American Journal of Hematology最新文献

{"title":"Classification of Myelodysplastic, Myeloproliferative, and Myelodysplastic/Myeloproliferative Neoplasms: The Past, Present, and Future","authors":"Daniel A. Arber, Attilio Orazi","doi":"10.1002/ajh.27656","DOIUrl":"https://doi.org/10.1002/ajh.27656","url":null,"abstract":"With the recent publication of new classification systems of hematopoietic neoplasms, understanding how recognition of disease entities has occurred over time and the subsequent development of formal disease classifications is of importance. This review focuses on the early recognition of myeloid disorders, especially chronic myeloid disorders, and how clinical observations became associated with specific cytologic, histologic, immunophenotypic, and eventually genetic features. This combined approach to disease classification is of particular importance in the evaluation of chronic myeloid neoplasms and has resulted in the definition of clinicopathologic disease entities that allow for more customized treatment approaches. The constant incorporation of ever-increasing information related to these disorders illustrates that disease classification is a constantly evolving process that requires constant updates as we strive to better understand the disorders we diagnose and treat.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"23 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575531","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":"Donor Age Matters for Haploidentical HCT Patients Even After Adjusting for HLA Factors: A Machine Learning Approach","authors":"Rohtesh S. Mehta, Rodney Sparapani, Tao Wang, Stephen Spellman, Stephanie J. Lee, Effie W. Petersdorf","doi":"10.1002/ajh.27648","DOIUrl":"10.1002/ajh.27648","url":null,"abstract":"<p>A study by the Center for International Blood and Marrow Transplant Research (CIBMTR) assessed associations between HLA mismatching at individual loci and clinical outcomes after haploidentical donor hematopoietic cell transplantation (HCT) [<span>1</span>]. The HLA factors associated with superior progression-free survival (PFS) were HLA-B leader match, HLA-DRB1 mismatch, HLA-DQB1 match, and non-permissive T-cell epitope HLA-DPB1 mismatch. Although donor age was noted to be a significant predictor of overall survival, it was not identified as a risk factor for PFS; however, the study was not designed to examine the joint effects of donor age and HLA factors. An online calculator based on the PFS results is available (https://haplodonorselector.b12x.org/v1.0/) to aid in donor selection. The calculator may suggest choosing a much older donor over a younger one, for example, a 65-year-old B leader matched/DRB1 mismatched donor would be recommended over a 30-year-old HLA-B leader-mismatched/DRB1-mismatched donor.</p><p>As donor age is a known predictor of survival after haploidentical donor HCT [<span>2-6</span>], we hypothesized that the non-significant effect of donor age on PFS in the original study might be related to categorization, not fully capturing its impact. The complexity of haploidentical HCT, where multiple predictors (donor age and relationship) are interrelated and correlated with recipient factors (age), may make it difficult to separate the impact of donor age. Therefore, we reanalyzed the publicly available CIBMTR dataset from the Fuchs et al. study [<span>1</span>] using gradient boosting machines (GBM), a powerful machine learning regression methodology, with donor age as a continuous variable. As GBM models can capture complex, non-linear relationships and interactions between covariates and survival, this approach is particularly attractive. Additionally, we performed Cox proportional hazard (PH) analysis, again using donor age as a continuous variable, and compared the results of both models.