American Journal of Hematology最新文献

{"title":"Elderly Patients With Aplastic Anemia: Treatment Patterns and Outcomes in the Real World","authors":"Bruno Fattizzo,&nbsp;Carmelo Gurnari,&nbsp;Sabrina Giammarco,&nbsp;Antony Ricchiuti,&nbsp;Hussein Awada,&nbsp;Marta Bortolotti,&nbsp;Nicole Galli,&nbsp;Giacinto Luca Pedone,&nbsp;Francesco Versino,&nbsp;Dario Consonni,&nbsp;Roochi Trikha,&nbsp;Shreyans Gandhi,&nbsp;Simona Sica,&nbsp;Jaroslaw P. Maciejewski,&nbsp;Austin Kulasekararaj,&nbsp;Wilma Barcellini","doi":"10.1002/ajh.27611","DOIUrl":"10.1002/ajh.27611","url":null,"abstract":"<p>We retrospectively analyzed a large international cohort of 1113 patients with aplastic anemia to evaluate treatment choice and outcome in elderly patients as compared with a younger population. Overall, 319 (29%) patients were &gt; 60 years old at diagnosis (60–64 years (<i>n</i> = 85), 106 65–69 years (<i>n</i> = 106), and 128 &gt; 70 years (<i>n</i> = 128)). Elderly patients showed a more severe thrombocytopenia at onset and a significantly lower overall response (complete plus partial) to first-line therapy at 6 months as compared to younger patients (47% vs. 65%, <i>p</i> &lt; 0.0001), irrespective of treatment modality (ATG or CyA combinations, eltrombopag, or androgens); 27 (8%) received transplant as second line therapy and 11 (41%) died, mainly due to transplant complications. The rate of evolution to MDS was greater in elderly patients (12% vs. 7% in younger AA, <i>p</i> = 0.002), whilst the rate of evolution to AML was similar (1.8 vs. 1.3%). By multivariable analysis, older age remained the main factor associated with mortality [HR 1.64 (95% CI 1.5–1.7), <i>p</i> &lt; 0.001], followed by disease severity by Camitta classification [HR 2.24 (95% CI 1.6–3.1) for severe AA; HR 3.8 (95% CI 2.4–6) for very severe AA], and male gender [1.45 (95% CI 1.1–1.8), <i>p</i> &lt; 0.001]. In this large study, elderly AA was associated with inferior outcome even in the TPO-RA era, highlighting the need for further optimization of clinical management.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 4","pages":"584-591"},"PeriodicalIF":10.1,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27611","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055300","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":"Chronic Lymphocytic Leukemia: 2025 Update on the Epidemiology, Pathogenesis, Diagnosis, and Therapy","authors":"Michael Hallek","doi":"10.1002/ajh.27546","DOIUrl":"10.1002/ajh.27546","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Disease Overview&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Chronic lymphocytic leukemia (CLL) is the most frequent type of leukemia. It typically occurs in older patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that interfere with the regulation of proliferation and apoptosis in clonal B-cells.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Diagnosis&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B-lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen as well as typical B-cell markers.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Prognosis and Staging&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Two clinical staging systems, Rai and Binet, provide prognostic information by using the results of physical examination and blood counts. Various biological and genetic markers provide additional prognostic information. Deletions of the short arm of chromosome 17 (del(17p)) and/or mutations of the &lt;i&gt;TP53&lt;/i&gt; gene predict a shorter time to progression with most targeted therapies. The CLL international prognostic index (CLL-IPI) integrates genetic, biological, and clinical variables to identify distinct risk groups of patients with CLL. The CLL-IPI retains its significance in the era of targeted agents, but the overall prognosis of CLL patients with high-risk stages has improved.