Yuelian Sun, Katalin Veres, Hans Carl Hasselbalch, Henrik Frederiksen, Lene Sofie Granfeldt Østgård, Erzsébet Horváth-Puhó, Victor W. Henderson, Henrik Toft Sørensen
<p>Dementia is a severely disabling condition that affected 50 million people and is likely to triple by 2050, thus placing a heavy burden on families and society [<span>1</span>]. Several dementia risk factors have been identified, including age, sex, and environmental and lifestyle factors together with genetic factors [<span>2, 3</span>]. Many of the known risk factors, such as obesity, diabetes, hypertension, and smoking, are potentially modifiable [<span>2, 3</span>].</p><p>Chronic inflammation is a potential key pathogenic factor in the development of dementia [<span>4, 5</span>], but many of its aspects and clinical implications are poorly understood. Philadelphia chromosome–negative chronic myeloproliferative neoplasms (MPNs) are chronic blood cancers caused by the somatic driver mutations <i>JAK2V617F</i>, <i>CALR</i>, and <i>MPL</i> in hematopoietic stem cells [<span>6</span>]. These specific gene mutations contribute to the inflammatory and thrombogenic state in patients diagnosed with MPNs, and the prediagnostic phase of MPNs may span as many as 15–20 years [<span>7</span>]. MPNs have been proposed as a human neuroinflammation model for studying the development of dementia [<span>8</span>]. To our knowledge, no population-based studies have examined associations between MPNs and dementia risk.</p><p>We conducted a cohort study to examine these associations in comparison with a general population comparison cohort. The study also used chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML) as control diseases. CLL has a long clinical course, like MPNs, but chronic inflammation is not considered a driving force for CLL development and disease progression [<span>9</span>]. CML is another chronic myeloproliferative blood cancer caused by a specific reciprocal chromosome translocation (Philadelphia chromosome) and does not involve a chronic inflammatory state to the same extent as Philadelphia chromosome–negative MPNs [<span>10</span>].</p><p>We identified 9895 patients with MPNs, 9465 patients with CLL, and 1530 patients with CML (Figure S1a–c). The patients with MPNs included 3090 with ET, 3910 with PV, 410 with MF, and 2520 with unspecified MPN. Table 1 shows the baseline characteristics and follow-up information for the MPN, CLL, and CML cohorts. Patients with MPNs had more chronic inflammatory comorbidities than did their matched general population comparators, whereas patients with CLL did not (Table 1, Figure S2). Patients with CML were more likely to have comorbidities than were their comparison cohort comparators, but this difference was less pronounced than that observed in the MPN cohort (Table 1, Figure S2).</p><p>During the follow-up (median of 5 years for the MPN cohort and 7 years for the general population cohort), 520 (5.3%) people in the MPN cohort and 7070 (7.4%) people in the general population cohort were diagnosed with dementia, and 50.0% (<i>n</i> = 4945) of the MPN cohort and 31.4% (<i>n</i> = 30 1
{"title":"Myeloproliferative Neoplasms and Dementia Risk: A Population-Based Cohort Study","authors":"Yuelian Sun, Katalin Veres, Hans Carl Hasselbalch, Henrik Frederiksen, Lene Sofie Granfeldt Østgård, Erzsébet Horváth-Puhó, Victor W. Henderson, Henrik Toft Sørensen","doi":"10.1111/ejh.14297","DOIUrl":"10.1111/ejh.14297","url":null,"abstract":"<p>Dementia is a severely disabling condition that affected 50 million people and is likely to triple by 2050, thus placing a heavy burden on families and society [<span>1</span>]. Several dementia risk factors have been identified, including age, sex, and environmental and lifestyle factors together with genetic factors [<span>2, 3</span>]. Many of the known risk factors, such as obesity, diabetes, hypertension, and smoking, are potentially modifiable [<span>2, 3</span>].</p><p>Chronic inflammation is a potential key pathogenic factor in the development of dementia [<span>4, 5</span>], but many of its aspects and clinical implications are poorly understood. Philadelphia chromosome–negative chronic myeloproliferative neoplasms (MPNs) are chronic blood cancers caused by the somatic driver mutations <i>JAK2V617F</i>, <i>CALR</i>, and <i>MPL</i> in hematopoietic stem cells [<span>6</span>]. These specific gene mutations contribute to the inflammatory and thrombogenic state in patients diagnosed with MPNs, and the prediagnostic phase of MPNs may span as many as 15–20 years [<span>7</span>]. MPNs have been proposed as a human neuroinflammation model for studying the development of dementia [<span>8</span>]. To our knowledge, no population-based studies have examined associations between MPNs and dementia risk.</p><p>We conducted a cohort study to examine these associations in comparison with a general population comparison cohort. The study also used chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML) as control diseases. CLL has a long clinical course, like MPNs, but chronic inflammation is not considered a driving force for CLL development and disease progression [<span>9</span>]. CML is another chronic myeloproliferative blood cancer caused by a specific reciprocal chromosome translocation (Philadelphia chromosome) and does not involve a chronic inflammatory state to the same extent as Philadelphia chromosome–negative MPNs [<span>10</span>].</p><p>We identified 9895 patients with MPNs, 9465 patients with CLL, and 1530 patients with CML (Figure S1a–c). The patients with MPNs included 3090 with ET, 3910 with PV, 410 with MF, and 2520 with unspecified MPN. Table 1 shows the baseline characteristics and follow-up information for the MPN, CLL, and CML cohorts. Patients with MPNs had more chronic inflammatory comorbidities than did their matched general population comparators, whereas patients with CLL did not (Table 1, Figure S2). Patients with CML were more likely to have comorbidities than were their comparison cohort comparators, but this difference was less pronounced than that observed in the MPN cohort (Table 1, Figure S2).