American Journal of Hematology最新文献

{"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":"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><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 dev","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 3","pages":"505-506"},"PeriodicalIF":10.1,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27556","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"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><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 lifespan, ","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 3","pages":"501-504"},"PeriodicalIF":10.1,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27557","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"10-Year Risk of Gallstones in Congenital Red Blood Cell Disorder Patients: A Nationwide Cohort Study","authors":"Anders Blach Naamansen,&nbsp;Dennis Lund Hansen,&nbsp;Jesper Petersen,&nbsp;Andreas Glenthøj,&nbsp;Henrik Toft Sørensen,&nbsp;Henrik Frederiksen","doi":"10.1002/ajh.27558","DOIUrl":"10.1002/ajh.27558","url":null,"abstract":"<div>\u0000 \u0000 <p>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.</p>\u0000 </div>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 2","pages":"229-235"},"PeriodicalIF":10.1,"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}

{"title":"Prevalence of BTK and PLCG2 Mutations in CLL Patients With Disease Progression on BTK Inhibitor Therapy: A Meta-Analysis","authors":"Stefano Molica,&nbsp;David Allsup,&nbsp;Diana Giannarelli","doi":"10.1002/ajh.27544","DOIUrl":"10.1002/ajh.27544","url":null,"abstract":"&lt;p&gt;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 (&lt;i&gt;C481&lt;/i&gt;) residue of the BTK molecule inhibiting B-cell receptor (BCR)-mediated intracellular signals crucial for CLL-cell survival [&lt;span&gt;1&lt;/span&gt;]. Despite its efficacy, long-term BTKi therapy often leads to therapy resistance with subsequent disease progression (DP) [&lt;span&gt;2&lt;/span&gt;]. Resistance mechanisms predominantly relate to mutations in &lt;i&gt;BTK&lt;/i&gt; gene, particularly the mutation at &lt;i&gt;C481S&lt;/i&gt;, which disrupts covalent BTKi binding. Additionally, mutations in phospholipase Cγ2 (&lt;i&gt;PLCG2&lt;/i&gt;), which encodes for a downstream effector of BCR signaling, are emerging as significant additional contributors to resistance [&lt;span&gt;3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;To comprehensively assess the prevalence and significance of these resistance mechanisms, we conducted a systematic review and meta-analysis to quantify the prevalence of &lt;i&gt;BTK&lt;/i&gt; and &lt;i&gt;PLCG2&lt;/i&gt; 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 [&lt;span&gt;4&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Studies were included if they reported upon CLL patients treated with covalent BTKis and reported assessments for &lt;i&gt;BTK&lt;/i&gt; and/or &lt;i&gt;PLCG2&lt;/i&gt; 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 &lt;i&gt;BTK&lt;/i&gt; and &lt;i&gt;PLCG2&lt;/i&gt; 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 (&lt;i&gt;χ&lt;/i&gt;\u0000 &lt;sup&gt;2&lt;/sup&gt;) &lt;i&gt;Q&lt;/i&gt; test and the &lt;i&gt;I&lt;/i&gt;\u0000 &lt;sup&gt;2&lt;/sup&gt; statistic, with an &lt;i&gt;I&lt;/i&gt;\u0000 &lt;sup&gt;2&lt;/sup&gt; value greater than 50% indicating substantial heterogeneity.