Mayasa Abu Ata, Israel Henig, Dana Yehudai-Ofir, Inna Tzoran, Shimrit Ringelstein-Harlev, Tsofia Inbar, Ilana Slouzkey, Michal Karmona Fintuch, Anat Stern, Olesya Stanevsky, Michal Weiler-Sagie, Yaniv Zohar, Ido Livneh, Goni Merhav, Ayelet Eran, Tsila Zuckerman, Ofrat Beyar Katz
Introduction: Chimeric antigen receptor T (CAR-T) cell therapy, emerging as an efficient treatment option for patients with secondary central nervous system (CNS) lymphoma, is frequently complicated with immune effector cell-associated neurotoxicity syndrome (ICANS).
Case presentation: We report a case of a 64-year-old woman with transformed follicular lymphoma, developing high-grade ICANS with eosinophilic pleocytosis following third-line therapy with CAR-T cells (tisagenlecleucel). During bridging therapy, she declined neurologically and was diagnosed with secondary CNS lymphoma. She received methotrexate-cytarabine-thiotepa-rituximab regimen with clinical and radiological improvement. Post-CAR-T cell infusion she developed cytokine release syndrome grade II and ICANS grade III. Given the lack of response to steroids, anakinra was initiated with complete ICANS resolution. Cerebrospinal fluid (CSF) analysis, performed only on day +10 due to thrombocytopenia, revealed eosinophils, while infections were excluded.
Conclusion: This report emphasizes the importance of CSF analysis in individuals with CAR-T-related neurotoxicity for elucidating the role of specific immune cells in such complications.
简介CAR-T细胞疗法是继发性中枢神经系统(CNS)淋巴瘤患者的一种有效治疗方法,但经常并发免疫效应细胞相关神经毒性综合征(ICANS):我们报告了一例64岁的女性患者,她患有转化型滤泡性淋巴瘤,在接受CAR-T细胞(tisagenlecleucel)三线治疗后出现了高级别ICANS,并伴有嗜酸性粒细胞增多。在桥接治疗期间,她的神经功能下降,被诊断为继发性中枢神经系统淋巴瘤。她接受了甲氨蝶呤-西妥昔单抗-噻替派-利妥昔单抗方案治疗,临床和影像学情况均有所改善。在输注 CAR-T 细胞后,她出现了细胞因子释放综合征 II 级和 ICANS III 级。由于对类固醇类药物没有反应,她开始使用阿那金拉,ICANS完全缓解。由于血小板减少,脑脊液(CSF)分析在第 +10 天才进行,结果显示有嗜酸性粒细胞,但排除了感染:本报告强调了对CAR-T相关神经毒性患者进行脑脊液分析对于阐明特异性免疫细胞在此类并发症中的作用的重要性。
{"title":"Eosinophilic Pleocytosis in the Cerebrospinal Fluid following CAR-T Cell Therapy for Central Nervous System Lymphoma: A Case for Warning?","authors":"Mayasa Abu Ata, Israel Henig, Dana Yehudai-Ofir, Inna Tzoran, Shimrit Ringelstein-Harlev, Tsofia Inbar, Ilana Slouzkey, Michal Karmona Fintuch, Anat Stern, Olesya Stanevsky, Michal Weiler-Sagie, Yaniv Zohar, Ido Livneh, Goni Merhav, Ayelet Eran, Tsila Zuckerman, Ofrat Beyar Katz","doi":"10.1159/000539354","DOIUrl":"10.1159/000539354","url":null,"abstract":"<p><strong>Introduction: </strong>Chimeric antigen receptor T (CAR-T) cell therapy, emerging as an efficient treatment option for patients with secondary central nervous system (CNS) lymphoma, is frequently complicated with immune effector cell-associated neurotoxicity syndrome (ICANS).</p><p><strong>Case presentation: </strong>We report a case of a 64-year-old woman with transformed follicular lymphoma, developing high-grade ICANS with eosinophilic pleocytosis following third-line therapy with CAR-T cells (tisagenlecleucel). During bridging therapy, she declined neurologically and was diagnosed with secondary CNS lymphoma. She received methotrexate-cytarabine-thiotepa-rituximab regimen with clinical and radiological improvement. Post-CAR-T cell infusion she developed cytokine release syndrome grade II and ICANS grade III. Given the lack of response to steroids, anakinra was initiated with complete ICANS resolution. Cerebrospinal fluid (CSF) analysis, performed only on day +10 due to thrombocytopenia, revealed eosinophils, while infections were excluded.</p><p><strong>Conclusion: </strong>This report emphasizes the importance of CSF analysis in individuals with CAR-T-related neurotoxicity for elucidating the role of specific immune cells in such complications.</p>","PeriodicalId":6981,"journal":{"name":"Acta Haematologica","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yeyi Yang, Yezhen Yang, Ye Meng, Lihua Huang, Zuocheng Yang
Introduction: Recessive congenital methemoglobinemia (RCM) caused by CYB5R3 deficiency due to the mutations in the reduced nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase (CYB5R) gene is an autosomal recessive inherited disease. Clinically, it can be divided into two types, namely red blood cell affected type (RCM I) and systemically affected type (RCM II).
