Chia-Yu Wang, Emiliano Melgar-Bermudez, Diana Welch, Kevin B. Dagbay, Seemana Bhattacharya, Evan Lema, Tyler Daman, Olivia Sierra, Radina Todorova, Papa Makhtar Drame, Rosa Grenha, Ffolliott M. Fisher, Dena Grayson, Lorena Lerner, Samuel M. Cadena, Jasbir Seehra, Jennifer Lachey
Patients with chronic inflammation are burdened with anemia of inflammation (AI), where inflammatory cytokines inhibit erythropoiesis, impede erythropoietin production, and limit iron availability by inducing the iron regulator hepcidin. High hepcidin hinders iron absorption and recycling, thereby worsening the impaired erythropoiesis by restricting iron availability. AI management is important as anemia impacts quality of life and potentially affects morbidity and mortality. The bone morphogenetic protein (BMP)-SMAD pathway is crucial for hepcidin regulation. Here, we characterized a research antibody against BMP receptor ALK2, RKER-216, and investigated its mechanism in suppressing hepcidin and improving anemia in acute/chronic inflammation. Additive effects of RKER-216 and recombinant human erythropoietin (rhEPO) on erythropoiesis and iron utilization were also explored. We showed that RKER-216 neutralized ALK2 activity by competing with the binding of BMP6. RKER-216 reduced hepcidin transcription in Hep3B cells, and a subcutaneous dose of RKER-216 at 3 mg/kg suppressed serum hepcidin and increased circulating iron for 3–4 days in wildtype mice. Moreover, RKER-216 decreased hepcidin by inhibiting SMAD1/5/9 signaling in lipopolysaccharide-mediated inflammation and liberated iron from the recycling pathway to alleviate anemia in mice with adenine-induced chronic kidney disease (CKD), a mouse model of AI. Finally, RKER-216 reversed iron-restricted erythropoiesis in CKD mice and supplied the iron requirement for complete resolution of anemia when coupled with rhEPO in addressing AI. Our data support that ALK2 is a key hepcidin regulator and that a neutralizing ALK2 antibody has the potential to restore iron homeostasis as monotherapy or in combination with rhEPO to ameliorate AI.
{"title":"A Recombinant Antibody Against ALK2 Promotes Tissue Iron Redistribution and Contributes to Anemia Resolution in a Mouse Model of Anemia of Inflammation","authors":"Chia-Yu Wang, Emiliano Melgar-Bermudez, Diana Welch, Kevin B. Dagbay, Seemana Bhattacharya, Evan Lema, Tyler Daman, Olivia Sierra, Radina Todorova, Papa Makhtar Drame, Rosa Grenha, Ffolliott M. Fisher, Dena Grayson, Lorena Lerner, Samuel M. Cadena, Jasbir Seehra, Jennifer Lachey","doi":"10.1002/ajh.27578","DOIUrl":"https://doi.org/10.1002/ajh.27578","url":null,"abstract":"Patients with chronic inflammation are burdened with anemia of inflammation (AI), where inflammatory cytokines inhibit erythropoiesis, impede erythropoietin production, and limit iron availability by inducing the iron regulator hepcidin. High hepcidin hinders iron absorption and recycling, thereby worsening the impaired erythropoiesis by restricting iron availability. AI management is important as anemia impacts quality of life and potentially affects morbidity and mortality. The bone morphogenetic protein (BMP)-SMAD pathway is crucial for hepcidin regulation. Here, we characterized a research antibody against BMP receptor ALK2, RKER-216, and investigated its mechanism in suppressing hepcidin and improving anemia in acute/chronic inflammation. Additive effects of RKER-216 and recombinant human erythropoietin (rhEPO) on erythropoiesis and iron utilization were also explored. We showed that RKER-216 neutralized ALK2 activity by competing with the binding of BMP6. RKER-216 reduced hepcidin transcription in Hep3B cells, and a subcutaneous dose of RKER-216 at 3 mg/kg suppressed serum hepcidin and increased circulating iron for 3–4 days in wildtype mice. Moreover, RKER-216 decreased hepcidin by inhibiting SMAD1/5/9 signaling in lipopolysaccharide-mediated inflammation and liberated iron from the recycling pathway to alleviate anemia in mice with adenine-induced chronic kidney disease (CKD), a mouse model of AI. Finally, RKER-216 reversed iron-restricted erythropoiesis in CKD mice and supplied the iron requirement for complete resolution of anemia when coupled with rhEPO in addressing AI. Our data support that ALK2 is a key hepcidin regulator and that a neutralizing ALK2 antibody has the potential to restore iron homeostasis as monotherapy or in combination with rhEPO to ameliorate AI.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"82 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ramón Lecumberri, Pedro Ruiz-Artacho, Javier Trujillo-Santos, María Marcos-Jubilar, Montserrat Pérez-Pinar, Isabelle Quéré, Gisela Claver, Juan Gorostidi, Behnood Bikdeli, Manuel Monreal
Managing acute venous thromboembolism (VTE) in patients with thrombocytopenia is challenging. We used data from the RIETE registry to investigate the impact of baseline thrombocytopenia on early VTE-related outcomes, depending on the initial presentation as pulmonary embolism (PE) or isolated lower-limb deep vein thrombosis (DVT). From March 2003 to November 2022, 90 418 patients with VTE were included. Thrombocytopenia was categorized as severe (< 50 000/μL, n = 303) or moderate (50 000–99 999/μL, n = 1882). The primary outcome, fatal PE within 15 days after diagnosis, and secondary outcomes, including major bleeding and recurrent VTE, were analyzed using multivariable-adjusted models. Among 52 703 patients with PE, the 15-day case-fatality rates from PE were 5.8% for severe thrombocytopenia, 4.5% for moderate thrombocytopenia, and 1.1% for normal platelet counts. In 37 715 patients with isolated DVT, the cumulative incidence of fatal PE were 0, 0.2%, and 0.05%, respectively. Multivariable analysis revealed a five-fold increase in the risk for fatal PE in severe thrombocytopenia (adjusted HR: 4.89; 95%CI: 2.55–9.39) without significant differences between severe and moderate thrombocytopenia. Thrombocytopenia, either moderate or severe, was also associated with increased risk for both, major bleeding and recurrent VTE at 15 days. Initial presentation with PE substantially worsened prognosis compared to isolated DVT. In conclusion, in patients with acute VTE, thrombocytopenia at baseline was associated with increased risk of early death from PE, a finding that was driven by the subgroup whose initial presentation was PE.
