<p>Additional mutations at chronic myeloid leukemia (CML) diagnosis have been shown to variably affect tyrosine kinase inhibitor (TKI) response [<span>1</span>], and were inconstantly detected at loss of response [<span>2</span>]. Contradictory observations may have resulted from difficulties in reliably inferring CML clonal architecture from mutations quantified by NGS, <i>BCR::ABL1 by qRT-PCR</i>, and ABL1-tyrosine kinase domain (<i>ABL1</i>-TKD) mutations by RNA-Seq. In the RESIDIAG (RESistance molecular markers at DIAGnosis) study, the mutational profile of 117 CML patients (<i>n</i> = 60 responders and <i>n</i> = 57 nonresponders) (Table S1) was analyzed at diagnosis (both groups) and at relapse (nonresponders only) by asymmetric capture sequencing (aCAP-Seq, Table S2) [<span>3</span>] to identify molecular events that predict TKI failure and decipher the clonal architecture and the order of acquisition of mutations relative to <i>BCR</i> and <i>ABL1</i> fusion. This study complied with French regulations and was approved (no. 2019_048) by the Henri Mondor Institutional Review Board (No. 00011558). The study methodologies conformed to the standards set by the Declaration of Helsinki. All patient data were anonymized and de-identified before analysis. Informed consent was obtained from all participants.</p> <p>The median time follow-up of responders was 7.1 years. There were no significant differences in terms of age, sex, CML stage, first-line treatment, additional chromosomal abnormalities (ACA), or first-line therapy between the two groups, while the proportions of patients with high Sokal or The EUTOS long-term survival (ELTS) scores were significantly increased among nonresponders (<i>p</i> < 0.001, Pearson's chi-square test, Table S3). Both ELTS and Sokal scores predicted failure-free survival (<i>p</i> < 0.001, Log-rank test, Figure S1). Patients in both groups were mainly treated first-line with Imatinib (61.5%), Nilotinib (25.6%), or Dasatinib (10.3%). TKI switch before failure analysis was mostly due to first-line intolerance. Blast crisis (BC) progression occurred in eight nonresponders, including four myeloid and four lymphoid BC, with a median time of transformation from diagnosis at 15 months [8.6–24.3 months].</p> <p>At diagnosis, the number of additional mutations per patient was higher in nonresponders (<i>p</i> < 0.001, Pearson's chi-squared test, Table S4), especially in <i>ASXL1, DNMT3A</i>, and <i>TET2</i> referred to as epigenetic genes hereafter (<i>p</i> < 0.001, <i>p</i> = 0.02, <i>p</i> = 0.02, respectively, Pearson's chi-squared test, Figure 1A, Figure S2A,B and Table S4). The average A<i>SXL1</i> mutation VAF in nonresponders (23.6% ± 3.6%, <i>n</i> = 21) were significantly different from the <i>BCR::ABL1</i> frequency (47.9% ± 0.8%, <i>p</i> < 0.0001, Dunnett's multiple comparison test, Figure S2C) suggesting that <i>ASXL1</i> mutant were either CML subclones or clones driving an independent clonal
{"title":"Mutation of Epigenetic Regulators at Diagnosis Is an Independent Predictor of Tyrosine Kinase Inhibitor Treatment Failure in Chronic Myeloid Leukemia: A Report From the RESIDIAG Study","authors":"Hippolyte Guerineau, Jean-Michel Cayuela, Stéphanie Dulucq, Violaine Tran Quang, Sihem Tarfi, Guillaume Gricourt, Quentin Barathon, Corine Joy, Orianne Wagner-Ballon, Stéphane Morisset, Frank-Emmanuel Nicolini, Erika Brunet, Sébastien Maury, Lydia Roy, Gabriel Etienne, Delphine Réa, Ivan Sloma","doi":"10.1002/ajh.27553","DOIUrl":"https://doi.org/10.1002/ajh.27553","url":null,"abstract":"<p>Additional mutations at chronic myeloid leukemia (CML) diagnosis have been shown to variably affect tyrosine kinase inhibitor (TKI) response [<span>1</span>], and were inconstantly detected at loss of response [<span>2</span>]. Contradictory observations may have resulted from difficulties in reliably inferring CML clonal architecture from mutations quantified by NGS, <i>BCR::ABL1 by qRT-PCR</i>, and ABL1-tyrosine kinase domain (<i>ABL1</i>-TKD) mutations by RNA-Seq. In the RESIDIAG (RESistance molecular markers at DIAGnosis) study, the mutational profile of 117 CML patients (<i>n</i> = 60 responders and <i>n</i> = 57 nonresponders) (Table S1) was analyzed at diagnosis (both groups) and at relapse (nonresponders only) by asymmetric capture sequencing (aCAP-Seq, Table S2) [<span>3</span>] to identify molecular events that predict TKI failure and decipher the clonal architecture and the order of acquisition of mutations relative to <i>BCR</i> and <i>ABL1</i> fusion. This study complied with French regulations and was approved (no. 2019_048) by the Henri Mondor Institutional Review Board (No. 00011558). The study methodologies conformed to the standards set by the Declaration of Helsinki. All patient data were anonymized and de-identified before analysis. Informed consent was obtained from all participants.</p>\u0000<p>The median time follow-up of responders was 7.1 years. There were no significant differences in terms of age, sex, CML stage, first-line treatment, additional chromosomal abnormalities (ACA), or first-line therapy between the two groups, while the proportions of patients with high Sokal or The EUTOS long-term survival (ELTS) scores were significantly increased among nonresponders (<i>p</i> < 0.001, Pearson's chi-square test, Table S3). Both ELTS and Sokal scores predicted failure-free survival (<i>p</i> < 0.001, Log-rank test, Figure S1). Patients in both groups were mainly treated first-line with Imatinib (61.5%), Nilotinib (25.6%), or Dasatinib (10.3%). TKI switch before failure analysis was mostly due to first-line intolerance. Blast crisis (BC) progression occurred in eight nonresponders, including four myeloid and four lymphoid BC, with a median time of transformation from diagnosis at 15 months [8.6–24.3 months].</p>\u0000<p>At diagnosis, the number of additional mutations per patient was higher in nonresponders (<i>p</i> < 0.001, Pearson's chi-squared test, Table S4), especially in <i>ASXL1, DNMT3A</i>, and <i>TET2</i> referred to as epigenetic genes hereafter (<i>p</i> < 0.001, <i>p</i> = 0.02, <i>p</i> = 0.02, respectively, Pearson's chi-squared test, Figure 1A, Figure S2A,B and Table S4). The average A<i>SXL1</i> mutation VAF in nonresponders (23.6% ± 3.6%, <i>n</i> = 21) were significantly different from the <i>BCR::ABL1</i> frequency (47.9% ± 0.8%, <i>p</i> < 0.0001, Dunnett's multiple comparison test, Figure S2C) suggesting that <i>ASXL1</i> mutant were either CML subclones or clones driving an independent clonal ","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"141 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797739","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}
