American Journal of Hematology最新文献

{"title":"First-line treatment of Waldenström's macroglobulinemia in Italy: A multicenter real-life study on 547 patients to evaluate the long-term efficacy and tolerability of different chemoimmunotherapy strategies","authors":"Francesco Autore, A. Tedeschi, G. Benevolo, V. Mattiello, E. Galli, N. Danesin, R. Rizzi, J. Olivieri, E. Cencini, B. Puccini, I. Ferrarini, D. Marino, M. Bullo, B. Rossini, M. Motta, I. Innocenti, A. Fresa, L. Stirparo, D. Petrilli, R. Pasquale, P. Musto, G. Scapinello, A. Noto, V. Peri, G. Zamprogna, S. Hohaus, A. M. Frustaci, F. Piazza, S. Ferrero, L. Laurenti","doi":"10.1002/ajh.27524","DOIUrl":"10.1002/ajh.27524","url":null,"abstract":"<p>Treatment is indicated in Waldenström macroglobulinemia (WM) when clinical manifestations arise due to the IgM paraprotein or lymphoplasmacytic infiltrate.<span><sup>1</sup></span> The main classes of drugs used for WM treatment include monoclonal antibodies, chemotherapeutic agents, proteasome inhibitors, and Bruton Tyrosine Kinase inhibitors (BTKi). The most frequently used chemotherapeutic agent is bendamustine, which is largely administered for its efficacy and relatively favorable toxicity profile with low rates of non-hematological adverse events.<span><sup>2</sup></span> Bendamustine plus rituximab (BR) is considered to be especially useful in fit patients in need of rapid disease control.<span><sup>3</sup></span></p><p>Rituximab has been evaluated in combination not only with bendamustine (BR), but also with dexamethasone and cyclophosphamide (DRC).<span><sup>4</sup></span> A retrospective comparison between BR and DRC was performed at Mayo Clinic, reporting a significantly greater two-year progression free survival (PFS) for BR (88% vs. 61%, respectively) but without a significant difference in overall response rate (ORR) at 18 months (93% vs. 96%, respectively).<span><sup>4</sup></span> In contrast, both a superior ORR (98% vs. 85%, respectively) and major response rate (96% vs. 60%, respectively) were reported for BR in the study of Abeykoon et al.<span><sup>5</sup></span></p><p>To further evaluate the efficacy and safety of the different chemoimmunotherapy regimens used for the treatment of WM patients, we conducted a retrospective multicenter study involving 14 different Italian centers of the Fondazione Italiana Linfomi (FIL). The study group included unselected, consecutive WM patients who received frontline treatment with a chemoimmunotherapy regimen between January 2008 and December 2022. Primary outcome measures included ORR, PFS, and OS, as defined by the International Workshop on Waldenström's macroglobulinemia.<span><sup>6</sup></span> Primary outcomes were also assessed based on the total received bendamustine dose, which was categorized using the percentage of the relative dose intensity (RDI). The RDI was calculated for each patient as the percentage of drug actually administered compared to that estimated at the beginning of treatment. The starting dose was 90 mg/m<sup>2</sup>/day, administered on days 1 and 2 of each of the six planned cycles.</p><p>The statistical analyses were conducted on four different treatment groups which included BR, DRC, and two other groups that were named “other R-chemo” and “chemo alone.” The “other R-chemo” group included patients treated with a Rituximab-containing regimen other than BR, such as Chl-R (chlorambucil-rituximab), FCR (fludarabine-cyclophosphamide-rituximab), or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), whereas the “chemo alone” group included patients treated with chemotherapeutic agents such as chlorambucil or cyclophosphamide as singl","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 1","pages":"189-191"},"PeriodicalIF":10.