Case presentation: A 5-year-old male patient was diagnosed with cyanosis for 5 years. Physical examination showed cyanosis in areas such as the lips, fingers, and toes. Laboratory examination revealed low pulse oxygen saturation (81%) and increased blood methemoglobin (23.6%). Gene testing revealed the compound heterozygous mutations in the CYB5R3 gene, c.149G>A (p.Arg50Gln) and c.331A>G (p.Lys111Glu), respectively originating from his parents. By constructing 3D models of CYB5R3 wild-type and mutant types using SWISS-MODEL software, it was found that the mutation caused significant structural abnormalities in the CYB5R protein. The relationship between CYB5R3 gene mutation sites, amino acid change, enzyme activity, and methemoglobinemia type I and II were listed and analyzed.
Conclusion: A case of congenital RCM type I caused by compound heterozygous mutations in the CYB5R3 gene was reported, with c.331A>G (p.Lys111Glu) being the newly reported mutation. The homozygosity or heterozygosity of CYB5R3 gene mutations that lead to premature termination, loss of exons, and change in amino acid properties in FAD or NADH binding domains, is positively correlated with the severity (from type I to type II) of methemoglobinemia.
简介由于还原型烟酰胺腺嘌呤二核苷酸(NADH)细胞色素 b5 还原酶(CYB5R)基因突变导致 CYB5R3 缺乏而引起的先天性高铁血红蛋白血症(RCM)是一种常染色体隐性遗传病。临床上,该病可分为两种类型,即红细胞受累型(RCM I)和全身受累型(RCM II):病例介绍:一名 5 岁的男性患者被诊断为紫绀 5 年。体格检查显示嘴唇、手指和脚趾等部位发绀。实验室检查显示脉搏氧饱和度低(81%),血液高铁血红蛋白增加(23.6%)。基因检测显示,他父母的 CYB5R3 基因分别出现了 c.149G>A(p.Arg50Gln)和 c.331A>G(p.Lys111Glu)的复合杂合突变。通过使用SWISS-MODEL软件构建CYB5R3野生型和突变型的三维模型,发现该突变导致CYB5R蛋白出现明显的结构异常。列出并分析了 CYB5R3 基因突变位点、氨基酸变化、酶活性与高铁血红蛋白血症 I 型和 II 型之间的关系:报告了一例由 CYB5R3 基因复合杂合突变引起的先天性 RCM I 型,c.331A>G(p.Lys111Glu)是新报告的突变。CYB5R3基因突变导致过早终止、外显子缺失、FAD或NADH结合域的氨基酸性质改变,其同源性或杂合性与高铁血红蛋白血症的严重程度(从I型到II型)呈正相关。
{"title":"Novel Compound Heterogeneous Mutations in CYB5R3 Gene Leading to Methemoglobinemia (Type I) in a Chinese Boy: Case Report and Relevant Comprehensive Analysis.","authors":"Yeyi Yang, Yezhen Yang, Ye Meng, Lihua Huang, Zuocheng Yang","doi":"10.1159/000539448","DOIUrl":"10.1159/000539448","url":null,"abstract":"<p><strong>Introduction: </strong>Recessive congenital methemoglobinemia (RCM) caused by CYB5R3 deficiency due to the mutations in the reduced nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase (CYB5R) gene is an autosomal recessive inherited disease. Clinically, it can be divided into two types, namely red blood cell affected type (RCM I) and systemically affected type (RCM II).</p><p><strong>Case presentation: </strong>A 5-year-old male patient was diagnosed with cyanosis for 5 years. Physical examination showed cyanosis in areas such as the lips, fingers, and toes. Laboratory examination revealed low pulse oxygen saturation (81%) and increased blood methemoglobin (23.6%). Gene testing revealed the compound heterozygous mutations in the CYB5R3 gene, c.149G>A (p.Arg50Gln) and c.331A>G (p.Lys111Glu), respectively originating from his parents. By constructing 3D models of CYB5R3 wild-type and mutant types using SWISS-MODEL software, it was found that the mutation caused significant structural abnormalities in the CYB5R protein. The relationship between CYB5R3 gene mutation sites, amino acid change, enzyme activity, and methemoglobinemia type I and II were listed and analyzed.</p><p><strong>Conclusion: </strong>A case of congenital RCM type I caused by compound heterozygous mutations in the CYB5R3 gene was reported, with c.331A>G (p.Lys111Glu) being the newly reported mutation. The homozygosity or heterozygosity of CYB5R3 gene mutations that lead to premature termination, loss of exons, and change in amino acid properties in FAD or NADH binding domains, is positively correlated with the severity (from type I to type II) of methemoglobinemia.</p>","PeriodicalId":6981,"journal":{"name":"Acta Haematologica","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maria Dampmann, Sarah Flossdorf, Julius Keyl, Hans Christian Reinhardt, Christine Hanoun
Introduction: Plasma cell leukemia (PCL) can occur de novo as primary PCL (pPCL), or in patients with prior diagnosis of multiple myeloma (MM) as secondary PCL (sPCL). In 2021, the diagnostic criteria have been revised, establishing a new cut-off of ≥5% plasma cells in the peripheral blood. Lacking specific clinical trials, PCL is treated similarly to MM; however, outcome for patients with PCL remains poor. Here, we report outcomes for patients with pPCL and sPCL in the era of novel agents.
