HemaSphere最新文献

{"title":"Nivolumab in combination with AVD as frontline treatment for patients with classic Hodgkin lymphoma: A real-world analysis from 20 US centers","authors":"Allison M. Bock, Peirong Hao, Yizhe Xu, Efrat Luttwak, Swetha Kambhampati Thiruvengadam, Kanithra Sekaran, Dahlia Sano, John Vaughn, John Sharp, Ajay Major, Vrutti Patel, Gordon Smilnak, Nicole Araujo, Ritwick Mynam, Daniel Reef, Marisa Palmeri, Drew Gerber, Anuja Abhyankar, Grace Baek, Ayo Falade, Madiha Iqbal, Boyu Hu, Praveen Ramakrishnan Geethakumari, Urshila Durani, Mengyang Di, Alex Niu, Hua-Jay J. Cherng, Joanna M. Rhodes, Natalie Grover, Priyanka Pophali, Tatyana Feldman, Krithika Shanmugasundaram, Jakub Svoboda, Timothy Voorhees, Catherine Diefenbach, Yasmin Karimi, Reem Karmali, Alex F. Herrera, Pallawi Torka, Narendranath Epperla","doi":"10.1002/hem3.70346","DOIUrl":"10.1002/hem3.70346","url":null,"abstract":"<p>Advanced-stage (AS) classic Hodgkin lymphoma (cHL) has been historically treated with combination chemotherapy regimens such as doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP).<span><sup>1, 2</sup></span> While these approaches have achieved high cure rates, they pose significant short- and long-term toxicities for a young patient population. Recently, immunotherapy with programmed death-1 (PD-1) blockade via nivolumab has been established as an effective strategy for relapsed/refractory cHL.<span><sup>3, 4</sup></span> The S1826 study was a randomized Phase 3 trial comparing nivolumab in combination with AVD (NAVD) versus BV-AVD in 994 patients with previously untreated AS cHL, including approximately one quarter pediatric patients.<span><sup>5</sup></span> S1826 demonstrated a 1-year investigator-assessed progression-free survival (PFS) of 94% for NAVD compared to 86% for BV-AVD.<span><sup>6</sup></span> With a longer follow-up of 3.1 years, the 3-year PFS of NAVD was durable at 91% compared to 82% in the BV-AVD arm.<span><sup>5, 7</sup></span> Immune-related adverse events (irAEs) were reported to be infrequent and consistent with the known safety profile of nivolumab. Based on these promising results, NAVD has been incorporated into US guidelines as a standard first-line treatment option for AS cHL.<span><sup>8</sup></span> AEs and efficacy of NAVD as frontline therapy in cHL patients have not been reported outside of a clinical trial. Therefore, we conducted a multicenter retrospective study to evaluate the safety and efficacy of NAVD in newly diagnosed patients with AS cHL.</p><p>This study included adult patients (≥18 years) with newly diagnosed, histologically confirmed, AS cHL treated with NAVD as standard-of-care frontline therapy between January 1, 2023, and October 1, 2025, at one of the 20 participating US sites (Figure S1).</p><p>Characteristics of the 327 patients are shown in Table S1. Median age was 37 years (range 18–88), with 24% older patients ≥ 60 years of age. Most patients had stage IV disease (61%), nodular sclerosis subtype (84%), and extranodal involvement (62%). Among patients with complete data, 29% had an International Prognostic Score (IPS) of 4–7, 26% were EBV positive, and 8% had a history of an autoimmune (AI) disease. Treatment was ongoing in 11% of patients (<i>n</i> = 35). Granulocyte colony-stimulating factor (G-CSF) was given in 64% of patients (56% as primary prophylaxis). Treatment was interrupted (any length) in 26% (Table S2). AEs were the most common reason for treatment interruption (16%) with a median delay of 8 days. The most common AE leading to treatment interruption was infection/febrile neutropenia in 6%. Chemotherapy was reduced in 11%, most commonly for neuropathy due to vinblastine, which occurred in 5%. Any treatment was discontinued in 15% of patients.","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 4","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70346","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147686346","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":"HbSC disease: Not as benign as you think","authors":"Edeghonghon Olayemi","doi":"10.1002/hem3.70311","DOIUrl":"10.1002/hem3.70311","url":null,"abstract":"<p>Hemoglobin C (HbC) arises from a missense mutation in the beta Hb (HBB) gene, leading to the replacement of glutamic acid with lysine in the beta globin chain. This mutation is very common in West Africa, where it is believed to have originated, providing some protection against malaria.