接受crt的5年OS为:31.3%,两种治疗的5年OS为:86.7%)。这些显著差异仅在房颤组中观察到(P = 0.003)。非房颤组分析结果见辅助信息S1:图S5A。使用1:1匹配的数据集进行额外的OS分析,其中包含大量匹配因素,包括年龄、充血性心力衰竭、糖尿病、动脉高血压、肾功能异常以及血栓栓塞和血管事件史。该分析得出的结果与单独使用年龄的匹配分析相似(支持信息S1:图S9)。同样,与ATT和CRT联合治疗的患者相比,仅接受ATT治疗的AF患者的TEFS和BEFS最差(图1E,F)。通过年龄匹配的OS、TEFS和BEFS分析,我们观察到联合ATT和CRT治疗的MPN AF患者比单独ATT或CRT治疗的预后更好。我们想强调的是,所有年龄匹配的生存分析,以ATT和CRT分层,只有在房颤患者中才有意义。在非房颤患者中,经ATT和CRT分层的OS、TEFS和BEFS无统计学意义,见支持信息S1:图S5。OS, TEFS和BEFS分析,分别用于ATT和CRT,可在支持信息S1:图S6-S8中找到。我们的数据表明,除了ATT外,MPN特异性CRT对于预防合并房颤的MPN患者的TEs和BEs有有益的作用。正如目前MPN管理指南中概述的那样,血栓栓塞和出血的风险必须仔细平衡。2,15本研究的局限性之一是,我们的研究无法评估新发房颤伴MPN随时间的患病率。房颤是在登记时记录的,因此不清楚房颤是发生在MPN诊断之前还是之后。此外,虽然我们观察到与非MPN人群相比,MPN人群中AF的患病率更高,但由于我们研究的观察性,我们无法证明因果关系,而只能提出这种有趣的关联。最后,在本研究中,是否在开始CRT后停用ATTs并没有一致的记录。在未来的研究中,这些数据可以进行更细致的分析,并为AF和MPN之间的相互作用提供更深入的见解。然而,我们研究的优势之一是大量的患者和包括所有主要的MPN亚型。它增加了关于MPN患者房颤管理的重要数据,在缺乏该主题的对照临床试验的情况下,这些数据是迫切需要的。总之,我们的研究为CRT作为MPN合并房颤的额外治疗的有益效果提供了证据,不仅包括60岁以上的老年患者,也包括年轻患者。需要前瞻性研究来验证这些发现,并确定不同MPN亚型的患者是否需要不同的治疗方法。作者确认他们对论文的个人贡献如下:Hyunyee Rosa Cho(投稿作者):构思和设计研究,收集数据,进行统计分析,执行大部分数据解释,起草原始手稿,并对手稿进行批判性审查和修改。 Steffen Koschmieder(通讯作者):参与生物登记数据的收集,参与数据评估的解释,获得资金,在整个项目中提供监督,并参与手稿的审查和修改。Susanne Isfort, Kim Kricheldorf, Frank Stegelmann, Martine Klausmann, Florian Heidel, Martin Griesshammer, Holger Schulz, Andreas Hochhaus, Joachim Göthert, Rudolf Schlag, Wiebke Hollburg, Lino Teichmann, Katja Sockel, Stefan Wilop, Deniz Gezer, Martin Kirschner, Konstanze Döhner和Tim H. brmmendorf参与了生物登记数据的收集,参与了数据评估的解释,并参与了手稿的审查。每位作者都审查了稿件,认为它代表了有效的工作,并批准了稿件的提交。Susanne Isfort报道了葛兰素史克、辉瑞、Incyte和诺华咨询委员会的酬金,诺华、BMS、辉瑞、Incyte、AOP Orphan的酬金;以及来自Alexion、Novartis、Pfizer、Mundipharma、Roche、Hexal和AOP Orphan的其他财务支持(例如差旅支持)。Frank Stegelmann报告了BMS/Celgene、Incyte、MorphoSys、Novartis的咨询费用,并从AbbVie、AOP Orphan、Incyte、Novartis和辉瑞获得了酬金。Florian H. Heidel曾获得Novartis、Celgene/BMS和CTI BioPharma的研究资助,并曾担任Novartis、BMS、AOP、Janssen、Abbvie、GSK和Kartos的顾问。Martin Griesshammer从AOP Orphan、Novartis、BMS、AbbVie、Pfizer、Roche、Janssen、Gilead、AstraZeneca、Sierra、Lilly、GSK收取了咨询费,并报告了AOP Orphan、Novartis、BMS、AbbVie、Pfizer、Roche、Janssen、Gilead、AstraZeneca、Sierra、Lilly和GSK的酬金。Andreas Hochhaus报道了诺华、BMS、辉瑞、Incyte、Enliven、TERNS的研究支持。Lino Teichmann报道AOP Pharma, BMS, Jazz的酬金。制药公司,诺华,索比,安斯泰来,蓝皮书咨询公司。医药,BMS, GSK,辉瑞和Sobi。Katja Sockel从BMS、Novartis、GSK、AbbVie、Jazz获得讲学费,从BMS、Novartis、GSK、Blueprint和SOBI R获得咨询费,并从Active Biotech获得报告研究支持。Stefan Wilop报告BMS的顾问委员会酬金和演讲费。Deniz Gezer报道了安进、武田和新基的顾问委员会活动,以及安进、新基和百时美施贵宝的差旅费。Konstanze Döhner获得了诺华、Celgene/BMS、安斯泰来和Agios的研究支持,并获得了诺华、杨森、Celgene/BMS、Daiichi Sankyo、JAZZ、Rosche和GSK的酬金。报告诺华、杨森、Celgene/BMS、Daiichi Sankyo、JAZZ、罗氏、艾伯维和葛兰素史克顾问委员会的酬金。Tim H. brmmendorf在诺华、辉瑞、Synlab、Incyte、默克和罗氏公司报道COI。