</p><p>During the follow-up (median of 5 years for the MPN cohort and 7 years for the general population cohort), 520 (5.3%) people in the MPN cohort and 7070 (7.4%) people in the general population cohort were diagnosed with dementia, and 50.0% (<i>n</i> = 4945) of the MPN cohort and 31.4% (<i>n</i> = 30 1","PeriodicalId":11955,"journal":{"name":"European Journal of Haematology","volume":"114 1","pages":"45-56"},"PeriodicalIF":2.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ejh.14297","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Bucelli, I. Capodanno, M. C. Miggiano, F. Cavazzini, S. Leonetti Crescenzi, S. Russo, I. Carmosino, M. Annunziata, F. Sorà, M. Bonifacio, L. Luciano, G. Caocci, G. Loglisci, C. Elena, F. Lunghi, R. Mullai, I. Attolico, G. Binotto, E. Crisà, P. Sportoletti, A. Di Veroli, A. R. Scortechini, A. P. Leporace, A. Maggi, M. Crugnola, F. Stagno, R. Sancetta, P. Murgano, D. Rapezzi, D. Luzi, D. I. Vincelli, S. Galimberti, M. Bocchia, C. Fava, A. Malato, E. Abruzzese, G. Saglio, G. Specchia, M. Breccia, A. Iurlo, M. Tiribelli, R. Latagliata
Objectives
The study aimed to evaluate the utilization of frontline TKI therapy in a large cohort of elderly CP-CML patients.
Methods
A retrospective analysis was conducted on 332 CP-CML patients aged 75 years or older among 1929 diagnosed from January 2012 to December 2019 followed at 36 participating Hematology Centers involved in the “Campus CML” project.
Results
Among the patients analyzed, 85.8% received imatinib (IM) while 14.2% received second-generation TKIs (2G-TKI), 59.5% dasatinib, and 40.5% nilotinib. Most patients initiated IM at standard dose (67.3%) while 32.7% at reduced dose. A similar trend was observed with 2G-TKIs. The cumulative incidence of permanent TKI discontinuation at 12 months was 28.4%, primarily due to primary resistance (10.1%) and extra-hematologic toxicity (9.5%), with no significant difference between IM and 2G-TKI groups. Following the introduction of generic IM in Italy in 2018, IM usage increased significantly compared with 2G-TKIs.
Conclusions
IM was in our Centers the preferred frontline therapy for older CP-CML patients, with increasing utilization after the introduction of generic formulations. However, 2G-TKIs are still used in a substantial proportion of patients, suggesting individualized physician assessments regarding patient suitability and expectations. Further investigation is needed to assess efficacy and safety of reduced TKI doses in this patient population.
{"title":"Choice of Frontline Tyrosine-Kinase Inhibitor and Early Events in Very Elderly Patients With Chronic Myeloid Leukemia in Chronic Phase: A “Campus CML” Study","authors":"C. Bucelli, I. Capodanno, M. C. Miggiano, F. Cavazzini, S. Leonetti Crescenzi, S. Russo, I. Carmosino, M. Annunziata, F. Sorà, M. Bonifacio, L. Luciano, G. Caocci, G. Loglisci, C. Elena, F. Lunghi, R. Mullai, I. Attolico, G. Binotto, E. Crisà, P. Sportoletti, A. Di Veroli, A. R. Scortechini, A. P. Leporace, A. Maggi, M. Crugnola, F. Stagno, R. Sancetta, P. Murgano, D. Rapezzi, D. Luzi, D. I. Vincelli, S. Galimberti, M. Bocchia, C. Fava, A. Malato, E. Abruzzese, G. Saglio, G. Specchia, M. Breccia, A. Iurlo, M. Tiribelli, R. Latagliata","doi":"10.1111/ejh.14299","DOIUrl":"10.1111/ejh.14299","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The study aimed to evaluate the utilization of frontline TKI therapy in a large cohort of elderly CP-CML patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A retrospective analysis was conducted on 332 CP-CML patients aged 75 years or older among 1929 diagnosed from January 2012 to December 2019 followed at 36 participating Hematology Centers involved in the “Campus CML” project.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among the patients analyzed, 85.8% received imatinib (IM) while 14.2% received second-generation TKIs (2G-TKI), 59.5% dasatinib, and 40.5% nilotinib. Most patients initiated IM at standard dose (67.3%) while 32.7% at reduced dose. A similar trend was observed with 2G-TKIs. The cumulative incidence of permanent TKI discontinuation at 12 months was 28.4%, primarily due to primary resistance (10.1%) and extra-hematologic toxicity (9.5%), with no significant difference between IM and 2G-TKI groups. Following the introduction of generic IM in Italy in 2018, IM usage increased significantly compared with 2G-TKIs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>IM was in our Centers the preferred frontline therapy for older CP-CML patients, with increasing utilization after the introduction of generic formulations. However, 2G-TKIs are still used in a substantial proportion of patients, suggesting individualized physician assessments regarding patient suitability and expectations. Further investigation is needed to assess efficacy and safety of reduced TKI doses in this patient population.</p>\u0000 </section>\u0000 </div>","PeriodicalId":11955,"journal":{"name":"European Journal of Haematology","volume":"114 1","pages":"37-44"},"PeriodicalIF":2.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ejh.14299","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142201686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jelena Jelicic, Karen Juul-Jensen, Zoran Bukumiric, Mikkel Runason Simonsen, Michael Roost Clausen, Ahmed Ludvigsen Al-Mashhadi, Robert Schou Pedersen, Christian Bjørn Poulsen, Anne Ortved Gang, Peter Brown, Tarec Christoffer El-Galaly, Thomas Stauffer Larsen
Objectives
Recent front-line clinical trials used the International Prognostic Index (IPI) to identify trial-eligible patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). However, many IPI-like variants with improved accuracy have been developed over the years for rituximab-treated patients.