<span><sup>1, 2</sup></span> HbC is less soluble than normal HbA, causing intra-cellular HbC crystal formation, which increases blood viscosity and shortens red cell lifespan. HbS is another hemoglobin mutant that causes sickle cell disease (SCD) when both alleles are mutated (HbSS), which is the most common form of SCD. Globally, compound heterozygosity for HbS and HbC (HbSC) is the second most common SCD genotype.</p><p>In both forms of SCD, the lifespan of red blood cells is significantly decreased compared to healthy individuals (average 120 days) and is about 30 days in HbSC and 20 days in HbSS. Compared to anemia and hemolysis, hyperviscosity plays a disproportionate role in HbSC morbidity. In Ghana, HbSC makes up 30%–40% of people living with SCD, which is comparable to 30% in the United States and the United Kingdom. Globally, it is estimated that between 55,000 and 100,000 babies are born with HbSC annually.<span><sup>3, 4</sup></span></p><p>Due to the delayed onset of complications, people living with HbSC disease tend to have a longer life expectancy than those living with HbSS disease. This is largely influenced by demographics, with those living in high-income countries surviving longer than those in low- and middle-income countries (LMICS), where the majority of people with the disease reside. Thus, while HbSC disease has an overall milder clinical phenotype compared to HbSS disease, this is not always the case. Unfortunately, due to this wrong assumption, people living with HbSC disease were until recently usually excluded from clinical trials for disease-modifying therapies. For example, hydroxyurea (HU) was approved by the US Food and Drug Administration (FDA) for the management of adults living with HbSS disease in 1998. For decades afterwards, there were no specific disease-modifying therapies for those living with HbSC disease, and physicians were often not sure if therapies like HU approved for HbSS could be extended to HbSC. Similarly, in 2023, the US FDA approved gene therapy for the management of SCD patients 12 years and older with recurrent vaso-occlusive crises. The clinical trials for the approved agents were primarily conducted in people with HbSS disease and HbS-β° thalassemia, again, excluding those living with HbSC disease.</p><p>A retrospective study from Ghana found that approximately 10% of individuals with HbSC had one or more severe complications that if they had HbSS would have qualified them for HU therapy by the American Society for Hematology (ASH) criteria.<span><sup>5</sup></span> In that study, pain and acute chest syndrome (ACS) incidence rates among individuals with HbSC were 74.6 (95% CI, 67.9–81.3) and 2.3 (95% CI","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 4","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70311","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147686352","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":"Neuroinflammatory changes in acute myeloid leukemia: Evidence for blood–brain barrier disruption and glial activation","authors":"Marta Febo, Daniele Sorcini, Alessandra Mirarchi, Paolo Cogliati, Arianna Stella, Paolo Sportoletti, Olga Ermakova, Martina Mandarano, Maria Cristina Marchetti, Carlo Riccardi, Brunangelo Falini, Graziella Migliorati, Cataldo Arcuri, Stefano Bruscoli, Oxana Bereshchenko","doi":"10.1002/hem3.70341","DOIUrl":"10.1002/hem3.70341","url":null,"abstract":"<p>Acute myeloid leukemia (AML) is the most aggressive form of hematologic malignancies in adults, driven by somatically acquired mutations in genes regulating myeloid lineage differentiation, proliferation, and survival.<span><sup>1</sup></span> Among cytogenetically normal AML (CN-AML), which accounts for 40%–50% of cases, recurrent mutations in <i>NPM1</i>, <i>FLT3</i>, and <i>DNMT3A</i> are most common.<span><sup>2</sup></span> Mutations in NPM1 nuclear localization signal disrupt its nuclear function, but on their own are usually insufficient to induce AML, and cooperating lesions such as FLT3-Internal tandem duplication (ITD) mutations are often required to promote leukemic transformation.