HemaSphere最新文献

{"title":"Current and future role of carfilzomib-based quadruplet combinations as therapy for newly diagnosed multiple myeloma","authors":"Ola Landgren,&nbsp;Noa Biran,&nbsp;Elizabeth K. O'Donnell,&nbsp;Joseph Mikhael,&nbsp;Katja C. Weisel,&nbsp;Annemiek Broijl,&nbsp;Saad Z. Usmani,&nbsp;Philippe Moreau,&nbsp;Francesca M. Gay,&nbsp;Roberto Mina,&nbsp;Paula Rodríguez-Otero,&nbsp;Andrzej J. Jakubowiak,&nbsp;Benjamin A. Derman","doi":"10.1002/hem3.70178","DOIUrl":"https://doi.org/10.1002/hem3.70178","url":null,"abstract":"<p>The treatment of newly diagnosed multiple myeloma (NDMM) has advanced rapidly in recent years, with the standard of care (SOC) now including not only triplet combinations of proteasome inhibitors (PIs), immunomodulatory agents, and steroids but also quadruplet combinations that add the anti-CD38 monoclonal antibodies isatuximab (Isa) or daratumumab (D) to a triplet backbone. In addition to the widely used bortezomib–lenalidomide–dexamethasone (VRd) combination, an alternative triplet option that can be considered is the combination of the second-generation PI carfilzomib (K) with lenalidomide–dexamethasone (KRd). In patients with transplant-eligible NDMM, US treatment guidelines have included the KRd triplet as a recommended regimen and the quadruplet combinations of either Isa-KRd or D-KRd as additional options. However, currently, KRd does not have regulatory approval for use in the NDMM population. This review describes the current evidence for using KRd as a backbone of therapy in frontline treatment regimens for patients with NDMM. In addition to multiple studies that have examined the KRd triplet in this population, several clinical trials have been investigating anti-CD38-KRd quadruplets. The data reported from these various trials are revealing deep and durable responses with Isa-KRd and D-KRd, including minimal residual disease negativity. Importantly, these benefits have also been demonstrated in high-risk NDMM populations. KRd-based combinations may represent a suitable alternative to VRd for some patients. This article discusses measures that may help to establish KRd-based quadruplets as an additional SOC in this setting, including proper patient selection, steps to mitigate safety concerns, and the establishment of optimal dosing schedules.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 7","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70178","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polypharmacy independently predicts survival, hospitalization, and infections in patients with lymphoid cancer","authors":"Christian Brieghel,&nbsp;Thomas Lacoppidan,&nbsp;Esben Packness,&nbsp;Casper Møller Frederiksen,&nbsp;Mikkel Werling,&nbsp;Michael Asger Andersen,&nbsp;Christian Bjørn Poulsen,&nbsp;Emelie Curovic Rotbain,&nbsp;Carsten Utoft Niemann","doi":"10.1002/hem3.70172","DOIUrl":"https://doi.org/10.1002/hem3.70172","url":null,"abstract":"<p>Polypharmacy is a result of multimorbidity and may limit treatment options in patients with lymphoid cancer (LC). To investigate the clinical impact of polypharmacy, we gathered a prediagnostic 1-year medication history from the Danish prescription register for 46,803 newly diagnosed patients with six lymphoma subtypes, chronic lymphocytic leukemia, and multiple myeloma (MM). Medication was grouped into individual drug classes (<i>n</i> = 79), polypharmacy, and the number of prescription medications and correlated with overall survival (OS), hospitalization, and severe infection. Adjusting for age, sex, and multiple testing, we demonstrated associations between 39 drug classes and OS, 29 drug classes and hospitalization, and 27 drug classes and severe infection. Although polypharmacy (&lt;5 vs. ≥5) was associated with adverse outcomes (hazard ratio [HR] 1.4 for OS, hospitalization, and severe infection; P &lt; 0.001), the number of medications (0–3 vs. 4–7 vs. 8–11 vs. &gt;11) gradually stratified OS (HR 1.0 vs. 1.2 vs. 1.4 vs. 1.9, respectively; P &lt; 0.001), hospitalization (HR 1.0 vs. 1.3 vs. 1.4 vs. 1.9, respectively; P &lt; 0.001), and severe infection (HR 1.0 vs. 1.2 vs. 1.5 vs. 1.9, respectively; P &lt; 0.001) in multivariable analyses adjusted for age, sex, comorbidity, and prognostic indices. Lastly, the time to next treatment for Hodgkin lymphoma, mantle cell lymphoma, and MM was gradually shorter with an increasing number of medications (P &lt; 0.001). In conclusion, a 1-year medication history summarized as the number of medications is a strong, independent prognostic and predictive marker that should be considered as a key baseline characteristic in randomized clinical trials and in clinical practice for LC patients.