Methods
We assessed the impact of International Prognostic Indices on patient enrolment in clinical trials, aiming to exclude low-risk IPI patients based on POLARIX/EPCORE DLBCL-2 trial criteria.
Results
We identified 2877 patients in the Danish Lymphoma Registry who would have been eligible for the POLARIX trial if patients with IPI 0–1 scores were included. IPI and NCCN-IPI assigned 33.3% and 11.9% of patients to the low-risk group, respectively. Shorter 5-year overall survival (91.4% vs. 97.5%), higher relapse rate (9.9% vs. 4.4%), and more deaths (16.1% vs. 4.4%) occurred in the low-risk IPI group compared with low-risk NCCN-IPI group. Analyzed models failed to identify true high-risk patients with poor prognosis. Similar results were found in the confirmatory cohort developed based on EPCORE DLBCL-2 trial eligibility criteria.
Conclusion
True low-risk patients are more optimal identified by NCCN-IPI and should be excluded from front-line clinical trials due to their excellent prognosis. However, additional high-risk factors besides clinical prognostic models need to be considered when selecting trial-eligible patients.
{"title":"A Real-World Data-Based Analysis of Prognostic Indices as Part of Trial Eligibility Criteria in Diffuse Large B-Cell Lymphoma Patients","authors":"Jelena Jelicic, Karen Juul-Jensen, Zoran Bukumiric, Mikkel Runason Simonsen, Michael Roost Clausen, Ahmed Ludvigsen Al-Mashhadi, Robert Schou Pedersen, Christian Bjørn Poulsen, Anne Ortved Gang, Peter Brown, Tarec Christoffer El-Galaly, Thomas Stauffer Larsen","doi":"10.1111/ejh.14301","DOIUrl":"10.1111/ejh.14301","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Recent front-line clinical trials used the International Prognostic Index (IPI) to identify trial-eligible patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). However, many IPI-like variants with improved accuracy have been developed over the years for rituximab-treated patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We assessed the impact of International Prognostic Indices on patient enrolment in clinical trials, aiming to exclude low-risk IPI patients based on POLARIX/EPCORE DLBCL-2 trial criteria.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified 2877 patients in the Danish Lymphoma Registry who would have been eligible for the POLARIX trial if patients with IPI 0–1 scores were included. IPI and NCCN-IPI assigned 33.3% and 11.9% of patients to the low-risk group, respectively. Shorter 5-year overall survival (91.4% vs. 97.5%), higher relapse rate (9.9% vs. 4.4%), and more deaths (16.1% vs. 4.4%) occurred in the low-risk IPI group compared with low-risk NCCN-IPI group. Analyzed models failed to identify true high-risk patients with poor prognosis. Similar results were found in the confirmatory cohort developed based on EPCORE DLBCL-2 trial eligibility criteria.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>True low-risk patients are more optimal identified by NCCN-IPI and should be excluded from front-line clinical trials due to their excellent prognosis. However, additional high-risk factors besides clinical prognostic models need to be considered when selecting trial-eligible patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":11955,"journal":{"name":"European Journal of Haematology","volume":"114 1","pages":"26-36"},"PeriodicalIF":2.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ejh.14301","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142201687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kai Wille, Marvin Dumke, Nadine Wilsdorf, Parvis Sadjadian, Artur Schneider, Stephanie Jender-Bartling, Vera Kolatzki, Anette Horstmann, Raphael Meixner, Marina Jiménez-Muñoz, Christiane Fuchs, Hans-Joachim Tischler, Martin Griesshammer
Introduction
The prognosis of patients with refractory or relapsed AML (R/R-AML) is very limited. To (re)achieve complete remission, there has recently been increasing evidence that the combination of venetoclax (VEN) with chemotherapy is associated with improved outcomes.
Patients and Methods
Our retrospective, single-center study of 53 R/R-AML patients with a median follow-up time of 11.0 months compared standard salvage chemotherapy (FLAG-Ida or HAM in n = 35 patients) with a combination of venetoclax (VEN) and FLAG-Ida (FLAVIDA in n = 18 patients) concerning safety and efficacy.