Portia Smallbone, Mallika Sekhar, Samer A. Srour, Jeremy L. Ramdial, Crystal L. Carmicheal Kusy, Elizabeth J. Shpall, Uday R. Popat
<p>Myeloproliferative neoplasms (MPN) are associated with increased risk of splanchnic vein thrombosis (SVT), which contributes to morbidity and mortality. SVT, including portal, superior mesenteric, splenic, and hepatic vein thrombosis, disrupts portal pressures, leading to the development of portal hypertension (PHT) and complications such as varices, splenomegaly and liver failure, which increase the morbidity and mortality. The impact of prior SVT on outcomes of patients undergoing allogeneic hematopoietic stem cell transplantation (HCT) for myelofibrosis (MF) is not well understood. Although a small case series found a strong correlation between SVT and hyperbilirubinemia [<span>1</span>], the data is limited, making the optimal management of anticoagulation, hepatic comorbidities, and PHT sequelae challenging in this patient population. This study evaluates the impact of pre-existing SVT and its treatment on transplant outcomes.</p> <p>We screened 334 consecutive patients who underwent HCT for MF at The University of Texas MD Anderson Cancer Center between January 2000 and August 2023 and identified 12 with pre-existing SVT. Patient characteristics, liver and thrombosis-related data, transplant details and outcomes were collected through retrospective review. Model for End-Stage Liver Disease (MELD) scores were calculated using creatinine, bilirubin, INR, and sodium levels to stratify the degree of chronic liver dysfunction. Continuous variables are reported as median and range, while categorical variables as number and percentage. Overall survival was estimated using the Kaplan–Meier method.</p> <p>With regards to patient characteristics, the median age was 53 years (range: 39–73). Five patients had primary MF, four had post-essential thrombocythemia (PET-MF), and three had post-polycythaemia vera (PPV-MF). The majority (<i>n</i> = 8, 66.6%) were JAK2 V617F-positive. One patient was MPL positive. Patients received conditioning regimens based on institutional protocols, considering age and comorbidities. Individual characteristics and outcomes for all patients are summarized in Table 1. Other baseline characteristics are seen in Table S1.</p> <div> <header><span>TABLE 1. </span>Detailed patient characteristics.</header> <div tabindex="0"> <table> <thead> <tr> <th>Patient</th> <th>Age at transplant</th> <th>Sex</th> <th>JAK2 status</th> <th>Additional mutations via NGS</th> <th>Thrombosis type</th> <th>Days SVT prior to transplant</th> <th>Splenectomy prior to thrombosis</th> <th>Yerdel classification</th> <th>Anticoagulation</th> <th>Date of transplant</th> <th>Conditioning regimen</th> </tr> </thead> <tbody> <tr> <td>1</td> <td>40</td> <td>F</td> <td>Positive</td> <td>No</td> <td>Splenic vein thrombosis</td> <td>109</td> <td>No</td> <td>NE</td> <td>No</td> <td>3-Jul-23</td> <td>Bu/Cy</td> </tr> <tr> <td>2</td> <td>70</td> <td>F</td> <td>Positive</td> <td>No</td> <td>Portal vein, SMV and splenic vein thrombosis</td> <td>145</td> <td>Yes</td
{"title":"Hematopoietic Stem Cell Transplantation in Patients With Myelofibrosis and Splanchnic Vein Thrombosis: A Case Series","authors":"Portia Smallbone, Mallika Sekhar, Samer A. Srour, Jeremy L. Ramdial, Crystal L. Carmicheal Kusy, Elizabeth J. Shpall, Uday R. Popat","doi":"10.1002/ajh.27542","DOIUrl":"https://doi.org/10.1002/ajh.27542","url":null,"abstract":"<p>Myeloproliferative neoplasms (MPN) are associated with increased risk of splanchnic vein thrombosis (SVT), which contributes to morbidity and mortality. SVT, including portal, superior mesenteric, splenic, and hepatic vein thrombosis, disrupts portal pressures, leading to the development of portal hypertension (PHT) and complications such as varices, splenomegaly and liver failure, which increase the morbidity and mortality. The impact of prior SVT on outcomes of patients undergoing allogeneic hematopoietic stem cell transplantation (HCT) for myelofibrosis (MF) is not well understood. Although a small case series found a strong correlation between SVT and hyperbilirubinemia [<span>1</span>], the data is limited, making the optimal management of anticoagulation, hepatic comorbidities, and PHT sequelae challenging in this patient population. This study evaluates the impact of pre-existing SVT and its treatment on transplant outcomes.</p>\u0000<p>We screened 334 consecutive patients who underwent HCT for MF at The University of Texas MD Anderson Cancer Center between January 2000 and August 2023 and identified 12 with pre-existing SVT. Patient characteristics, liver and thrombosis-related data, transplant details and outcomes were collected through retrospective review. Model for End-Stage Liver Disease (MELD) scores were calculated using creatinine, bilirubin, INR, and sodium levels to stratify the degree of chronic liver dysfunction. Continuous variables are reported as median and range, while categorical variables as number and percentage. Overall survival was estimated using the Kaplan–Meier method.