</p><p>We used the publicly available CIBMTR dataset from the original publication [<span>1</span>]. The local Institutional Review Board (FHIRB0020181) approved the study, which was conducted in accordance with the Declaration of Helsinki. Our study population included patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia, or myelodysplastic neoplasm who underwent a haploidentical donor HCT between 2008 and 2017. All patients received posttransplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis.</p><p>The primary outcome of interest was PFS. The dataset included 1434 patients. As donor age and HLA factors were key variables of interest, we excluded 1 patient with missing HLA-DRB1 data, 2 patients with missing HLA-DQB1 data, and 2 patients with missing donor age, in addition to excluding 22 patients with missing PFS data. A significant proportion of patients (54%) had missing HLA-DPB1 dat","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 5","pages":"937-940"},"PeriodicalIF":10.1,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27648","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575533","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":"Emerging Pathogenetic Mechanisms and New Drugs for Anemia in Myelofibrosis and Myelodysplastic Syndromes","authors":"Naseema Gangat, Ayalew Tefferi","doi":"10.1002/ajh.27659","DOIUrl":"https://doi.org/10.1002/ajh.27659","url":null,"abstract":"Anemia in myeloid neoplasms is multifaceted, with heterogeneous pathogenetic mechanisms that include ineffective erythropoiesis, hepcidin-induced iron-restricted erythropoiesis, and abnormal inflammatory cytokine production. Current management of anemia is challenged by limited approved drugs that specifically treat anemia in myelofibrosis (MF) and myelodysplastic syndrome (MDS). Newer therapies target the transforming growth factor beta (TGF-β)-bone morphogenic protein/sons of mothers against decapentaplegic (BMP-SMAD) signaling pathway, which plays a significant role in ineffective erythropoiesis (SMAD 2/3) and abnormal hepcidin production (SMAD 1/5/8). These include TGF-β ligand traps (luspatercept, elritercept), activin A receptor type 1 (ACVR1)/activin receptor-like kinase 2 (ALK2) inhibitors (momelotinib, zilurgisertib), and anti-hemojuvelin antibody-based therapies (DISC-0974). Luspatercept and momelotinib are approved for anemia related to lower-risk MDS and MF, respectively, and represent an important addition to the treatment armamentarium, along with imetelstat, a telomerase inhibitor, recently ratified for anemia in lower-risk MDS. A promising strategy to overcome the limitations of existing anemia-directed therapies includes the use of drug combinations with complementary mechanisms (luspatercept + erythropoiesis stimulating agents, luspatercept + momelotinib, DISC-0974 + momelotinib), and harnessing the erythropoietic potential of sodium-glucose co-transporter-2 inhibitors (SGLT-2I). Future research should address the complex pathophysiology of anemia, standardize definitions for anemia with gender-specified cutoffs, implement uniform erythroid response criteria, and consider early therapeutic intervention in clinical trials for anemia-directed therapies.","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"15 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575530","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":"Expanding the Phenotype of DNA Ligase 1 Deficiency: First Report of Macrocytic Sideroblastic Anemia","authors":"Debbie Jiang, Emily Vistica Sampino, Kira Rosenlind, Dean R. Campagna, Stephanie DiTroia, Mark D. Fleming, Siobán B. Keel","doi":"10.1002/ajh.27649","DOIUrl":"10.1002/ajh.27649","url":null,"abstract":"<p>DNA Ligase 1 (LIG1) is 1 of 3 ATP-dependent DNA ligases expressed in vertebrates that play a key role in DNA replication by joining Okazaki fragments [<span>1</span>]. LIG1 also mediates single-strand DNA repair by catalyzing the final step of the base excision repair pathway and has a redundant function alongside LIG3 in mediating alternative end-joining of double-strand DNA breaks. LIG1 deficiency is a rare inborn error of immunity reported in 8 cases to date that is typically characterized by recurrent infections, early-onset hypogammaglobulinemia, and erythrocyte macrocytosis [<span>2-4</span>]. Seven