Steffen Koschmieder获得了Geron、Janssen、AOP Pharma和Novartis的研究资助;从辉瑞、Incyte、Ariad、Novartis、AOP Pharma、Bristol Myers Squibb、Celgene、Geron、Janssen、CTI BioPharma、Roche、Bayer、GSK、Sierra Oncology和PharmaEssentia获得咨询费;从诺华、BMS/Celgene和辉瑞获得付款或酬金;获得了Alexion、Novartis、Bristol Myers Squibb、Incyte、AOP Pharma、CTI BioPharma、Pfizer、Celgene、Janssen、Geron、Roche、AbbVie、GSK、Sierra Oncology和Kartos的差旅/住宿支持;在亚琛工业大学获得了一种BET抑制剂的专利;参与了辉瑞、Incyte、Ariad、Novartis、AOP Pharma、BMS、Celgene、Geron、Janssen、CTI BioPharma、Roche、Bayer、GSK、Sierra Oncology和PharmaEssentia的顾问委员会,并担任HemaSphere的编辑。其余作者声明没有利益冲突。这项工作得到了德国研究基金会(DFG)临床研究单位CRU344 to S.K. (KO 2155/9-2,项目编号417911533)和tb (BR 1782/5-2和BR 1782/6-1,项目编号428857858)以及亚琛信息技术中心综合肿瘤学中心的支持。
Mitigation of atrial fibrillation-related complications with antithrombotic and cytoreductive therapy in patients with Myeloproliferative Neoplasms: Implications from the GSG-MPN bioregistry
Vascular complications such as thromboembolic events (TEs) and severe bleeding events (BEs) are the major causes of morbidity and mortality in patients (pts) with Myeloproliferative Neoplasms (MPNs).1 TEs are promoted by the hypercoagulable state in MPN, caused by elevated blood counts, activation of platelets, leukocytes, and endothelial cells, the presence of the JAK2V617F mutation, and increased circulating procoagulant microparticles and the occurrence of acquired activated protein C resistance. Disease-associated bleeding may occur via acquired von Willebrand syndrome, platelet dysfunction, antiplatelet agents (APAs), and thrombocytopenia.2 In addition, hemostasis can be disturbed by anticoagulation therapy, acquired hemophilia,3 or complications such as liver dysfunction or disseminated intravascular coagulopathies due to infection.2
Atrial fibrillation (AF) is the most common sustained arrhythmia, with increasing prevalence with age.4, 5 The incidence of AF has rarely been studied in MPN, but was suggested to be higher compared to the general population.6 The same study found that MPN pts with AF had a higher frequency of cardiovascular risk factors (CVRFs) and thrombotic complications and a shorter thrombosis-free survival than MPN pts without AF.6 However, in a separate study comparing 63 pts with polycythemia vera (PV) and AF to 124 control pts with AF only, no increased incidence of thrombosis was found.7 Both studies found no increase in major BE. However, none of the two studies reported the use and effects of cytoreductive therapy (CRT) in their cohorts, a critical means to decrease the risk of both initial and recurrent thrombosis in high-risk MPN pts.