</p>\u0000<p>With regards to patient characteristics, the median age was 53 years (range: 39–73). Five patients had primary MF, four had post-essential thrombocythemia (PET-MF), and three had post-polycythaemia vera (PPV-MF). The majority (<i>n</i> = 8, 66.6%) were JAK2 V617F-positive. One patient was MPL positive. Patients received conditioning regimens based on institutional protocols, considering age and comorbidities. Individual characteristics and outcomes for all patients are summarized in Table 1. Other baseline characteristics are seen in Table S1.</p>\u0000<div>\u0000<header><span>TABLE 1. </span>Detailed patient characteristics.</header>\u0000<div tabindex=\"0\">\u0000<table>\u0000<thead>\u0000<tr>\u0000<th>Patient</th>\u0000<th>Age at transplant</th>\u0000<th>Sex</th>\u0000<th>JAK2 status</th>\u0000<th>Additional mutations via NGS</th>\u0000<th>Thrombosis type</th>\u0000<th>Days SVT prior to transplant</th>\u0000<th>Splenectomy prior to thrombosis</th>\u0000<th>Yerdel classification</th>\u0000<th>Anticoagulation</th>\u0000<th>Date of transplant</th>\u0000<th>Conditioning regimen</th>\u0000</tr>\u0000</thead>\u0000<tbody>\u0000<tr>\u0000<td>1</td>\u0000<td>40</td>\u0000<td>F</td>\u0000<td>Positive</td>\u0000<td>No</td>\u0000<td>Splenic vein thrombosis</td>\u0000<td>109</td>\u0000<td>No</td>\u0000<td>NE</td>\u0000<td>No</td>\u0000<td>3-Jul-23</td>\u0000<td>Bu/Cy</td>\u0000</tr>\u0000<tr>\u0000<td>2</td>\u0000<td>70</td>\u0000<td>F</td>\u0000<td>Positive</td>\u0000<td>No</td>\u0000<td>Portal vein, SMV and splenic vein thrombosis</td>\u0000<td>145</td>\u0000<td>Yes</td","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"12 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793366","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}
Anita Hill, Christophe Hotermans, Gianluca Pirozzi
<p>Patient safety is paramount and ingrained in our mission at Alexion, and with our leadership in complement biology for over 30 years, we strive to provide the most efficacious and safe therapeutic products for patients. It must be remembered that the most significant risks to patients with paroxysmal nocturnal hemoglobinuria (PNH) come from intravascular hemolysis (IVH) and thrombosis, and these are mediated by terminal complement activity.</p> <p>Risitano et al. details the experience of three patients previously treated with vemircopan monotherapy, who were switched to ravulizumab when the clinical trial NCT04170023 was discontinued [<span>1</span>]. The authors conclude that hemolysis following discontinuation of effective proximal complement inhibitors poses a significant clinical risk that cannot be fully mitigated by switching to C5 inhibitors and recommend pursuing an alternative proximal complement inhibitor. The phenomenon described is expected, having first been seen in the PEGASUS trial where patients were managed supportively with transfusions when necessary [<span>2</span>]. The current correspondence contributes further to the evidence of this phenomenon for patients when they are discontinued from proximal complement inhibition.</p> <p>Terminal complement inhibitors have transformed the natural history of patients suffering from PNH by providing effective disease control over the last two decades with a well-established safety profile. Furthermore, long term efficacy and safety data have demonstrated reduced risk of thrombosis, improved survival rates, and control of IVH with low and less severe rates of breakthrough intravascular hemolysis (BT-IVH) in patients with PNH. The improvement in survival for patients with PNH has been achieved by terminal complement inhibition alone, reinforcing the critical role that terminal complement plays in the progression of this disease.</p> <p>In the phase II, proof of concept study evaluating safety and dosing of vemircopan (a proximal inhibitor) as a monotherapy in patients with PNH (NCT04170023), the trial was terminated due to inadequate and inconsistent IVH control, which results in poor disease outcomes. Lactate dehydrogenase (LDH), a marker of terminal complement activity, was not consistently and sufficiently suppressed amongst all patients resulting in LDH excursions (defined as LDH values > 2× upper limit of normal [ULN]) and unacceptably high rates of BT-IVH. This raised concerns about potential risk for thrombotic events and premature mortality in this group of patients. Control of terminal complement activity and IVH, as reflected by LDH, is the primary aim for patients with PNH to prevent significant morbidity and mortality. In the best interest of patients' safety, the clinical trial was discontinued with due consideration given to availability of terminal complement inhibitors. A manuscript that reports the phase 2 clinical trial results with vemircopan (NCT04170023) is in
{"title":"The Importance of Controlling Terminal Complement Activity and Intravascular Hemolysis in Paroxysmal Nocturnal Hemoglobinuria (PNH)","authors":"Anita Hill, Christophe Hotermans, Gianluca Pirozzi","doi":"10.1002/ajh.27556","DOIUrl":"https://doi.org/10.1002/ajh.27556","url":null,"abstract":"<p>Patient safety is paramount and ingrained in our mission at Alexion, and with our leadership in complement biology for over 30 years, we strive to provide the most efficacious and safe therapeutic products for patients. It must be remembered that the most significant risks to patients with paroxysmal nocturnal hemoglobinuria (PNH) come from intravascular hemolysis (IVH) and thrombosis, and these are mediated by terminal complement activity.</p>\u0000<p>Risitano et al. details the experience of three patients previously treated with vemircopan monotherapy, who were switched to ravulizumab when the clinical trial NCT04170023 was discontinued [<span>1</span>]. The authors conclude that hemolysis following discontinuation of effective proximal complement inhibitors poses a significant clinical risk that cannot be fully mitigated by switching to C5 inhibitors and recommend pursuing an alternative proximal complement inhibitor. The phenomenon described is expected, having first been seen in the PEGASUS trial where patients were managed supportively with transfusions when necessary [<span>2</span>]. The current correspondence contributes further to the evidence of this phenomenon for patients when they are discontinued from proximal complement inhibition.