管理急性静脉血栓栓塞（VTE）患者与血小板减少是具有挑战性的。我们使用来自RIETE登记的数据来研究基线血小板减少对早期血栓栓塞相关结果的影响，这取决于最初表现为肺栓塞（PE）或孤立性下肢深静脉血栓形成（DVT）。从2003年3月至2022年11月，共纳入90418例静脉血栓栓塞患者。血小板减少分为重度（50 000/μL, n = 303）和中度（50 000 ~ 99 999/μL, n = 1882）。主要结局（诊断后15天内致死性PE）和次要结局（包括大出血和复发性静脉血栓栓塞）使用多变量调整模型进行分析。在52703例PE患者中，重度血小板减少患者的15天病死率为5.8%，中度血小板减少患者为4.5%，正常血小板计数患者为1.1%。在37715例孤立性DVT患者中，致死性PE的累积发生率分别为0、0.2%和0.05%。多变量分析显示，严重血小板减少患者发生致死性PE的风险增加了5倍(校正HR: 4.89；95%CI: 2.55-9.39)，重度和中度血小板减少症之间无显著差异。中度或重度的血小板减少症也与15天发生大出血和静脉血栓栓塞复发的风险增加有关。与孤立的DVT相比，PE的初始表现明显恶化了预后。总之，在急性静脉血栓栓塞患者中，基线时血小板减少与PE早期死亡风险增加相关，这一发现是由最初表现为PE的亚组推动的。
{"title":"Impact of Baseline Thrombocytopenia on Early Outcomes in Patients With Acute Venous Thromboembolism","authors":"Ramón Lecumberri, Pedro Ruiz-Artacho, Javier Trujillo-Santos, María Marcos-Jubilar, Montserrat Pérez-Pinar, Isabelle Quéré, Gisela Claver, Juan Gorostidi, Behnood Bikdeli, Manuel Monreal","doi":"10.1002/ajh.27579","DOIUrl":"https://doi.org/10.1002/ajh.27579","url":null,"abstract":"Managing acute venous thromboembolism (VTE) in patients with thrombocytopenia is challenging. We used data from the RIETE registry to investigate the impact of baseline thrombocytopenia on early VTE-related outcomes, depending on the initial presentation as pulmonary embolism (PE) or isolated lower-limb deep vein thrombosis (DVT). From March 2003 to November 2022, 90 418 patients with VTE were included. Thrombocytopenia was categorized as severe (< 50 000/μL, <i>n</i> = 303) or moderate (50 000–99 999/μL, <i>n</i> = 1882). The primary outcome, fatal PE within 15 days after diagnosis, and secondary outcomes, including major bleeding and recurrent VTE, were analyzed using multivariable-adjusted models. Among 52 703 patients with PE, the 15-day case-fatality rates from PE were 5.8% for severe thrombocytopenia, 4.5% for moderate thrombocytopenia, and 1.1% for normal platelet counts. In 37 715 patients with isolated DVT, the cumulative incidence of fatal PE were 0, 0.2%, and 0.05%, respectively. Multivariable analysis revealed a five-fold increase in the risk for fatal PE in severe thrombocytopenia (adjusted HR: 4.89; 95%CI: 2.55–9.39) without significant differences between severe and moderate thrombocytopenia. Thrombocytopenia, either moderate or severe, was also associated with increased risk for both, major bleeding and recurrent VTE at 15 days. Initial presentation with PE substantially worsened prognosis compared to isolated DVT. In conclusion, in patients with acute VTE, thrombocytopenia at baseline was associated with increased risk of early death from PE, a finding that was driven by the subgroup whose initial presentation was PE.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"204 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ioannis Ntanasis-Stathopoulos, Charalampos Filippatos, Anastasios Ntanasis-Stathopoulos, Panagiotis Malandrakis, Efstathios Kastritis, Ourania E. Tsitsilonis, Meletios A. Dimopoulos, Evangelos Terpos, Maria Gavriatopoulou
This meta-analysis examined the association between minimal residual disease (MRD) negativity and survival outcomes in 15 304 patients with multiple myeloma (MM) enrolled in randomized controlled trials published until June 2, 2024. Overall, there was a significant, negative and strong association between MRD negativity odds ratios and survival hazard ratios (β_PFS = -0.20, p < 0.001, β_OS = -0.12, p = 0.023). These associations remained significant for newly diagnosed patients (β_PFS = -0.35, p < 0.001), and they were consistent but not significant for relapsed/refractory patients (β_PFS = -0.06, p = 0.635). Sustained MRD negativity at 1 year was strongly correlated with prolonged PFS (β_PFS = -0.30, p < 0.001). In conclusion, this comprehensive meta-analysis supports MRD as a surrogate for survival in MM.