Therefore, we conducted this retrospective analysis of 2,780 MPN pts enrolled in the GSG-MPN bioregistry, in order to identify the characteristics of AF in MPN pts and to assess the benefit–risk profile of antithrombotic therapies (ATTs) alone or in combination with MPN-specific CRT. The German Study Group MPN bioregistry (GSG-MPN bioregistry) is an ambispective observational study of MPN pts, with over 70 centers participating. Recruitment started in August 2012, with a data cut-off date of January 2020.
As in the general population,6 the median age of AF pts in our MPN cohort was higher than those without AF (Supporting Information S1: Table S3). The prevalence of AF in pts older than 80 years of age in our MPN cohort was higher than that in the general population (18.2% [Supporting Information S1: Figure S1] vs. 8.8% in the FRAMINGHAM study8).
Since the incidence and complication rate of MPN pts increase with age and since CRT is recommended in an age-adapted manner, we performed a case–control analysis following a 1:1 pattern, with age as a matching factor (Table 1, n = 134 with AF vs. n = 134 without AF). Here, unlike in non-age-matched analyses (Supporting Information S1: Table S3), which showed higher incidence of TEs and BEs in AF pts, no significant difference in the prevalence of TEs and BEs was observed after age-matching. Also, the higher percentage of arterial TE in AF pts was no longer observed after age-matching, suggesting that all pts (MPN pts as well as non-MPN pts) develop a preponderance of arterial over venous TE with increasing age, as has been described before.1, 9, 10
While cardiovascular comorbidities are reported to be risk factors for the development of AF,8, 11 in our age-matched cohort, it was revealed that AF pts had more cardiac comorbidities than non-AF pts. In addition, use of any type of ATT, including vitamin K antagonists (VKAs) and direct oral anticoagulant (DOAC), was more prominent in AF pts. Conversely, a higher percentage of non-AF pts were treated with APA.
When analyzing the entire cohort of MPN pts without age-matching, our Kaplan–Meier survival analyses showed significantly inferior OS in pts with coexisting AF (Supplemental Figure 4A). 5-year OS was 92% in pts without AF and 82% in pts with AF. When focusing on the time after diagnosis of MPN (as opposed to the lifetime of a patient), the incidence of events in AF pts was higher only for BEs but not for TEs when compared to non-AF pts (Supporting Information S1: Figure S4B,C). 10-year BEFS was 97% in pts without AF and 89% in pts with AF. In current guidelines on the management of pts with AF in the general population, anticoagulants are recommended for pts with AF and an elevated CHA2DS2-VASc score of ≥2 in men or ≥3 in women.12 Thus, it is likely that the increased incidence of cardiovascular comorbidities in our MPN pts with AF led to higher CHA2DS2-VASc scores and to a higher rate of prophylactic ATTs, independently from the MPN management. The increased prevalence of bleeding after but rarely before the MPN diagnosis in this group of pts (Supporting Information S1: Figure 4C) may at least in part be explained by this increase in ATTs, as described earlier.9 Importantly, the fact that no difference in thromboembolic event-free survival (TEFS) was observed between our MPN pts with AF vs. those without AF (Supporting Information S1: Figure 4B) suggests that management of AF pts in our cohort successfully prevented excess TEs in these pts. The definition of TEFS and bleeding event-free survival (BEFS) is provided in the methods section of the supplemental file.
We then performed survival analysis after age-matching of the cohort to reduce the influence of differences in the sample size and the age difference between the pts with vs without AF. The inferior survival outcomes were no longer observed in age-matched analyses. The presence of AF did not have a significant overall influence on the OS, TEFS, or BEFS in MPN pts (Figure 1A–C). We speculate that this was due to the success of the combined use of ATTs and CRT in an aging MPN population at high risk for TEs due to coexisting AF. The difference in BEFS was no longer significant in age-matched analysis, which may indicate that management of anticoagulation has become better tolerated during the past few years, possibly through the increased use of DOACs instead of VKAs, also shown in more recent MPN cohort analyses.13, 14
The importance of ATTs and CRTs was evident from our study, particularly in pts with coexisting AF. OS was worse when AF pts received neither of the therapies, or when they were treated only with CRTs (Figure 1D). Compared to patients who received both therapies, patients who received neither therapy or only CRTs had significantly inferior OS (5-year OS for neither: not obtainable, for only CRTs: 31.3%, for Both: 86.7%). These significant differences were observed only in the AF group (P = 0.003). The result of the analysis of the non-AF group is shown in Supporting Information S1: Figure S5A.