</p>\u0000<p>Terminal complement inhibitors have transformed the natural history of patients suffering from PNH by providing effective disease control over the last two decades with a well-established safety profile. Furthermore, long term efficacy and safety data have demonstrated reduced risk of thrombosis, improved survival rates, and control of IVH with low and less severe rates of breakthrough intravascular hemolysis (BT-IVH) in patients with PNH. The improvement in survival for patients with PNH has been achieved by terminal complement inhibition alone, reinforcing the critical role that terminal complement plays in the progression of this disease.</p>\u0000<p>In the phase II, proof of concept study evaluating safety and dosing of vemircopan (a proximal inhibitor) as a monotherapy in patients with PNH (NCT04170023), the trial was terminated due to inadequate and inconsistent IVH control, which results in poor disease outcomes. Lactate dehydrogenase (LDH), a marker of terminal complement activity, was not consistently and sufficiently suppressed amongst all patients resulting in LDH excursions (defined as LDH values > 2× upper limit of normal [ULN]) and unacceptably high rates of BT-IVH. This raised concerns about potential risk for thrombotic events and premature mortality in this group of patients. Control of terminal complement activity and IVH, as reflected by LDH, is the primary aim for patients with PNH to prevent significant morbidity and mortality. In the best interest of patients' safety, the clinical trial was discontinued with due consideration given to availability of terminal complement inhibitors. A manuscript that reports the phase 2 clinical trial results with vemircopan (NCT04170023) is in ","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"117 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793367","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>β-Thalassemia is characterized by ineffective erythropoiesis (IE), anemia, and iron overload. It involves both intramedullary apoptosis and the destruction of red blood cells (RBCs) owing to membranes developing abnormalities as a result of an excess of unpaired globin chains [<span>1</span>]. RBC destruction caused by IE or hemolysis shortens the lifespan of these cells. Although laboratory indicators can detect increased RBC destruction and compensatory hyperplasia in the bone marrow, studies performed on this to date have primarily relied on surrogate markers instead of direct measurements. Direct quantitative assessment of RBC lifespan is therefore essential for advancing thalassemia research and evaluating treatment strategies.</p> <p>To enhance the interpretation of studies in which surrogate markers of RBC survival in β-thalassemia were used, the correlations between these markers and directly measured data should be clarified. Toward this goal, this report presents a prospective study examining the use of carbon monoxide (CO) breath tests to quantify RBC lifespan in patients with transfusion-dependent β-thalassemia (TDT). We determined the correlations of the obtained data with markers of hemolysis, erythropoiesis, iron regulation, and oxidative stress, and discussed the effects of thalidomide treatment on RBC lifespan in these patients.</p> <p>RBC lifespan was assessed using an automatic device (ELS TESTER; Seekya Biotec Co. Ltd., Shenzhen, China). CO breath tests were conducted at least 2 weeks post-transfusion, after ensuring that the participants had not smoked within 24 h and had an empty stomach. The majority of TDT patients in this study were treated with thalidomide. Patients were informed of its benefits and side effects and warned against becoming pregnant or impregnating a woman while taking the drug. Thalidomide was administered daily at a dose of 100 mg/day for 3 months. Blood transfusion was recommended to maintain hemoglobin levels of > 9.0 g/dL during the treatment. The hematological responses to thalidomide were defined as follows: major response, transfusion independence, and maintenance of hemoglobin level > 9.0 g/dL; minor response, ≥ 50% reduction in transfusion requirement and maintenance of hemoglobin level > 9.0 g/dL; and no response, < 50% reduction in transfusion requirement to maintain a pretransfusion hemoglobin level of 9.0 g/dL.</p> <p>The baseline characteristics of our cohort, consisting of 33 patients with TDT (18 β0/β0, 12 β+/β0, 3 β+/β+), are detailed in Table S1. The median age was 16 years (range 12–37), and 51.5% were male, 36.4% had undergone splenectomy, and 12.1% had co-inherited α-thalassemia. Our findings indicated that RBC lifespan was significantly shorter in patients with TDT than in normal controls, being nearly eight times longer in the latter group (median 15 vs. 119 days, Table S2). Univariate logistic regression analysis revealed no significant factors affecting RBC lifespa
相比之下，无应答者RBC寿命无显著变化(p = 0.688, n = 5；图1 j)。主要应答者（15例）红细胞寿命延长5（−10-31）天，次要应答者（5例）红细胞寿命延长3（−1-11）天。总体而言，血液学反应[5（−10-31）天]的患者红细胞寿命明显长于无反应[1（−2-3）天]的患者；p = 0.037]。此外，血液学应答者治疗后红细胞寿命明显长于基线时（p = 0.003）和无应答者（p = 0.048），尽管仍短于正常对照组(p < 0.001；图S1)。基线和随访期间RBC寿命见表S5。红细胞寿命与溶血、红细胞生成和铁调节指标之间的关系。（A-G）红细胞寿命与总胆红素（r = - 0.570, p = 0.001）、间接胆红素（r = - 0.602, p < 0.001）、乳酸脱氢酶（r = - 0.529, p = 0.002）、促红细胞生成素（r = - 0.467, p = 0.006）、可溶性转铁蛋白受体（r = - 0.642, p = 0.001）呈负相关，与haptoglobin （r = 0.517, p = 0.002）、hepcidin （r = 0.351, p = 0.045）呈正相关。所有患者沙利度胺治疗前后的红细胞寿命(H)，应答者(I)，无应答者(J)。我们还研究了在沙利度胺治疗后，溶血、红细胞生成和铁调节标志物的变化与延长红细胞寿命的关系。延长红细胞寿命与hepcidin的变化呈正相关(r = 0.605, p = 0.001；图S2A)，与sTfR变化呈负相关(r = - 0.625, p = 0.001；图开通)。没有其他参数与红细胞寿命延长显著相关（表S6）。最近的研究表明，测量红细胞寿命可以帮助指导治疗决策，评估药物疗效，并有助于了解贫血和相关疾病背后的机制。一氧化碳呼气试验和血红蛋白测量相结合提供了一种简单、快速、无创的方法来测定红细胞寿命。先前的研究表明，Levitt的CO呼气测试产生的结果可与15N甘氨酸标记技术获得的结果相媲美。我们的研究证实了TDT患者红细胞寿命与溶血、红细胞生成和铁调节标志物之间的相关性。结果表明，红细胞寿命不仅反映溶血的严重程度，而且与红细胞生成和铁调节密切相关。