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 7","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70172","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reproductive health concerns of women living with sickle cell disease","authors":"Edeghonghon Olayemi","doi":"10.1002/hem3.70167","DOIUrl":"https://doi.org/10.1002/hem3.70167","url":null,"abstract":"&lt;p&gt;With advancements in care, people living with sickle cell disease (SCD) now live to reproductive age and beyond; however, improvements in care for their reproductive health have lagged far behind, leading to excess mortality and morbidity among pregnant women living with SCD compared to those without the disease.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Globally, there is insufficient knowledge regarding reproductive health among women living with SCD. The association between chronic diseases such as SCD and mental health is well known. Unfortunately, women with SCD face additional mental stress, worrying about the risk of passing the disease and/or the sickle cell gene to their children. Three major themes emerged from a new study led by Lisa Roberts,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; using a qualitative research approach to investigate reproductive health concerns of women with SCD and sickle cell trait (SCD/T).&lt;/p&gt;&lt;p&gt;Under this theme the authors outlined the effect of SCD/T on dating, fertility, and family choices. They demonstrated that women living with SCD in the reproductive age bracket are faced with uncertainty about their reproductive future. Choices like romantic relationships and marriage, which their peers without the disease take for granted, can have significant health implications because they have to juggle their desire for fulfilling romantic relationships and procreation with the risks posed by the disease to themselves and their offspring.&lt;/p&gt;&lt;p&gt;This theme revealed that some participants had insufficient knowledge of SCD/T and the possible effects of SCD/T on reproductive health. As a result, they felt unprepared and had difficulty asking pertinent questions even when they had the opportunity to do so during encounters with health care personnel. On the other hand, those who were knowledgeable about the disease faced the dilemma of when and how to discuss this with a new partner, who may not be as knowledgeable.&lt;/p&gt;&lt;p&gt;This mental toll interferes with relationships with partners, peers, and close relatives, the very people needed to provide support during difficult times like sickle cell crises and pregnancy. So, some people living with SCD spend time and energy trying to conceal their symptoms instead of dealing with them. This makes living with SCD even more difficult for both the person living with it and their caregivers.&lt;/p&gt;&lt;p&gt;This study by Roberts and colleagues&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; lays the foundation for further investigation in this area. It reaffirms the lack of support or the perceived lack of support provided by health care workers to people living with SCD, which is similar to that reported by earlier studies. Although it is not clear why the authors included people with sickle cell trait (HbAS), which is essentially a benign condition, in their study, a possible reason may be the risk of their offspring inheriting the sickle cell gene.