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Therapy&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Only patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. When treatment is indicated, several therapeutic options exist: combinations of the BCL2 inhibitor venetoclax with obinutuzumab, or venetoclax with ibrutinib, or monotherapy with one of the inhibitors of Bruton tyrosine kinase (BTK). At relapse, the initial treatment may be repeated if the treatment-free interval exceeds 3 years. If the leukemia relapses earlier, therapy should be changed using an alternative regimen.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Future Challenges&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Combinations of targeted agents now provide efficient therapies with a fixed duration that generate deep and durable remissions. These fixed-duration therapies have gained territory in the management of CLL, as they are cost-effective, avoid the emergence of resistance, and offer treatment free time to the patient. The cure rate of these novel combination regimens is unknown. Moreover, the optimal sequencing of targeted therapies remains to be determined. A medical challenge is to treat patien","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 3","pages":"450-480"},"PeriodicalIF":10.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27546","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143050827","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":"Clinical and Prognostic Significance of Additional Chromosomal Abnormalities at Diagnosis of Chronic Myeloid Leukemia","authors":"Jiří Mayer,&nbsp;Petra Čičátková,&nbsp;Lenka Kováčová,&nbsp;Marie Jarošová,&nbsp;Michal Karas,&nbsp;Pavel Jindra,&nbsp;Hana Klamová,&nbsp;Kateřina Machová Poláková,&nbsp;Olga Černá,&nbsp;Eduard Cmunt,&nbsp;Petra Bělohlávková,&nbsp;Pavel Žák,&nbsp;Edgar Faber,&nbsp;Tomáš Papajík,&nbsp;Lukáš Stejskal,&nbsp;Ivana Ježíšková,&nbsp;Barbora Weinbergerová,&nbsp;Tomáš Jurček,&nbsp;Tomáš Horňák,&nbsp;Daniela Žáčková,&nbsp;Šárka Ransdorfová,&nbsp;Milena Holzerová,&nbsp;Tomáš Pavlík","doi":"10.1002/ajh.27608","DOIUrl":"10.1002/ajh.27608","url":null,"abstract":"<p>The influence of t(v;22) sole, major route ACAs all (+8, <i>n</i> = 14; +Ph, <i>n</i> = 10; +19, <i>n</i> = 1), and -Y sole on progression-free survival. Survival curves are compared with those of patients with the standard t(9;22) translocation. Other ACAs or complex karyotypes did not influence survival.\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 4","pages":"729-734"},"PeriodicalIF":10.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27608","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143050835","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":"TP53 Mutations in Myeloproliferative Neoplasms: Context-Dependent Evaluation of Prognostic Relevance","authors":"Ayalew Tefferi,&nbsp;Maymona Abdelmagid,&nbsp;Giuseppe G. Loscocco,&nbsp;Saubia Fathima,&nbsp;Kebede H. Begna,&nbsp;Aref Al-Kali,&nbsp;James Foran,&nbsp;Jeanne Palmer,&nbsp;Talha Badar,&nbsp;Mrinal M. Patnaik,&nbsp;Kaaren K. Reichard,&nbsp;Rong He,&nbsp;Cinthya J. Zepeda Mendoza,&nbsp;Mithun Shah,&nbsp;Attilio Orazi,&nbsp;Daniel A. Arber,&nbsp;Animesh Pardanani,&nbsp;Alessandro M. Vannucchi,&nbsp;Devendra Hiwase,&nbsp;Naseema Gangat,&nbsp;Paola Guglielmelli","doi":"10.1002/ajh.27609","DOIUrl":"10.1002/ajh.27609","url":null,"abstract":"<p>The clinical relevance of <i>TP53</i> mutations (<i>TP53</i>\u0000 ^{\u0000 <i>MUT</i>\u0000}) in myeloproliferative neoplasms (MPN) and their prognostic interaction with MPN subtype designation has not been systematically studied. In the current study, 114 patients with MPN harboring <i>TP53</i>\u0000 ^{\u0000 <i>MUT</i>\u0000} (VAF ≥ 2%) were evaluated for overall survival (OS), calculated from the time of <i>TP53</i>\u0000 ^{\u0000 <i>MUT</i>\u0000} detection: chronic phase myelofibrosis (MF-CP; <i>N</i> = 61); blast-phase (MPN-BP; <i>N</i> = 31) or accelerated-phase (MPN-AP; <i>N</i> = 16) MPN, and polycythemia vera/essential thrombocythemia (PV/ET; <i>N</i> = 6). Sixty-five (57%) patients harbored International Consensus Classification (ICC)-defined multihit <i>TP53</i>\u0000 ^{\u0000 <i>MUT</i>\u0000} and 56 (49%) monosomal/complex karyotype (MK/CK). Majority of MPN-BP (90%) and MPN-AP (81%) while 39% of MF-CP and none of PV/ET patients harbored multihit <i>TP53</i>\u0000 ^{\u0000 <i>MUT</i>\u0000}. OS in MPN-BP and MPN-AP was equally dismal (median 6 vs. 4.5 months, respectively; <i>p</i> = 1.0), regardless of multihit configuration (<i>p</i> = 0.44), while OS in <i>TP53</i>\u0000 ^{\u0000 <i>MUT</i>\u0000} MPN-BP/AP (<i>N</i> = 47; median 4 months) was inferior to that of a separate cohort (<i>N</i> = 49) with <i>TP53</i> wild-type MPN-BP/AP (median 11 months; <i>p</i> &lt; 0.01). OS in MF-CP was significantly shorter with multihit versus non-multihit <i>TP53</i>\u0000 ^{\u0000 <i>MUT</i>\u0000} (median 10 vs. 35 months; HR 2.9; <i>p</i> &lt; 0.01), independent of other MF-relevant genetic risk factors, including <i>ASXL1/SRSF2/U2AF1</i> mutations. Multihit <i>TP53</i>\u0000 ^{\u0000 <i>MUT</i>\u0000} was also associated with inferior survival following allogeneic stem cell transplant (ASCT): median 9 months versus “not reached” in patients with (<i>N</i> = 9) versus without (<i>N</i> = 8) multihit <i>TP53</i>\u0000 ^MUT (<i>p</i> &lt; 0.01). The presence of multihit or non-multihit <i>TP53</i>\u0000 ^MUT in MPN-BP/AP or multihit <i>TP53</i>\u0000 ^MUT in MF-CP is associated with exceptionally poor prognosis and justifies inclusion into the ICC category of “myeloid neoplasms with mutated <i>TP53</i>.” By contrast, detection of non-multihit <i>TP53</i>\u0000 ^MUT, by itself, might not endanger short-term survival in MF-CP, PV, or ET.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 4","pages":"552-560"},"PeriodicalIF":10.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27609","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143050826","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":"Prospective Pharmacokinetic Evaluation of Venetoclax in AML Supports Re-Evaluation of Recommended Dose Adjustments With Azole Antifungals","authors":"Jitesh D. Kawedia,&nbsp;Caitlin R. Rausch,&nbsp;Xiaoqian Liu,&nbsp;Wei Qiao,&nbsp;Courtney D. Dinardo,&nbsp;Naval Daver,&nbsp;Gautam Borthakur,&nbsp;Naveen Pemmaraju,&nbsp;Patrick Reville,&nbsp;Dimitrios P. Kontoyiannis,&nbsp;Nicholas Short,&nbsp;Marina Konopleva,&nbsp;Elias Jabbour,&nbsp;Guillermo Garcia-Manero,&nbsp;Farhad Ravandi,&nbsp;Hagop Kantarjian,&nbsp;Tapan M. Kadia","doi":"10.1002/ajh.27613","DOIUrl":"10.1002/ajh.27613","url":null,"abstract":"&lt;p&gt;Incorporation of the BCL-2 inhibitor, venetoclax (VEN), into the treatment paradigm of acute myelogenous leukemia (AML) has led to a dramatic improvement in outcomes for older and unfit patients, demonstrating an overall survival benefit when added to azacitidine in patients with newly diagnosed (ND) AML ≥ 75 years, or otherwise ineligible for intensive chemotherapy [&lt;span&gt;1&lt;/span&gt;]. Posaconazole prophylaxis has improved overall survival in patients with ND AML undergoing remission induction chemotherapy anticipated to experience neutropenia for &gt; 7 days [&lt;span&gt;2&lt;/span&gt;]. As a result, prophylaxis with any mold-active triazole antifungal is recommended [&lt;span&gt;3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;The triazole antifungals inhibit CYP3A4, the enzyme responsible for VEN metabolism, to varying degrees. As a result, specific VEN dose reductions are