<span><sup>3</sup></span> FLT3-ITD mutations lead to constitutive kinase activation, resulting in increased blast survival and more aggressive disease progression.<span><sup>1, 3</sup></span></p><p>Several hematologic malignancies show persistent inflammation arising from both leukemia-intrinsic and microenvironmental sources.<span><sup>4</sup></span> Importantly, several AML-associated mutations have been linked not only to leukemogenesis but also to dysregulation of inflammatory pathways. Somatic mutations can activate innate immune pathways, such as TLR–NF-κB signaling, inflammasome activation, and type-I interferon responses, within malignant cells, while altered stromal and immune cells in the bone marrow further amplify these inflammatory circuits. Elevated plasma levels of proinflammatory cytokines such as IL-6, IL-1β, TNF-α, and IFN-γ, which are commonly observed in AML patients, contribute to leukemic survival and resistance to therapies.<span><sup>4, 5</sup></span> Epidemiologic data show increased AML incidence in individuals with autoimmune conditions,<span><sup>6, 7</sup></span> indicating that pre-existing inflammation may promote leukemogenesis. On the other hand, AML itself can act as a driver of systemic inflammation.</p><p>While these findings highlight the importance of inflammation in AML, it remains unclear whether AML-associated inflammatory signals extend beyond the hematopoietic system to affect other organs, such as the central nervous system (CNS). This question is particularly relevant considering recent work showing that clonal hematopoiesis of indeterminate potential (CHIP) can drive systemic inflammation and influence neurological outcomes. For example, <i>TET2</i>-driven CHIP lowers Alzheimer's disease (AD) risk,<span><sup>8</sup></span> and brain-infiltrating Tet2 mutant monocytic cells were protective in a mouse model of AD.<span><sup>9</sup></span> In contrast, <i>DNMT3A</i>-mutant monocyte-derived microglia accumulate in nigrostriatal regions and induce Parkinson's disease-like motor deficits,<span><sup>10</sup></span> demonstrating that premalignant hematopoietic clones can modulate neuroinflammatory processes and neurological function. In addition, hematologic therapies, such as involving CAR-T cells, can induce CNS inf","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 4","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70341","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147686902","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":"Toxicity outcomes in phase 1 lymphoma trials abstracts are under-reported, with high use of minimizing language","authors":"Marsali Maclean, Niamh Waters, Dawn Swan, Arina Martynchyk, Charmaine Smith, Darcy Vickers, Denise Lee, Geoffrey Chong, Eliza A. Hawkes","doi":"10.1002/hem3.70351","DOIUrl":"10.1002/hem3.70351","url":null,"abstract":"<p>Lymphoma is the most common blood cancer<span><sup>1</sup></span> and is experiencing a therapeutic renaissance with cellular therapies, bispecific antibodies, antibody drug conjugates, and other targeted agents, resulting in a rapidly changing treatment landscape. Early-phase trials are key to this evolution and are carefully designed to assess, report, and mitigate harmful toxicities, with meticulous recording of grades, rates, timing, and causality to determine safety and dosage for new treatments. Subsequent drug development decisions are guided by such data.</p><p>However, a major disconnect exists between the tight regulatory environment mandating strict toxicity definitions, grading, causality, and regulatory reporting, and the publication of toxicity findings from early-phase trials. No standardized methods exist for the publication of phase 1 trial results, with significant variation in details included in publications. Publications have seen a recent rise in the use of “minimizing-terms” in concluding statements.<span><sup>2</sup></span> However, in lymphoma, as in other cancers, no guidance exists to define an “acceptable safety profile” based on rates or severity of toxicity seen.<span><sup>3</sup></span> “Acceptability” thresholds for toxicity must also consider disease severity, life expectancy, and likelihood of therapy success or cure.