Results
Regarding the primary endpoints, there was a statistically significant increased event free survival (EFS) in the FLAVIDA group compared to patients with standard chemotherapy based on the univariate log-rank-test and in the multivariate Cox regression analysis (HR 0.22 [95% CI 0.05, 0.97]). There were no differences between the two groups in terms of patients developing febrile neutropenia CTCAE III° and IV° or a delay in hematological recovery. In addition, a clear trend towards an improved overall response rate (78% vs. 51%) was demonstrated in the FLAVIDA group.
Conclusions
The FLAVIDA regimen represents a promising treatment alternative for R/R AML patients with a high response rate and significantly improved EFS compared to standard chemotherapy.
{"title":"Venetoclax Combined With FLAG-IDA in Refractory or Relapsed Acute Myeloid Leukemia","authors":"Kai Wille, Marvin Dumke, Nadine Wilsdorf, Parvis Sadjadian, Artur Schneider, Stephanie Jender-Bartling, Vera Kolatzki, Anette Horstmann, Raphael Meixner, Marina Jiménez-Muñoz, Christiane Fuchs, Hans-Joachim Tischler, Martin Griesshammer","doi":"10.1111/ejh.14302","DOIUrl":"10.1111/ejh.14302","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>The prognosis of patients with refractory or relapsed AML (R/R-AML) is very limited. To (re)achieve complete remission, there has recently been increasing evidence that the combination of venetoclax (VEN) with chemotherapy is associated with improved outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Patients and Methods</h3>\u0000 \u0000 <p>Our retrospective, single-center study of 53 R/R-AML patients with a median follow-up time of 11.0 months compared standard salvage chemotherapy (FLAG-Ida or HAM in <i>n</i> = 35 patients) with a combination of venetoclax (VEN) and FLAG-Ida (FLAVIDA in <i>n</i> = 18 patients) concerning safety and efficacy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Regarding the primary endpoints, there was a statistically significant increased event free survival (EFS) in the FLAVIDA group compared to patients with standard chemotherapy based on the univariate log-rank-test and in the multivariate Cox regression analysis (HR 0.22 [95% CI 0.05, 0.97]). There were no differences between the two groups in terms of patients developing febrile neutropenia CTCAE III° and IV° or a delay in hematological recovery. In addition, a clear trend towards an improved overall response rate (78% vs. 51%) was demonstrated in the FLAVIDA group.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The FLAVIDA regimen represents a promising treatment alternative for R/R AML patients with a high response rate and significantly improved EFS compared to standard chemotherapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":11955,"journal":{"name":"European Journal of Haematology","volume":"114 1","pages":"17-25"},"PeriodicalIF":2.3,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ejh.14302","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142201688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The role of glycogen synthase kinase (GSK)-3β in adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1) is paradoxical and enigmatic. Here, we investigated the role of GSK-3β and its potential as a therapeutic target for ATL.
Methods
Cell proliferation/survival, cell cycle, apoptosis, and reactive oxygen species (ROS) generation were examined using the WST-8 assay, flow cytometry, and Hoechst 33342 staining, respectively. Expression of GSK-3β and cell cycle/death-related proteins, and survival signals was analyzed using RT-PCR, immunofluorescence staining, and immunoblotting.
Results
HTLV-1-infected T-cell lines showed nuclear accumulation of GSK-3β. GSK-3β knockdown and its inhibition with 9-ING-41 and LY2090314 suppressed cell proliferation/survival. 9-ING-41 induced G2/M arrest by enhancing the expression of γH2AX, p53, p21, and p27, and suppressing the expression of CDK1, cyclin A/B, and c-Myc. It induced caspase-mediated apoptosis by decreasing the expression of Bcl-xL, Mcl-1, XIAP, c-IAP1/2, and survivin, and increasing the expression of Bak and Bax. 9-ING-41 also induced ferroptosis and necroptosis, promoted JNK phosphorylation, and suppressed IKKγ and JunB expression. It inhibited the phosphorylation of IκBα, Akt, and STAT3/5, induced ROS production, and reduced glycolysis-derived lactate levels.
Conclusion
GSK-3β functions as an oncogene in ATL and could be a potential therapeutic target.