因此，测量红细胞寿命可以提高我们对地中海贫血的认识，并为治疗评估提供信息。β-地中海贫血的主要致病机制是IE，外周溶血是次要因素。这种IE是由珠蛋白链失衡引起的，导致贫血和促红细胞生成素的增加，促红细胞生成素刺激红细胞生成，抑制肝细胞内的hepcidin。这一连串的事件导致肠道铁吸收增加，导致铁超载。事实上，它是TDT患者铁超载的主要原因，与输血并列。人体产生的CO大部分来自红细胞的破坏；其他航线产生的二氧化碳约占总量的30%，这一比例相对固定。鉴于此，并考虑到β-地中海贫血中红细胞破坏主要由IE驱动，我们提出过期CO的浓度可以反映IE的严重程度。目前的研究结果表明，CO呼气试验得出的红细胞寿命与TDT患者的IE和铁调节指标密切相关。因此，以这种方式确定的红细胞寿命可以作为评估β-地中海贫血患者病情和治疗效果的有用指标。传统上，对地中海贫血治疗效果的研究主要集中在血红蛋白水平和输血量的变化上。然而，在我们的队列中，一些对治疗有反应的患者RBC寿命没有显着变化，而少数患者甚至出现了减少。无应答者红细胞寿命的增加反映了应答者的最小改善。虽然沙利度胺治疗延长了红细胞的总寿命，但增加的程度有限，这意味着可能涉及其他机制。换句话说，红细胞寿命的延长并不能完全解释应答者血红蛋白水平的提高。对这些应答者的回顾性分析表明，IBIL、LDH、EPO和hepcidin水平在治疗后没有显著改善，这表明血红蛋白的变化可能不能准确反映应答者的溶血和红细胞生成情况。 监测红细胞寿命可作为溶血变化的一个有价值的指标，也可用于评估红细胞生成和铁调节。我们观察到，治疗后红细胞寿命不仅与血红蛋白增加呈正相关，而且与hepcidin和sTfR的变化密切相关，表明其在评估β-地中海贫血严重程度和治疗效果方面的潜在价值，特别是在临床试验中。总之，本研究提供了一种使用呼气CO来评估地中海贫血患者红细胞寿命的简单易行的方法。我们的研究结果表明，红细胞寿命不仅反映了溶血的严重程度，而且为IE和铁调节提供了见解。重要的是，我们观察到沙利度胺治疗增加了TDT患者的红细胞寿命，尽管程度有限。我们相信分析红细胞寿命将增强我们对地中海贫血和其他贫血的理解，从而促进新治疗方法的评估。
{"title":"Evaluating the Role of Red Blood Cell Lifespan in Transfusion-Dependent β-Thalassemia and Impact of Thalidomide Treatment","authors":"Kun Yang, Yuping Gong, Jian Xiao","doi":"10.1002/ajh.27557","DOIUrl":"https://doi.org/10.1002/ajh.27557","url":null,"abstract":"<p>β-Thalassemia is characterized by ineffective erythropoiesis (IE), anemia, and iron overload. It involves both intramedullary apoptosis and the destruction of red blood cells (RBCs) owing to membranes developing abnormalities as a result of an excess of unpaired globin chains [<span>1</span>]. RBC destruction caused by IE or hemolysis shortens the lifespan of these cells. Although laboratory indicators can detect increased RBC destruction and compensatory hyperplasia in the bone marrow, studies performed on this to date have primarily relied on surrogate markers instead of direct measurements. Direct quantitative assessment of RBC lifespan is therefore essential for advancing thalassemia research and evaluating treatment strategies.</p>\u0000<p>To enhance the interpretation of studies in which surrogate markers of RBC survival in β-thalassemia were used, the correlations between these markers and directly measured data should be clarified. Toward this goal, this report presents a prospective study examining the use of carbon monoxide (CO) breath tests to quantify RBC lifespan in patients with transfusion-dependent β-thalassemia (TDT). We determined the correlations of the obtained data with markers of hemolysis, erythropoiesis, iron regulation, and oxidative stress, and discussed the effects of thalidomide treatment on RBC lifespan in these patients.</p>\u0000<p>RBC lifespan was assessed using an automatic device (ELS TESTER; Seekya Biotec Co. Ltd., Shenzhen, China). CO breath tests were conducted at least 2 weeks post-transfusion, after ensuring that the participants had not smoked within 24 h and had an empty stomach. The majority of TDT patients in this study were treated with thalidomide. Patients were informed of its benefits and side effects and warned against becoming pregnant or impregnating a woman while taking the drug. Thalidomide was administered daily at a dose of 100 mg/day for 3 months. Blood transfusion was recommended to maintain hemoglobin levels of > 9.0 g/dL during the treatment. The hematological responses to thalidomide were defined as follows: major response, transfusion independence, and maintenance of hemoglobin level > 9.0 g/dL; minor response, ≥ 50% reduction in transfusion requirement and maintenance of hemoglobin level > 9.0 g/dL; and no response, < 50% reduction in transfusion requirement to maintain a pretransfusion hemoglobin level of 9.0 g/dL.</p>\u0000<p>The baseline characteristics of our cohort, consisting of 33 patients with TDT (18 β0/β0, 12 β+/β0, 3 β+/β+), are detailed in Table S1. The median age was 16 years (range 12–37), and 51.5% were male, 36.4% had undergone splenectomy, and 12.1% had co-inherited α-thalassemia. Our findings indicated that RBC lifespan was significantly shorter in patients with TDT than in normal controls, being nearly eight times longer in the latter group (median 15 vs. 119 days, Table S2). Univariate logistic regression analysis revealed no significant factors affecting RBC lifespa","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"211 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793293","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}
Anders Blach Naamansen, Dennis Lund Hansen, Jesper Petersen, Andreas Glenthøj, Henrik Toft Sørensen, Henrik Frederiksen
Chronic hemolysis potentially elevates the risk of gallstones in several types of congenital red blood cell (RBC) disorders. However, the magnitude of the risk is unknown. We investigate the risk of gallstone disease in congenital RBC disorder patients, compared with general population comparators. Patients were identified from the Danish National Patient Registry covering all Danish hospitals and the National Reference Laboratory for RBC disorders during 1980–2016. Patients were matched by sex, age, and region of origin with up to 50 general population comparators. Gallstone events were identified using hospital-registered diagnoses and surgery codes. Our study included 9354 congenital RBC disorder patients, grouped according to type of congenital RBC disorder, and 416 994 general population comparators. The cumulative 10-year incidence of gallstone disease was 4.2% in patients with congenital RBC disorders and 1.7% among comparators. Adjusted csHR's [95% confidence interval] were 8.1 [6.8, 9.7] for hereditary spherocytosis; 3.3 [1.6, 6.8] for glucose-6-phosphate dehydrogenase deficiency; 21.6 [10.6, 44.1] for pyruvate kinase deficiency; 3.7 [1.9, 7.0] for sickle cell disease; 0.8 [0.4, 1.6] for sickle cell trait; 1.5 [1.1, 2.2] for α-thalassemia trait; 1.8 [1.4, 2.3] for β-thalassemia minor; and 2.1 [1.8, 2.6] for other congenital hemolysis. We found a markedly higher risk of hospital-registered gallstone diseases in nearly all groups of patients with congenital RBC disorders compared with the general population.