</p><p>Compounding these issues, as few as 35% of phase 1 trials reach publication.<span><sup>4, 5</sup></span> Data are mainly disseminated by conference abstracts. Even conference presentations and posters are publicly inaccessible, thus published abstracts, despite significant limits on information permitted, are the main formal citation in justification and discussion of further development. Toxicity data are presented to stakeholders in heterogenous, and often incomplete formats, which may have significant consequences: misinterpretation of safety, duplication of research, subsequent failure of later phase trials, delayed regulatory approvals, and post-approval dose changes, surveillance and/or reporting due to excessive toxicity.<span><sup>6</sup></span></p><p>In order to quantify variations in toxicity reporting and use of minimizing terms, we analyzed lymphoma early-phase trials published as international conference abstracts.</p><p>First in human (FIH), phase 1, phase 1b/2, and phase 1/2 trials in lymphoma were identified manually from published abstract books from seven international conferences between 2022 and 2024 [American Society of Hematology (ASH) annual scientific meeting, European Hematology Association (EHA) annual meeting and American Society of Clinical Oncology (ASCO) and International Conference on Malignant Lymphoma (ICML)]. Data were collected from published conference abstracts, with no data collected from posters, oral presentation slides, or recordings. Encore abstracts reporting identical data were excluded; those reporting a different number of patients or more advan","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 4","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70351","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147686286","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":"Correction to “Outcomes of patients with relapsed or refractory primary mediastinal B-cell lymphoma treated with anti-CD19 CAR-T cells: CARTHYM, a study from the French national DESCAR-T registry”","authors":"","doi":"10.1002/hem3.70335","DOIUrl":"https://doi.org/10.1002/hem3.70335","url":null,"abstract":"<p>Galtier J, Mesguich C, Sesques P, et al. Outcomes of patients with relapsed or refractory primary mediastinal B-cell lymphoma treated with anti-CD19 CAR-T cells: CARTHYM, a study from the French national DESCAR-T registry. <i>HemaSphere</i>. 2025;9(2):e70091. doi:10.1002/hem3.70091</p><p>In Table 1, the ranges for the ages at first infusion were missing. These have now been added.</p><p>Additionally, a typographical error in the last sentence of the Abstract has been corrected; this sentence now reads as “In conclusion, this study confirms that anti-CD19 CAR-T cells is a valid standard-of-care…”.</p><p>The original article has been updated. We apologize for this error.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 3","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70335","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147615032","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":"CD3xCD20 bispecific antibodies in transformed Waldenström macroglobulinemia/lymphoplasmacytic lymphoma","authors":"Morgane Brocard,&nbsp;Damien Roos-Weil,&nbsp;Lukshe Kanagaratnam,&nbsp;Thomas Hueso,&nbsp;Lucile Bussot,&nbsp;Benjamin Papoular,&nbsp;Cécile Tomowiak,&nbsp;Steeve Chevreux,&nbsp;Gilles Crochet,&nbsp;Tristan Vaugeois,&nbsp;Elise Toussaint,&nbsp;Simone Ferrero,&nbsp;Charalampia Kyriakou,&nbsp;Anne Quinquenel,&nbsp;Prashant Kapoor,&nbsp;Eric Durot","doi":"10.1002/hem3.70339","DOIUrl":"https://doi.org/10.1002/hem3.70339","url":null,"abstract":"&lt;p&gt;Histological transformation (HT) of Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) represents a rare complication, occurring in less than 5% of cases. Patients usually present with high-risk features, including extra-nodal involvement, elevated lactate dehydrogenase levels, high IPI scores, and frequent central nervous system (CNS) involvement.&lt;span&gt;&lt;sup&gt;1-5&lt;/sup&gt;&lt;/span&gt; These patients carry a poor prognosis after standard treatments, with shorter survival compared to non-transformed WM and de novo large B-cell lymphoma (LBCL),&lt;span&gt;&lt;sup&gt;2, 6&lt;/sup&gt;&lt;/span&gt; especially those who are not eligible or relapsing after high-dose chemotherapy with autologous stem cell transplant (SCT) and/or chimeric antigen receptor (CAR) T-cell therapy.