recommended when co-administered with CYP3A4 inhibitors (CYP3A4i). A pharmacokinetic (PK) analysis of 11 patients receiving VEN with posaconazole 300 mg daily demonstrated an increase in mean &lt;i&gt;C&lt;/i&gt;\u0000 &lt;sub&gt;max&lt;/sub&gt; by 53% and AUC by 76% with VEN 50 mg daily (VEN50), and a 93% increase in &lt;i&gt;C&lt;/i&gt;\u0000 &lt;sub&gt;max&lt;/sub&gt; and 155% increase in AUC with VEN 100 mg (VEN100) [&lt;span&gt;4&lt;/span&gt;]. As a result, the FDA recommends VEN 70 mg daily in combination with posaconazole. Notably, in the VIALE-A trial, all patients receiving any strong CYP3A4i were dose-reduced to VEN50 [&lt;span&gt;1&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;We and others have reported a delay in time to platelet count recovery among patients with ND AML receiving increased VEN exposure as a result of increased VEN doses or when VEN is given in combination with azole antifungals, particularly posaconazole [&lt;span&gt;5, 6&lt;/span&gt;]. As a result, we hypothesized that VEN serum levels may be supratherapeutic when given in combination with posaconazole and that higher VEN levels could be associated with prolonged myelosuppression.&lt;/p&gt;&lt;p&gt;As part of an ongoing phase 2 study of VEN combined with cladribine and LDAC in older patients with ND AML (NCT03586609), we prospectively characterized VEN pharmacokinetics including &lt;i&gt;C&lt;/i&gt;\u0000 &lt;sub&gt;max&lt;/sub&gt;, AUC, &lt;i&gt;C&lt;/i&gt;\u0000 &lt;sub&gt;trough&lt;/sub&gt; and clearance when given with or without a strong CYP3A4i during induction. VEN100 was administered with voriconazole, VEN50 and VEN100 with posaconazole, and VEN 400 mg (VEN400) with caspofungin. Steady state VEN PK analysis was conducted on day 8. Blood samples were collected prior to the dose, and 2, 4, 8, and 24 h post dose. Trough (24-h post dose) levels were collected on days 12 and 16 of cycle 1 (Figure S1). We also evaluated the association between VEN trough levels and AUC as well as clinical outcomes. Complete methodology is in the Data S1.&lt;/p&gt;&lt;p&gt;Thirty-nine patients, median age 68 years (range, 61–77), were included for PK analysis (Table S1), of whom 33 (85%) achieved CR (&lt;i&gt;n&lt;/i&gt; = 29) or CRi (&lt;i&gt;n&lt;/i&gt; = 4) after induction. Among responders, 28 patients (85%) achieved MRD-negativit","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 4","pages":"740-743"},"PeriodicalIF":10.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27613","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143050834","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":"Association Between Red-Cell Transfusion in Childbirth and Long-Term Risk of Lymphoma and Autoimmune Disease: A Swedish Nationwide Cohort Study","authors":"Anne Brynolf,&nbsp;Anna Sandström,&nbsp;Henrik Hjalgrim,&nbsp;Gustaf Edgren","doi":"10.1002/ajh.27610","DOIUrl":"10.1002/ajh.27610","url":null,"abstract":"&lt;p&gt;Red-cell transfusions during childbirth are essential for managing significant blood loss, but may have long-term immunological implications. While immediate risks like transfusion-transmitted infections are well-documented, less understood are the potential associated risks of future lymphoma and autoimmune disease [&lt;span&gt;1&lt;/span&gt;]. We performed a study that aimed to assess the long-term risk of developing non-Hodgkin lymphoma (NHL), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis, among women who received red-cell transfusions during childbirth.