这项荟萃分析研究了15304名多发性骨髓瘤（MM）患者的最小残留病（MRD）阴性与生存结果之间的关系，这些患者参加了随机对照试验，发表于2024年6月2日。总体而言，MRD阴性优势比与生存风险比之间存在显著的负相关和强相关（β_PFS = -0.20, p < 0.001, β_OS = -0.12, p = 0.023）。这些相关性在新诊断患者中仍然显著（β_PFS = -0.35, p < 0.001），在复发/难治性患者中也一致但不显著（β_PFS = -0.06, p = 0.635）。1年MRD持续阴性与PFS延长密切相关（β_PFS = -0.30, p < 0.001）。总之，这项综合荟萃分析支持MRD作为MM患者生存率的替代指标。
{"title":"Evaluating Minimal Residual Disease Negativity as a Surrogate Endpoint for Treatment Efficacy in Multiple Myeloma: A Meta-Analysis of Randomized Controlled Trials","authors":"Ioannis Ntanasis-Stathopoulos, Charalampos Filippatos, Anastasios Ntanasis-Stathopoulos, Panagiotis Malandrakis, Efstathios Kastritis, Ourania E. Tsitsilonis, Meletios A. Dimopoulos, Evangelos Terpos, Maria Gavriatopoulou","doi":"10.1002/ajh.27582","DOIUrl":"https://doi.org/10.1002/ajh.27582","url":null,"abstract":"This meta-analysis examined the association between minimal residual disease (MRD) negativity and survival outcomes in 15 304 patients with multiple myeloma (MM) enrolled in randomized controlled trials published until June 2, 2024. Overall, there was a significant, negative and strong association between MRD negativity odds ratios and survival hazard ratios (β_PFS = -0.20, <i>p</i> < 0.001, β_OS = -0.12, <i>p</i> = 0.023). These associations remained significant for newly diagnosed patients (β_PFS = -0.35, <i>p</i> < 0.001), and they were consistent but not significant for relapsed/refractory patients (β_PFS = -0.06, <i>p</i> = 0.635). Sustained MRD negativity at 1 year was strongly correlated with prolonged PFS (β_PFS = -0.30, <i>p</i> < 0.001). In conclusion, this comprehensive meta-analysis supports MRD as a surrogate for survival in MM.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"28 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Piyanuch Kongtim, Piyatida Chumnumsiriwath, Pongthep Vittayawacharin, Deepa Jeyakumar, Benjamin J. Lee, Jean Doh, Shawn P. Griffin, Richard A. Van Etten, Stefan Ciurea
Oral budesonide exerts local effects with negligible systemic glucocorticoid activity, due to rapid first-pass metabolism, therefore, could potentially be efficacious in preventing gastrointestinal (GI) acute GVHD (aGVHD). We explored the use of budesonide, added to posttransplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate mofetil, for prevention of GI aGVHD after allogeneic hematopoietic stem cell transplantation (AHSCT) in a prospective observational study and treated 80 patients with a median age of 53 years (range 19–74). Results were compared with a publicly available CIBMTR dataset of 646 patients who received PTCy-based GVHD prophylaxis (CIBMTR Study # GV17-02) (control). Cumulative incidence (CI) of 3-month grade 2–4 and grade 3–4 aGVHD in the budesonide and control groups were 3.8% vs. 34.4% (p < 0.001) and 1.3% vs. 9.8% (p = 0.029), respectively. One-year GRFS (70.5% vs. 31.5%, p < 0.001), PFS (73.4% vs. 52.8%, p = 0.003), and OS (80.1% vs. 64.2%, p = 0.038) were significantly higher in the budesonide group compared with control group. Propensity score-adjusted analyses showed that the addition of budesonide significantly decreased risk of aGVHD grade 2–4 (HR 0.29, p < 0.001), grade 3–4 (HR 0.12, p = 0.045), and cGVHD (HR 0.22, p < 0.001), which resulted in better GRFS (HR 0.38, p < 0.001), PFS (HR 0.58, p = 0.012), and OS (HR 0.72, p = 0.044). Similar results were found when using propensity score-matched analysis restricted to recipients of haploidentical transplantation. In conclusion, addition of budesonide to PTCy-based GVHD prophylaxis is safe and effective in preventing severe acute GI GVHD with significantly improved GRFS. These results could facilitate transition to peripheral blood grafts for all allogeneic transplant recipients.