{"title":"10-Year Risk of Gallstones in Congenital Red Blood Cell Disorder Patients: A Nationwide Cohort Study","authors":"Anders Blach Naamansen, Dennis Lund Hansen, Jesper Petersen, Andreas Glenthøj, Henrik Toft Sørensen, Henrik Frederiksen","doi":"10.1002/ajh.27558","DOIUrl":"https://doi.org/10.1002/ajh.27558","url":null,"abstract":"Chronic hemolysis potentially elevates the risk of gallstones in several types of congenital red blood cell (RBC) disorders. However, the magnitude of the risk is unknown. We investigate the risk of gallstone disease in congenital RBC disorder patients, compared with general population comparators. Patients were identified from the Danish National Patient Registry covering all Danish hospitals and the National Reference Laboratory for RBC disorders during 1980–2016. Patients were matched by sex, age, and region of origin with up to 50 general population comparators. Gallstone events were identified using hospital-registered diagnoses and surgery codes. Our study included 9354 congenital RBC disorder patients, grouped according to type of congenital RBC disorder, and 416 994 general population comparators. The cumulative 10-year incidence of gallstone disease was 4.2% in patients with congenital RBC disorders and 1.7% among comparators. Adjusted csHR's [95% confidence interval] were 8.1 [6.8, 9.7] for hereditary spherocytosis; 3.3 [1.6, 6.8] for glucose-6-phosphate dehydrogenase deficiency; 21.6 [10.6, 44.1] for pyruvate kinase deficiency; 3.7 [1.9, 7.0] for sickle cell disease; 0.8 [0.4, 1.6] for sickle cell trait; 1.5 [1.1, 2.2] for α-thalassemia trait; 1.8 [1.4, 2.3] for β-thalassemia minor; and 2.1 [1.8, 2.6] for other congenital hemolysis. We found a markedly higher risk of hospital-registered gallstone diseases in nearly all groups of patients with congenital RBC disorders compared with the general population.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"19 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793365","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>Bruton's tyrosine kinase inhibitors (BTKis) have revolutionized the treatment of chronic lymphocytic leukemia (CLL), with significantly improved outcomes for both treatment-naïve (TN) and relapsed/refractory (R/R) patients. BTKis bind irreversibly to the cysteine 481 (<i>C481</i>) residue of the BTK molecule inhibiting B-cell receptor (BCR)-mediated intracellular signals crucial for CLL-cell survival [<span>1</span>]. Despite its efficacy, long-term BTKi therapy often leads to therapy resistance with subsequent disease progression (DP) [<span>2</span>]. Resistance mechanisms predominantly relate to mutations in <i>BTK</i> gene, particularly the mutation at <i>C481S</i>, which disrupts covalent BTKi binding. Additionally, mutations in phospholipase Cγ2 (<i>PLCG2</i>), which encodes for a downstream effector of BCR signaling, are emerging as significant additional contributors to resistance [<span>3</span>].</p> <p>To comprehensively assess the prevalence and significance of these resistance mechanisms, we conducted a systematic review and meta-analysis to quantify the prevalence of <i>BTK</i> and <i>PLCG2</i> mutations in CLL patients who experience DP while treated with BTKis. We performed a comprehensive search of the PubMed database and manually reviewed abstracts from major hematology conferences (American Society Hematology [ASH] and European Hematology Association [EHA]) to identify relevant studies. The analysis adhered to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines to ensure methodological rigor and transparency [<span>4</span>].</p> <p>Studies were included if they reported upon CLL patients treated with covalent BTKis and reported assessments for <i>BTK</i> and/or <i>PLCG2</i> mutations at DP. Two reviewers (SM and DG) independently performed data extraction, with discrepancies resolved by consensus. The primary outcome was the pooled prevalence of <i>BTK</i> and <i>PLCG2</i> mutations amongst patients with DP while treated with BTKis. A separate analysis compared patients treated with first-generation BTKi (ibrutinib) versus second-generation BTKis (acalabrutinib, zanubrutinib). Cross study heterogeneity was assessed using the chi-squared (<i>χ</i><sup>2</sup>) <i>Q</i> test and the <i>I</i><sup>2</sup> statistic, with an <i>I</i><sup>2</sup> value greater than 50% indicating substantial heterogeneity.</p> <p>Seventeen studies with 724 patients provided data on <i>BTK</i> somatic mutations [<span>2, 3</span>] (Figure S1; Table S1; Supporting Information: References [1–11]). These studies included six post hoc analyses of Phase 3 clinical trials (ALPINE, ELEVATE R/R, RESONATE, RESONATE-2, ILLUMINATE, FLAIR), five Phase 2 trials (PCYC-1122, RESONATE-17, NCT02337829, NCT01500733, NCT03740529 [BRUIN]), and three retrospective multicenter analyses (French Innovative Leukemia Organization [FILO], European Research Initiative on CLL [ERIC], Hungarian Ibrutinib Resistance Analysis Initiative). Addit
{"title":"Prevalence of BTK and PLCG2 Mutations in CLL Patients With Disease Progression on BTK Inhibitor Therapy: A Meta‐Analysis","authors":"Stefano Molica, David Allsup, Diana Giannarelli","doi":"10.1002/ajh.27544","DOIUrl":"https://doi.org/10.1002/ajh.27544","url":null,"abstract":"<p>Bruton's tyrosine kinase inhibitors (BTKis) have revolutionized the treatment of chronic lymphocytic leukemia (CLL), with significantly improved outcomes for both treatment-naïve (TN) and relapsed/refractory (R/R) patients. BTKis bind irreversibly to the cysteine 481 (<i>C481</i>) residue of the BTK molecule inhibiting B-cell receptor (BCR)-mediated intracellular signals crucial for CLL-cell survival [<span>1</span>]. Despite its efficacy, long-term BTKi therapy often leads to therapy resistance with subsequent disease progression (DP) [<span>2</span>]. Resistance mechanisms predominantly relate to mutations in <i>BTK</i> gene, particularly the mutation at <i>C481S</i>, which disrupts covalent BTKi binding. Additionally, mutations in phospholipase Cγ2 (<i>PLCG2</i>), which encodes for a downstream effector of BCR signaling, are emerging as significant additional contributors to resistance [<span>3</span>].</p>\u0000<p>To comprehensively assess the prevalence and significance of these resistance mechanisms, we conducted a systematic review and meta-analysis to quantify the prevalence of <i>BTK</i> and <i>PLCG2</i> mutations in CLL patients who experience DP while treated with BTKis. We performed a comprehensive search of the PubMed database and manually reviewed abstracts from major hematology conferences (American Society Hematology [ASH] and European Hematology Association [EHA]) to identify relevant studies. The analysis adhered to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines to ensure methodological rigor and transparency [<span>4</span>].