Methods: We performed a retrospective analysis and identified 19 patients (11 pPCL, 8 sPCL) who have been treated for PCL between 2010 and 2022 at University Hospital Essen.
Results: Patients with pPCL had a median overall survival (OS) of 37.8 months (95% CI: [15.4; 52.3] months) from diagnosis, with a median time to next treatment (TTNT) of 18.4 (2.0; 22.9) months. All patients were treated with a proteasome-inhibitor (PI)-based induction therapy, and the majority was consolidated with an autologous stem cell transplantation (SCT). Five of these patients received a tandem transplantation. Patients with sPCL had a median OS of only 1.5 months after diagnosis of PCL. Only 1 patient achieved a remission with daratumumab and subsequent allogenic SCT.
Conclusion: With our study, we add evidence for a PI-based induction therapy followed by a consolidating autologous SCT for patients with pPCL and give further evidence that a tandem transplant concept might be beneficial. The diagnosis of sPCL remains devastating and needs new therapeutic approaches.
{"title":"Single-Center Experience of Patients with Plasma Cell Leukemia in the Era of New Therapeutics.","authors":"Maria Dampmann, Sarah Flossdorf, Julius Keyl, Hans Christian Reinhardt, Christine Hanoun","doi":"10.1159/000539223","DOIUrl":"10.1159/000539223","url":null,"abstract":"<p><strong>Introduction: </strong>Plasma cell leukemia (PCL) can occur de novo as primary PCL (pPCL), or in patients with prior diagnosis of multiple myeloma (MM) as secondary PCL (sPCL). In 2021, the diagnostic criteria have been revised, establishing a new cut-off of ≥5% plasma cells in the peripheral blood. Lacking specific clinical trials, PCL is treated similarly to MM; however, outcome for patients with PCL remains poor. Here, we report outcomes for patients with pPCL and sPCL in the era of novel agents.</p><p><strong>Methods: </strong>We performed a retrospective analysis and identified 19 patients (11 pPCL, 8 sPCL) who have been treated for PCL between 2010 and 2022 at University Hospital Essen.</p><p><strong>Results: </strong>Patients with pPCL had a median overall survival (OS) of 37.8 months (95% CI: [15.4; 52.3] months) from diagnosis, with a median time to next treatment (TTNT) of 18.4 (2.0; 22.9) months. All patients were treated with a proteasome-inhibitor (PI)-based induction therapy, and the majority was consolidated with an autologous stem cell transplantation (SCT). Five of these patients received a tandem transplantation. Patients with sPCL had a median OS of only 1.5 months after diagnosis of PCL. Only 1 patient achieved a remission with daratumumab and subsequent allogenic SCT.</p><p><strong>Conclusion: </strong>With our study, we add evidence for a PI-based induction therapy followed by a consolidating autologous SCT for patients with pPCL and give further evidence that a tandem transplant concept might be beneficial. The diagnosis of sPCL remains devastating and needs new therapeutic approaches.</p>","PeriodicalId":6981,"journal":{"name":"Acta Haematologica","volume":null,"pages":null},"PeriodicalIF":2.4,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141064633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Debora S Bruno, Manoj Khanal, Xiaohong I Li, Maricer P Escalon, Katherine B Winfree, Lisa M Hess
Introduction: This study was designed to compare outcomes among patients by race and ethnicity in the post-covalent Bruton tyrosine kinase inhibitor (cBTKi) treatment era.
Methods: A nationwide electronic health record (EHR)-derived de-identified database was utilized that included patients diagnosed with CLL from 2013 to 2022 who received systemic therapy for their disease. Use of cBTKi therapy, time to next treatment or death (TTNT-D), and overall survival (OS) were compared by race in unadjusted (Kaplan-Meier method) and adjusted analyses (Cox proportional hazards regression).