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; This work exposes the apprehension faced by young women living with SCD/","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 7","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70167","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting thrombotic risk in patients with classical Hodgkin lymphoma: Thro-HL multicenter study","authors":"Giovanni Manfredi Assanto,&nbsp;Eleonora Alma,&nbsp;Alessandro Cellini,&nbsp;Giovanni Marsili,&nbsp;Gianluca Maiorana,&nbsp;Cristina Santoro,&nbsp;Martina Salvatori,&nbsp;Natalia Cenfra,&nbsp;Vladimir Otasevic,&nbsp;Darko Antic,&nbsp;Gianna Maria D'Elia,&nbsp;Maria Paola Bianchi,&nbsp;Giorgia Annechini,&nbsp;Silvio Ligia,&nbsp;Alessandro Pulsoni,&nbsp;Agostino Tafuri,&nbsp;Andrea Visentin,&nbsp;Alfonso Piciocchi,&nbsp;Stefan Hohaus,&nbsp;Maurizio Martelli,&nbsp;Ilaria Del Giudice,&nbsp;Antonio Chistolini","doi":"10.1002/hem3.70163","DOIUrl":"https://doi.org/10.1002/hem3.70163","url":null,"abstract":"<p>Thrombosis Lymphoma (ThroLy) and Khorana scores have been conceived to predict the thrombotic risk in oncohematologic patients. Currently, there is no univocal indication to perform thromboprophylaxis in classical Hodgkin lymphoma (cHL). We performed a retrospective study to validate scores and risk factors in a cohort of consecutive patients with cHL, treated from 2014 to 2022 outside clinical trials. A total of 470 cHL patients without thromboprophylaxis were included, of whom 57 (12%) experienced a thrombotic event (TE) at 3.3 months (range 1–52) from diagnosis. Neither Khorana nor ThroLy score significantly predicted the thrombotic risk. In a multivariate analysis including Throly parameters and other risk factors, an independent prognostic impact on the TE risk was found for bulky disease (3 points), ECOG PS 2–4 (2 points), presence of peripherally implanted central venous catheter (2 points), mediastinal involvement (1 point), which were combined in a new risk model (Thro-HL). Low-risk (score 0–1; 39%, <i>n</i> = 183), intermediate-risk (score 2–3; 46%, <i>n</i> = 214), and high-risk (score &gt; 3; 15%, <i>n</i> = 72) patients had a significantly different TE rate, of 2.7%, 16%, and 25% (P &lt; 0.001), respectively. Three-year-thrombotic event-free survival was 97% (CI 95–100) for low-risk and 76% (CI 66–86) for high-risk patients (P &lt; 0.0001, Harrel's <i>C</i>-index = 0.70). Thro-HL could be a promising tool to be validated in larger series.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 7","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70163","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term follow-up and combined Phase 2 results of eprenetapopt and azacitidine in patients with TP53 mutant MDS/AML","authors":"David A. Sallman,&nbsp;Rami S. Komrokji,&nbsp;Amy E. Dezern,&nbsp;Marie Sebert,&nbsp;Guillermo Garcia-Manero,&nbsp;Ramy Rahmé,&nbsp;Eric S. Winer,&nbsp;Jacqueline Lehmann-Che,&nbsp;Gail J. Roboz,&nbsp;Isabelle Madelaine,&nbsp;Mikkael A. Sekeres,&nbsp;Pierre Peterlin,&nbsp;Onyee Chan,&nbsp;Odile Beyne-Rauzy,&nbsp;Andrew Kuykendall,&nbsp;Christian Recher,&nbsp;Amy McLemore,&nbsp;Aspasia Stamatoullas,&nbsp;Ling Zhang,&nbsp;Lise Willems,&nbsp;Qianxing Mo,&nbsp;Emmanuel Raffoux,&nbsp;Lisa Nardelli,&nbsp;Céline Berthon,&nbsp;Najla H. Al Ali,&nbsp;Bruno Quesnel,&nbsp;Eric Padron,&nbsp;Hagop M. Kantarjian,&nbsp;Alan F. List,&nbsp;Lionel Ades,&nbsp;Jeffrey E. Lancet,&nbsp;Pierre Fenaux,&nbsp;Thomas Cluzeau","doi":"10.1002/hem3.70164","DOIUrl":"https://doi.org/10.1002/hem3.70164","url":null,"abstract":"<p><i>TP53</i> gene mutations (m<i>TP53</i>) represent a distinct molecular cohort with poor outcomes. Eprenetapopt (APR-246) is a novel, first-in-class small molecule that reactivates p53 and targets cellular redox balance, ultimately inducing apoptosis and ferroptosis in m<i>TP53</i> cancer cells. This is a multicenter, international collaboration of the US myelodysplastic syndromes/neoplasms (MDS) clinical research symposium and the Groupe Francophone des Myelodysplasies (GFM) of hypomethylating agents-naïve m<i>TP53</i> higher risk MDS and oligoblastic acute myeloid leukemia (AML; ≤30% blasts; NCT03072043/NCT03588078). Patients received eprenetapopt 4500 mg iv (Days 1–4) + azacitidine 75 mg/m² sc/iv × 7 days in 28-day cycles. The primary objective was the complete remission (CR) rate by International Working