&lt;span&gt;&lt;sup&gt;7, 8&lt;/sup&gt;&lt;/span&gt; CD3xCD20 bispecific monoclonal antibodies (BsAb) (epcoritamab and glofitamab) provide overall and complete responses of around 60% and 40%, respectively, in relapsed/refractory (R/R) aggressive B-cell lymphomas, including de novo LBCL and transformed indolent lymphomas.&lt;span&gt;&lt;sup&gt;9-11&lt;/sup&gt;&lt;/span&gt; However, no data exist for BsAb in patients with transformed WM. In the pivotal studies, only patients with transformed follicular lymphoma (FL) were included in the glofitamab study, and no information was provided on the antecedent histology for the 40 patients with transformed indolent lymphomas in the epcoritamab study. The aim of this study was to evaluate the efficacy and safety of CD3xCD20 BsAb in patients with R/R transformed WM.&lt;/p&gt;&lt;p&gt;Here, we retrospectively identified patients with HT-WM treated with CD3xCD20 BsAb in FILO/LYSA centers (&lt;i&gt;n&lt;/i&gt; = 16 patients), two other European centers (&lt;i&gt;n&lt;/i&gt; = 3 patients), and one US center (&lt;i&gt;n&lt;/i&gt; = 1 patient). Adult patients with a confirmed diagnosis of WM/LPL and R/R HT-WM who were treated with epcoritamab or glofitamab for biopsy-proven LBCL were included. The diagnosis of LBCL was made in accordance with the World Health Organization classification of malignant lymphoma and confirmed for FILO/LYSA cases by an expert hematopathologist from the Lymphopath network. The primary endpoint was the best overall response rate (ORR), according to the Lugano 2014 classification.&lt;span&gt;&lt;sup&gt;12&lt;/sup&gt;&lt;/span&gt; The secondary endpoints included the best complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and safety, including specific toxicities such as cytokine-release syndromes (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), infections, and hematological toxicity. CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) grading system. Other adverse effects were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0).&lt;/p&gt;&lt;p&gt;This study enrolled 20 patients treated between February 2023 and May 2025. The median age at diagnosis of WM was 63 years (range, 38–83). &lt;i&gt;MYD","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 3","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70339","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147579866","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":"Dynamics of BCR::ABL1 transcript levels and clinical outcomes after switch to second-line therapy in pediatric chronic myeloid leukemia","authors":"Stephanie Sembill,&nbsp;Thomas Zerjatke,&nbsp;Micha Winterstein,&nbsp;Tabita Ghete,&nbsp;Elke Schirmer,&nbsp;Zofia Wotschofsky,&nbsp;Meinolf Suttorp,&nbsp;Manuela Krumbholz,&nbsp;Axel Karow,&nbsp;Ingmar Glauche,&nbsp;Markus Metzler","doi":"10.1002/hem3.70347","DOIUrl":"https://doi.org/10.1002/hem3.70347","url":null,"abstract":"&lt;p&gt;Since its approval in 2003, imatinib has maintained its status as the primary first-line tyrosine kinase inhibitor (TKI) for children and adolescents diagnosed with chronic myeloid leukemia (CML).&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; Second-generation (2G)-TKIs, including dasatinib and nilotinib, were not approved for pediatric use until 2017 and 2018, respectively, despite their earlier availability for adult patients.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Consequently, imatinib remained the most widely used first-line agent due to the significantly greater long-term clinical experience, while 2G-TKIs have primarily been used as second-line therapy in cases of resistance or intolerance.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Randomized first-line adult trials have shown faster and deeper molecular responses with 2G-TKIs compared with imatinib; corresponding pediatric data from randomized studies are lacking.&lt;span&gt;&lt;sup&gt;5, 6&lt;/sup&gt;&lt;/span&gt; However, Phase II trials in children with newly diagnosed chronic-phase CML (CML-CP) demonstrated similar trends, with 12-month major molecular response (MMR) rates of approximately 50%–65% under 2G-TKIs, versus 30%–40% typically reported with imatinib.