</p>\u0000<p>Studies were included if they reported upon CLL patients treated with covalent BTKis and reported assessments for <i>BTK</i> and/or <i>PLCG2</i> mutations at DP. Two reviewers (SM and DG) independently performed data extraction, with discrepancies resolved by consensus. The primary outcome was the pooled prevalence of <i>BTK</i> and <i>PLCG2</i> mutations amongst patients with DP while treated with BTKis. A separate analysis compared patients treated with first-generation BTKi (ibrutinib) versus second-generation BTKis (acalabrutinib, zanubrutinib). Cross study heterogeneity was assessed using the chi-squared (<i>χ</i><sup>2</sup>) <i>Q</i> test and the <i>I</i><sup>2</sup> statistic, with an <i>I</i><sup>2</sup> value greater than 50% indicating substantial heterogeneity.</p>\u0000<p>Seventeen studies with 724 patients provided data on <i>BTK</i> somatic mutations [<span>2, 3</span>] (Figure S1; Table S1; Supporting Information: References [1–11]). These studies included six post hoc analyses of Phase 3 clinical trials (ALPINE, ELEVATE R/R, RESONATE, RESONATE-2, ILLUMINATE, FLAIR), five Phase 2 trials (PCYC-1122, RESONATE-17, NCT02337829, NCT01500733, NCT03740529 [BRUIN]), and three retrospective multicenter analyses (French Innovative Leukemia Organization [FILO], European Research Initiative on CLL [ERIC], Hungarian Ibrutinib Resistance Analysis Initiative). Addit","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"37 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788404","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}
Ilenia Di Cola, Léa Savey, Marion Delplanque, Rim Bourguiba, Alessandra Bartoli, Zohra Aknouche, Fatima Bensalek, Isabelle Kone‐Paut, Linda Rossi‐Semerano, Isabelle Melki, Brigitte Bader‐Meunier, Piero Ruscitti, Bénédicte Neven, Pierre Quartier, Guilaine Boursier, Irina Giurgea, Laurence Cuisset, Gilles Grateau, Véronique Hentgen, Sophie Georgin‐Lavialle
<p>Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease worldwide associated with <i>MEFV</i> mutations. Patients display recurrent and self-limited attacks of fever, abdominal and thoracic pain [<span>1</span>]. There is no specific association between anemia and FMF, except that patients with chronic inflammation may have inflammatory microcytic anemia [<span>2</span>]. However, chronic anemia can lead to fatigue, and fatigue is known to be a trigger for FMF attacks [<span>2, 5</span>]. Therefore, patients with fatigue due to anemia may have more flare-ups of the disease and worse quality of life [<span>2</span>]. Iron deficiency can cause fatigue even in the absence of anemia [<span>3</span>]. Fatigue is also commonly reported in FMF [<span>2</span>]. Therefore, it may be beneficial to look for iron deficiency without anemia as one of the curable causes of fatigue in FMF, especially as fatigue may be considered a trigger of their attacks.</p> <p>Although a variety of laboratory assessments of iron status is available, serum ferritin, a circulating protein in equilibrium with tissue ferritin, is the most sensitive and specific test for detecting isolated iron deficiency [<span>4</span>]. However, the assessment of serum ferritin could be biased by the inflammatory background in an acute inflammatory attack of such an autoinflammatory disease because in case of a normal or high rate it may not inform on the real absence of iron deficiency.</p> <p>Our aim was to assess the prevalence of iron deficiency in FMF and its association with clinical features, laboratory parameters, and therapies.</p> <p>From 2016 to 2023, a retrospective evaluation of prospectively followed FMF patients at the French national FMF-reference center was performed to analyze the prevalence of iron deficiency and its association with clinical features, laboratory parameters, and therapies. The presence of iron deficiency was defined according to the ferritin threshold of our hospital laboratory (ferritin < 27.0 ng/mL), thus, homogeneously collected and measured. Ferritin levels were collected from medical records of follow-up visits. Considering the retrospective nature of our study, we collected what reported in clinical chart of patients; however, some relevant parameters (i.e., transferrin saturation, serum transferrin receptor levels) were not included in the analyses since they are not performed in routine care.</p> <p>All FMF displayed two pathogenic exon 10 <i>MEFV</i> mutations either M694V (pMet694Val) and/or M694I (pMet694Ile). After collection of informed consents, we extracted data from the Juvenile Inflammatory Rheumatism (JIR) cohort, an international multicentric data repository authorized by the National Commission on Informatics and Liberties (CNIL, authorization number 914677).</p> <p>For the statistics, clinical features were exploratively compared, according to the presence of iron deficiency (ferritin < 27.0 ng/m
{"title":"Iron Deficiency in Familial Mediterranean Fever: A Study on 211 Adult Patients From the JIR Cohort","authors":"Ilenia Di Cola, Léa Savey, Marion Delplanque, Rim Bourguiba, Alessandra Bartoli, Zohra Aknouche, Fatima Bensalek, Isabelle Kone‐Paut, Linda Rossi‐Semerano, Isabelle Melki, Brigitte Bader‐Meunier, Piero Ruscitti, Bénédicte Neven, Pierre Quartier, Guilaine Boursier, Irina Giurgea, Laurence Cuisset, Gilles Grateau, Véronique Hentgen, Sophie Georgin‐Lavialle","doi":"10.1002/ajh.27549","DOIUrl":"https://doi.org/10.1002/ajh.27549","url":null,"abstract":"<p>Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease worldwide associated with <i>MEFV</i> mutations. Patients display recurrent and self-limited attacks of fever, abdominal and thoracic pain [<span>1</span>]. There is no specific association between anemia and FMF, except that patients with chronic inflammation may have inflammatory microcytic anemia [<span>2</span>]. However, chronic anemia can lead to fatigue, and fatigue is known to be a trigger for FMF attacks [<span>2, 5</span>]. Therefore, patients with fatigue due to anemia may have more flare-ups of the disease and worse quality of life [<span>2</span>]. Iron deficiency can cause fatigue even in the absence of anemia [<span>3</span>]. Fatigue is also commonly reported in FMF [<span>2</span>]. Therefore, it may be beneficial to look for iron deficiency without anemia as one of the curable causes of fatigue in FMF, especially as fatigue may be considered a trigger of their attacks.</p>\u0000<p>Although a variety of laboratory assessments of iron status is available, serum ferritin, a circulating protein in equilibrium with tissue ferritin, is the most sensitive and specific test for detecting isolated iron deficiency [<span>4</span>]. However, the assessment of serum ferritin could be biased by the inflammatory background in an acute inflammatory attack of such an autoinflammatory disease because in case of a normal or high rate it may not inform on the real absence of iron deficiency.