Group (IWG) 2006 criteria. In total, 100 patients were enrolled with a median age of 68 years (34–87; 47% male). Febrile neutropenia occurred in 37% of patients. Thirty- and 60-day mortality was 1% and 7%, respectively. By intention-to-treat, overall response rate by IWG was 69% with 41% CR. The median duration of CR was 10.2 months (95% CI 8.7–11.8). With a median follow-up of 52 months, median overall survival (OS) was 11.8 months (95% CI 9.4–14.3). Although allogeneic hematopoietic cell transplantation (allo-HCT) was borderline predictive of OS in the overall cohort by landmark analysis (14.7 vs. 14.4 months; P = 0.046), OS was significantly improved in allo-HCT patients based on CR/<i>TP53</i> next-generation sequencing (NGS) negativity (P = 0.00085; 2-year OS of 54%). In this international, combined analysis of Phase 2 eprenetapopt + azacitidine patients, the combination was well-tolerated with synergistic response rates in m<i>TP53</i> MDS/AML. Quality of response and NGS negativity strongly predicted OS, particularly in the setting of allo-HCT, validating NGS clearance as a critical biomarker of allo-HCT outcomes in m<i>TP53</i> patients.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 7","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70164","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PRC2-mediated apoptosis evasion is a therapeutic target of MDS/AML harboring inv(3)/t(3;3) and monosomy 7","authors":"Hiroyoshi Kunimoto,&nbsp;Ayaka Miura,&nbsp;Maiko Sagisaka,&nbsp;Mieko Ito,&nbsp;Ryoichi Maenosono,&nbsp;Hirofumi Yamauchi,&nbsp;Kazuki Nishimura,&nbsp;Daisuke Honma,&nbsp;Shinji Tsutsumi,&nbsp;Akiko Adachi,&nbsp;Takayuki Sakuma,&nbsp;Takuma Ohashi,&nbsp;Hiroshi Teranaka,&nbsp;Junji Ikeda,&nbsp;Sei Samukawa,&nbsp;Takashi Toya,&nbsp;Yuka Harada,&nbsp;Noriko Doki,&nbsp;Sheng F. Cai,&nbsp;Hiroaki Maki,&nbsp;Hiroaki Goto,&nbsp;Akihide Yoshimi,&nbsp;Hideaki Nakajima","doi":"10.1002/hem3.70149","DOIUrl":"https://doi.org/10.1002/hem3.70149","url":null,"abstract":"<p>Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) harboring both inv(3)/t(3;3) and monosomy 7 (−7) are highly aggressive myeloid cancers of which molecular pathogenesis and therapeutic vulnerability remain elusive. High throughput drug screens, CUT&amp;Tag/RNA sequence, and functional assays using human MDS/AML cells revealed that EZH2 inhibitors efficiently induce apoptosis preferentially in MDS/AML with inv(3)/t(3;3) and −7 through the activation of GADD45γ-p38-p53 axis. EVI1 activated in 3q-rearranged MDS/AML was responsible for <i>GADD45γ</i> silencing by direct binding to its consensus sequence within GADD45γ promoter and recruitment of PRC2 complex via interaction with EZH2, which can be therapeutically targeted by EZH2 inhibition. MDS/AML with inv(3)/t(3;3) and −7 showed preferential sensitivity to EZH2 inhibition in both mouse model and patient samples. Thus, MDS/AML cells with inv(3)/t(3;3) and −7 possess apoptosis evasion mechanism through EVI1-PRC2-mediated repression of GADD45γ-p38-p53 axis, which is a potential therapeutic vulnerability in MDS/AML patients with these high-risk cytogenetic lesions.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 7","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70149","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Surface downmodulation of TIM3 safeguards healthy cells but not acute myeloid leukemia from CAR T-cell therapy","authors":"Jort J. van der Schans,&nbsp;Paresh Vishwasrao,&nbsp;Renée Poels,&nbsp;Morgan Antti,&nbsp;Ziyu Wang,&nbsp;Marjolein Quik,&nbsp;Jennemiek van Arkel,&nbsp;Tom Reuvekamp,&nbsp;Niels W. C. J. van de Donk,&nbsp;Maria Themeli,&nbsp;Gert J. Ossenkoppele,&nbsp;Arjan A. van de Loosdrecht,&nbsp;Rebecca Richards,&nbsp;Tuna Mutis","doi":"10.1002/hem3.70155","DOIUrl":"https://doi.org/10.1002/hem3.70155","url":null,"abstract":"<p>T-cell immunoglobulin and mucin-domain containing-3 (TIM3), generally known as an immune checkpoint receptor, is expressed on leukemic stem and progenitor cells (LSPCs) in acute myeloid leukemia (AML), and has an active role in LSC self-renewal. Therefore, TIM3 has been suggested as a potential target for AML