{"title":"A New Strategy for Adult T-Cell Leukemia Treatment Targeting Glycogen Synthase Kinase-3β","authors":"Chie Ishikawa, Naoki Mori","doi":"10.1111/ejh.14300","DOIUrl":"10.1111/ejh.14300","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The role of glycogen synthase kinase (GSK)-3β in adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1) is paradoxical and enigmatic. Here, we investigated the role of GSK-3β and its potential as a therapeutic target for ATL.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Cell proliferation/survival, cell cycle, apoptosis, and reactive oxygen species (ROS) generation were examined using the WST-8 assay, flow cytometry, and Hoechst 33342 staining, respectively. Expression of GSK-3β and cell cycle/death-related proteins, and survival signals was analyzed using RT-PCR, immunofluorescence staining, and immunoblotting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>HTLV-1-infected T-cell lines showed nuclear accumulation of GSK-3β. GSK-3β knockdown and its inhibition with 9-ING-41 and LY2090314 suppressed cell proliferation/survival. 9-ING-41 induced G2/M arrest by enhancing the expression of γH2AX, p53, p21, and p27, and suppressing the expression of CDK1, cyclin A/B, and c-Myc. It induced caspase-mediated apoptosis by decreasing the expression of Bcl-xL, Mcl-1, XIAP, c-IAP1/2, and survivin, and increasing the expression of Bak and Bax. 9-ING-41 also induced ferroptosis and necroptosis, promoted JNK phosphorylation, and suppressed IKKγ and JunB expression. It inhibited the phosphorylation of IκBα, Akt, and STAT3/5, induced ROS production, and reduced glycolysis-derived lactate levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>GSK-3β functions as an oncogene in ATL and could be a potential therapeutic target.</p>\u0000 </section>\u0000 </div>","PeriodicalId":11955,"journal":{"name":"European Journal of Haematology","volume":"113 6","pages":"852-862"},"PeriodicalIF":2.3,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kimberly S. Ryan, Kylee L. Martens, Bharti Garg, Boris I. Chobrutskiy, Madeline A. Hedges, Olivia L. Hagen, Jean M. G. Sabile, Adam K. Lewkowitz, Methodius G. Tuuli, Thomas G. Deloughery, Joseph J. Shatzel, Jamie O. Lo, Ashley E. Benson
Objective
To determine maternal and neonatal outcomes in individuals with iron deficiency receiving antepartum intravenous (IV) iron supplementation, stratified by the degree of anemia.
Study Design
Retrospective cohort study of iron-deficient pregnant patients who received at least one IV infusion of iron (iron sucrose, low molecular weight iron dextran [LMWID], or ferric carboxymaltose) during their pregnancy from January 1, 2011 through June 16, 2022. Our primary outcomes included both neonatal composite morbidity and maternal composite morbidity in the context of maternal anemia.
Results
Patients who received LMWID had fewer infusion visits, received higher total doses of iron and had a more substantial correction of hemoglobin compared to those who received iron sucrose (p < 0.01). Maternal anemia at the time of admission was not associated with neonatal composite morbidity. However, there was a significant association between anemia status and maternal composite outcome (p = 0.05). Anemia at time of delivery was associated with the likelihood of requiring a blood transfusion (p = 0.01).
Conclusion
This study reinforces previous findings emphasizing the adverse effects of iron deficiency on maternal health and the role of IV iron in reducing these risks.
{"title":"Perinatal Outcomes Following Intravenous Iron for Treatment of Iron Deficiency With and Without Anemia","authors":"Kimberly S. Ryan, Kylee L. Martens, Bharti Garg, Boris I. Chobrutskiy, Madeline A. Hedges, Olivia L. Hagen, Jean M. G. Sabile, Adam K. Lewkowitz, Methodius G. Tuuli, Thomas G. Deloughery, Joseph J. Shatzel, Jamie O. Lo, Ashley E. Benson","doi":"10.1111/ejh.14298","DOIUrl":"10.1111/ejh.14298","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To determine maternal and neonatal outcomes in individuals with iron deficiency receiving antepartum intravenous (IV) iron supplementation, stratified by the degree of anemia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Study Design</h3>\u0000 \u0000 <p>Retrospective cohort study of iron-deficient pregnant patients who received at least one IV infusion of iron (iron sucrose, low molecular weight iron dextran [LMWID], or ferric carboxymaltose) during their pregnancy from January 1, 2011 through June 16, 2022. Our primary outcomes included both neonatal composite morbidity and maternal composite morbidity in the context of maternal anemia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Patients who received LMWID had fewer infusion visits, received higher total doses of iron and had a more substantial correction of hemoglobin compared to those who received iron sucrose (<i>p</i> < 0.01). Maternal anemia at the time of admission was not associated with neonatal composite morbidity. However, there was a significant association between anemia status and maternal composite outcome (<i>p</i> = 0.05). Anemia at time of delivery was associated with the likelihood of requiring a blood transfusion (<i>p</i> = 0.01).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study reinforces previous findings emphasizing the adverse effects of iron deficiency on maternal health and the role of IV iron in reducing these risks.</p>\u0000 </section>\u0000 </div>","PeriodicalId":11955,"journal":{"name":"European Journal of Haematology","volume":"113 6","pages":"842-851"},"PeriodicalIF":2.3,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marley Blommers, Sorin Selegean, Richard K. Wood, Mateo Sarmiento Bustamante, Saishravan Shyamsundar, E. Ashley Wiley, Emilie Comeau, Allam A. Shawwa, Stefan Rose-John, David C. Fajgenbaum, Luke Y. C. Chen
Background
Idiopathic multicentric Castleman disease (iMCD) is a rare inflammatory disorder mediated by excessive proinflammatory cytokine signaling, most notably by interleukin 6 (IL-6). IL-6-induced extramedullary hematopoiesis (EMH) has been reported in murine models of iMCD. Herein we present four cases of iMCD with EMH in humans.