口服布地奈德具有局部作用，全身糖皮质激素活性可忽略不计，由于其快速的首过代谢，因此可能有效预防胃肠道（GI）急性GVHD （aGVHD）。在一项前瞻性观察性研究中，我们探讨了布地奈德与移植后环磷酰胺（PTCy）、他克莫司和霉酚酸酯一起用于预防异基因造血干细胞移植（AHSCT）后GI aGVHD的使用，共治疗了80例患者，中位年龄为53岁（范围19-74岁）。结果与公开的CIBMTR数据集进行了比较，该数据集包括646名接受基于ptc的GVHD预防的患者（CIBMTR Study # GV17-02）（对照组）。布地奈德组和对照组3个月2-4级和3-4级aGVHD累积发生率（CI）分别为3.8% vs. 34.4% （p < 0.001）和1.3% vs. 9.8% （p = 0.029）。布地奈德组1年GRFS （70.5% vs. 31.5%, p < 0.001）、PFS （73.4% vs. 52.8%, p = 0.003）和OS （80.1% vs. 64.2%, p = 0.038）均显著高于对照组。倾向评分调整分析显示，布地奈德的加入显著降低了2-4级aGVHD （HR 0.29, p < 0.001）、3-4级aGVHD （HR 0.12, p = 0.045）和cGVHD （HR 0.22, p < 0.001）的风险，从而改善了GRFS （HR 0.38, p < 0.001）、PFS （HR 0.58, p = 0.012）和OS （HR 0.72, p = 0.044）。当使用倾向评分匹配分析仅限于单倍体移植受者时，发现了类似的结果。综上所述，在基于ptc的GVHD预防中添加布地奈德是安全有效的，可预防严重急性GI GVHD，并显著改善GRFS。这些结果有助于所有同种异体移植受者向外周血移植过渡。
{"title":"Budesonide, Added to PTCy-Based Regimen, for Prevention of Acute GI GVHD After Allogeneic Stem Cell Transplantation","authors":"Piyanuch Kongtim, Piyatida Chumnumsiriwath, Pongthep Vittayawacharin, Deepa Jeyakumar, Benjamin J. Lee, Jean Doh, Shawn P. Griffin, Richard A. Van Etten, Stefan Ciurea","doi":"10.1002/ajh.27581","DOIUrl":"https://doi.org/10.1002/ajh.27581","url":null,"abstract":"Oral budesonide exerts local effects with negligible systemic glucocorticoid activity, due to rapid first-pass metabolism, therefore, could potentially be efficacious in preventing gastrointestinal (GI) acute GVHD (aGVHD). We explored the use of budesonide, added to posttransplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate mofetil, for prevention of GI aGVHD after allogeneic hematopoietic stem cell transplantation (AHSCT) in a prospective observational study and treated 80 patients with a median age of 53 years (range 19–74). Results were compared with a publicly available CIBMTR dataset of 646 patients who received PTCy-based GVHD prophylaxis (CIBMTR Study # GV17-02) (control). Cumulative incidence (CI) of 3-month grade 2–4 and grade 3–4 aGVHD in the budesonide and control groups were 3.8% vs. 34.4% (<i>p</i> < 0.001) and 1.3% vs. 9.8% (<i>p</i> = 0.029), respectively. One-year GRFS (70.5% vs. 31.5%, <i>p</i> < 0.001), PFS (73.4% vs. 52.8%, <i>p</i> = 0.003), and OS (80.1% vs. 64.2%, <i>p</i> = 0.038) were significantly higher in the budesonide group compared with control group. Propensity score-adjusted analyses showed that the addition of budesonide significantly decreased risk of aGVHD grade 2–4 (HR 0.29, <i>p</i> < 0.001), grade 3–4 (HR 0.12, <i>p</i> = 0.045), and cGVHD (HR 0.22, <i>p</i> < 0.001), which resulted in better GRFS (HR 0.38, <i>p</i> < 0.001), PFS (HR 0.58, <i>p</i> = 0.012), and OS (HR 0.72, <i>p</i> = 0.044). Similar results were found when using propensity score-matched analysis restricted to recipients of haploidentical transplantation. In conclusion, addition of budesonide to PTCy-based GVHD prophylaxis is safe and effective in preventing severe acute GI GVHD with significantly improved GRFS. These results could facilitate transition to peripheral blood grafts for all allogeneic transplant recipients.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"13 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acute myeloid leukemia (AML) is a genetically heterogeneous disease with high rates of relapse after initial treatment. Identifying measurable residual disease (MRD) following initial therapy is essential to assess response, predict patient outcomes, and identify those in need of additional intervention. Currently, MRD analysis relies on invasive, serial bone marrow (BM) biopsies, which complicate sample availability and processing time and negatively impact patient experience. Additionally, finding a positive result can generate more questions than answers, causing anxiety for both the patient and the provider. Peripheral blood (PB) evaluation has shown promise in detecting MRD and is now recommended by the European Leukemia Net for AML for certain genetic abnormalities. PB-based sampling allows for more frequent testing intervals and better temporal resolution of malignant expansion while sparing patients additional invasive procedures. In this review, we will discuss the current state of PB testing for MRD evaluation with a focus on next-generation sequencing methodologies that are capable of MRD detection across AML subtypes.