of the 8 prior cases feature variants affecting coding regions that result in impaired LIG1 catalytic activity [<span>2</span>]. The remaining patient presented with severe combined immunodeficiency and Omenn-like erythematous-exfoliative skin lesions and was found to have a novel splice variant (c.776+5G>T) leading to a shift in reading frame and a premature stop codon [<span>4</span>]. Here, we report on 2 cases of LIG1 deficiency that presented with macrocytic sideroblastic anemia, a phenotype not previously recognized in this disease. Additionally, Patient 1 is the first reported case of LIG1 deficiency diagnosed in adulthood.</p><p>Patient 1 is a 37-year-old female of Northern European ancestry who was referred to adult hematologic care with a long-standing history of a mild underproduction macrocytic anemia (hemoglobin [Hb] 11.6 g/L; mean corpuscular volume [MCV] 125 fL) with normal vitamin B12 and folate levels. She had a history of recurrent sinopulmonary infections as a child, including several hospitalizations for community-acquired pneumonias, seizure disorder, moderate-persistent asthma, mild obstructive sleep apnea, and attention-deficit/hyperactivity disorder. Her mother died at age 64 from complications related to transverse myelitis; a full brother and 2 maternal half-sisters are healthy (Figure 1A). Bone marrow aspirate and biopsy showed a normocellular marrow for age with a relative erythroid hyperplasia (myeloid to erythroid ratio of 0.6:1) associated with dyserythropoiesis in a subset of erythroids, including nuclear irregularities, binucleation, and budding, as well as megaloblastic maturation. Iron stain revealed > 15% ring sideroblasts (Figure 1C). Flow cytometry on the marrow identified no abnormal myeloid, B, or T cell populations, and routine karyotype was 46, XX. Clinical <i>ALAS2</i> sequencing was negative. She had hypogammaglobulinemia (Table S1). Immunophenotyping showed mildly reduced CD19+ B cells, normal numbers of CD27+ memory B cells, and reduced immunoglobulin (Ig) class-switching with low IgM/IgD memory cells and virtual absence of IgA+ and IgG+ class-switched memory B cells. Vaccination titers were protective for only 3 of 23 pneumococcal serotypes. T and NK cell numbers were normal, and response to mitogen stimulation with phytohemagglutinin and CD3 was normal. The patient was started on replaceme","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 5","pages":"941-943"},"PeriodicalIF":10.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27649","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569543","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 Detected by NGS Are a Major Clinical Risk Factor for Stratifying Mantle Cell Lymphoma","authors":"Grégory Lazarian,&nbsp;Lotfi Chemali,&nbsp;Merieme Bensalah,&nbsp;Carla Zindel,&nbsp;Valérie Lefebvre,&nbsp;Catherine Thieblemont,&nbsp;Antoine Martin,&nbsp;Giulia Tueur,&nbsp;Rémi Letestu,&nbsp;Carole Fleury,&nbsp;Vincent Leymarie,&nbsp;Valérie Vidal,&nbsp;Audrey Bidet,&nbsp;Elsa Maitre,&nbsp;Florence Cymbalista,&nbsp;Vincent Levy,&nbsp;Thierry Soussi,&nbsp;Fanny Baran-Marszak","doi":"10.1002/ajh.27650","DOIUrl":"10.1002/ajh.27650","url":null,"abstract":"<p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 5","pages":"933-936"},"PeriodicalIF":10.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27650","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143560785","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 Outcomes and Treatment Strategies of Adult Transplant-Associated Thrombotic Microangiopathy: External Validation of Harmonizing Definitions and High-Risk Criteria","authors":"Aldo A. Acosta-Medina,&nbsp;Meera Sridharan,&nbsp;Ronald S. Go,&nbsp;Ann M. Moyer,&nbsp;Nelson Leung,&nbsp;Maria Alice V. Willrich,&nbsp;Robert Wolf,&nbsp;Rabee Kassis,&nbsp;Almothana Manasrah,&nbsp;Mira A. Kohorst,&nbsp;Urshila Durani,&nbsp;Aasiya Matin,&nbsp;Mehrdad Hefazi,&nbsp;Saad J. Kenderian,&nbsp;Abhishek A. Mangaonkar,&nbsp;Mithun V. Shah,&nbsp;Mark R. Litzow,&nbsp;William J. Hogan,&nbsp;David Dingli,&nbsp;Hassan