Results: This study included 4,572 White (71.8%) and 558 Black (8.8%) patients with CLL; 270 were Hispanic or Latino (4.2%). Patients who were Black were significantly younger, more were female, had later stage disease, were of lower socioeconomic status (SES), and were more likely to have unmutated immunoglobulin heavy chain gene (IGHV) and to have received cBTKi therapy than White patients (all p ≤ 0.002). SES was also significantly different by ethnicity. TTNT-D and OS were not different by race in either unadjusted or adjusted analyses (all p > 0.05).
Conclusion: In unadjusted and adjusted analyses, TTNT-D and OS were not different by race. These data did not identify racial healthcare disparities in the era following the introduction of cBTKi therapy despite differences in baseline characteristics.
背景 本研究旨在比较后共价布鲁顿酪氨酸激酶抑制剂(cBTKi)治疗时代不同种族和族裔患者的治疗效果。方法 利用全国范围内的电子健康记录(EHR)生成的去标识数据库,其中包括 2013-2022 年期间诊断为 CLL 并接受系统治疗的患者。在未调整分析(卡普兰-梅耶法)和调整分析(Cox比例危险回归)中,对cBTKi疗法的使用、下一次治疗或死亡时间(TTNT-D)和总生存率(OS)按种族进行了比较。结果 本研究共纳入 4572 名白人(71.8%)和 558 名黑人(8.8%)CLL 患者;其中 270 名患者为西班牙裔或拉丁裔(4.2%)。与白人患者相比,黑人患者明显更年轻,女性患者更多,疾病处于晚期,社会经济地位(SES)更低,免疫球蛋白重链基因(IGHV)未突变的可能性更大,接受过 cBTKi 治疗的可能性更大(均 p≤0.002)。不同种族的 SES 也有明显差异。在未经调整或调整后的分析中,TTNT-D 和 OS 因种族而异(均 p>0.05)。结论 在未调整分析和调整分析中,TTNT-D 和 OS 没有种族差异。尽管基线特征存在差异,但这些数据并未发现在引入 cBTKi 疗法后的时代存在种族医疗保健差异。
{"title":"Racial and Ethnic Characteristics and Outcomes of Patients Diagnosed with CLL/SLL in the USA.","authors":"Debora S Bruno, Manoj Khanal, Xiaohong I Li, Maricer P Escalon, Katherine B Winfree, Lisa M Hess","doi":"10.1159/000538836","DOIUrl":"10.1159/000538836","url":null,"abstract":"<p><strong>Introduction: </strong>This study was designed to compare outcomes among patients by race and ethnicity in the post-covalent Bruton tyrosine kinase inhibitor (cBTKi) treatment era.</p><p><strong>Methods: </strong>A nationwide electronic health record (EHR)-derived de-identified database was utilized that included patients diagnosed with CLL from 2013 to 2022 who received systemic therapy for their disease. Use of cBTKi therapy, time to next treatment or death (TTNT-D), and overall survival (OS) were compared by race in unadjusted (Kaplan-Meier method) and adjusted analyses (Cox proportional hazards regression).</p><p><strong>Results: </strong>This study included 4,572 White (71.8%) and 558 Black (8.8%) patients with CLL; 270 were Hispanic or Latino (4.2%). Patients who were Black were significantly younger, more were female, had later stage disease, were of lower socioeconomic status (SES), and were more likely to have unmutated immunoglobulin heavy chain gene (IGHV) and to have received cBTKi therapy than White patients (all p ≤ 0.002). SES was also significantly different by ethnicity. TTNT-D and OS were not different by race in either unadjusted or adjusted analyses (all p > 0.05).</p><p><strong>Conclusion: </strong>In unadjusted and adjusted analyses, TTNT-D and OS were not different by race. These data did not identify racial healthcare disparities in the era following the introduction of cBTKi therapy despite differences in baseline characteristics.</p>","PeriodicalId":6981,"journal":{"name":"Acta Haematologica","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction: Major histocompatibility complex II (MHC-II)-mediated antigen presentation contributes to the pathogenesis of immune thrombocytopenia (ITP). Human leukocyte antigen (HLA)-DRB5 is an MHC-II molecule and this study aims to investigate its role and mechanisms in ITP development.
Methods: Guinea pig anti-mouse platelet (PLT) serum-induced ITP mice received tail vein injection of HLA-DRB5 overexpressing adenoviral vector/immune receptor expressed on myeloid cells-1 (IREM-1) monoclonal antibody (mAb). PLT count changes in mice blood were assessed by a hematology analyzer. MHC-II/CD80/CD86 expression in mice blood was measured by quantitative real-time-PCR and immunofluorescence assay. CD8+ T-cell proportion in mice blood was detected by flow cytometry.
Results: HLA-DRB5 overexpression exacerbated PLT reduction since the 5th day of the establishment of ITP mice model and enhanced MHC-II/CD80/CD86 expression upregulation as well as CD8+ T-cell ratio elevation in the blood of ITP mice, while its effects were reversed by IREM-1 mAb.