treatment. Hence, we explored the feasibility of targeting TIM3 with chimeric antigen receptor (CAR) T-cells. Despite the expression of TIM3 on activated T-cells, TIM3 CAR T-cells were successfully generated from different healthy individuals with excellent in vitro expansion without signs of fratricide and sustained central-memory phenotype with minimal expression of exhaustion-related markers, including complete loss of TIM3 expression. TIM3 loss also did not affect effector functions since TIM3 CAR T-cells efficiently lysed TIM3⁺ leukemic cell lines, produced Th1-predominant cytokines, successfully inhibited the colony-forming of TIM3⁺ AML-derived LSPCs, and showed excellent AML tumor control in xenogeneic mouse models. Notably, TIM3 CAR T-cells did not affect healthy hematopoietic progenitor cells and healthy mature hematopoietic cells that express TIM3 at moderate levels, suggesting an optimal therapeutic window for the treatment of AML.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 7","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70155","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Luspatercept versus mitapivat for non-transfusion-dependent β-thalassemia: Dare to compare?","authors":"Khaled M. Musallam,&nbsp;Sujit Sheth,&nbsp;Maria Domenica Cappellini,&nbsp;Kevin H. M. Kuo,&nbsp;Antonis Kattamis,&nbsp;Yesim Aydinok,&nbsp;Vip Viprakasit,&nbsp;Ali T. Taher","doi":"10.1002/hem3.70165","DOIUrl":"https://doi.org/10.1002/hem3.70165","url":null,"abstract":"&lt;p&gt;There is now ample evidence that untreated anemia in patients with non-transfusion-dependent β-thalassemia (NTDT) is associated with significantly increased risks of morbidity and mortality, challenging previous management strategies relying largely on conservative observation.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Hemoglobin levels &lt;10 g/dL are now used to indicate the need for intervention, and increases ≥1 g/dL are believed to be clinically meaningful based on data from observational studies.&lt;span&gt;&lt;sup&gt;2-5&lt;/sup&gt;&lt;/span&gt; The key challenge has been the lack of options beyond regular transfusions to treat anemia in NTDT, the latter being associated with secondary iron overload precluding its wide, long-term application.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Repurposing of drugs such as hydroxycarbamide was largely unsuccessful in NTDT.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Splenectomy, which was once a common choice, has now become obsolete owing to increased risks of infections and thrombotic events.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; A new era of novel disease-modifying therapeutics development has thus emerged in the past 10 years to address the unmet need of treating anemia in NTDT patients.&lt;/p&gt;&lt;p&gt;Several novel agents targeting hepcidin dysregulation have been evaluated for their effect on both iron overload and ineffective erythropoiesis or red cell survival, based on data from animal studies indicating a bidirectional relationship between both pathophysiologic mechanisms. However, results from clinical trials did not echo these findings, and most such programs have been terminated.&lt;span&gt;&lt;sup&gt;7, 8&lt;/sup&gt;&lt;/span&gt; By targeting ineffective erythropoiesis via different modes of action, two novel agents “made it through” to late development as treatment options for anemia in NTDT. Luspatercept is a recombinant fusion protein made of a modified extracellular domain of the human activin receptor Type IIB fused to the Fc domain of human IgG1. These in turn bind to select transforming growth factor β superfamily ligands, block SMAD2/3 signaling, and enhance erythroid maturation during late-stage erythropoiesis. Mitapivat is a first-in-class oral, small-molecule, allosteric activator of the red blood cell-specific form of pyruvate kinase that increases ATP levels and mitigates oxidative damage during erythropoiesis. Both agents have been shown to improve red cell survival and reduce hemolysis and/or ineffective erythropoiesis in β-thalassemia mouse models.