An additional OS analysis was conducted using a 1:1 matched data set with a larger number of matching factors, including age, congestive heart failure, diabetes mellitus, arterial hypertension, abnormal renal function, and a history of thromboembolic and vascular events. This analysis yielded a similar result as the matching analysis using age alone (Supporting Information S1: Figure S9).
Similarly, the worst TEFS and BEFS was observed in pts with AF who were treated only with ATT (Figure 1E,F) compared to pts treated with combined therapy with ATT and CRT.
Through age-matched OS, TEFS, and BEFS analyses, we observed that MPN pts with AF treated with combined ATT and CRTs have better prognoses than those with ATT or CRT alone. We would like to emphasize that all age-matched survival analyses stratified by ATT and CRT were significant only in AF patients. In non-AF patients, OS, TEFS, and BEFS stratified by ATT and CRT showed no significance, as shown in Supporting Information S1: Figure S5. OS, TEFS, and BEFS analyses, separate for ATT and CRT, can be found in Supporting Information S1: Figures S6–S8.
Our data demonstrate the beneficial effects of MPN-specific CRT in addition to ATT for the prevention of TEs and BEs in MPN pts with coexisting AF. As outlined in current management guidelines for MPN, the risks of thromboembolism and bleeding have to be carefully balanced.2, 15 One of the limitations of our study is that the prevalence of newly developed AF along with MPN over time could not be assessed in our study. AF was recorded at the time of registration, and it is hence unclear if the AF occurred before or after the MPN diagnosis. Moreover, while we observed a higher prevalence of AF in the MPN population compared to the non-MPN population, due to the observational nature of our study, we cannot prove a causal relationship, but can only suggest this interesting association. Finally, whether the ATTs were discontinued after the initiation of CRT was not consistently documented in this study. In future studies, such data could enable more nuanced analyses and offer deeper insights into the interplay between AF and MPN.
However, one of the strengths of our study is the large number of pts and the inclusion of all major MPN subtypes. It adds significant data on the management of AF in MPN pts, which are urgently needed in the absence of controlled clinical trials on this topic.
In conclusion, our study provides evidence for beneficial effects of CRT as additional treatment for MPN pts with coexisting AF, including not only elderly pts older than 60 years of age but also younger pts. Prospective studies are needed to validate these findings and determine whether pts with different MPN subtypes need to be managed differently.
The authors confirm their individual contributions to the manuscript as follows: Hyunyee Rosa Cho (Submitting author): Conceptualized and designed the study, collected the data, performed the statistical analyses, performed most of the data interpretation, drafted the original manuscript, and contributed to the critical review and revision of the manuscript. Steffen Koschmieder (Corresponding Author): Contributed to the collection of bioregistry data, contributed to interpretation of data evaluation, secured funding, provided supervision throughout the project, and participated in the review and revision of the manuscript. Susanne Isfort, Kim Kricheldorf, Frank Stegelmann, Martine Klausmann, Florian Heidel, Martin Griesshammer, Holger Schulz, Andreas Hochhaus, Joachim Göthert, Rudolf Schlag, Wiebke Hollburg, Lino Teichmann, Katja Sockel, Stefan Wilop, Deniz Gezer, Martin Kirschner, Konstanze Döhner, and Tim H. Brümmendorf contributed to the collection of bioregistry data, contributed to interpretation of data evaluation, and participated in the review of the manuscript. Each author reviewed the manuscript, believes it represents valid work, and approves it for submission.