Conclusion: HLA-DRB5 overexpression upregulates MHC-II-mediated antigen presentation to CD8+ T cells, thus lowering PLT count in the ITP mice model.
{"title":"HLA-DRB5 Overexpression Promotes Platelet Reduction in Immune Thrombocytopenia Mice Model by Facilitating MHC-II-Mediated Antigen Presentation.","authors":"Yujuan Ren, Qianqian Ying, Ying Chen, Cong Liao, Anrong Li, Qidong Ye","doi":"10.1159/000538749","DOIUrl":"10.1159/000538749","url":null,"abstract":"<p><strong>Introduction: </strong>Major histocompatibility complex II (MHC-II)-mediated antigen presentation contributes to the pathogenesis of immune thrombocytopenia (ITP). Human leukocyte antigen (HLA)-DRB5 is an MHC-II molecule and this study aims to investigate its role and mechanisms in ITP development.</p><p><strong>Methods: </strong>Guinea pig anti-mouse platelet (PLT) serum-induced ITP mice received tail vein injection of HLA-DRB5 overexpressing adenoviral vector/immune receptor expressed on myeloid cells-1 (IREM-1) monoclonal antibody (mAb). PLT count changes in mice blood were assessed by a hematology analyzer. MHC-II/CD80/CD86 expression in mice blood was measured by quantitative real-time-PCR and immunofluorescence assay. CD8+ T-cell proportion in mice blood was detected by flow cytometry.</p><p><strong>Results: </strong>HLA-DRB5 overexpression exacerbated PLT reduction since the 5th day of the establishment of ITP mice model and enhanced MHC-II/CD80/CD86 expression upregulation as well as CD8+ T-cell ratio elevation in the blood of ITP mice, while its effects were reversed by IREM-1 mAb.</p><p><strong>Conclusion: </strong>HLA-DRB5 overexpression upregulates MHC-II-mediated antigen presentation to CD8+ T cells, thus lowering PLT count in the ITP mice model.</p>","PeriodicalId":6981,"journal":{"name":"Acta Haematologica","volume":null,"pages":null},"PeriodicalIF":2.4,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Julie Barberio, Timothy L Lash, Ajay K Nooka, Ashley I Naimi, Rachel E Patzer, Christopher Kim
Introduction: Most multiple myeloma (MM) patients experience cytopenias, likely driven by both disease and treatment-related factors. Immunomodulatory agents (IMiDs), which form the backbone of most anti-myeloma regimens, are known to cause higher grade cytopenias. In this context, the impact of sequential IMiD treatments on cytopenia risk is unknown.
Methods: We evaluated the cumulative risks of severe cytopenias following second line of therapy (LOT) initiation in 5,573 MM patients in the Flatiron Health database. Patients for whom both LOTs 1 and 2 contained IMiDs were considered "sequentially exposed"; those for whom neither contained IMiDs were "never exposed."
Results: For the neutropenia outcome, compared to the never exposed, the sequentially exposed had the highest 1-year risk (risk difference [RD] 12%), followed by those only recently exposed during LOT 2 (RD 8%), then by those with only past exposure during LOT 1 (RD 5%). A similar pattern was observed for leukopenia, but no meaningful differences were observed for anemia or thrombocytopenia. The associations between sequential exposure, versus never, with neutropenia and leukopenia were even stronger among those with a recent cytopenia history.
Conclusion: Results suggest that sequential exposure to IMiDs is a risk factor for higher grade cytopenias. These findings have profound clinical implications in choosing newer LOTs with potential risks of cytopenia.