&lt;span&gt;&lt;sup&gt;9-15&lt;/sup&gt;&lt;/span&gt; Luspatercept has been evaluated in adult patients with NTDT in the BEYOND trial and is now approved in Europe since 2023 (but not the United States) for this indication.&lt;span&gt;&lt;sup&gt;16&lt;/sup&gt;&lt;/span&gt; Mitapivat has also been evaluated in adult patients with NTDT in the ENERGIZE trial, which recently met its endpoints, and is awaiting regulatory approvals and marketing authorization.&lt;span&gt;&lt;sup&gt;17, 18&lt;/sup&gt;&lt;/span&gt; With no head-to-head comparison trial on the horizon and considering potential treatment choices (between the t","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 7","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70165","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144612022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can health inequalities in sickle cell disease be addressed through novel therapies?","authors":"Stephen P. Hibbs,&nbsp;Richard J. Buka,&nbsp;Mary Shaniqua,&nbsp;Paul Greaves,&nbsp;John James,&nbsp;Paul Telfer","doi":"10.1002/hem3.70175","DOIUrl":"https://doi.org/10.1002/hem3.70175","url":null,"abstract":"&lt;p&gt;On 31st January 2025, the UK's National Institute for Health and Clinical Excellence (NICE) approved the gene therapy product exagamglogene autotemcel (exa-cel) for use in some people living with sickle cell disease (SCD).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; This decision is a historical victory on several levels: a new potent treatment option for people living with a severe disease, an advocacy success to ensure access to a high-cost medication for a marginalised group and a scientific milestone deploying CRISPR-Cas9 gene editing in clinical practice.&lt;/p&gt;&lt;p&gt;Despite reasons for celebration, the reception to exa-cel's approval is complicated. Although UK National Health Service (NHS) press statements and media reports focus on progress and hope, they rarely mention the recent history of two other novel therapies for SCD. These medications—crizanlizumab and voxelotor—were both developed specifically for people living with SCD, approved by NICE, administered to patients across the UK and withdrawn abruptly during 2024 due to efficacy and safety concerns&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; (Figure 1).&lt;/p&gt;&lt;p&gt;In this Perspective, we grapple with a challenging dilemma: Do health inequalities faced by people with SCD justify early access to new therapies? Or does reducing the requirement of clinical evidence expose patients to inadequately tested treatments, compounding inequalities as well as damaging trust? We argue that the current approach favouring early approval requires changes in how we communicate about regulatory decisions and how treatment withdrawals are navigated. Finally, we call for investment into ‘familiar therapies’: established but inadequately implemented strategies to address health inequalities for people living with SCD. Whilst our article is based on the UK experience, these considerations apply to novel therapies in diverse contexts.&lt;/p&gt;&lt;p&gt;Life expectancy and quality of life for individuals born with SCD have steadily improved over recent decades, but the condition continues to present profound challenges. Many patients suffer frequent hospitalisations and chronic organ damage, and some die prematurely from SCD complications.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Most patients experience painful crises and significant fatigue. Although blood transfusions and hydroxycarbamide are accessible and transformative therapies for some, for others, these treatments are ineffective, unsuitable or cause intolerable side effects. Compounding the direct health impacts of SCD, individuals face significant health inequalities (Box 1). Patients, clinicians, advocates and regulatory bodies want to address these inequalities, in part through access to new SCD treatments.&lt;/p&gt;&lt;p&gt;Three decades ago, a review article on SCD concluded that ‘the once-distant goal of providing gene therapy for haemoglobinopathies is rapidly approaching reality’.