&lt;/p&gt;&lt;p&gt;Seventeen studies with 724 patients provided data on &lt;i&gt;BTK&lt;/i&gt; somatic mutations [&lt;span&gt;2, 3&lt;/span&gt;] (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 Re","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 2","pages":"334-337"},"PeriodicalIF":10.1,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27544","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iron Deficiency in Familial Mediterranean Fever: A Study on 211 Adult Patients From the JIR Cohort","authors":"Ilenia Di Cola,&nbsp;Léa Savey,&nbsp;Marion Delplanque,&nbsp;Rim Bourguiba,&nbsp;Alessandra Bartoli,&nbsp;Zohra Aknouche,&nbsp;Fatima Bensalek,&nbsp;Isabelle Kone-Paut,&nbsp;Linda Rossi-Semerano,&nbsp;Isabelle Melki,&nbsp;Brigitte Bader-Meunier,&nbsp;Piero Ruscitti,&nbsp;Bénédicte Neven,&nbsp;Pierre Quartier,&nbsp;Guilaine Boursier,&nbsp;Irina Giurgea,&nbsp;Laurence Cuisset,&nbsp;Gilles Grateau,&nbsp;Véronique Hentgen,&nbsp;Sophie Georgin-Lavialle","doi":"10.1002/ajh.27549","DOIUrl":"10.1002/ajh.27549","url":null,"abstract":"<p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 2","pages":"310-313"},"PeriodicalIF":10.1,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27549","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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,&nbsp;Matthieu Resche-Rigon,&nbsp;David Michonneau,&nbsp;Aurélien Sutra Del Galy,&nbsp;Nathalie Dhedin,&nbsp;Alienor Xhaard,&nbsp;Flore Sicre de Fontbrune,&nbsp;Marie Robin,&nbsp;Gérard Socié,&nbsp;Régis Peffault de Latour","doi":"10.1002/ajh.27541","DOIUrl":"10.1002/ajh.27541","url":null,"abstract":"&lt;p&gt;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 [&lt;span&gt;1&lt;/span&gt;]. 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.&lt;/p&gt;&lt;p&gt;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 [&lt;span&gt;2&lt;/span&gt;], such as cytomegalovirus (CMV) or Epstein–Barr virus (EBV).&lt;/p&gt;&lt;p&gt;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.&lt;/p&gt;&lt;p&gt;We conducted a long-term single-center retrospective study to evaluate ATLG in HSCT from an unrelated donor after MAC. aGvHD CI at D100 was 46% for Grades II–IV and 15% for Grades III and IV. At 2 years, cGvHD CI was 35% for all grades and 17% for moderate/severe. CI of Infection was high, including fungal and viral infections in 21% and 87%, respectively. Infection was the second cause of death after relapse. The 5-year OS was 72%.&lt;/p&gt;&lt;p&gt;In vivo T-cell depletion for HSCT remains controversial. ATG was associated with a lower risk of extensive cGvHD, but a higher risk of CMV reactivation. In our population, the D100-CI of aGvHD was similar than in the no-ATLG or &lt;i&gt;placebo&lt;/i&gt; arms of prospective trials evaluating ATLG in matched unrelated transplantation with MAC [&lt;span&gt;3, 4&lt;/span&gt;]. Because of the young median age and the significant proportion of ALL, our population included 67% of TBI, increasing aGvHD, which could at least partly explain the higher-than-expected rate of cGvHD.&lt;/p&gt;&lt;p&gt;The CI of cGvHD at 2 years in our population was higher than in the ATLG versus &lt;i&gt;placebo&lt;/i&gt; trial [&lt;span&gt;3&lt;/span&gt;]. However, our population was particularly at risk, with only 63.7% of patients in first complete remission after first-line therapy, 95% peripheral HSCT graft, and 21% HLA-mismatched donor. Moreover, HLA matching was determined at 10 alleles in our population versus eight alleles in the no-ATLG study.&lt;/p&gt;&lt;p&gt;Despite the absence of control group, our high incidence of infections confirms that ATLG is associated with an increased risk of infections, especially viral and fungal. No major delay in immune reconstitution was observed. Most fungal infections occurred here before D3","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 2","pages":"330-333"},"PeriodicalIF":10.