导言:大多数多发性骨髓瘤(MM)患者都会出现细胞减少,这可能是由疾病和治疗相关因素造成的。众所周知,免疫调节剂(IMiDs)是大多数抗骨髓瘤治疗方案的骨干,会导致较高程度的细胞减少症。在这种情况下,连续使用 IMiD 治疗对细胞减少症风险的影响尚不清楚:我们评估了 Flatiron Health 数据库中 5573 名 MM 患者接受二线治疗(LOT)后出现严重细胞减少症的累积风险。LOT1和LOT2均含有IMiDs的患者被视为 "连续暴露";LOT1和LOT2均不含有IMiDs的患者被视为 "从未暴露":就中性粒细胞减少症结果而言,与从未暴露者相比,连续暴露者的1年风险最高(风险差异[RD]为12%),其次是最近才在LOT 2中暴露的患者(风险差异为8%),然后是仅在LOT 1中暴露过的患者(风险差异为5%)。在白细胞减少症方面也观察到类似的模式,但在贫血或血小板减少症方面没有观察到有意义的差异。在有近期细胞减少病史的人群中,连续暴露与从未暴露与中性粒细胞减少症和白细胞减少症之间的关联性更强:结果表明,连续暴露于 IMiDs 是导致高等级细胞减少症的风险因素。这些发现对选择有潜在细胞减少风险的新型 LOTs 有深远的临床意义。
{"title":"Real-World Risk of Severe Cytopenias in Multiple Myeloma Patients Sequentially Treated with Immunomodulatory Drugs.","authors":"Julie Barberio, Timothy L Lash, Ajay K Nooka, Ashley I Naimi, Rachel E Patzer, Christopher Kim","doi":"10.1159/000539127","DOIUrl":"10.1159/000539127","url":null,"abstract":"<p><strong>Introduction: </strong>Most multiple myeloma (MM) patients experience cytopenias, likely driven by both disease and treatment-related factors. Immunomodulatory agents (IMiDs), which form the backbone of most anti-myeloma regimens, are known to cause higher grade cytopenias. In this context, the impact of sequential IMiD treatments on cytopenia risk is unknown.</p><p><strong>Methods: </strong>We evaluated the cumulative risks of severe cytopenias following second line of therapy (LOT) initiation in 5,573 MM patients in the Flatiron Health database. Patients for whom both LOTs 1 and 2 contained IMiDs were considered \"sequentially exposed\"; those for whom neither contained IMiDs were \"never exposed.\"</p><p><strong>Results: </strong>For the neutropenia outcome, compared to the never exposed, the sequentially exposed had the highest 1-year risk (risk difference [RD] 12%), followed by those only recently exposed during LOT 2 (RD 8%), then by those with only past exposure during LOT 1 (RD 5%). A similar pattern was observed for leukopenia, but no meaningful differences were observed for anemia or thrombocytopenia. The associations between sequential exposure, versus never, with neutropenia and leukopenia were even stronger among those with a recent cytopenia history.</p><p><strong>Conclusion: </strong>Results suggest that sequential exposure to IMiDs is a risk factor for higher grade cytopenias. These findings have profound clinical implications in choosing newer LOTs with potential risks of cytopenia.</p>","PeriodicalId":6981,"journal":{"name":"Acta Haematologica","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140911212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aimaz Afrough, Pearl Rajan Abraham, Laura Turer, Gurbakhash Kaur, Aishwarya Sannareddy, Doris K Hansen, Larry D Anderson
Background: Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are novel chimeric antigen receptor (CAR)-T cell therapies targeting B-cell maturation antigen (BCMA), and both have recently gained approval by the US Food Drug Administration (FDA) for the treatment of relapsed and refractory multiple myeloma (RRMM).
Summary: These therapies offer unprecedented responses in RRMM but present new challenges including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), non-ICANS neurotoxicity, cytopenias, infections, and hypogammaglobulinemia.
Key messages: In the evolving CAR-T landscape, a primary objective is to develop innovative strategies for managing associated toxicities. Through meticulous exploration of underlying mechanisms and tailored interventions, we aim to enhance safety and enable broader outpatient utilization. Refinement of protocols, biomarker identification, and robust monitoring are imperative for sustained efficacy. This comprehensive approach guarantees the continuous advancement and optimization of CAR-T therapy.
{"title":"Toxicity of CAR T-Cell Therapy for Multiple Myeloma.","authors":"Aimaz Afrough, Pearl Rajan Abraham, Laura Turer, Gurbakhash Kaur, Aishwarya Sannareddy, Doris K Hansen, Larry D Anderson","doi":"10.1159/000539134","DOIUrl":"10.1159/000539134","url":null,"abstract":"<p><strong>Background: </strong>Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are novel chimeric antigen receptor (CAR)-T cell therapies targeting B-cell maturation antigen (BCMA), and both have recently gained approval by the US Food Drug Administration (FDA) for the treatment of relapsed and refractory multiple myeloma (RRMM).</p><p><strong>Summary: </strong>These therapies offer unprecedented responses in RRMM but present new challenges including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), non-ICANS neurotoxicity, cytopenias, infections, and hypogammaglobulinemia.</p><p><strong>Key messages: </strong>In the evolving CAR-T landscape, a primary objective is to develop innovative strategies for managing associated toxicities. Through meticulous exploration of underlying mechanisms and tailored interventions, we aim to enhance safety and enable broader outpatient utilization. Refinement of protocols, biomarker identification, and robust monitoring are imperative for sustained efficacy. This comprehensive approach guarantees the continuous advancement and optimization of CAR-T therapy.</p>","PeriodicalId":6981,"journal":{"name":"Acta Haematologica","volume":null,"pages":null},"PeriodicalIF":2.4,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140891042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) has become part of standard of care (SOC) in newly diagnosed multiple myeloma. In this review, we provide a historical perspective on ASCT since its introduction in the 1990s.