Case Series
The index case is a 24-year-old white woman who presented with pancytopenia, hepatosplenomegaly, and diffuse lymphadenopathy (LAD) with EMH in core lymph node biopsies. We then searched ACCELERATE, a Castleman disease (CD) natural history registry, and identified three additional CD cases with EMH reported in biopsies: A 23-year-old Asian man with fatigue, edema, LAD, and splenomegaly; a 20-year-old white man with fever, dyspnea, LAD, and hepatosplenomegaly; and a 50-year-old white man with constitutional symptoms, LAD, and myelodysplastic syndrome in bone marrow with a KRAS mutation.
Results
All four patients presented with thrombocytopenia and fever and/or markedly elevated C-reactive protein. Patient 1 had iMCD-NOS (not otherwise specified) with severe thrombocytopenia, reticulin fibrosis in bone marrow, small volume LAD and organomegaly but no anasarca. The other three patients had iMCD-TAFRO (thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly). Two had mixed CD and two had hypervascular CD in lymph nodes. All four had bone marrow hypercellularity and megakaryocyte hyperplasia and two had reticulin fibrosis.
Conclusions
This case series demonstrates that EMH can be seen in CD, particularly in iMCD-TAFRO. Given the similarity of this finding to previous murine models of IL-6-induced marrow and lymph node changes we hypothesize that this is an IL-6-mediated phenomenon.
{"title":"Idiopathic multicentric Castleman disease with marrow fibrosis and extramedullary hematopoiesis","authors":"Marley Blommers, Sorin Selegean, Richard K. Wood, Mateo Sarmiento Bustamante, Saishravan Shyamsundar, E. Ashley Wiley, Emilie Comeau, Allam A. Shawwa, Stefan Rose-John, David C. Fajgenbaum, Luke Y. C. Chen","doi":"10.1111/ejh.14295","DOIUrl":"10.1111/ejh.14295","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Idiopathic multicentric Castleman disease (iMCD) is a rare inflammatory disorder mediated by excessive proinflammatory cytokine signaling, most notably by interleukin 6 (IL-6). IL-6-induced extramedullary hematopoiesis (EMH) has been reported in murine models of iMCD. Herein we present four cases of iMCD with EMH in humans.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Case Series</h3>\u0000 \u0000 <p>The index case is a 24-year-old white woman who presented with pancytopenia, hepatosplenomegaly, and diffuse lymphadenopathy (LAD) with EMH in core lymph node biopsies. We then searched ACCELERATE, a Castleman disease (CD) natural history registry, and identified three additional CD cases with EMH reported in biopsies: A 23-year-old Asian man with fatigue, edema, LAD, and splenomegaly; a 20-year-old white man with fever, dyspnea, LAD, and hepatosplenomegaly; and a 50-year-old white man with constitutional symptoms, LAD, and myelodysplastic syndrome in bone marrow with a KRAS mutation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>All four patients presented with thrombocytopenia and fever and/or markedly elevated C-reactive protein. Patient 1 had iMCD-NOS (not otherwise specified) with severe thrombocytopenia, reticulin fibrosis in bone marrow, small volume LAD and organomegaly but no anasarca. The other three patients had iMCD-TAFRO (thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly). Two had mixed CD and two had hypervascular CD in lymph nodes. All four had bone marrow hypercellularity and megakaryocyte hyperplasia and two had reticulin fibrosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This case series demonstrates that EMH can be seen in CD, particularly in iMCD-TAFRO. Given the similarity of this finding to previous murine models of IL-6-induced marrow and lymph node changes we hypothesize that this is an IL-6-mediated phenomenon.</p>\u0000 </section>\u0000 </div>","PeriodicalId":11955,"journal":{"name":"European Journal of Haematology","volume":"113 6","pages":"833-841"},"PeriodicalIF":2.3,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ejh.14295","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Utkarsh Goel, Danai Dima, James Davis, Nausheen Ahmed, Hira Shaikh, Jonathan Lochner, Al-Ola Abdallah, Jack Khouri, Hamza Hashmi, Faiz Anwer
Clinical trials evaluating chimeric antigen receptor (CAR) T-cell therapy in relapsed/refractory multiple myeloma (RRMM) have typically excluded patients with AL amyloidosis. As a result, there are limited data on the safety and efficacy of CAR T-cell therapy in this patient population. We retrospectively reviewed eight consecutive patients with RRMM and AL amyloidosis who were treated with standard of care CAR T-cell therapy. Cytokine release syndrome was seen in 75% of patients (grade ≥3: 0%) and immune effector cell-associated neurotoxicity syndrome (grade 1) in only one patient. Low-grade cytopenias were common (any grade/grade ≥3: neutropenia 62.5%/37.5%, anemia 37.5%/0%, thrombocytopenia 25%/0%). CAR T-cell therapy led to rapid and deep responses with a median time to best response of 43 days and a hematologic very good partial response or better rate of 62.5%. Overall, we found that commercial CAR T-cell therapy was feasible, and effective in patients with RRMM and concurrent AL amyloidosis.
