American Journal of Hematology最新文献

{"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, Nico Gagelmann, Anita Badbaran, Claudia Langebrake, Adrin Dadkhah, Johanna Richter, Radwan Massoud, Mathias Schäfersküpper, Franziska E. Marquard, Sofia Oechsler, Evgeny Klyuchnikov, Ina Rudolph, Silke Heidenreich, Christian Niederwieser, Catherina Lueck, Dietlinde Janson, Christine Wolschke, Boris Fehse, Francis Ayuk, Nicolaus Kröger","doi":"10.1002/ajh.27529","DOIUrl":"https://doi.org/10.1002/ajh.27529","url":null,"abstract":"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.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"48 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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}

{"title":"Globalization in clinical drug development for sickle cell disease","authors":"Enrico Costa,&nbsp;Russell E. Ware,&nbsp;Léon Tshilolo,&nbsp;Julie Makani,&nbsp;Hubert G. M. Leufkens,&nbsp;Lucio Luzzatto","doi":"10.1002/ajh.27525","DOIUrl":"10.1002/ajh.27525","url":null,"abstract":"&lt;p&gt;Globalization of clinical trials, defined operationally as conduct in the international arena, has grown over the past few decades. The pharmaceutical industry is expanding its activities not only in High-Income countries but also in Low- and Middle-Income countries (LMICs).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;For pharmaceutical companies, this shift can be associated with several benefits: a larger pool of potential participants, faster enrollment in trials, and substantial cost savings.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; At the same time, there may be advantages also for LMICs in terms of capacity building, gaining experience, and access to innovation.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Drug development and access to medicines in LMICs is certainly a challenge for patients with sickle cell disease (SCD), a condition that is most highly prevalent in malaria-endemic countries in the global South, but that, through the tragedy of the transatlantic slave trade and subsequent migrations, is also prominent in the global North.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The prevalence of SCD outside Africa has accelerated the development of new medicinal products, enhanced by a conducive regulatory framework. The orphan drug legislation in the United States (US) and the European Union (EU) have provided pharmaceutical developers with special incentives (e.g., periods of market exclusivity) to counterbalance the limited market size. In addition, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have implemented special pathways to expedite the review and approval of treatments for serious and life-threatening diseases. Accordingly, in both the US and the EU, treatments for SCD can be approved based on surrogate endpoints or more flexible evidence.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;To assess the trends and impact of globalization on the development of SCD drugs, we analyzed data from industry-sponsored studies initiated in the time interval from 1 January 1990 through 30 June 2024 (see Appendix S1). In the study period, a total of 79 pharmaceutical active substances were tested in 156 clinical trials.&lt;/p&gt;&lt;p&gt;Overall, 56.4% of enrolling centers were in North America, 20.5% in Europe, 7.9% in Africa, 5.7% in Latin America, 9.1% in Asia and Middle East, and 0.4% in Australia. Temporal trends from the early 2000s to the last 5 years showed a relative decrease of enrolling centers in North America from 63.1% to 44.0%, and in Europe from 28.5% to 22.2%. By contrast, in African centers there was an increase from 0.5% to 13.2%, in Latin America from 1.1% to 9.0%, and in Asia and the Middle East from 5.7% to 11.4%. The number of Australian centers remained low over time.&lt;/p&gt;&lt;p&gt;Similar trends were mirrored in the drug development phases: for instance, enrolling centers in Africa increased from 2.8% in Phase 1 trials to 4.2% in Phase 2, and to 10.6% in Phase 3 and 11.9% in Phase 4 trials. Similar increases were observed in Latin America, Asia, and the Middle East ","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 1","pages":"4-9"},"PeriodicalIF":10.1,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27525","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599907","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":"Efficacy and safety of zanubrutinib monotherapy for chronic lymphocytic leukemia/small lymphocytic lymphoma: A multicenter, real-world study in China","authors":"Jing Luo,&nbsp;Jiaojiao Zhang,&nbsp;Ligen Liu,&nbsp;Rong Wei,&nbsp;Yonghua Yao,&nbsp;Min Xu,&nbsp;Jumei Shi,&nbsp;Jianmin Yang,&nbsp;Jian Hou,&nbsp;Jin Wang,&nbsp;Jian-Qing Mi","doi":"10.1002/ajh.27519","DOIUrl":"10.1002/ajh.27519","url":null,"abstract":"&lt;p&gt;Bruton tyrosine kinase (BTK) inhibitor is now the standard of care for both treatment-naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Zanubrutinib, a next-generation BTK inhibitor with better BTK specificity and less off-target inhibition, has demonstrated superior efficacy and improved safety profile compared with first-generation BTK inhibitor ibrutinib in large phase III ALPINE study.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Zanubrutinib is the first next-generation BTK inhibitor approved in China for CLL/SLL in June 2020, and so far, the real-world data of zanubrutinib have not been reported. Thus, we present this multicenter real-world study detailing the efficacy and safety profile of zanubrutinib monotherapy in Chinese patients with CLL/SLL.&lt;/p&gt;&lt;p&gt;Chronic lymphocytic leukemia/small lymphocytic lymphoma patients treated with zanubrutinib monotherapy for at least 3 months were enrolled in 9 medical centers in Shanghai, China. The last follow-up time was September 15, 2024. CLL diagnosis, treatment indications, response assessment, and hematologic adverse events were evaluated in accordance with the International Workshop on Chronic Lymphocytic Leukemia 2018 guidelines. Patients switched from ibrutinib to zanubrutinib were not required to meet criteria for initiation of treatment. Imaging and laboratory assessments at zanubrutinib initiation were considered baseline for response assessment. Non-hematologic adverse events were graded according to the Common Terminology Criteria for Adverse Events version 5.0.&lt;/p&gt;&lt;p&gt;A total of 138 patients were included. Ninety (65.2%) patients were TN, and 48 (34.8%) were R/R, with their types of prior treatment regimens listed in Table S1. The median age at zanubrutinib initiation was 68 years. Baseline characteristics at zanubrutinib initiation were described in Table S2. Among 109 patients with available data, primary TP53 deletion and/or mutation were detected in 27 (24.8%) patients, and the ratios of TP53 aberration in TN and R/R patients were 21.9% and 30.6%, respectively. Main characteristics of zanubrutinib administration were listed in Table S3. Forty-two (30.4%) patients switched from ibrutinib to zanubrutinib, with a median duration of prior ibrutinib treatment of 12.9 months (IQR, 4.5–22.2 months). Twenty-eight (20.3%) patients had zanubrutinib dose reduction, with a median time to reduction of 2.1 months (IQR, 0.7–10.8 months), and these patients received zanubrutinib 80 mg twice daily after reduction. The median time to discontinuation among the 31 patients was 15.0 months (IQR, 7.4–23.1 months), with 48.4% discontinued due to disease progression.&lt;/p&gt;&lt;p&gt;Among 121 efficacy-evaluable patients, the overall response rate (ORR) was 86.0% and 10 (8.3%) patients achieved complete remission (CR). Seventeen patients who achieved CR with prior ibrutinib treatment at the time of zanubrutinib initiation were excluded in the sensitivity analysis of ORR. Among all","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 1","pages":"172-175"},"PeriodicalIF":10.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27519","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567748","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}