B. Alkhateeb","doi":"10.1002/ajh.27651","DOIUrl":"10.1002/ajh.27651","url":null,"abstract":"<p>Transplant-associated thrombotic microangiopathy (TA-TMA) is an endothelial dysfunction syndrome observed after allogeneic hematopoietic cell transplant (alloHCT). Our aim was to externally validate the impact of high-risk features on the clinical outcomes of adult patients meeting the updated TA-TMA harmonizing criteria. Between 2005 and 2022, 99 patients were diagnosed with TA-TMA at Mayo Clinic Rochester (incidence 6.2%) after a median of 137 days post alloHCT (IQR: 34–283 days). The development of TA-TMA was associated with an inferior overall survival posttransplant (HR: 3.8, 95% CI: 2.97–4.72). High-risk features, including concomitant infection, acute graft-versus-host disease (GVHD), and organ dysfunction, were associated with poor survival, while LDH elevation was not associated with inferior outcomes. The most common treatment strategy for TA-TMA was discontinuation of calcineurin or mTOR inhibitors in 80 (81%) patients. Thirty (37.5%) patients experienced worsening of GVHD with this strategy, of which 26 (86.7%) patients had died at last follow-up. The most common cause of death among these patients was worsening GVHD (69%; <i>n</i> = 18), followed by infection (11%; <i>n</i> = 3), disease relapse (8%; <i>n</i> = 2), other/unknown causes (8%; <i>n</i> = 2), or TA-TMA (4%; <i>n</i> = 1). Objective response rate (ORR) to initial treatment for the cohort was 56.6%. Eculizumab was used in 11 patients with an observed ORR of 70%, including 5 complete responses. In conclusion, TA-TMA remains a significant contributor to non-relapse mortality and is associated with worse survival following alloHCT. Not all high-risk features, particularly LDH elevation, have consistently demonstrated a negative impact in adult cohorts. Patients with TA-TMA may benefit from immune suppression dose adjustment, rather than a discontinuation, and the addition of complement-directed therapy, particularly among high-risk patients.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 5","pages":"830-839"},"PeriodicalIF":10.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27651","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143560784","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 Molecular Features of Chronic Eosinophilic Leukemia, Not Otherwise Specified","authors":"Shiqiang Qu,&nbsp;Ningning Liu,&nbsp;Qi Sun,&nbsp;Huijun Wang,&nbsp;Yujiao Jia,&nbsp;Tiejun Qin,&nbsp;Zefeng Xu,&nbsp;Bing Li,&nbsp;Lijuan Pan,&nbsp;Qingyan Gao,&nbsp;Meng Jiao,&nbsp;Zhijian Xiao","doi":"10.1002/ajh.27645","DOIUrl":"10.1002/ajh.27645","url":null,"abstract":"&lt;p&gt;Chronic eosinophilic leukemia, not otherwise specified (CEL-NOS), is an extremely rare type of myeloid neoplasm, belonging to a subclass of myeloproliferative neoplasms (MPNs). Due to the lack of specific molecular markers, it remains a diagnosis by exclusion. Although previous next-generation sequencing (NGS) studies on hypereosinophilic syndrome (HES) have included subsets of CEL-NOS patients, no studies to date have specifically focused on consecutively diagnosed CEL-NOS cohorts.&lt;/p&gt;&lt;p&gt;Here, we summarize the clinical and laboratory data of 15 consecutively diagnosed patients with CEL-NOS, who referred to our hospital between July 2019 and October 2024. Diagnosis of CEL-NOS were reviewed and reclassified according to the 2022 World Health Organization (WHO) criteria [&lt;span&gt;1&lt;/span&gt;]. Peripheral eosinophils ≥ 10% of leukocytes and an absolute eosinophil count (AEoC) ≥ 1.5 × 10&lt;sup&gt;9&lt;/sup&gt;/L were observed in all CEL-NOS patients. Protein-coding region analysis was performed on bone marrow (BM) samples from all patients using a targeted panel of 137 hematolymphoid tumor-associated genes (see Data S1: Supplementary methods). A cohort of 65 patients with Idiopathic HES (IHES) diagnosed during the same period was collected as a control group. Statistical analysis is based on the clinical and laboratory parameters collected at the time of referral (see Data S1: Supplementary methods).