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27541","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Feasibility of a Biomarker-Based Screening for Pre-Symptomatic AL Amyloidosis in Patients With Intermediate/High-Risk MGUS","authors":"Silvia Mangiacavalli,&nbsp;Paolo Milani,&nbsp;Claudio Salvatore Cartia,&nbsp;Marzia Varettoni,&nbsp;Michele Palumbo,&nbsp;Marco Basset,&nbsp;Valeria Masoni,&nbsp;Mario Nuvolone,&nbsp;Andrea Foli,&nbsp;Virginia Valeria Ferretti,&nbsp;Giampaolo Merlini,&nbsp;Luca Arcaini,&nbsp;Giovanni Palladini","doi":"10.1002/ajh.27545","DOIUrl":"10.1002/ajh.27545","url":null,"abstract":"<p>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.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 2","pages":"342-345"},"PeriodicalIF":10.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27545","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overall Survival in Male Patients With Advanced Hematological Disease (Mostly Acute Leukemia) Is Influenced by CYP1B1 C432G Polymorphism and Donor Sex in Allogeneic Stem Cell Transplantation","authors":"Norbert Stute,&nbsp;Michael Koldehoff","doi":"10.1002/ajh.27538","DOIUrl":"10.1002/ajh.27538","url":null,"abstract":"&lt;p&gt;Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic key enzyme involved in estrogen metabolism, steroid synthesis, and pro-carcinogen activation. &lt;i&gt;CYP1B1&lt;/i&gt; is strongly overexpressed in multiple human malignancies and has been used as a target for cancer chemotherapy and immunotherapy. &lt;i&gt;CYP1B1&lt;/i&gt; is also overexpressed in acute lymphocytic leukemia, acute myeloid leukemia, lymphoma, and myeloma [&lt;span&gt;1&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;In allogeneic hematopoietic stem cell transplantation (HSCT), disease stage is an established risk factor for overall survival [&lt;span&gt;2&lt;/span&gt;]. Our cohort of 118 male patients with advanced disease consisted of advanced forms and stages of AML (&lt;i&gt;n&lt;/i&gt; = 47), ALL (&lt;i&gt;n&lt;/i&gt; = 17), MDS (&lt;i&gt;n&lt;/i&gt; = 12), myeloma (&lt;i&gt;n&lt;/i&gt; = 10), CML (&lt;i&gt;n&lt;/i&gt; = 9), NHL (&lt;i&gt;n&lt;/i&gt; = 8), OMF (&lt;i&gt;n&lt;/i&gt; = 6), CLL (&lt;i&gt;n&lt;/i&gt; = 6), and CMML (&lt;i&gt;n&lt;/i&gt; = 3).&lt;/p&gt;&lt;p&gt;In our recent paper of 382 patients who underwent allogeneic HSCT, we reported a lower overall survival (OS) in male patients with advanced disease (AD) associated with mutant &lt;i&gt;CYP1B1&lt;/i&gt; Leu432Val polymorphism (&lt;i&gt;n&lt;/i&gt; = 118, &lt;i&gt;p&lt;/i&gt; = 0.002): OS 44% ± 8% (CC) vs. 32% ± 6% (CG) vs. 6% ± 6% (GG). Multivariate analysis for OS in male patients with AD revealed &lt;i&gt;CYP1B1&lt;/i&gt; polymorphism as the only prognostic factor: RR 1.78, &lt;i&gt;p&lt;/i&gt; = 0.001 [&lt;span&gt;1&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;We then tested whether donor sex played a role in the outcome of this subgroup of patients and found a surprising result. In our original study we investigated the outcome of male patients with advanced disease (&lt;i&gt;n&lt;/i&gt; = 118) and results were stratified by donor sex: male (&lt;i&gt;n&lt;/i&gt; = 93) versus female (&lt;i&gt;n&lt;/i&gt; = 25). We did not find a major difference in this subgroup of patients by sex mismatch, see supplementary results [&lt;span&gt;1&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;An interesting and very different picture emerges when recipient &lt;i&gt;CYP1B1&lt;/i&gt; polymorphism (R SNP) data is included in the analysis and the results are stratified by donor sex. In the case of male patients with AD and male donors, the estimated 5-year OS was 47% (wildtype, wt) versus 21% (mutant, mut). Median OS was reached after 4.5 versus 1.2 years (Figure 1A), &lt;i&gt;p&lt;/i&gt; = 0.002 (log-rank). For female donors the estimated 5-year OS was 30% (wt) versus 47% (mut) and median OS was reached after 0.6 versus 2.2 years (Figure 1B), not significant. While OS is similar in case of sex mismatch, the difference in OS between wt and mut SNP is biggest if the donor is male. Patients with wt SNP have significantly better