Susanne Isfort reports advisory board honoraria from GSK, Pfizer, Incyte, and Novartis, honoraria from Novartis, BMS, Pfizer, Incyte, AOP Orphan; and other financial support (e.g., travel support) from Alexion, Novartis, Pfizer, Mundipharma, Roche, Hexal, and AOP Orphan. Frank Stegelmann reports consulting fees from BMS/Celgene, Incyte, MorphoSys, Novartis and received honoraria from AbbVie, AOP Orphan, Incyte, Novartis, and Pfizer. Florian H. Heidel has received research funding from Novartis, Celgene/BMS, and CTI BioPharma and has served as a consultant for Novartis, BMS, AOP, Janssen, Abbvie, GSK, and Kartos. Martin Griesshammer received consulting fees from AOP Orphan, Novartis, BMS, AbbVie, Pfizer, Roche, Janssen, Gilead, AstraZeneca, Sierra, Lilly, GSK and reports honoraria from AOP Orphan, Novartis, BMS, AbbVie, Pfizer, Roche, Janssen, Gilead, AstraZeneca, Sierra, Lilly, and GSK. Andreas Hochhaus reports Research support by Novartis, BMS, Pfizer, Incyte, Enliven, TERNS. Lino Teichmann reports honoraria from AOP Pharma, BMS, Jazz. Pharmaceuticals, Novartis, and Sobi and consultancy for Astellas, Blueprint. Medicines, BMS, GSK, Pfizer, and Sobi. Katja Sockel received lecture fees from BMS, Novartis, GSK, AbbVie, Jazz, advisory fees from BMS, Novartis, GSK, Blueprint, and SOBI R, and reports research support from Active Biotech. Stefan Wilop reports advisory board honoraria and presentation fees from BMS. Deniz Gezer reports advisory board activity for AMGEN, Takeda and Celgene and travel money from AMGEN, Celgene, and Bristol-Myers Squibb. Konstanze Döhner received research support from Novartis, Celgene/BMS, Astellas and Agios, received honoraria from Novartis, Janssen, Celgene/BMS, Daiichi Sankyo, JAZZ, Rosche and GSK. Reports advisory board honoraria from Novartis, Janssen, Celgene/BMS, Daiichi Sankyo, JAZZ, Rosche, AbbVie, and GSK. Tim H. Brümmendorf reports COI from Novartis, Pfiyer, Synlab, Incyte, Merck, and Rosche. Steffen Koschmieder received research funding from Geron, Janssen, AOP Pharma, and Novartis; received consulting fees from Pfizer, Incyte, Ariad, Novartis, AOP Pharma, Bristol Myers Squibb, Celgene, Geron, Janssen, CTI BioPharma, Roche, Bayer, GSK, Sierra Oncology, and PharmaEssentia; received payment or honoraria from Novartis, BMS/Celgene, and Pfizer; received travel/accommodation support from Alexion, Novartis, Bristol Myers Squibb, Incyte, AOP Pharma, CTI BioPharma, Pfizer, Celgene, Janssen, Geron, Roche, AbbVie, GSK, Sierra Oncology, and Kartos; had a patent issued for a BET inhibitor at RWTH Aachen University; participated on advisory boards for Pfizer, Incyte, Ariad, Novartis, AOP Pharma, BMS, Celgene, Geron, Janssen, CTI BioPharma, Roche, Bayer, GSK, Sierra Oncology, and PharmaEssentia, and is an Editor of HemaSphere. The remaining authors declare no conflict of interest.
This work was supported by the German Research Foundation (DFG) within the Clinical Research Unit CRU344 to S.K. (KO 2155/9-2, project number 417911533) and T.B. (BR 1782/5-2 and BR 1782/6-1, project number 428857858) and Center for Integrated Oncology, CIO-Aachen.
期刊介绍:
HemaSphere, as a publication, is dedicated to disseminating the outcomes of profoundly pertinent basic, translational, and clinical research endeavors within the field of hematology. The journal actively seeks robust studies that unveil novel discoveries with significant ramifications for hematology.
In addition to original research, HemaSphere features review articles and guideline articles that furnish lucid synopses and discussions of emerging developments, along with recommendations for patient care.
Positioned as the foremost resource in hematology, HemaSphere augments its offerings with specialized sections like HemaTopics and HemaPolicy. These segments engender insightful dialogues covering a spectrum of hematology-related topics, including digestible summaries of pivotal articles, updates on new therapies, deliberations on European policy matters, and other noteworthy news items within the field. Steering the course of HemaSphere are Editor in Chief Jan Cools and Deputy Editor in Chief Claire Harrison, alongside the guidance of an esteemed Editorial Board comprising international luminaries in both research and clinical realms, each representing diverse areas of hematologic expertise.