&lt;/p&gt;&lt;p&gt;A nationwide cohort study was conducted using data from SCANDAT3-S, the Swedish portion of the Scandinavian Donations and Transfusions database, covering blood donations and transfusions from 1968 to 2017. The database is linked to national health registers, including the National Patient Registers, National Medical Birth Register, National Cancer Register, and the National Prescribed Drug Register, providing comprehensive delivery information and health outcomes [&lt;span&gt;2&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;The study included women aged 18–50 years who had their first childbirth between January 1, 1987, and December 31, 2017. Women with prior diagnoses of autoimmune diseases, lymphoma, or those who had received blood transfusions before their first childbirth were excluded. The cohort comprised 1 043 713 women with 1 999 013 registered deliveries. Of these women, 42 333 (4.1%) received one or more red-cell transfusions during one or several deliveries.&lt;/p&gt;&lt;p&gt;The primary exposure was the receipt of at least one red-cell transfusion in the period from 3 days before delivery until 7 days postpartum. Exposure status was updated at each delivery; women who received transfusions during any delivery were categorized as “transfused” from that point onwards. The main outcomes were the first recorded diagnosis of NHL, SLE, systemic sclerosis, or RA, identified through the Swedish National Patient and Cancer Registers using ICD codes, which are available in Appendix A.&lt;/p&gt;&lt;p&gt;Cox proportional hazards models were used to estimate hazard ratios (HRs) for each outcome, comparing red-cell transfused women around delivery to those who were never transfused. We used “time since the most recent delivery” as the time scale, and follow-up began 6 months postpartum to minimize reverse causation. This choice allowed us to align the follow-up period with the postpartum interval for each childbirth. If a woman had more than one delivery during the study period, the time scale was reset at each delivery, and exposure status was updated accordingly.&lt;/p&gt;&lt;p&gt;Models were adjusted for potential confounders, including maternal age (years), body mass index (BMI), parity, mode of delivery, preeclampsia, socioeconomic factors (income, education), smoking status, ABO blood group, and birth origin. Follow-up continued until an outcome occurred, at which point a woman diagnosed with the outcome no longer contributed","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 4","pages":"735-739"},"PeriodicalIF":10.1,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27610","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044333","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":"Chromoanagenesis Is Frequently Associated With Highly Complex Karyotypes, Extensive Clonal Heterogeneity, and Treatment Refractoriness in Acute Myeloid Leukemia","authors":"Qing Wei,&nbsp;Shimin Hu,&nbsp;Sanam Loghavi,&nbsp;Gokce A. Toruner,&nbsp;Farhad Ravandi-Kashani,&nbsp;Zhenya Tang,&nbsp;Shaoying Li,&nbsp;Jie Xu,&nbsp;Naval Daver,&nbsp;L. Jeffrey Medeiros,&nbsp;Guilin Tang","doi":"10.1002/ajh.27575","DOIUrl":"10.1002/ajh.27575","url":null,"abstract":"<div>\u0000 \u0000 <p>Chromoanagenesis (CAG) encompasses a spectrum of catastrophic genomic events, including chromothripsis, chromoanasynthesis, and chromoplexy. We studied CAG in 410 patients with a diagnosis of acute myeloid leukemia (AML), 292 newly diagnosed (ND), and 118 refractory/relapsed, using optical genome mapping. CAG was identified by the presence of clusters (with 10 or more breakpoints) of structural abnormalities and/or segmental copy number alterations within one or more chromosomal regions. CAG was detected in 65 (16%) patients. Compared with patients without CAG, those with CAG showed significantly (<i>p</i> &lt; 0.0001) higher frequencies of highly complex karyotype (92% vs. 11%), monosomal karyotype (88% vs. 12%), extensive clonal heterogeneity (75% vs. 7%), gene amplification (49% vs. 1%), and <i>TP53</i> deletion/mutation (92% vs. 9%). Overall, CAG was detected in about two-thirds of AML