results regarding OS with a male donor (&lt;i&gt;n&lt;/i&gt; = 93), and worse with a female donor (&lt;i&gt;n&lt;/i&gt; = 25). In patients with mut SNP both donor sexes perform poorly. The main finding of our recent analysis (mut R SNP does worse in male patients with advanced disease compared to wt R SNP) is especially true if the donor is male and less so when the donor is female (sex mismatch). There was no difference between mut and wt SNP in male patients with early disease irrespective of the do","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 2","pages":"323-325"},"PeriodicalIF":10.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27538","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methotrexate Versus Mycophenolate Mofetil Prophylaxis in Allogeneic Hematopoietic Cell Transplantation for Chronic Myeloid Malignancies: A Retrospective Analysis on Behalf of the Chronic Malignancies Working Party of the EBMT","authors":"Thomas Luft,&nbsp;Luuk Gras,&nbsp;Linda Koster,&nbsp;Nicolaus Kröger,&nbsp;Thomas Schröder,&nbsp;Uwe Platzbecker,&nbsp;Katja Sockel,&nbsp;Régis Peffault de Latour,&nbsp;Matthias Stelljes,&nbsp;Henrik Sengeloev,&nbsp;Matthias Eder,&nbsp;Igor Wolfgang Blau,&nbsp;Peter Dreger,&nbsp;Ibrahim Yakoub-Agha,&nbsp;Johan Maertens,&nbsp;Urpu Salmenniemi,&nbsp;Wolfgang Bethge,&nbsp;Stephan Mielke,&nbsp;Guido Kobbe,&nbsp;Anastasia Pouli,&nbsp;Liesbeth C. de Wreede,&nbsp;Kavita Raj,&nbsp;Joanna Drozd-Sokolowska,&nbsp;Donal P. McLornan,&nbsp;Marie Robin","doi":"10.1002/ajh.27531","DOIUrl":"10.1002/ajh.27531","url":null,"abstract":"<div>\u0000 \u0000 <p>Prophylaxis strategies for Graft versus host disease (GVHD) in allogeneic hematopoietic cell transplantation (allo-HCT) frequently encompass a combination of a calcineurin inhibitor (CNI) with either methotrexate (MTX) or mycophenolate mofetil (MMF). The aim of this retrospective, EBMT registry-based study was to determine outcome differences for chronic myeloid malignancies and secondary acute myeloid leukemia (sAML) between MTX- and MMF-based prophylaxis regimens while taking potential heterogeneity between subgroups into consideration. Eligible were patients transplanted between 2007 and 2017 who received either MTX- or MMF prophylaxis in combination with a CNI. Endpoints after allo-HCT were overall survival, relapse-free survival (RFS), relapse incidence, non-relapse mortality (NRM), and Grades 2–4 acute GVHD (aGvHD). Overall, 13 699 patients from 321 centers were included. Median follow-up was 42.8 months (IQR 19.8–74.5 months). MTX prophylaxis was associated with reduced overall mortality (HR 0.87, 95% CI 0.81–0.95, <i>p</i> = 0.001) and NRM (HR 0.86, 95% CI 0.78–0.96, <i>p</i> = 0.006) compared with MMF in multivariable Cox regression models in the whole cohort without significant interaction between prophylaxis and subgroups. In contrast, there was no significant association of prophylaxis with risk of relapse (HR 1.03 MTX vs. MMF, 95% CI 0.94–1.14, <i>p</i> = 0.53) or RFS (HR 0.95, 95% CI 0.88–1.01, <i>p</i> = 0.12). There was a reduced risk of Grades 2–4 acute GVHD and reduced mortality after acute GVHD with MTX prophylaxis but no association with outcome in a landmark analysis in patients without aGvHD at 3 months after allo-HCT. In conclusion, MTX-complemented CNI prophylaxis was associated with favorable survival, and with favorable survival after aGVHD compared with MMF.</p>\u0000 </div>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 1","pages":"38-51"},"PeriodicalIF":10.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738065","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}