&lt;/p&gt;&lt;p&gt;Compared to patients with IHES, CEL-NOS patients have a higher median age at presentation. The primary clinical manifestations at presentation are splenomegaly and constitutional symptoms, while skin, digestive, and respiratory symptoms are relatively uncommon (Table 1). Patients with CEL-NOS have higher WBC and lower hemoglobin and platelet concentrations. Although the absolute eosinophil and basophil counts in the complete blood count (CBC) are higher in the CEL-NOS group, there is no significant difference in their relative proportions between the two groups. CEL-NOS patients have higher serum levels of vitamin B12 and lactate dehydrogenase (LDH), as well as lower immunoglobulin E (IgE) levels. There is no significant difference in serum interleukin-5 (IL-5) levels between the two groups. In each group, clonal T-cell receptor (TCR) rearrangements were detected in 2 patients, but no abnormal lymphocyte immunophenotypes were found by multi-parameter flow cytometry (MPFC). Patients with CEL-NOS have increased BM cellularity and myeloid-to-erythroid (M:E) ratios compared to those with IHES. Among the 15 CEL-NOS patients, only one (6.7%) had a BM blast percentage of ≥ 5% at the time of presentation; however, fibrosis of grade ≥ 2 was observed in 5 patients (33.3%).&lt;/p&gt;&lt;p&gt;Cytogenetic abnormalities were detected in 8 (53.3%) CEL-NOS patients, with trisomy 8 and del(20q) identified in 3 (20%) and 2 (13.3%) cases, respectively. Other abnormalities were detected in single cases (see Tables 1 and S2). In comparison, among 65 IHES patients, only one case demonstrated an ","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 5","pages":"928-932"},"PeriodicalIF":10.1,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27645","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485819","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":"Five-Year Real-World Safety of Inotuzumab Ozogamicin Before Hematopoietic Stem Cell Transplantation in B-Cell Precursor Acute Lymphoblastic Leukemia","authors":"Marcos de Lima,&nbsp;Partow Kebriaei,&nbsp;Francesco Lanza,&nbsp;Christina Cho,&nbsp;Gizelle Popradi,&nbsp;Manmeet Kaur,&nbsp;Mei-Jie Zhang,&nbsp;Fan Zhang,&nbsp;Richa Shah,&nbsp;Erik Vandendries,&nbsp;Kofi Asomaning,&nbsp;Stephanie Dorman,&nbsp;Matthias Stelljes,&nbsp;David I. Marks,&nbsp;Wael Saber","doi":"10.1002/ajh.27637","DOIUrl":"10.1002/ajh.27637","url":null,"abstract":"&lt;p&gt;Acute lymphoblastic leukemia (ALL) is rapidly fatal without appropriate treatment [&lt;span&gt;1&lt;/span&gt;]. Chemotherapy and targeted agents have improved survival rates, but some patients need allogeneic hematopoietic stem cell transplantation (HSCT) or chimeric antigen T cell therapy to achieve long-term remission [&lt;span&gt;1&lt;/span&gt;]. Inotuzumab ozogamicin (InO) is a CD22-directed antibody-drug conjugate approved for relapsed/refractory (R/R) B-cell precursor ALL based on results from the phase 3 INO-VATE trial [&lt;span&gt;2&lt;/span&gt;]. Despite its substantial clinical benefit, InO has been linked to an increased risk of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) [&lt;span&gt;3&lt;/span&gt;]. VOD/SOS can occur from injury to the sinusoidal endothelium of the liver, typically following myeloablative (high-dose) chemo-radio therapy and HSCT, and can evolve into severe liver dysfunction and multi-organ failure [&lt;span&gt;4&lt;/span&gt;]. Pooled results from INO-VATE and the phase 1/2 Study 1010 demonstrated higher transplant-related mortality (TRM) in patients with R/R ALL receiving InO before HSCT versus those receiving standard therapy before HSCT, due in part to complications from VOD/SOS [&lt;span&gt;5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;This observational, non-interventional, post-authorization safety study used real-world data from the Center for International Blood and Marrow Transplant Research (CIBMTR) to evaluate post-HSCT outcomes in patients with B-cell precursor ALL who received InO and subsequent HSCT in the US between August 