Summary: Overall survival (OS) benefit for HDT followed by ASCT was demonstrated in studies comparing HDT with ASCT to standard-dose therapy (SDT) before the era of novel agents. Conditioning is done with melphalan 200 mg/m2. Lower doses (MEL140, MEL150) for older patients with comorbidities are safe and have comparable results. The addition of busulfan to melphalan improves progression-free survival (PFS) but not OS. HDT with ASCT after induction with novel agents prolongs PFS but not OS compared to SDT alone. The benefit is more evident in patients with high-risk cytogenetics. Mobilization can be achieved with granulocyte colony-stimulating factor alone, but is improved with the addition of chemotherapy. Plerixafor reduces mobilization failure and enables sufficient stem cell collection after induction with novel agents. ASCT is safe with a low rate of mortality (1%), and selected patients can be managed as outpatients.
Key messages: HDT followed by ASCT remains part of SOC due to its PFS benefit and relatively low toxicity.
{"title":"Historical Perspective of High-Dose Therapy Followed by Autologous Stem Cell Transplantation in Multiple Myeloma.","authors":"Inbar Cohen, Iuliana Vaxman, Morie A Gertz","doi":"10.1159/000539225","DOIUrl":"10.1159/000539225","url":null,"abstract":"<p><strong>Background: </strong>High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) has become part of standard of care (SOC) in newly diagnosed multiple myeloma. In this review, we provide a historical perspective on ASCT since its introduction in the 1990s.</p><p><strong>Summary: </strong>Overall survival (OS) benefit for HDT followed by ASCT was demonstrated in studies comparing HDT with ASCT to standard-dose therapy (SDT) before the era of novel agents. Conditioning is done with melphalan 200 mg/m2. Lower doses (MEL140, MEL150) for older patients with comorbidities are safe and have comparable results. The addition of busulfan to melphalan improves progression-free survival (PFS) but not OS. HDT with ASCT after induction with novel agents prolongs PFS but not OS compared to SDT alone. The benefit is more evident in patients with high-risk cytogenetics. Mobilization can be achieved with granulocyte colony-stimulating factor alone, but is improved with the addition of chemotherapy. Plerixafor reduces mobilization failure and enables sufficient stem cell collection after induction with novel agents. ASCT is safe with a low rate of mortality (1%), and selected patients can be managed as outpatients.</p><p><strong>Key messages: </strong>HDT followed by ASCT remains part of SOC due to its PFS benefit and relatively low toxicity.</p>","PeriodicalId":6981,"journal":{"name":"Acta Haematologica","volume":null,"pages":null},"PeriodicalIF":2.4,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140846838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Taku Kikuchi, Nobuhiro Tsukada, Kodai Kunisada, Moe Nomura-Yogo, Yuki Oda, Kota Sato, Tomomi Takei, M. Ogura, Y. Abe, Kenshi Suzuki, Tadao Ishida
INTRODUCTION Some treatments are associated with cytomegalovirus (CMV) reactivation (CMVRA) in patients with multiple myeloma (MM). However, no reports exist on the association between elotuzumab and CMVRA. Therefore, we assessed the incidence of CMVRA in patients with MM who received elotuzumab therapy. METHODS The medical records of 85 patients who underwent elotuzumab therapy were included in the retrospective analysis for CMV positivity. RESULTS Thirty patients were tested for CMV antigenemia during elotuzumab therapy, and 16 were positive for CMV antigenemia; the cumulative incidence rate of CMVRA six months after elotuzumab initiation was 18.4%. A history of allogeneic stem cell transplantation (allo-HSCT) was significantly more common in the CMVRA group (31.2%) than that of the group without CMVRA (8.7%). However, even among patients who did not undergo allo-HSCT, the cumulative incidence rate of CMVRA at six months was 15.1%. During CMVRA, the symptoms included fever in seven cases, while retinitis and septic shock were observed in one case each. Five patients required antiviral therapy and CMV antigenemia resolved in all but one case. CONCLUSION Although the patient population was heterogeneous, CMVRA cannot be underestimated during elotuzumab therapy, and evaluation of CMVRA, especially in symptomatic cases, is clinically important.