评估嵌合抗原受体（CAR）T细胞疗法治疗复发性/难治性多发性骨髓瘤（RRMM）的临床试验通常不包括AL淀粉样变性患者。因此，有关CAR T细胞疗法在这一患者群体中的安全性和有效性的数据非常有限。我们回顾性研究了8例连续接受标准疗法CAR T细胞治疗的RRMM和AL淀粉样变性患者。75%的患者出现细胞因子释放综合征（≥3级：0%），只有一名患者出现免疫效应细胞相关神经毒性综合征（1级）。低级别细胞减少症很常见（任何级别/级别≥3：中性粒细胞减少 62.5%/37.5%，贫血 37.5%/0%，血小板减少 25%/0%）。CAR T细胞疗法可迅速产生深度反应，达到最佳反应的中位时间为43天，血液学非常好的部分反应或更好的反应率为62.5%。总之，我们发现商业 CAR T 细胞疗法是可行的，而且对 RRMM 和并发 AL 淀粉样变性的患者有效。
{"title":"Safety and efficacy of B cell maturation antigen-directed CAR T-cell therapy in patients with relapsed/refractory multiple myeloma and concurrent light chain amyloidosis","authors":"Utkarsh Goel, Danai Dima, James Davis, Nausheen Ahmed, Hira Shaikh, Jonathan Lochner, Al-Ola Abdallah, Jack Khouri, Hamza Hashmi, Faiz Anwer","doi":"10.1111/ejh.14293","DOIUrl":"10.1111/ejh.14293","url":null,"abstract":"<p>Clinical trials evaluating chimeric antigen receptor (CAR) T-cell therapy in relapsed/refractory multiple myeloma (RRMM) have typically excluded patients with AL amyloidosis. As a result, there are limited data on the safety and efficacy of CAR T-cell therapy in this patient population. We retrospectively reviewed eight consecutive patients with RRMM and AL amyloidosis who were treated with standard of care CAR T-cell therapy. Cytokine release syndrome was seen in 75% of patients (grade ≥3: 0%) and immune effector cell-associated neurotoxicity syndrome (grade 1) in only one patient. Low-grade cytopenias were common (any grade/grade ≥3: neutropenia 62.5%/37.5%, anemia 37.5%/0%, thrombocytopenia 25%/0%). CAR T-cell therapy led to rapid and deep responses with a median time to best response of 43 days and a hematologic very good partial response or better rate of 62.5%. Overall, we found that commercial CAR T-cell therapy was feasible, and effective in patients with RRMM and concurrent AL amyloidosis.</p>","PeriodicalId":11955,"journal":{"name":"European Journal of Haematology","volume":"113 6","pages":"817-823"},"PeriodicalIF":2.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ejh.14293","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To study the cytogenetic characteristics of extramedullary disease (EMD) in patients with multiple myeloma (MM) and their impact on prognosis.
Methods
Patients with newly diagnosed MM (NDMM) at Peking Union Medical College Hospital (Beijing, China) between June 2007 and December 2019 were recruited for this study. Demographic information, clinical data, fluorescence in situ hybridization (FISH) results of marrow and tissue samples, and survival outcome data were collected.
Results
A total of 439 patients with NDMM were divided into those without EMD (non-EMD, n = 339), those with EMD with primary paraosseous plasmacytoma (pEMD-B, n = 48), those with primary EMD with soft-tissue involvement (pEMD-S, n = 33), and those with secondary EMD (sEMD, n = 19). The incidence of EMD was 18.5% (81/439) at diagnosis and 22.8% (100/439) throughout the disease course. Comparison of FISH results showed a higher proportion of RB1 deletion (n = 20; 60.0% vs. 20.0%, p = .013) and MYC translocation (n = 12; 44.4% vs. 12.5%, p = .041) in the extramedullary tissues than in the paired bone marrow samples. At diagnosis, the percentage of MYC translocations in the sEMD group was notably higher than that in the non-EMD group (55.6% vs. 15.5%, p = .012). The median overall survival (OS) of patients with pEMD-S (32 months) and sEMD (17 months) was significantly shorter (both p = .001) than that of non-EMD patients (60 months).
Conclusion
Soft-tissue EMD can be considered a high-risk condition, even in the era of novel agents. MYC translocation can serve as a valuable marker that correlates with extramedullary spread and relapse in patients with MM and should be considered for inclusion in routine FISH panels in clinical practice.