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; In contrast to this prediction, the development of both gene therapy and other new disease-modifying treatments has be","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 7","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70175","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating tumor-associated and neoantigen-specific endogenous T cells in children treated for B-acute lymphoblastic leukemia","authors":"Eliane Huwiler,&nbsp;Anne-Christine Thierry,&nbsp;Justine Michaux,&nbsp;Huisong Pak,&nbsp;Florian Huber,&nbsp;Caroline Arber,&nbsp;Michal Bassani-Sternberg,&nbsp;Alexandre Harari,&nbsp;Francesco Ceppi","doi":"10.1002/hem3.70171","DOIUrl":"https://doi.org/10.1002/hem3.70171","url":null,"abstract":"&lt;p&gt;Like most pediatric cancers, B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is considered poorly immunogenic due to its low tumor mutational burden (TMB).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; As a result, research has primarily focused on synthetic approaches that actively induce novel immune responses targeting tumor antigens, irrespective of naturally occurring antitumor immunity.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; Notable examples include bi-specific CD19-CD3 antibody and foremost chimeric antigen receptor (CAR) T cell therapy, which has revolutionized treatment and significantly improved relapse-free survival in chemorefractory pediatric BCP-ALL.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; Nevertheless, severe immune-mediated toxicities, on-target off-tumor toxicity like B-cell aplasia, and disease relapse due to antigen escape associated with these treatments underscore the need for safer, more specific, and durable therapies.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In contrast, natural immunity-based approaches, such as tumor-infiltrating lymphocyte (TIL) therapy and cancer vaccines, have shown remarkable success in adult cancers with high mutational load,&lt;span&gt;&lt;sup&gt;6-8&lt;/sup&gt;&lt;/span&gt; yet remain largely unexplored in pediatric cancers. Interestingly, increasing evidence challenges the notion of TMB as the sole determinant of immunogenicity.&lt;span&gt;&lt;sup&gt;9, 10&lt;/sup&gt;&lt;/span&gt; A pivotal study in the field of pediatric cancer demonstrated that patients with BCP-ALL mount, in the Bone marrow (BM), a robust endogenous CD8+ T cell response against a majority of predicted private neoantigens,&lt;span&gt;&lt;sup&gt;11&lt;/sup&gt;&lt;/span&gt; suggesting that pediatric cancers may also exhibit substantial natural immunity. Although private neoantigens are associated with potent antitumoral immunity, tumor-associated antigens (TAAs) are also relevant targets for immune responses in this cancer type.&lt;span&gt;&lt;sup&gt;7, 12, 13&lt;/sup&gt;&lt;/span&gt; Additionally, it is unclear whether a systemic immune response is mounted in these patients. Compared to the previously described study,&lt;span&gt;&lt;sup&gt;11&lt;/sup&gt;&lt;/span&gt; we therefore expanded our analysis to peripheral blood (PB) and directly identified TAAs through high-throughput immunopeptidomics, while employing an experimentally validated multiparameter pipeline for refined neoantigen prediction.&lt;/p&gt;&lt;p&gt;Building on these insights, we set out to investigate the presence of endogenous T cells recognizing tumor antigens in the PB of pediatric BCP-ALL patients after remission (Supporting Information S2: Methods and Materials). Eight pediatric patients diagnosed with BCP-ALL and treated at the Centre hospitalier universitaire vaudois (CHUV) in Lausanne were included (Supporting Information S1: Table 1). BM and PB samples were collected respectively at diagnosis (V1) and timepoints after remission subsequent to treatment (V3 or follow-up) (Supporting Information S1: Figure 1). HLA-I and HLA-II restricted TAAs and neoantigens were respectively identified and predicted. Peptide-specific T-cell re","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 7","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70171","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144573921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}