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27524","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666905","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":"Prognostic significance of mutation type and chromosome fragility in Fanconi anemia","authors":"María José Ramírez,&nbsp;Roser Pujol,&nbsp;Jordi Minguillón,&nbsp;Massimo Bogliolo,&nbsp;Ilaria Persico,&nbsp;Debora Cavero,&nbsp;Aurora de la Cal,&nbsp;Paula Río,&nbsp;Susana Navarro,&nbsp;José Antonio Casado,&nbsp;Almudena Bailador,&nbsp;Antonio Sanchez de la Fuente,&nbsp;Miguel López de Heredia,&nbsp;Francisco Almazán,&nbsp;M. Luisa Antelo,&nbsp;Bienvenida Argilés,&nbsp;Isabel Badell,&nbsp;Marta Baragaño,&nbsp;Cristina Beléndez,&nbsp;Mar Bermúdez,&nbsp;Marta Bernués,&nbsp;María Isabel Buedo,&nbsp;Estela Carrasco,&nbsp;Albert Català,&nbsp;Dolors Costa,&nbsp;Isabel Cuesta,&nbsp;Rafael Fernandez-Delgado,&nbsp;Ana Fernández-Teijeiro,&nbsp;Ángela Figuera,&nbsp;Marta García,&nbsp;Ainhoa Gondra,&nbsp;Macarena González,&nbsp;Soledad González Muñiz,&nbsp;Ines Hernández-Rodríguez,&nbsp;Fátima Ibañez,&nbsp;Nicholas John Kelleher,&nbsp;Francisco Lendínez,&nbsp;Mónica López,&nbsp;Ricardo López-Almaraz,&nbsp;Inmaculada Marchante,&nbsp;Carmen Mendoza,&nbsp;José Nieto,&nbsp;Emilio Ojeda,&nbsp;Salvador Payán-Pernía,&nbsp;Irene Peláez,&nbsp;Inmaculada Pérez de Soto,&nbsp;Raquel Portugal,&nbsp;María A. Ramos-Arroyo,&nbsp;Alexandra Regueiro,&nbsp;Ana Rodríguez,&nbsp;Jordi Rosell,&nbsp;Raquel Saez,&nbsp;José Sánchez,&nbsp;Martha Sánchez,&nbsp;MªLeonor Senent,&nbsp;María Tapia,&nbsp;Juan Pablo Trujillo-Quintero,&nbsp;José Manuel Vagace,&nbsp;Jaime Verdú-Amorós,&nbsp;Victória Verdugo,&nbsp;Isabel Vidales,&nbsp;Jasson Villarreal,&nbsp;Cristina Díaz-de-Heredia,&nbsp;Julián Sevilla,&nbsp;Juan Antonio Bueren,&nbsp;Jordi Surrallés","doi":"10.1002/ajh.27520","DOIUrl":"10.1002/ajh.27520","url":null,"abstract":"<p>Fanconi anemia (FA) is a rare genetic disease characterized by high phenotypic and genotypic heterogeneity, and extreme chromosome fragility. To better understand the natural history of FA, identify genetic risk and prognostic factors, and develop novel therapeutic strategies, the Spanish Registry of Patients with FA collects data on clinical features, chromosome fragility, genetic subtypes, and DNA sequencing with informed consent of participating individuals. In this article, we describe the clinical evolution of 227 patients followed up for up to 30 years, for whom our data indicate a cumulative cancer incidence of 86% by age 50. We found that patients with lower chromosome fragility had a milder malformation spectrum and better outcomes in terms of later-onset hematologic impairment, less severe bone marrow failure, and lower cancer risk. We also found that outcomes were better for patients with mutations leading to mutant FANCA protein expression (genetic hypomorphism) than for patients lacking this protein. Likewise, prognosis was consistently better for patients with biallelic mutations in <i>FANCD2</i> (mainly hypomorphic mutations) than for patients with biallelic mutations in <i>FANCA</i> and <i>FANCG</i>, with the lack of the mutant protein in patients with biallelic mutations in <i>FANCG</i> contributing to their poorer outcomes. Our results regarding the clinical impact of chromosome fragility and genetic hypomorphism suggest that mutant FA proteins retain residual activity. This finding should encourage the development of novel therapeutic strategies aimed at partially or fully enhancing mutant FA function, thereby preventing or delaying bone marrow failure and cancer in patients with FA.