patients who exhibited the abovementioned high-risk cytogenetic abnormalities/karyotype. Among the 42 patients with ND AML and CAG, 36 received treatments and follow-ups, and 28 (78%) had no or only partial response to therapy. Among patients with ND AML, those with CAG had a shorter overall survival than those without CAG (median survival: 5 vs. 14 months, <i>p</i> &lt; 0.0001). However, in multivariate analysis, CAG did not appear to be an independent risk factor for survival. These results indicate that CAG is frequently associated with high-risk chromosomal alterations and genomic instability in AML and may contribute to treatment refractoriness and inferior survival in this subset of AML patients.</p>\u0000 </div>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 3","pages":"417-426"},"PeriodicalIF":10.1,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143050825","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":"Novel Flow Cytometric Antibody Panel and Dedicated Analysis Algorithm for Automated Fully Standardized Minimal Residual Disease Detection in Chronic Lymphocytic Leukemia","authors":"Robby Engelmann,&nbsp;Juan Flores-Montero,&nbsp;Joyce Schilperoord-Vermeulen,&nbsp;Matthias Ritgen,&nbsp;Paul J. Hengeveld,&nbsp;Saskia Kohlscheen,&nbsp;Georgiana Grigore,&nbsp;Rafael Fluxa Rodriguez,&nbsp;Quentin Lecrevisse,&nbsp;Jan Philippé,&nbsp;Neus Villamor,&nbsp;Paula Fernandez,&nbsp;Leire Burgos,&nbsp;Jacques J. M. van Dongen,&nbsp;Alberto Orfao,&nbsp;Anton W. Langerak,&nbsp;Sebastian Böttcher,&nbsp;the EuroFlow Consortium","doi":"10.1002/ajh.27604","DOIUrl":"10.1002/ajh.27604","url":null,"abstract":"&lt;p&gt;Submicroscopic levels of leukemic cells that persist after treatment are commonly designated as measurable residual disease (MRD). The last decade has witnessed a growing body of evidence proving the prognostic significance of MRD for both progression-free and overall survival in chronic lymphocytic leukemia (CLL) [&lt;span&gt;1, 2&lt;/span&gt;]. Moreover, MRD detection is now increasingly used to tailor treatment in accordance with the needs of the individual patient [&lt;span&gt;3&lt;/span&gt;]. Currently accepted flow cytometry assays reach a detection limit of 10&lt;sup&gt;−4&lt;/sup&gt;, but logically, MRD detection with higher sensitivity (e.g., 10&lt;sup&gt;−5&lt;/sup&gt;) holds promise for further improved prediction.&lt;/p&gt;&lt;p&gt;The European Research Initiative on CLL (ERIC) has successfully developed a standardized 4-color MRD flow assay featuring a fixed combination of markers, gates, and instructions for the application of gates with a sensitivity of 10&lt;sup&gt;−4&lt;/sup&gt; [&lt;span&gt;4&lt;/span&gt;]. The more recent ERIC 8-color MRD flow tube reportedly achieves a sensitivity of 10&lt;sup&gt;−5&lt;/sup&gt; [&lt;span&gt;5&lt;/span&gt;], but lacks the precise description of an analysis strategy. Therefore, we assessed the reproducibility of the current benchmark ERIC 8-color CLL MRD method (Figure 1A, Figure S1A, Table S1, see also supplemental materials and methods). A total of 99 samples from our dilution experiments were acquired and fully blinded. MRD levels were reported by four recognized experts with long-standing experience in CLL MRD flow (including multicentric international trials performed at national MRD reference laboratories). MRD levels down to an expected MRD level of 10&lt;sup&gt;−4&lt;/sup&gt; were reproducibly and accurately reported by the experts (average agreement to expected: 92%). However, MRD levels between 10&lt;sup&gt;−4&lt;/sup&gt; and 10&lt;sup&gt;−5&lt;/sup&gt; from the dilution series were scored as expected in 74% of all cases only. Importantly, 23% of normal donor samples were considered MRD positive, albeit usually at very low levels (mean reported level: 5.3 × 10&lt;sup&gt;−5&lt;/sup&gt; range: 