</p>\u0000<p>Our aim was to assess the prevalence of iron deficiency in FMF and its association with clinical features, laboratory parameters, and therapies.</p>\u0000<p>From 2016 to 2023, a retrospective evaluation of prospectively followed FMF patients at the French national FMF-reference center was performed to analyze the prevalence of iron deficiency and its association with clinical features, laboratory parameters, and therapies. The presence of iron deficiency was defined according to the ferritin threshold of our hospital laboratory (ferritin < 27.0 ng/mL), thus, homogeneously collected and measured. Ferritin levels were collected from medical records of follow-up visits. Considering the retrospective nature of our study, we collected what reported in clinical chart of patients; however, some relevant parameters (i.e., transferrin saturation, serum transferrin receptor levels) were not included in the analyses since they are not performed in routine care.</p>\u0000<p>All FMF displayed two pathogenic exon 10 <i>MEFV</i> mutations either M694V (pMet694Val) and/or M694I (pMet694Ile). After collection of informed consents, we extracted data from the Juvenile Inflammatory Rheumatism (JIR) cohort, an international multicentric data repository authorized by the National Commission on Informatics and Liberties (CNIL, authorization number 914677).</p>\u0000<p>For the statistics, clinical features were exploratively compared, according to the presence of iron deficiency (ferritin < 27.0 ng/m","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"35 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788403","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}
Marion Divoux, Matthieu Resche-Rigon, David Michonneau, Aurélien Sutra Del Galy, Nathalie Dhedin, Alienor Xhaard, Flore Sicre de Fontbrune, Marie Robin, Gérard Socié, Régis Peffault de Latour
Graft-versus-host disease (GvHD) is a frequent complication of hematopoietic stem cell transplantation (HSCT) and remains among the leading causes of post-transplant morbidity and mortality. Acute GvHD (aGvHD) affects 30%–50% of HSCT patients, while chronic GvHD (cGvHD) affects 30%–70%. In vivo T depletion using rabbit antithymocyte globulins (ATG) during conditioning has been shown to reduce the occurrence of both aGvHD and cGvHD, with no impact on overall survival (OS) or relapse [1]. Among available antihuman lymphocytes serums, ATG (Thymoglobulin; Sanofi-Genzyme, Saint-Germain-en-Laye, France) and ATG Fresenius (ATLG) (Grafalon; Neovii, Rapperswil-Jona, Switzerland) can be used as GvHD prophylaxis.
In myeloablative conditioning (MAC), ATG infusion is correlated with a significant reduction in aGvHD and cGvHD, with no impact on OS, relapse, disease-free survival (DFS), or non-relapse mortality (NRM). However, initial trials using a high dose of ATG reported an increased rate of lethal viral infections [2], such as cytomegalovirus (CMV) or Epstein–Barr virus (EBV).
Since little real-life data has been reported so far, we aimed to study the impact of ATLG on a long-term real-life perspective in unrelated transplantation after MAC.
{"title":"Antihuman T Lymphocyte Globulin Fresenius in Graft-Versus-Host Disease Prophylaxis for Unrelated Hematopoietic Stem Cell Transplantation After Myeloablative Conditioning: A Long-Term Real-Life Retrospective Study","authors":"Marion Divoux, Matthieu Resche-Rigon, David Michonneau, Aurélien Sutra Del Galy, Nathalie Dhedin, Alienor Xhaard, Flore Sicre de Fontbrune, Marie Robin, Gérard Socié, Régis Peffault de Latour","doi":"10.1002/ajh.27541","DOIUrl":"https://doi.org/10.1002/ajh.27541","url":null,"abstract":"<p>Graft-versus-host disease (GvHD) is a frequent complication of hematopoietic stem cell transplantation (HSCT) and remains among the leading causes of post-transplant morbidity and mortality. Acute GvHD (aGvHD) affects 30%–50% of HSCT patients, while chronic GvHD (cGvHD) affects 30%–70%. In vivo T depletion using rabbit antithymocyte globulins (ATG) during conditioning has been shown to reduce the occurrence of both aGvHD and cGvHD, with no impact on overall survival (OS) or relapse [<span>1</span>]. Among available antihuman lymphocytes serums, ATG (Thymoglobulin; Sanofi-Genzyme, Saint-Germain-en-Laye, France) and ATG Fresenius (ATLG) (Grafalon; Neovii, Rapperswil-Jona, Switzerland) can be used as GvHD prophylaxis.</p>\u0000<p>In myeloablative conditioning (MAC), ATG infusion is correlated with a significant reduction in aGvHD and cGvHD, with no impact on OS, relapse, disease-free survival (DFS), or non-relapse mortality (NRM). However, initial trials using a high dose of ATG reported an increased rate of lethal viral infections [<span>2</span>], such as cytomegalovirus (CMV) or Epstein–Barr virus (EBV).</p>\u0000<p>Since little real-life data has been reported so far, we aimed to study the impact of ATLG on a long-term real-life perspective in unrelated transplantation after MAC.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"82 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763185","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}
Silvia Mangiacavalli, Paolo Milani, Claudio Salvatore Cartia, Marzia Varettoni, Michele Palumbo, Marco Basset, Valeria Masoni, Mario Nuvolone, Andrea Foli, Virginia Valeria Ferretti, Giampaolo Merlini, Luca Arcaini, Giovanni Palladini
Biomarker-based screening enables early detection of AL amyloidosis in intermediate/high-risk MGUS patients. Our study shows that identifying pre-symptomatic AL through biomarker longitudinal monitoring allows early treatment, leading to significant organ function recovery.
{"title":"Feasibility of a Biomarker-Based Screening for Pre-Symptomatic AL Amyloidosis in Patients With Intermediate/High-Risk MGUS","authors":"Silvia Mangiacavalli, Paolo Milani, Claudio Salvatore Cartia, Marzia Varettoni, Michele Palumbo, Marco Basset, Valeria Masoni, Mario Nuvolone, Andrea Foli, Virginia Valeria Ferretti, Giampaolo Merlini, Luca Arcaini, Giovanni Palladini","doi":"10.1002/ajh.27545","DOIUrl":"https://doi.org/10.1002/ajh.27545","url":null,"abstract":"Biomarker-based screening enables early detection of AL amyloidosis in intermediate/high-risk MGUS patients. Our study shows that identifying pre-symptomatic AL through biomarker longitudinal monitoring allows early treatment, leading to significant organ function recovery.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"46 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763367","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：