</p><p>Clinical Trial Registration number: NCT06490510.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 2","pages":"272-284"},"PeriodicalIF":10.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674485","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":"RAS signaling pathway is essential in regulating PIEZO1-mediated hepatic iron overload in dehydrated hereditary stomatocytosis","authors":"Barbara Eleni Rosato,&nbsp;Vanessa D'Onofrio,&nbsp;Roberta Marra,&nbsp;Antonella Nostroso,&nbsp;Federica Maria Esposito,&nbsp;Anthony Iscaro,&nbsp;Vito Alessandro Lasorsa,&nbsp;Mario Capasso,&nbsp;Achille Iolascon,&nbsp;Roberta Russo,&nbsp;Immacolata Andolfo","doi":"10.1002/ajh.27523","DOIUrl":"10.1002/ajh.27523","url":null,"abstract":"<p><i>PIEZO1</i> encodes a mechanoreceptor, a cation channel activated by mechanical stimuli. Gain-of-function (GoF) variants in PIEZO1 cause dehydrated hereditary stomatocytosis (DHS), or xerocytosis, a pleiotropic syndrome characterized by anemia and iron overload. DHS patients develop hepatic iron overload independent of the degree of anemia and transfusion regimen. PIEZO1-GoF variants suppress hepcidin expression in both hepatic cellular model and constitutive/macrophage-specific Piezo1-GoF mice model. Therefore, PIEZO1-GoF variants regulate hepcidin expression by a crosstalk between hepatocytes (HCs) and macrophages with a still unknown mechanism. Transcriptomic and proteomics analysis in the human hepatic Hep3B cells engineered for the PIEZO1-R2456H variant (PIEZO1-KI) revealed alterations in the actin cytoskeleton regulation, MAPK cascade, and RAS signaling. These changes mainly occur through a novel key regulator, RRAS, whose protein and mRNA levels are regulated by PIEZO1 activation and inhibition. This regulation was further confirmed in C57BL/6 mouse primary HCs treated with Yoda-1 and/or GsMTx-4. Indeed, PIEZO1-KI cells exhibited hyper-activated RAS-GTPase activity that is rescued by PIEZO1 inhibition, restoring expression of the hepcidin gene <i>HAMP</i>. A negative correlation between RAS signaling and <i>HAMP</i> regulation was confirmed by inhibiting RAS-GTPase and MEK1-2 activity. Conversely, rescued <i>HAMP</i> gene expression requires downregulation of RRAS, confirming negative feedback between RAS-MAPK and BMP/SMADs pathways in <i>HAMP</i> regulation. We demonstrated that PIEZO1-GoF variants influence the actin cytoskeleton organization by activating the hepatic RAS signaling system. Understanding the role of RAS signaling in regulating iron metabolism could pave the way for new therapeutic strategies in DHS and other conditions characterized by iron overload.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 1","pages":"52-65"},"PeriodicalIF":10.1,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11625994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666906","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":"The role of allogeneic stem cell transplantation in acute myeloid leukemia with translocation t(8;16)(p11;p13)","authors":"Ann-Kristin Schmälter,&nbsp;Myriam Labopin,&nbsp;Jurjen Versluis,&nbsp;Maria Pilar Gallego Hernanz,&nbsp;Matthias Eder,&nbsp;Peter von dem Borne,&nbsp;Gerard Socié,&nbsp;Patrice Chevallier,&nbsp;Edouard Forcade,&nbsp;Andreas Neubauer,&nbsp;Frédéric Baron,&nbsp;Ali Bazarbachi,&nbsp;Gesine Bug,&nbsp;Arnon Nagler,&nbsp;Christoph Schmid,&nbsp;Jordi Esteve,&nbsp;Mohamad Mohty,&nbsp;Fabio