18, 2017, and August 17, 2022. The CIBMTR is a research collaboration between the National Marrow Donor Program/Be The Match and the Medical College of Wisconsin charged with collecting data on allogeneic HSCTs performed in the US (https://cibmtr.org). The National Marrow Donor Program/Be The Match Central Institutional Review Board, which is fully accredited by the Association for the Accreditation of Human Research Protection Programs, reviewed and approved this study. The study was conducted in accordance with the FDA Guidance for Industry and FDA Staff: Best Practices for Conducting and Reporting of Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data Sets, Good Pharmacoepidemiology Practices issued by the International Society for Pharmacoepidemiology, the International Society for Pharmacoeconomics and Outcomes Research guidance, and Pharmaceutical Research and Manufacturers Association guidelines.&lt;/p&gt;&lt;p&gt;The primary focus of this descriptive analysis was adults with ALL (and the subset of adults with R/R ALL) receiving first allogeneic HSCT after InO; outcomes in adults receiving allogeneic HSCT before InO are briefly described. Post-HSCT outcomes included TRM, non-TRM, relapse, overall survival (OS), and post-HSCT adverse events (AEs) of interest, including VOD/SOS. Multivariable analyses examined prognostic factors for TRM at 18 months and VOD/SOS at 100 days. See Supporting Information for additional details.&lt;/p&gt;&lt;p&gt;In al","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 5","pages":"909-912"},"PeriodicalIF":10.1,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27637","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477844","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":"Pyruvate Kinase Function Correlates With Red Blood Cell Properties and Clinical Manifestations in Sickle Cell Disease","authors":"M. J. M. Traets,&nbsp;J. F. Bos,&nbsp;S. van der Veen,&nbsp;L. van Pelt,&nbsp;M. J. van Dijk,&nbsp;B. A. van Oirschot,&nbsp;J. R. A. de Wilde,&nbsp;J. J. Jans,&nbsp;W. W. van Solinge,&nbsp;S. E. M. Schols,&nbsp;M. N. Lauw,&nbsp;M. H. Cnossen,&nbsp;E. Nur,&nbsp;B. J. Biemond,&nbsp;A. W. Rijneveld,&nbsp;E. J. van Beers,&nbsp;R. van Wijk,&nbsp;M. A. E. Rab","doi":"10.1002/ajh.27644","DOIUrl":"10.1002/ajh.27644","url":null,"abstract":"<p>Pyruvate kinase (PK) is a key enzyme involved in the final step of glycolysis, essential to produce adenosine triphosphate (ATP). Relatively decreased red blood cell (RBC) PK activity (reflected by a lower PK/hexokinase [HK] ratio) and PK thermostability (PK activity after exposure to heat) were recently identified as pathophysiological features of sickle cell disease (SCD). In this study, we investigated whether impaired PK function is associated with sickle RBC properties and SCD-related clinical manifestations. This study included 97 non-transfused patients with SCD (88 HbSS, 9 HbS/β0 thalassemia). PK thermostability was correlated with RBC parameters such as reticulocyte count (<i>r</i> = −0.402, <i>p</i> &lt; 0.0001) and hemoglobin F (<i>r</i> = 0.394, <i>p</i> &lt; 0.0001), and indicators of impaired functional properties of sickle RBCs, such as the point of sickling (<i>r</i> = −0.417, <i>p</i> &lt; 0.0001), oxygen affinity (<i>r</i> = 0.408, <i>p</i> &lt; 0.001) and RBC adhesion to laminin (<i>r</i> = −0.322, <i>p</i> = 0.024). Additionally, a low PK/HK ratio correlated with decreased PK thermostability (<i>r</i> = 0.308, <i>p</i> = 0.002), decreased RBC deformability (<i>r</i> = 0.268, <i>p</i> = 0.009), and elevated 2,3-diphosphoglycerate levels (<i>r</i> = −0.244, <i>p</i> = 0.016). Multivariate Poisson regression analysis demonstrated that reduced PK thermostability and PK/HK ratio were associated with a higher incidence of SCD-related clinical complications. For every 10-unit decrease in PK thermostability and 1-unit decrease in PK/HK ratio, the incidence of SCD-related clinical complications increased by 11% (<i>p</i> = 0.012) and 10% (<i>p</i> = 0.019), respectively. Altogether, these findings indicate that impaired PK function is related to compromised sickle RBC properties and SCD-related clinical manifestations. This supports the relevance and underlines the potential of PK activation therapy.