{"title":"Breaking the Bone Marrow Barrier: Peripheral Blood as a Gateway to Measurable Residual Disease Detection in Acute Myelogenous Leukemia","authors":"John T. Butler, William M. Yashar, Ronan Swords","doi":"10.1002/ajh.27586","DOIUrl":"https://doi.org/10.1002/ajh.27586","url":null,"abstract":"Acute myeloid leukemia (AML) is a genetically heterogeneous disease with high rates of relapse after initial treatment. Identifying measurable residual disease (MRD) following initial therapy is essential to assess response, predict patient outcomes, and identify those in need of additional intervention. Currently, MRD analysis relies on invasive, serial bone marrow (BM) biopsies, which complicate sample availability and processing time and negatively impact patient experience. Additionally, finding a positive result can generate more questions than answers, causing anxiety for both the patient and the provider. Peripheral blood (PB) evaluation has shown promise in detecting MRD and is now recommended by the European Leukemia Net for AML for certain genetic abnormalities. PB-based sampling allows for more frequent testing intervals and better temporal resolution of malignant expansion while sparing patients additional invasive procedures. In this review, we will discuss the current state of PB testing for MRD evaluation with a focus on next-generation sequencing methodologies that are capable of MRD detection across AML subtypes.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"20 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Therese Lassen, Torsten H. Nielsen, Annika von Heymann, Lene K. Nielsen, Morten K. Larsen, Anne O. Gang, Christoffer Johansen, Lars M. Pedersen
Despite advances in treatment, approximately 15% of patients with diffuse large B-cell lymphoma (DLBCL) who achieve complete remission (CR) after first-line therapy will experience a relapse. However, there is no consensus on the optimal follow-up strategies for detecting relapse after achieving CR. This population-based study, based on the Danish Lymphoma Registry (LYFO), identified a total of 1634 patients diagnosed with DLBCL between 2010 and 2017, including 105 patients who achieved CR following first-line R-CHOP-like therapy and subsequently relapsed. The median follow-up time was 6 years (range 3–8 years). Most cases of relapse were symptomatic (83%), with B symptoms and peripheral lymphadenopathy being the most common. Asymptomatic relapses were identified through physical examination (1%), blood tests (3%), or imaging findings (13%). The proportion of relapses identified outside routine visits was 70%. Only 5% of scheduled routine visits led to a relapse diagnosis, whereas 74% of unscheduled visits initiated by the patient outside routine follow-up resulted in relapse detection. Our findings highlight that systematic, scheduled monitoring of patients in remission after first-line treatment contributes only modestly to the early detection of disease recurrence. Future studies should explore alternative methods of relapse surveillance rather than relying solely on pre-scheduled clinical follow-up.
{"title":"Limited Benefit of Routine Clinical Follow-Up for Relapse Detection in Diffuse Large B-Cell Lymphoma Patients in Complete Remission Following First-Line Treatment","authors":"Therese Lassen, Torsten H. Nielsen, Annika von Heymann, Lene K. Nielsen, Morten K. Larsen, Anne O. Gang, Christoffer Johansen, Lars M. Pedersen","doi":"10.1002/ajh.27577","DOIUrl":"https://doi.org/10.1002/ajh.27577","url":null,"abstract":"Despite advances in treatment, approximately 15% of patients with diffuse large B-cell lymphoma (DLBCL) who achieve complete remission (CR) after first-line therapy will experience a relapse. However, there is no consensus on the optimal follow-up strategies for detecting relapse after achieving CR. This population-based study, based on the Danish Lymphoma Registry (LYFO), identified a total of 1634 patients diagnosed with DLBCL between 2010 and 2017, including 105 patients who achieved CR following first-line R-CHOP-like therapy and subsequently relapsed. The median follow-up time was 6 years (range 3–8 years). Most cases of relapse were symptomatic (83%), with B symptoms and peripheral lymphadenopathy being the most common. Asymptomatic relapses were identified through physical examination (1%), blood tests (3%), or imaging findings (13%). The proportion of relapses identified outside routine visits was 70%. Only 5% of scheduled routine visits led to a relapse diagnosis, whereas 74% of unscheduled visits initiated by the patient outside routine follow-up resulted in relapse detection. Our findings highlight that systematic, scheduled monitoring of patients in remission after first-line treatment contributes only modestly to the early detection of disease recurrence. Future studies should explore alternative methods of relapse surveillance rather than relying solely on pre-scheduled clinical follow-up.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"73 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hagop Kantarjian, Nicholas J. Short, Nitin Jain, Fadi G. Haddad, Tapan Kadia, Musa Yilmaz, Alessandra Ferrajoli, Koji Sasaki, Yesid Alvarado, Naveen Pemmaraju, Jayastu Senapati, Rebecca Garris, Farhad Ravandi, Elias Jabbour
Adding inotuzumab ozogamicin (InO) to hyper-CVAD and blinatumomab may improve outcomes in newly diagnosed Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukemia (B-ALL). Patients with newly diagnosed B-ALL received up to four cycles of hyper-CVAD followed by four cycles of blinatumomab. Beginning with patient #39, InO 0.3 mg/m2 was added on Days 1 and 8 to two cycles of high-dose methotrexate and cytarabine, and two cycles of blinatumomab. The primary endpoint was the relapse-free survival (RFS) rate. Seventy-five patients were treated (median age of 33 years; range, 18–59), of whom 37 (49%) received hyper-CVAD with blinatumomab and InO (cohort 2). Measurable residual disease (MRD) negativity by next-generation sequencing (sensitivity: 1 × 10−6) was achieved in 79% of patients in cohort 2. The median follow-up was 44 months (range, 13–90) overall, and 26 months (range, 8–39) in cohort 2. For the entire cohort, the estimated 3-year RFS rate was 82% and the 3-year overall survival rate was 90%. These rates were 90% versus 74% (p = 0.06) and 100% versus 82% (p = 0.01) in patients who did or did not receive InO, respectively. No sinusoidal obstruction syndrome was observed. In summary, hyper-CVAD with blinatumomab and InO improved the outcomes of patients with newly diagnosed B-ALL.