Ciceri","doi":"10.1002/ajh.27496","DOIUrl":"10.1002/ajh.27496","url":null,"abstract":"<p>Acute myeloid leukemia (AML) with translocation t(8;16)(p11;p13) represents a rare entity that has been categorized as a disease-defining recurring cytogenetic abnormality with adverse risk in the 2022 European LeukemiaNet classification. This rating was mainly based on a retrospective analysis comprising patients from several large clinical trials, which, however, included only 21 patients treated with allogeneic stem cell transplantation (alloSCT). Therefore, the European Society for Blood and Marrow Transplantation performed a registry study on a larger cohort to evaluate the role of alloSCT in t(8;16) AML. Sixty transplant recipients with t(8;16) AML were identified. Two-year overall and leukemia-free survival (OS/LFS) was 43/39%. Patients transplanted in first complete remission (CR1, <i>n</i> = 44) achieved a 2-year OS/LFS of 48%/48%. Following alloSCT in CR1, the multivariable analysis identified a complex karyotype (CK) as a major risk factor for relapse (HR 4.17, <i>p</i> = .016), lower LFS (HR 3.38, <i>p</i> = .01), and lower OS (HR 3.08, <i>p</i> = .017). Two-year OS/LFS of patients with CK was 19%/19%, in contrast to 67%/67% in patients with t(8;16) outside a CK. Other factors for inferior outcomes were older age and secondary AML. In summary, alloSCT could mitigate the adverse risk of patients with t(8;16) AML not harboring a CK, particularly when performed in CR1.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 1","pages":"85-92"},"PeriodicalIF":10.1,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11625973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666907","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":"Mini-consolidations or intermediate-dose cytarabine for the post-remission therapy of AML patients over 60. A retrospective study from the DATAML and SAL registries","authors":"Christian Récher,&nbsp;Pierre-Yves Dumas,&nbsp;Emilie Bérard,&nbsp;Suzanne Tavitian,&nbsp;Thibaut Leguay,&nbsp;Jean Galtier,&nbsp;Camille Alric,&nbsp;Audrey Bidet,&nbsp;Eric Delabesse,&nbsp;Jean Baptiste Rieu,&nbsp;Jean-Philippe Vial,&nbsp;François Vergez,&nbsp;Isabelle Luquet,&nbsp;Emilie Klein,&nbsp;Anne-Charlotte de Grande,&nbsp;Audrey Sarry,&nbsp;Sven Zukunft,&nbsp;Uwe Platzbecker,&nbsp;Carsten Müller-Tidow,&nbsp;Claudia D. Baldus,&nbsp;Martin Bornhäuser,&nbsp;Hubert Serve,&nbsp;Sarah Bertoli,&nbsp;Arnaud Pigneux,&nbsp;Christoph Röllig","doi":"10.1002/ajh.27510","DOIUrl":"10.1002/ajh.27510","url":null,"abstract":"<p>According to current recommendations, older AML patients in first complete remission (CR) after induction chemotherapy should receive consolidation with intermediate-dose cytarabine (IDAC). However, no study has demonstrated the superiority of IDAC over other regimen. In this retrospective study, we compared the efficacy of mini-consolidations (idarubicin 8 mg/m² day 1, cytarabine 50 mg/m²/12 h, day 1–5) and IDAC. Inclusion criteria were newly diagnosed AML, age &gt; 60 years, first CR after induction and at least 1 cycle of consolidation. Of the 796 included patients, 322 patients received mini-consolidations and 474 patients received IDAC. Mini-consolidation patients were older, and more often, they had de novo AML and unfavorable risk. The rate of allogeneic transplantation was higher in the IDAC group. The median number of cycles was higher in the mini-consolidation group (4 vs. 2; <i>p</i> &lt; .0001). Median relapse-free survival was 18 months with mini-consolidations and 12 months with IDAC (<i>p</i> = .0064). In multivariate analysis, the risk of relapse or death was significantly higher in the IDAC group (<i>p</i> = .004). Median OS was 36 versus 31 months with mini-consolidations or IDAC, respectively (<i>p</i> = .46). In multivariate analysis, the consolidation regimen had no significant influence on OS (<i>p</i> = .43). In older AML patients, post-remission therapy with mini-consolidations represents an alternative to IDAC.