7.3 × 10&lt;sup&gt;−6&lt;/sup&gt;–1 × 10&lt;sup&gt;−4&lt;/sup&gt;). Furthermore, the data suggested personal biases of individual experts (compare Figure 1A, left and right panels). Despite the described variability, we acknowledge that the accuracy of the ERIC 8-color CLL MRD method at levels below 10&lt;sup&gt;−4&lt;/sup&gt; might be better than reported herein if the individual pre-therapeutic immunophenotype is known. Conversely, we hypothesized that reproducible MRD assessments might be demanding even at levels above 10&lt;sup&gt;−4&lt;/sup&gt; for operators with lesser experience.&lt;/p&gt;&lt;p&gt;For broad applicability outside of specialized, expert-led centers, refined panels, and fully standardized analysis strategies would be desirable for reproducible operator-independent MRD detection at the 10&lt;sup&gt;−4&lt;/sup&gt; threshold or ideally even below. Therefore, the EuroFlow consortium developed an optimized 8-color CLL MRD panel in six consecutive design-validate-redesign rounds, using false-positivity r","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 4","pages":"724-728"},"PeriodicalIF":10.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27604","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031076","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":"NOTCH1 Mutations Are Associated With Therapy-Resistance in Patients With B-Cell Lymphoma Treated With CD20xCD3 Bispecific Antibodies","authors":"Emil R. Kyvsgaard,&nbsp;Morten Grauslund,&nbsp;Lene Sjø,&nbsp;Linea Cecilie Melchior,&nbsp;Trine Lønbo Grantzau,&nbsp;Lise Mette Rahbek Gjerdrum,&nbsp;Trine Trab,&nbsp;Lærke Sloth Andersen,&nbsp;Anne Ortved Gang,&nbsp;Marie Breinholt,&nbsp;Michael Boe Møller,&nbsp;Jacob Haaber Christensen,&nbsp;Thomas Stauffer Larsen,&nbsp;Michael Roost Clausen,&nbsp;Caroline H. Riley,&nbsp;Carsten U. Niemann,&nbsp;Kirsten Grønbæk,&nbsp;Martin Hutchings,&nbsp;Simon Husby","doi":"10.1002/ajh.27601","DOIUrl":"10.1002/ajh.27601","url":null,"abstract":"&lt;p&gt;CD20 × CD3 bispecific antibodies such as glofitamab, epcoritamab, and mosunetuzumab are novel T cell engaging antibodies which have all shown convincing results and obtained FDA and EMA approval for the treatment of relapsed/refractory diffuse large B cell lymphomas (DLBCL) or follicular lymphoma (FL) with ≥ 2 prior lines of treatment [&lt;span&gt;1&lt;/span&gt;]. However, approximately 50% of patients do not achieve remission when treated with single agent CD20 × CD3 bispecific antibodies.&lt;/p&gt;&lt;p&gt;Subgroup analysis of pivotal phase I/II trials have identified elevated LDH &gt; 250 U/L, high tumor burden, and refractory disease as risk factors for lack of response to bispecific antibodies for refractory/relapsed DLBCL [&lt;span&gt;1&lt;/span&gt;]. Downregulated TP53 target signatures, upregulated expression of MYC target genes, truncating mutations in &lt;i&gt;MS4A1&lt;/i&gt; (the gene encoding CD20), and loss of CD20 antigen have been identified as predictive factors for lack of response [&lt;span&gt;2-5&lt;/span&gt;]. Previously, tumor mutations in &lt;i&gt;TP53&lt;/i&gt; have been associated with poor response to both immunochemotherapy (i.e. R-CHOP) and CD19 CAR-T cell therapy in patients with B-cell lymphoma, but have not yet been examined thoroughly with long-term follow-up in patients treated with CD20 × CD3 bispecific antibodies.&lt;/p&gt;&lt;p&gt;In this retrospective study, we included patients from Rigshospitalet, Copenhagen, and Vejle University Hospital, both in Denmark, who received CD20 × CD3 bispecific antibodies between 2017 and 2023 as part of phase 1 or phase 2 clinical trials. The full list of regimens used are shown in Table S1. For exhaustive methods used, refer to the Supporting Information S1.