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 5","pages":"785-796"},"PeriodicalIF":10.1,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27644","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463040","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":"FDA Approval Based on Novel Surrogate Endpoints: Lessons From the Voluntary Withdrawal of Voxelotor in Sickle Cell Disease","authors":"Myung Sun Kim,&nbsp;Vinay Prasad","doi":"10.1002/ajh.27635","DOIUrl":"10.1002/ajh.27635","url":null,"abstract":"&lt;p&gt;On September 25, 2024, Pfizer Inc. announced the voluntary withdrawal of Oxbryta (voxelotor), a hemoglobin S polymerization inhibitor, in all markets where it is approved and the discontinuation of all active clinical trials worldwide [&lt;span&gt;1&lt;/span&gt;]. Voxelotor received accelerated US Food and Drug Administration (FDA) approval in 2019 for patients 12 years of age and older with sickle cell disease. The approval was based on the HOPE trial (NCT03036813) [&lt;span&gt;2&lt;/span&gt;]. HOPE showed the drug was capable of an increase in hemoglobin from baseline of more than 1.0 g/deciliter at week 24 (1.1 g/dL), which is the primary endpoint. The only clinically relevant endpoint of the study was vaso-occlusive crises, which was reported as a secondary outcome. The drug was developed by Global Blood Therapeutics, a biopharmaceutical company, which was acquired by Pfizer in 2022. In 2024, Pfizer's stated reason for withdrawal was due to an imbalance in vaso-occlusive crises and fatal events, where the overall benefit no longer outweighed the risk of the drug. Further information has not yet been provided.&lt;/p&gt;&lt;p&gt;A careful review of the regulatory history of voxelotor reveals concerns regarding the product, present since the initial submission. Specifically, how did a 1.0 g/dL rise in hemoglobin come to constitute a surrogate endpoint thought reasonably likely to predict benefit? The case of voxelotor raises lingering questions regarding the FDA's process for soliciting novel, surrogate endpoints from companies, and the timeliness of post-marketing studies to adjudicate benefit.&lt;/p&gt;&lt;p&gt;Over the last decade, the US FDA has encouraged the development of novel surrogate endpoints by sponsoring companies, and engages with sponsors to provide guidance regarding feasibility and acceptability. Novel biomarker endpoints are often developed for specific diseases—for instance, those lacking good treatment options or for agents with new mechanisms of action. One example is the recent approval of Xolremdi (mavorixafor) for WHIM syndrome, a rare genetic disease, that was based on improvement in absolute neutrophil count as a primary endpoint.&lt;/p&gt;&lt;p&gt;In the case of voxelotor, the FDA raised concern as early as the initial submission that a small rise in hemoglobin may not be considered a surrogate reasonably likely to predict clinical benefit [&lt;span&gt;3&lt;/span&gt;]. The sponsor responded with data from 2 trials, STOP2 (NCT00006182) [&lt;span&gt;4&lt;/span&gt;] and SIT (NCT00072761) [&lt;span&gt;5&lt;/span&gt;], that studied prophylactic transfusions in preventing stroke and silent cerebral infarction, respectively. The sponsor's argument was that the rise in hemoglobin is a surrogate for the reduction in transcranial doppler (TCD) flow velocity, and TCD velocity is a predictor of stroke and silent infarct risk. The FDA requested further evidence for the chosen cut-off (1 g/dL) and study duration.&lt;/p&gt;&lt;p&gt;At the time of approval, the logic behind utilizing a 1 g/dL hemoglobin rise was dubious. The American So","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 5","pages":"922-924"},"PeriodicalIF":10.1,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27635","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463044","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}