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 1","pages":"23-32"},"PeriodicalIF":10.1,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11625969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646763","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 Immune Effects of Peri-Transplantation JAK Inhibition for Myelofibrosis","authors":"Kristin Rathje,&nbsp;Nico Gagelmann,&nbsp;Anita Badbaran,&nbsp;Claudia Langebrake,&nbsp;Adrin Dadkhah,&nbsp;Johanna Richter,&nbsp;Radwan Massoud,&nbsp;Mathias Schäfersküpper,&nbsp;Franziska E. Marquard,&nbsp;Sofia Oechsler,&nbsp;Evgeny Klyuchnikov,&nbsp;Ina Rudolph,&nbsp;Silke Heidenreich,&nbsp;Christian Niederwieser,&nbsp;Catherina Lueck,&nbsp;Dietlinde Janson,&nbsp;Christine Wolschke,&nbsp;Boris Fehse,&nbsp;Francis Ayuk,&nbsp;Nicolaus Kröger","doi":"10.1002/ajh.27529","DOIUrl":"10.1002/ajh.27529","url":null,"abstract":"<p>Despite the introduction of JAK inhibitors, allogeneic hematopoietic cell transplant remains the only potentially curative treatment for patients with myelofibrosis but has considerable treatment-related complications. Whether the incorporation of JAK inhibition into the transplant algorithm leads to improved outcomes is still unclear. Here, we analyzed different transplant platforms in myelofibrosis patients undergoing a first transplant, comparing immune profiles and outcomes of (1) 33 patients continuing JAK inhibition at start of conditioning until stable engraftment (PERI-group), (2) 38 patients receiving JAK inhibition prior to transplant until start of conditioning (PRE-group), and (3) 38 patients that had never received JAK inhibition (NON-group). Patients in the PERI-group showed significantly higher early B-cell recovery as well as significantly increased late recovery of gamma-delta T cells and NK cells. We observed excellent neutrophil and platelet engraftment (100% for both) in the PERI-group and no hematotoxic effects or increased rates of infections following peri-transplant JAK inhibition. Cumulative incidence of acute graft-versus-host disease (GvHD) grade II-IV at day 100 after transplant was 15% in the PERI-group versus 29% in the PRE-group versus 34% in the NON-group. Cumulative incidence of relapse at 1 year after transplant was 9% in the PERI-group compared with 16% in the PRE-group and 18% in the NON-group. In conclusion, peri-transplant JAK inhibition was feasible with promising engraftment and acute GvHD rates, though deserves further investigation.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 2","pages":"200-209"},"PeriodicalIF":10.1,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27529","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643221","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":"High-grade B-cell lymphoma not otherwise specified, with diffuse large B-cell lymphoma gene expression signatures: Genomic analysis and potential therapeutics","authors":"Waseem Lone,&nbsp;Alyssa Bouska,&nbsp;Tyler A. Herek,&nbsp;Catalina Amador,&nbsp;Joo Song,&nbsp;Alexander M. Xu,&nbsp;Dylan Jochum,&nbsp;Issa Ismail Issa,&nbsp;Dennis D. Weisenburger,&nbsp;Xuan Zhang,&nbsp;Sharath Kumar Bhagavathi,&nbsp;Tayla B. Heavican-Foral,&nbsp;Sunandini