{"title":"Hyper-CVAD and Sequential Blinatumomab Without and With Inotuzumab in Young Adults With Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia","authors":"Hagop Kantarjian, Nicholas J. Short, Nitin Jain, Fadi G. Haddad, Tapan Kadia, Musa Yilmaz, Alessandra Ferrajoli, Koji Sasaki, Yesid Alvarado, Naveen Pemmaraju, Jayastu Senapati, Rebecca Garris, Farhad Ravandi, Elias Jabbour","doi":"10.1002/ajh.27576","DOIUrl":"https://doi.org/10.1002/ajh.27576","url":null,"abstract":"Adding inotuzumab ozogamicin (InO) to hyper-CVAD and blinatumomab may improve outcomes in newly diagnosed Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukemia (B-ALL). Patients with newly diagnosed B-ALL received up to four cycles of hyper-CVAD followed by four cycles of blinatumomab. Beginning with patient #39, InO 0.3 mg/m<sup>2</sup> was added on Days 1 and 8 to two cycles of high-dose methotrexate and cytarabine, and two cycles of blinatumomab. The primary endpoint was the relapse-free survival (RFS) rate. Seventy-five patients were treated (median age of 33 years; range, 18–59), of whom 37 (49%) received hyper-CVAD with blinatumomab and InO (cohort 2). Measurable residual disease (MRD) negativity by next-generation sequencing (sensitivity: 1 × 10<sup>−6</sup>) was achieved in 79% of patients in cohort 2. The median follow-up was 44 months (range, 13–90) overall, and 26 months (range, 8–39) in cohort 2. For the entire cohort, the estimated 3-year RFS rate was 82% and the 3-year overall survival rate was 90%. These rates were 90% versus 74% (<i>p</i> = 0.06) and 100% versus 82% (<i>p</i> = 0.01) in patients who did or did not receive InO, respectively. No sinusoidal obstruction syndrome was observed. In summary, hyper-CVAD with blinatumomab and InO improved the outcomes of patients with newly diagnosed B-ALL.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"75 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purna Nangia, Karen M. Wai, Adrienne W. Scott, Ehsan Rahimy, Prithvi Mruthyunjaya
{"title":"The Interplay Between Ophthalmic and Systemic Outcomes in Patients With Sickle Cell Disease and Concurrent Retinopathy—A Population‐Based Study","authors":"Purna Nangia, Karen M. Wai, Adrienne W. Scott, Ehsan Rahimy, Prithvi Mruthyunjaya","doi":"10.1002/ajh.27552","DOIUrl":"https://doi.org/10.1002/ajh.27552","url":null,"abstract":"","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"20 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder characterized by marked heterogeneity among patients, with severity ranging from mild to life-threatening [<span>1</span>]. Although cases have been documented across all age groups, the diagnosis of iMCD typically occurs in the fifth decade of life and is relatively uncommon in children [<span>1</span>].</p> <p>A previous analysis of the ACCELERATE dataset revealed that 95% of patients with iMCD diagnosed before the age of 30 (<i>n</i> = 35) had severe disease at onset [<span>2</span>]. A subsequent subgroup analysis focusing on the pediatric cohort (<i>n</i> = 19) highlighted a higher prevalence of the thrombocytopenia, anasarca, fever, renal dysfunction, and organomegaly (TAFRO) subtype [<span>3</span>]. These findings raise important questions about whether the severity and dominance of the TAFRO subtype in children suggest a poorer prognosis compared to that of adults. However, existing studies lack comprehensive data on pediatric iMCD. In this study, we aim to characterize the clinical features, treatment strategies, and outcomes of individuals diagnosed with iMCD at or under the age of 18, thereby contributing to a comprehensive understanding of the disease in this patient group.</p> <p>This retrospective cohort study was conducted at two tertiary hospitals: Peking Union Medical College Hospital and Beijing Children's Hospital. We enrolled patients aged ≤ 18 years who were diagnosed with iMCD based on the Castleman Disease Collaborative Network (CDCN) diagnostic consensus [<span>4</span>] between January 2012 and January 2024. Patients were further classified into three clinical phenotypes: TAFRO, not otherwise specified (NOS), and idiopathic plasmacytic lymphadenopathy (IPL) [<span>5</span>]. Severe iMCD was evaluated according to the CDCN criteria at diagnosis [<span>6</span>].</p> <p>The primary outcome was to describe the baseline characteristics. Other study outcomes included treatment regimens and responses, as well as prognosis. Treatments were further categorized into two main strategies: continual suppressive therapies, encompassing interleukin (IL)-6 targeting regimens, myeloma-like regimens, and mTOR-targeting regimens; and pulse therapy strategies, which include lymphoma-like regimens. The evaluation of treatment response adhered to the CDCN response criteria. Follow-up data, extending up to September 1st, 2024, were sourced from medical record systems and through telephone communication. Overall survival and time-to-next treatment (TTNT) were determined. Additional details on study methods are available in the Data S1 section.</p> <p>A total of 23 patients (16 males and seven females [ratio, 2.3:1]), with a median age of 12 years at diagnosis (range: 2–18 years), were included in this analysis (Table S1). While there was no statistically significant difference in the age distribution between sexes, all children diagnosed at or before the