{"title":"Cytomegalovirus Reactivation During Elotuzumab Therapy in Patients with Multiple Myeloma.","authors":"Taku Kikuchi, Nobuhiro Tsukada, Kodai Kunisada, Moe Nomura-Yogo, Yuki Oda, Kota Sato, Tomomi Takei, M. Ogura, Y. Abe, Kenshi Suzuki, Tadao Ishida","doi":"10.1159/000539066","DOIUrl":"https://doi.org/10.1159/000539066","url":null,"abstract":"INTRODUCTION\u0000Some treatments are associated with cytomegalovirus (CMV) reactivation (CMVRA) in patients with multiple myeloma (MM). However, no reports exist on the association between elotuzumab and CMVRA. Therefore, we assessed the incidence of CMVRA in patients with MM who received elotuzumab therapy.\u0000\u0000\u0000METHODS\u0000The medical records of 85 patients who underwent elotuzumab therapy were included in the retrospective analysis for CMV positivity.\u0000\u0000\u0000RESULTS\u0000Thirty patients were tested for CMV antigenemia during elotuzumab therapy, and 16 were positive for CMV antigenemia; the cumulative incidence rate of CMVRA six months after elotuzumab initiation was 18.4%. A history of allogeneic stem cell transplantation (allo-HSCT) was significantly more common in the CMVRA group (31.2%) than that of the group without CMVRA (8.7%). However, even among patients who did not undergo allo-HSCT, the cumulative incidence rate of CMVRA at six months was 15.1%. During CMVRA, the symptoms included fever in seven cases, while retinitis and septic shock were observed in one case each. Five patients required antiviral therapy and CMV antigenemia resolved in all but one case.\u0000\u0000\u0000CONCLUSION\u0000Although the patient population was heterogeneous, CMVRA cannot be underestimated during elotuzumab therapy, and evaluation of CMVRA, especially in symptomatic cases, is clinically important.","PeriodicalId":6981,"journal":{"name":"Acta Haematologica","volume":null,"pages":null},"PeriodicalIF":2.4,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140660375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chrysoula Boutari, E. Zarkada, Athanasios Vyzantiadis, E. Vlachaki, Genovefa Mantzou, Cristine Karipidou, S. Theodoridou
INTRODUCTION Venlafaxine (VEN) is a selective norepinephrine reuptake inhibitor (SNRI) that mainly helps treat major depressive disorder and anxiety and panic disorders. It works by inhibiting the reuptake of serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (NA) by presynaptic neurons. Additionally, VEN administration has been linked with a bleeding predisposition, that may be due to the inhibition of NA and 5-HT uptake by platelets which have their own receptors on their surface and are implicated in platelet aggregation. CASE PRESENTATION Herein, we report a case of a 54-year-old patient treated with VEN, who presented with a hematoma in the anterior abdominal muscle. We also present the observational studies and case reports highlighting the association of SNRIs use with various hemorrhagic complications ranging from gastrointestinal hemorrhage or vaginal bleeding to bleeding during or after surgery due to either thrombocytopenia or impaired platelet aggregation. CONCLUSION Given the cases of either reductions in the platelet count or impairment of platelet activity accompanied by bleeding events, every clinician should be aware of these possible adverse effects when prescribing SNRIs.
简介 文拉法辛(VEN)是一种选择性去甲肾上腺素再摄取抑制剂(SNRI),主要用于治疗重度抑郁症、焦虑症和恐慌症。它通过抑制突触前神经元对血清素(5-羟色胺,5-HT)和去甲肾上腺素(NA)的再摄取而发挥作用。此外,服用 VEN 与出血倾向有关,这可能是由于抑制了血小板对 NA 和 5-HT 的摄取,而血小板表面有自己的受体,与血小板聚集有关。我们还介绍了一些观察性研究和病例报告,这些研究和报告强调了 SNRIs 的使用与各种出血并发症的关联,这些并发症包括胃肠道出血或阴道出血,以及由于血小板减少或血小板聚集功能受损导致的术中或术后出血。
{"title":"A hematoma in the anterior abdominal muscle in a woman receiving venlafaxine. A literature review of the reports on similar cases.","authors":"Chrysoula Boutari, E. Zarkada, Athanasios Vyzantiadis, E. Vlachaki, Genovefa Mantzou, Cristine Karipidou, S. Theodoridou","doi":"10.1159/000538652","DOIUrl":"https://doi.org/10.1159/000538652","url":null,"abstract":"INTRODUCTION\u0000Venlafaxine (VEN) is a selective norepinephrine reuptake inhibitor (SNRI) that mainly helps treat major depressive disorder and anxiety and panic disorders. It works by inhibiting the reuptake of serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (NA) by presynaptic neurons. Additionally, VEN administration has been linked with a bleeding predisposition, that may be due to the inhibition of NA and 5-HT uptake by platelets which have their own receptors on their surface and are implicated in platelet aggregation.\u0000\u0000\u0000CASE PRESENTATION\u0000Herein, we report a case of a 54-year-old patient treated with VEN, who presented with a hematoma in the anterior abdominal muscle. We also present the observational studies and case reports highlighting the association of SNRIs use with various hemorrhagic complications ranging from gastrointestinal hemorrhage or vaginal bleeding to bleeding during or after surgery due to either thrombocytopenia or impaired platelet aggregation.\u0000\u0000\u0000CONCLUSION\u0000Given the cases of either reductions in the platelet count or impairment of platelet activity accompanied by bleeding events, every clinician should be aware of these possible adverse effects when prescribing SNRIs.","PeriodicalId":6981,"journal":{"name":"Acta Haematologica","volume":null,"pages":null},"PeriodicalIF":2.4,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140693984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}