{"title":"MYC translocation is a valuable marker for the development and relapse of extramedullary disease in multiple myeloma","authors":"Yuhang Song, Jianhua Du, Xianghong Jin, Hui Li, Congwei Jia, Yuanyuan Liu, Kaimi Li, Daobin Zhou, Junling Zhuang","doi":"10.1111/ejh.14296","DOIUrl":"10.1111/ejh.14296","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To study the cytogenetic characteristics of extramedullary disease (EMD) in patients with multiple myeloma (MM) and their impact on prognosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Patients with newly diagnosed MM (NDMM) at Peking Union Medical College Hospital (Beijing, China) between June 2007 and December 2019 were recruited for this study. Demographic information, clinical data, fluorescence in situ hybridization (FISH) results of marrow and tissue samples, and survival outcome data were collected.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 439 patients with NDMM were divided into those without EMD (non-EMD, <i>n</i> = 339), those with EMD with primary paraosseous plasmacytoma (pEMD-B, <i>n</i> = 48), those with primary EMD with soft-tissue involvement (pEMD-S, <i>n</i> = 33), and those with secondary EMD (sEMD, <i>n</i> = 19). The incidence of EMD was 18.5% (81/439) at diagnosis and 22.8% (100/439) throughout the disease course. Comparison of FISH results showed a higher proportion of <i>RB1</i> deletion (<i>n</i> = 20; 60.0% vs. 20.0%, <i>p</i> = .013) and <i>MYC</i> translocation (<i>n</i> = 12; 44.4% vs. 12.5%, <i>p</i> = .041) in the extramedullary tissues than in the paired bone marrow samples. At diagnosis, the percentage of <i>MYC</i> translocations in the sEMD group was notably higher than that in the non-EMD group (55.6% vs. 15.5%, <i>p</i> = .012). The median overall survival (OS) of patients with pEMD-S (32 months) and sEMD (17 months) was significantly shorter (both <i>p</i> = .001) than that of non-EMD patients (60 months).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Soft-tissue EMD can be considered a high-risk condition, even in the era of novel agents. <i>MYC</i> translocation can serve as a valuable marker that correlates with extramedullary spread and relapse in patients with MM and should be considered for inclusion in routine FISH panels in clinical practice.</p>\u0000 </section>\u0000 </div>","PeriodicalId":11955,"journal":{"name":"European Journal of Haematology","volume":"113 6","pages":"824-832"},"PeriodicalIF":2.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dominik Fric, Martin Stork, Ivanna Boichuk, Viera Sandecka, Zdenek Adam, Marta Krejci, Eva Ondrouskova, Anna Fidrichova, Lenka Radova, Zdenka Knechtova, Marie Jarosova, Ludek Pour
We performed retrospective analysis of relapsed/refractory multiple myeloma (RRMM) patients previously exposed to daratumumab treated with ixazomib, lenalidomide, dexamethasone (IRd) regimen in real clinical practice. Our aim was to evaluate efficacy of IRd in these patients and select a subset of patients that would benefit from this treatment the most. In total, we analyzed 43 daratumumab-exposed RRMM patients treated in our center. Minimal response or better was achieved by 53.5% of patients from the cohort. Median progression free survival (PFS) was 4.56 months (95% CI: 2.56, 8.03) and median overall survival (OS) was 28.92 months (95% CI: 5.4, NR). Duration of response (DOR) was evaluable in 28 patients and reached a median of 21.3 months (95% CI: 6.85, NR). Next, we evaluated hazard ratios (HR) for OS and PFS. There was improved OS in patients that were not-triple refractory or worse (HR = 0.39, 95%Cl (0.14; 1.10), p = .07) and in patients, that had less than three previous lines of treatment (LOT) (HR = 0.13, 95%Cl (0.03; 0.6) p = .003). Similar to OS, there was improved PFS in patients, that were not triple-refractory or worse (HR = 0.52, 95%Cl (0.25; 1.10), p = .08). We concluded, that the best survival benefit for RRMM patients pretreated with daratumumab to IRd regimen was observed in patients that were not triple-refractory and had less than three previous lines of treatment (LOT). The DOR in these patients was 21.3 months (95% CI: 6.85, NR).
{"title":"Efficacy of ixazomib, lenalidomide, dexamethasone regimen in daratumumab-exposed relapsed/refractory multiple myeloma patients: A retrospective analysis","authors":"Dominik Fric, Martin Stork, Ivanna Boichuk, Viera Sandecka, Zdenek Adam, Marta Krejci, Eva Ondrouskova, Anna Fidrichova, Lenka Radova, Zdenka Knechtova, Marie Jarosova, Ludek Pour","doi":"10.1111/ejh.14292","DOIUrl":"10.1111/ejh.14292","url":null,"abstract":"<p>We performed retrospective analysis of relapsed/refractory multiple myeloma (RRMM) patients previously exposed to daratumumab treated with ixazomib, lenalidomide, dexamethasone (IRd) regimen in real clinical practice. Our aim was to evaluate efficacy of IRd in these patients and select a subset of patients that would benefit from this treatment the most. In total, we analyzed 43 daratumumab-exposed RRMM patients treated in our center. Minimal response or better was achieved by 53.5% of patients from the cohort. Median progression free survival (PFS) was 4.56 months (95% CI: 2.56, 8.03) and median overall survival (OS) was 28.92 months (95% CI: 5.4, NR). Duration of response (DOR) was evaluable in 28 patients and reached a median of 21.3 months (95% CI: 6.85, NR). Next, we evaluated hazard ratios (HR) for OS and PFS. There was improved OS in patients that were not-triple refractory or worse (HR = 0.39, 95%Cl (0.14; 1.10), <i>p</i> = .07) and in patients, that had less than three previous lines of treatment (LOT) (HR = 0.13, 95%Cl (0.03; 0.6) <i>p</i> = .003). Similar to OS, there was improved PFS in patients, that were not triple-refractory or worse (HR = 0.52, 95%Cl (0.25; 1.10), <i>p</i> = .08). We concluded, that the best survival benefit for RRMM patients pretreated with daratumumab to IRd regimen was observed in patients that were not triple-refractory and had less than three previous lines of treatment (LOT). The DOR in these patients was 21.3 months (95% CI: 6.85, NR).</p>","PeriodicalId":11955,"journal":{"name":"European Journal of Haematology","volume":"113 6","pages":"810-816"},"PeriodicalIF":2.3,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ejh.14292","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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