Sharma,&nbsp;Ab Rauf Shah,&nbsp;Abdul Rouf Mir,&nbsp;Aisha Ahmad Alkhinji,&nbsp;Dalia El-Gamal,&nbsp;Bhavana J. Dave,&nbsp;Keenan Hartert,&nbsp;Jiayu Yu,&nbsp;Mallick Saumyaranjan,&nbsp;Timothy C. Greiner,&nbsp;Julie Vose,&nbsp;Timothy W. McKeithan,&nbsp;Kai Fu,&nbsp;Michael Green,&nbsp;Chengfeng Bi,&nbsp;Akil Merchant,&nbsp;Wing C. Chan,&nbsp;Javeed Iqbal","doi":"10.1002/ajh.27513","DOIUrl":"10.1002/ajh.27513","url":null,"abstract":"<p>High-grade B-cell lymphoma not otherwise specified (HGBCL, NOS) has overlapping morphological and genetic features with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL), leading to uncertainty in its diagnosis and clinical management. Using functional genomic approaches, we previously characterized HGBCL and NOS, that demonstrate gene expression profiling (GEP), and genetic signatures similar to BL. Herein, we characterize distinct HGBCL, NOS, cohort (<i>n</i> = 55) in adults (<i>n</i> = 45) and in children (<i>n</i> = 10), and compared the GEP, genomic DNA copy number (CN), and mutational spectrum with <i>de novo</i> DLBCL (<i>n</i> = 85) and BL (<i>n</i> = 52). This subgroup, representing ~60% of HGBCL, NOS, lack gene-expression signature of BL and double hit/dark zone lymphoma, but express DLBCL like signatures and are characterized by either GCB- or ABC-like mRNA signatures and exhibit higher genomic complexity, similar to <i>de novo</i> DLBCL, and show alteration in genes regulating B-cell activation (<i>CD79B</i>, <i>MYD88</i>, <i>PRDM1</i>, <i>TBLIXR1</i>, <i>CARD11</i>), epigenome (<i>KMT2D</i>, <i>TET2</i>) and cell cycle transition (<i>TP53</i>, <i>ASPM</i>). However, recurrent mutations in genes often mutated in BL (DDX3X, GNA13, CCND3), but rare in DLBCL, are also present in HGBCL-NOS, highlighting genetic heterogeneity. Consistent with mutation spectrum, frequent genomic CN alterations in genes regulating B-cell activation (del-<i>PRDM1</i>, gain-<i>BCL6</i>, -<i>REL</i>, -<i>STAT3</i>) and cell cycle regulators (del-<i>TP53</i>, del-<i>CDKN2A</i>, del-<i>RB1</i>, gain-<i>CCND3</i>) were observed. Pediatric cases showed GCB-DLBCL-like mRNA signatures, but also featured hallmark mutations of pediatric BL. Frequent oncogenic <i>PIM1</i> mutations were present in adult HGBCL, NOS. <i>In vitro</i> analyses with pharmacologic or genetic inhibition of <i>PIM1 expression</i> triggered B-cell activation and NF-κB-induced apoptosis, suggesting that <i>PIM1</i> is a rational therapeutic target.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 1","pages":"10-22"},"PeriodicalIF":10.1,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27513","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142642568","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":"A prophylactic tyrosine kinase inhibitor strategy based on measurable residual disease pre-transplantation for Ph+ acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation: A prospective multicenter cohort study","authors":"Hui Liu,&nbsp;Hui Xu,&nbsp;Peiru Chi,&nbsp;Zinan Feng,&nbsp;Xiaojun Xu,&nbsp;Danian Nie,&nbsp;Xudong Li,&nbsp;Xinquan Liang,&nbsp;Zhiping Fan,&nbsp;Na Xu,&nbsp;Fen Huang,&nbsp;Ren Lin,&nbsp;Zhixiang Wang,&nbsp;Hua Jin,&nbsp;Hongsheng Zhou,&nbsp;Xutao Guo,&nbsp;Dongjun Lin,&nbsp;Jing Sun,&nbsp;Qifa Liu,&nbsp;Li Xuan","doi":"10.1002/ajh.27516","DOIUrl":"10.1002/ajh.27516","url":null,"abstract":"<p>Relapse is the major cause of treatment failure in Philadelphia chromosome-positive (Ph⁺) acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed to evaluate the effect of a prophylactic tyrosine kinase inhibitor (TKI) strategy