{"title":"Autologous and Allogeneic Stem-Cell Transplantation for Transformed Waldenström Macroglobulinemia","authors":"Eric Durot,&nbsp;Lukshe Kanagaratnam,&nbsp;Saurabh Zanwar,&nbsp;Adrienne Kaufman,&nbsp;Shirley D'Sa,&nbsp;Elise Toussaint,&nbsp;Damien Roos-Weil,&nbsp;Miguel Alcoceba,&nbsp;Josephine M. I. Vos,&nbsp;Anne-Sophie Michallet,&nbsp;Dipti Talaulikar,&nbsp;Efstathios Kastritis,&nbsp;Jahanzaib Khwaja,&nbsp;Steven P. Treon,&nbsp;Ramon Garcia-Sanz,&nbsp;Pierre Morel,&nbsp;Javier Munoz,&nbsp;Jorge J. Castillo,&nbsp;Prashant Kapoor,&nbsp;Alain Delmer","doi":"10.1002/ajh.27543","DOIUrl":"10.1002/ajh.27543","url":null,"abstract":"&lt;p&gt;Waldenström macroglobulinemia (WM) is characterized by a clonal proliferation of plasmacytoid B-cells in the bone marrow and monoclonal IgM gammopathy, that ultimately require treatment in symptomatic patients. Moreover, a small subset of patients undergoes histological transformation (HT) [&lt;span&gt;1&lt;/span&gt;], mainly in the form of diffuse large B-cell lymphoma (DLBCL). They usually present with high-risk features, such as extranodal involvement, advanced stage, and elevated serum lactate dehydrogenase (LDH) [&lt;span&gt;2&lt;/span&gt;]. Immunochemotherapy (ICT) using anti-CD20 antibodies is commonly used for HT-WM patients, in line with the treatment paradigm for DLBCL. However, the response rates remain low for patients with HT-WM, and the median survival after HT is short (1.5–2.7 years). The role of hematopoietic stem-cell transplantation (HSCT) as consolidation therapy in HT-WM for fit patients is unknown. Data regarding the use of auto and allo-HSCT in transformed indolent lymphomas is limited to retrospective studies of small patient series with heterogeneous populations in terms of the antecedent histologies (predominantly transformed follicular lymphoma), the timing of HSCT (upfront or salvage), or the conditioning regimen. No dedicated study has specifically examined the outcome of patients with HT-WM who received HSCT.&lt;/p&gt;&lt;p&gt;In this context, results of a large, retrospective, multicenter, international study investigating the clinical course of patients with HT-WM who underwent autologous (auto-HSCT) or allogeneic (allo-HSCT) transplantation are reported here.&lt;/p&gt;&lt;p&gt;The database collected, comprising 283 patients with HT-WM, treated between January 1995 and December 2021, was compiled through a retrospective investigation of relevant cases in 20 French centers and 9 from other countries. The study protocol was conducted according to the Declaration of Helsinki.&lt;/p&gt;&lt;p&gt;Response rates were based on positron emission tomography (PET)-scan, according to the Lugano 2014 classification, as addressed by the treating physician (or computed tomography if a PET-scan was not performed). The primary endpoint was overall survival (OS), calculated from the date of HSCT until death from any cause or last follow-up (FU). Progression-free survival (PFS) was calculated from the date of HSCT to relapse, progression, death, or last FU. Other secondary endpoints were the rates of relapse/progression and non-relapse mortality (NRM). PFS and OS probabilities were calculated using Kaplan–Meier estimates and compared using log-rank test. Univariate and multivariate analyses were performed for the cohort of patients who received auto-HSCT fitting Cox proportional-hazard regression models for OS and PFS.&lt;/p&gt;&lt;p&gt;To study the added utility of auto-HSCT after a complete response (CR) to initial ICT, a cohort of 34 patients younger than 70 years, in CR after first-line therapy for HT-WM without HSCT was used. In this comparison, PFS and OS were calculated from the date of HT-WM d","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 2","pages":"338-341"},"PeriodicalIF":10.1,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27543","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142713083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}