&lt;/p&gt;&lt;p&gt;We collected pre-treatment formalin-fixed and paraffin-embedded (FFPE) archival specimens from 106 patients, of which 56 had sufficient DNA quantity and tumor involvement for clinical grade diagnostic next-generation sequencing (NGS). NGS was performed with a custom lymphoma panel designed in-house covering 59 commonly mutated genes in lymphoid malignancies.&lt;/p&gt;&lt;p&gt;We examined pre-treatment tumors from 56 patients with B-cell NHL, who received CD20 × CD3 bispecific antibodies between 2017 and 2023 and had sufficient tissue for NGS sequencing. The median age at first administration of CD20 × CD3 bispecific antibody was 70 years, 60.7% were male, and the median number of prior lines of therapy was three (Table S1). Median follow-up time was 24.2 months. Mutational profiling was additionally performed on 14 paired post-CD20 × CD3 bispecific antibody relapse samples.&lt;/p&gt;&lt;p&gt;Of all mutations found in pre-CD20 × CD3-treatment biopsies &lt;i&gt;NOTCH1&lt;/i&gt; (detected in 4/56 [7%] of patients, Figure S1), along with &lt;i&gt;BRAF&lt;/i&gt; and &lt;i&gt;EZH2,&lt;/i&gt; had the strongest association with inferior PFS in a univariate Cox model (HR: 3.46, 95% CI 1.16–10.3, &lt;i&gt;p&lt;/i&gt; = 0.026, Tables S2 and S4, Figure S8). Furthermore, pre-CD20 × CD3-treatment &lt;i&gt;NOTCH1&lt;/i&gt; mutated tumors conferred significantly worse outcomes in Kaplan–Meier an","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 4","pages":"712-716"},"PeriodicalIF":10.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27601","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031075","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":"Exploring the Clinical Diversity of Castleman Disease and TAFRO Syndrome: A Japanese Multicenter Study on Lymph Node Distribution Patterns","authors":"Mizuna Otsuka,&nbsp;Tomohiro Koga,&nbsp;Remi Sumiyoshi,&nbsp;Shoichi Fukui,&nbsp;Yuko Kaneko,&nbsp;Takayuki Shimizu,&nbsp;Atsushi Katsube,&nbsp;Shingo Yano,&nbsp;Yasufumi Masaki,&nbsp;Makoto Ide,&nbsp;Hajime Yoshifuji,&nbsp;Masayasu Kitano,&nbsp;Yasuharu Sato,&nbsp;Naoki Sawa,&nbsp;Hiroaki Niiro,&nbsp;Naoya Nakamura,&nbsp;David C. Fajgenbaum,&nbsp;Frits van Rhee,&nbsp;Atsushi Kawakami","doi":"10.1002/ajh.27612","DOIUrl":"10.1002/ajh.27612","url":null,"abstract":"<p>Individuals diagnosed with Castleman disease (CD) and TAFRO syndrome (characterized by thrombocytopenia, anasarca, fever, bone marrow fibrosis, and organomegaly) displays a wide range of clinical symptoms, including varying patterns of lymph node enlargement, systemic inflammation, and impaired organ function. Some patients may present with both CD and TAFRO syndrome concurrently. A retrospective study conducted across multiple centers in Japan examined 321 cases to determine if the quantity and position of swollen lymph nodes could forecast the clinical progression and intensity of these conditions. Interestingly, the study revealed that patients with TAFRO syndrome exhibited lymphadenopathy across all ranges of lymph node region counts. Moreover, no specific clinical patterns were associated with the number of affected lymph node regions in CD patients, regardless of whether they also had TAFRO syndrome. These results enhance our understanding of the clinical variability in CD and TAFRO syndrome, suggesting that a comprehensive clinical evaluation, rather than relying solely on lymph node count, is crucial for effectively managing these conditions. Additional studies are required to establish reliable diagnostic markers and to predict disease severity at the time of diagnosis, ultimately improving patient outcomes.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 4","pages":"592-605"},"PeriodicalIF":10.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27612","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031074","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}