on relapse in this population. Patients were assigned to prophylactic or control groups based on measurable residual disease (MRD) pre-transplantation. The primary endpoint was the cumulative incidence of relapse. A total of 110 patients with Ph⁺ ALL undergoing allo-HSCT were enrolled in this prospective study. Thirty-eight patients with positive MRD pre-transplantation were included in the prophylactic group, and 72 with negative MRD pre-transplantation were included in the control group. The 4-year cumulative incidence of relapse was 25.3% (95% CI: 12.1%–41.0%) and 20.3% (11.6%–30.7%; HR = 1.272, 95% CI: 0.551–2.940, <i>p</i> = .549), and non-relapse mortality was 10.5% (3.3%–22.7%) and 9.7% (4.2%–17.9%; HR = 1.094, 95% CI: 0.320–3.738, <i>p</i> = .928) in the prophylactic and control groups. The 4-year overall survival was 71.8% (53.2%–84.1%) and 84.1% (72.9%–90.9%; HR = 1.746, 95% CI: 0.741–4.112, <i>p</i> = .196), and leukemia-free survival was 64.1% (45.8%–77.7%) and 70.0% (57.6%–79.4%; HR = 1.212, 95% CI: 0.607–2.421, <i>p</i> = .585) in the prophylactic and control groups. Our results suggest that prophylactic TKI post-HSCT in patients with positive MRD pre-transplantation can produce outcomes comparable to negative MRD pre-transplantation without TKI post-HSCT.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 1","pages":"33-37"},"PeriodicalIF":10.1,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643229","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":"Clinical significance of complete remission and measurable residual disease in relapsed/refractory multiple myeloma patients treated with T-cell redirecting immunotherapy","authors":"Aintzane Zabaleta,&nbsp;Noemi Puig,&nbsp;Maria-Teresa Cedena,&nbsp;Aina Oliver-Caldes,&nbsp;José J. Perez,&nbsp;Cristina Moreno,&nbsp;Luis-Esteban Tamariz-Amador,&nbsp;Paula Rodriguez-Otero,&nbsp;Felipe Prosper,&nbsp;Veronica Gonzalez-Calle,&nbsp;Lucía López-Corral,&nbsp;Beatriz Rey-Búa,&nbsp;Borja Puertas,&nbsp;Fátima Mirás,&nbsp;José María Sánchez-Pina,&nbsp;Nieves López-Muñoz,&nbsp;Manel Juan,&nbsp;E. Azucena González-Navarro,&nbsp;Álvaro Urbano,&nbsp;Carlos Fernández de Larrea,&nbsp;Joan Blade,&nbsp;Juan-José Lahuerta,&nbsp;Joaquín Martinez-Lopez,&nbsp;Maria-Victoria Mateos,&nbsp;Jesús F. San Miguel,&nbsp;Bruno Paiva","doi":"10.1002/ajh.27526","DOIUrl":"10.1002/ajh.27526","url":null,"abstract":"<p>The impact of measurable residual disease (MRD) in relapse/refractory multiple myeloma (RRMM) patients treated with T-cell redirecting immunotherapy is uncertain. We analyzed MRD dynamics using next-generation flow in 201 patients treated in clinical trials with chimeric antigen receptor (CAR) T cells and T-cell engagers (TCE). Achieving MRD negativity at 10⁻⁶ was associated with 89% reduction in the risk of progression and/or death. Survival outcomes were improved in patients with sustained versus transient MRD negativity and were dismal in those who remained MRD positive. The intent-to-treat MRD negative rates were higher in patients treated with CAR T cells versus TCE. However, among patients achieving MRD negativity, there were no differences in survival outcomes when stratified according to treatment with CAR T cells versus TCE. In multivariate analysis including the number of prior lines of treatment, International Staging System, cytogenetic risk, extramedullary disease and type of T-cell redirecting immunotherapy, only the complete remission (CR) and MRD statuses showed independent prognostic value for progression-free and overall survival. In conclusion, our study shows that deep and sustained MRD negative CR is the most relevant prognostic factor and should be considered as the treatment endpoint in RRMM patients treated with CAR T cells and TCE.