{"title":"Clinical Characteristics and Prognosis of Pediatric Idiopathic Multicentric Castleman Disease","authors":"Yu-han Gao, Jia-feng Yao, Si-yuan Li, Yue Dang, Hao-yi Xu, Tong Zou, Jian Li, Lu Zhang, Rui Zhang","doi":"10.1002/ajh.27574","DOIUrl":"https://doi.org/10.1002/ajh.27574","url":null,"abstract":"<p>Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder characterized by marked heterogeneity among patients, with severity ranging from mild to life-threatening [<span>1</span>]. Although cases have been documented across all age groups, the diagnosis of iMCD typically occurs in the fifth decade of life and is relatively uncommon in children [<span>1</span>].</p>\u0000<p>A previous analysis of the ACCELERATE dataset revealed that 95% of patients with iMCD diagnosed before the age of 30 (<i>n</i> = 35) had severe disease at onset [<span>2</span>]. A subsequent subgroup analysis focusing on the pediatric cohort (<i>n</i> = 19) highlighted a higher prevalence of the thrombocytopenia, anasarca, fever, renal dysfunction, and organomegaly (TAFRO) subtype [<span>3</span>]. These findings raise important questions about whether the severity and dominance of the TAFRO subtype in children suggest a poorer prognosis compared to that of adults. However, existing studies lack comprehensive data on pediatric iMCD. In this study, we aim to characterize the clinical features, treatment strategies, and outcomes of individuals diagnosed with iMCD at or under the age of 18, thereby contributing to a comprehensive understanding of the disease in this patient group.</p>\u0000<p>This retrospective cohort study was conducted at two tertiary hospitals: Peking Union Medical College Hospital and Beijing Children's Hospital. We enrolled patients aged ≤ 18 years who were diagnosed with iMCD based on the Castleman Disease Collaborative Network (CDCN) diagnostic consensus [<span>4</span>] between January 2012 and January 2024. Patients were further classified into three clinical phenotypes: TAFRO, not otherwise specified (NOS), and idiopathic plasmacytic lymphadenopathy (IPL) [<span>5</span>]. Severe iMCD was evaluated according to the CDCN criteria at diagnosis [<span>6</span>].</p>\u0000<p>The primary outcome was to describe the baseline characteristics. Other study outcomes included treatment regimens and responses, as well as prognosis. Treatments were further categorized into two main strategies: continual suppressive therapies, encompassing interleukin (IL)-6 targeting regimens, myeloma-like regimens, and mTOR-targeting regimens; and pulse therapy strategies, which include lymphoma-like regimens. The evaluation of treatment response adhered to the CDCN response criteria. Follow-up data, extending up to September 1st, 2024, were sourced from medical record systems and through telephone communication. Overall survival and time-to-next treatment (TTNT) were determined. Additional details on study methods are available in the Data S1 section.</p>\u0000<p>A total of 23 patients (16 males and seven females [ratio, 2.3:1]), with a median age of 12 years at diagnosis (range: 2–18 years), were included in this analysis (Table S1). While there was no statistically significant difference in the age distribution between sexes, all children diagnosed at or before the","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"13 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jennifer E. Bruno, Christine A. Herne, Andrea M. Baran, Karl R. VanDerMeid, Paul M. Barr, Alyssa R. Williams, Sally A. Quataert, Tim R. Mosmann, Clive S. Zent, Charles C. Chu
<p>Therapeutic unconjugated anti-CD20 monoclonal antibodies (mAb) and small molecule inhibitors of the B cell receptor (BCR) signaling pathway and B cell lymphoma-2 (BCL2) have greatly improved therapy for patients with progressive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). However, these therapies are not curative, and their efficacy can be compromised by side effects and acquired drug resistance, especially with indefinite duration regimens [<span>1</span>]. To address these problems, we tested a limited–duration triple combination targeted therapy for relapsed/refractory CLL patients (U2-VEN, ClinicalTrials.gov NCT03379051) that involved three drugs with different mechanisms of action, which may increase effectiveness and reduce the likelihood of resistance (Figure 1A [<span>2</span>]). We chose: (1) ublituximab (UBL), a glycoengineered chimeric monoclonal antibody (mAb) targeting a unique epitope on CD20 antigen (Ag) on surface of CLL cells, which destroys CLL cells primarily by antibody-dependent cellular phagocytosis (ADCP); (2) umbralisib (UMB), a novel small molecule B cell receptor (BCR) signaling inhibitor that is highly selective for phosphoinositide 3-kinase delta (PI3Kδ, shown) and casein kinase 1 epsilon, which causes CLL cell death by preventing cell survival signals; and (3) venetoclax (VEN), a small molecule anti-apoptosis inhibitor that blocks cell survival promoted by BCL2, which stops mitochondria from initiating apoptosis. An initial 12 week treatment with UBL and UMB was utilized to allow the BCR signal inhibiting drug to mobilize CLL cells into the circulation where they are more susceptible to mAb cytotoxicity and thus decrease the CLL tumor burden and risk of VEN-induced tumor lysis syndrome when it is added in the 13th week of therapy (Figure 1B).