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 1","pages":"93-102"},"PeriodicalIF":10.1,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27526","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643222","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":"Hyperparathyroidism and the Hematologist","authors":"Hajer Oun, Kirsteen Harper, Mike Leach, Barbara J. Bain","doi":"10.1002/ajh.27527","DOIUrl":"https://doi.org/10.1002/ajh.27527","url":null,"abstract":"<div>\u0000<figure>\u0000<div><picture>\u0000<source media=\"(min-width: 1650px)\" srcset=\"/cms/asset/b04baa4a-6e9e-4b9c-9c1d-6db3d8f072e6/ajh27527-gra-0001-m.jpg\"/><img alt=\"image\" data-lg-src=\"/cms/asset/b04baa4a-6e9e-4b9c-9c1d-6db3d8f072e6/ajh27527-gra-0001-m.jpg\" loading=\"lazy\" src=\"/cms/asset/596227e9-704e-4d09-a9bc-5ecba0f0acec/ajh27527-gra-0001-m.png\" title=\"image\"/></picture><p></p>\u0000</div>\u0000</figure>\u0000</div>\u0000<p>A 76-year-old man with a history of chronic obstructive pulmonary disease with lung fibrosis, type 2 diabetes mellitus, and chronic kidney disease underwent computed tomography imaging of the chest due to increasing dyspnea. The bones appeared sclerotic, and a bone scan showed diffuse tracer uptake throughout the axial and appendicular skeleton. The prostate showed no features of malignancy on magnetic resonance imaging and prostate-specific antigen was 6.6 μg/L (normal range (NR) 0–5). Serum tryptase levels were mildly elevated at 16 μg/L (NR 2–14) on two occasions. Biochemical investigations showed vitamin D &lt; 14 nmol/L (NR &gt; 50), alkaline phosphatase 665 U/L (NR 30–130), parathyroid hormone 52.8 pmol/L (NR 1.6–7.5), calcium 2.43 mmol/L (NR 2.2–2.6) and phosphate 1.07 mmol/L (NR 0.8–1.5), in keeping with hyperparathyroidism secondary to vitamin D deficiency and chronic kidney disease (creatinine 169 μmol/L and estimated glomerular filtration rate 34 mL/min).</p>\u0000<p>Bone marrow trephine biopsy sections showed areas of active bone resorption by multinucleate osteoclasts forming recesses known as Howship's lacunae (top and bottom left, all histological images hematoxylin and eosin, ×50 objective). In other areas, lamellar bone was being actively laid down by rows of osteoblasts (top center). There was patchy fibrosis at sites of previous bone resorption (bottom center). Notably, there were osteoclasts also visible in the marrow aspirate (top and bottom right, May–Grünwald–Giemsa, ×100 objective). There was no abnormal mast cell population.</p>\u0000<p>These features are typical of hyperparathyroidism where osteoclasts strive to release calcium whilst osteoblasts attempt to repair the trabecular damage. This active bone remodeling with the associated trabecular changes generates the sclerotic radiological appearance of the affected bones. Osteoblasts and osteoclasts normally work together in bone repair, remodeling, and growth but this process is exaggerated under the influence of increased parathyroid hormone whether primary, due to a parathyroid adenoma, or secondary, as a result of vitamin D deficiency or chronic kidney disease. The recognition of the features of bone disorders with associated bone marrow fibrosis is important so that they are not confused with myeloproliferative neoplasms.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"19 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599906","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}