</p> <figure><picture> <source media="(min-width: 1650px)" srcset="/cms/asset/42baaa16-06ed-4c73-a745-641b06f16907/ajh27569-fig-0001-m.jpg"/><img alt="Details are in the caption following the image" data-lg-src="/cms/asset/42baaa16-06ed-4c73-a745-641b06f16907/ajh27569-fig-0001-m.jpg" loading="lazy" src="/cms/asset/75c81c34-f5b8-452b-9e04-cb8948d70b52/ajh27569-fig-0001-m.png" title="Details are in the caption following the image"/></picture><figcaption> <div><strong>FIGURE 1<span style="font-weight:normal"></span></strong><div>Open in figure viewer<i aria-hidden="true"></i><span>PowerPoint</span></div> </div> <div>UBL and UMB treatment in U2-VEN clinical trial results in rapid loss of CLL cells and CD20 levels. (A) Multi-drug combination targeting three different molecules to overcome single-agent resistance in relapsed/refractory CLL patients. (B) Diagram of U2-VEN clinical study design (ClinicalTrials.gov NCT03379051) [<span>2</span>]. Treatment consists of initially 12 cycles of 28 days. Ublituximab (purple) was administered intravenously on indicated days of first six cycles. Umbralisib (green) was orally administered daily for 12 cycles. Venetoclax was ad
{"title":"Treatment of Relapsed/Refractory CLL Patients With PI3Kδ Inhibitor and Anti-CD20 Antibody Rapidly Decreases Tumor Burden but Could Induce Resistance","authors":"Jennifer E. Bruno, Christine A. Herne, Andrea M. Baran, Karl R. VanDerMeid, Paul M. Barr, Alyssa R. Williams, Sally A. Quataert, Tim R. Mosmann, Clive S. Zent, Charles C. Chu","doi":"10.1002/ajh.27569","DOIUrl":"https://doi.org/10.1002/ajh.27569","url":null,"abstract":"<p>Therapeutic unconjugated anti-CD20 monoclonal antibodies (mAb) and small molecule inhibitors of the B cell receptor (BCR) signaling pathway and B cell lymphoma-2 (BCL2) have greatly improved therapy for patients with progressive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). However, these therapies are not curative, and their efficacy can be compromised by side effects and acquired drug resistance, especially with indefinite duration regimens [<span>1</span>]. To address these problems, we tested a limited–duration triple combination targeted therapy for relapsed/refractory CLL patients (U2-VEN, ClinicalTrials.gov NCT03379051) that involved three drugs with different mechanisms of action, which may increase effectiveness and reduce the likelihood of resistance (Figure 1A [<span>2</span>]). We chose: (1) ublituximab (UBL), a glycoengineered chimeric monoclonal antibody (mAb) targeting a unique epitope on CD20 antigen (Ag) on surface of CLL cells, which destroys CLL cells primarily by antibody-dependent cellular phagocytosis (ADCP); (2) umbralisib (UMB), a novel small molecule B cell receptor (BCR) signaling inhibitor that is highly selective for phosphoinositide 3-kinase delta (PI3Kδ, shown) and casein kinase 1 epsilon, which causes CLL cell death by preventing cell survival signals; and (3) venetoclax (VEN), a small molecule anti-apoptosis inhibitor that blocks cell survival promoted by BCL2, which stops mitochondria from initiating apoptosis. An initial 12 week treatment with UBL and UMB was utilized to allow the BCR signal inhibiting drug to mobilize CLL cells into the circulation where they are more susceptible to mAb cytotoxicity and thus decrease the CLL tumor burden and risk of VEN-induced tumor lysis syndrome when it is added in the 13th week of therapy (Figure 1B).</p>\u0000<figure><picture>\u0000<source media=\"(min-width: 1650px)\" srcset=\"/cms/asset/42baaa16-06ed-4c73-a745-641b06f16907/ajh27569-fig-0001-m.jpg\"/><img alt=\"Details are in the caption following the image\" data-lg-src=\"/cms/asset/42baaa16-06ed-4c73-a745-641b06f16907/ajh27569-fig-0001-m.jpg\" loading=\"lazy\" src=\"/cms/asset/75c81c34-f5b8-452b-9e04-cb8948d70b52/ajh27569-fig-0001-m.png\" title=\"Details are in the caption following the image\"/></picture><figcaption>\u0000<div><strong>FIGURE 1<span style=\"font-weight:normal\"></span></strong><div>Open in figure viewer<i aria-hidden=\"true\"></i><span>PowerPoint</span></div>\u0000</div>\u0000<div>UBL and UMB treatment in U2-VEN clinical trial results in rapid loss of CLL cells and CD20 levels. (A) Multi-drug combination targeting three different molecules to overcome single-agent resistance in relapsed/refractory CLL patients. (B) Diagram of U2-VEN clinical study design (ClinicalTrials.gov NCT03379051) [<span>2</span>]. Treatment consists of initially 12 cycles of 28 days. Ublituximab (purple) was administered intravenously on indicated days of first six cycles. Umbralisib (green) was orally administered daily for 12 cycles. Venetoclax was ad","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"340 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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