&lt;span&gt;&lt;sup&gt;7-11&lt;/sup&gt;&lt;/span&gt; These findings have encouraged an expanded use of 2G-TKIs in pediatric patients, not only for resistance or intolerance, but also to achieve deeper molecular remissions (DMR). However, there is a paucity of comprehensive real-world data on the frequency, rationale, and outcomes of treatment switches in pediatric CML, which engenders uncertainty about which patients benefit most from therapy modifications.&lt;/p&gt;&lt;p&gt;To address this gap, we present herein the analysis of data from the German CML-paed II trial and registry, focusing on the clinical parameters and molecular outcomes of pediatric patients switching from imatinib to 2G-TKIs. The CML-paed II trial was a prospective, investigator-initiated, multicenter, open-label Phase III study evaluating upfront imatinib therapy in children and adolescents with CML. The study was approved by institutional ethics committees (EK282 122 006; EK 236_18 B), registered at EUDRACT (2007-001339-69) and ClinicalTrials.gov (NCT00445822), and conducted in accordance with the Declaration of Helsinki. Diagnoses and molecular response assessments were performed in certified reference laboratories according to European LeukemiaNet (ELN) criteria.&lt;span&gt;&lt;sup&gt;12&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Patient characteristics were summarized using descriptive statistics and expressed as numbers and percentages or medians for categorical and continuous variables, respectively. Differences in baseline characteristics were assessed using the Mann–Whitney &lt;i&gt;U&lt;/i&gt; test for continuous data and Fisher's exact test for categorical data. To evaluate molecular response dynamics following the switch, segmented linear regression (“broken-stick”) models were fitted to individual time courses, with the switch defined as time point 0 and log-transformed &lt;i&gt;BCR::ABL1&lt;/i&gt; trans","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 3","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70347","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147579861","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":"Body composition predicts poor outcomes and reveals immunometabolic dysfunction via single-cell profiling in anti-BCMA CAR T-treated myeloma","authors":"Thomas C. Wiemers,&nbsp;Michael Rade,&nbsp;Nora Grieb,&nbsp;Maximilian Ferle,&nbsp;Tihomir Dermendzhiev,&nbsp;David Fandrei,&nbsp;Patrick Born,&nbsp;Luise Fischer,&nbsp;Sabine Seiffert,&nbsp;Anja Grahnert,&nbsp;Maik Friedrich,&nbsp;Ronny Baber,&nbsp;Markus Kreuz,&nbsp;Klaus H. Metzeler,&nbsp;Marco Herling,&nbsp;Carmen D. Herling,&nbsp;Madlen Jentzsch,&nbsp;Georg-Nikolaus Franke,&nbsp;Andreas Boldt,&nbsp;Thomas Neumuth,&nbsp;Urvi A. Shah,&nbsp;Ulrike Köhl,&nbsp;Kristin Reiche,&nbsp;Timm Denecke,&nbsp;Uwe Platzbecker,&nbsp;Vladan Vučinić,&nbsp;Hans-Jonas Meyer,&nbsp;Maximilian Merz","doi":"10.1002/hem3.70314","DOIUrl":"https://doi.org/10.1002/hem3.70314","url":null,"abstract":"<p>Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed or refractory multiple myeloma (RRMM), yet outcomes remain heterogenous. The prognostic role of body composition in this context is unknown. We retrospectively analyzed 108 RRMM patients treated with anti-B-cell maturation antigen (BCMA) CAR T-cell therapy. Pre-treatment Computed tomography imaging was utilized to quantify total adipose tissue (TAT), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and skeletal muscle area to assess sarcopenia. Longitudinal flow cytometric and single-cell multi-omic analyses were conducted to characterize the quantitative and qualitative influences of body composition on the immune microenvironment. Patients with BMI &lt; 25 kg/m² experienced significantly worse overall survival (OS) compared to high-BMI patients. Reduced TAT, primarily driven by low SAT, was associated with inferior OS, diminished response, and elevated soluble BCMA. Sarcopenia independently predicted poorer OS, while progression-free survival was unaffected by the respective parameters. Low SAT and sarcopenia correlated with lower bystander T-cell counts at leukapheresis. Longitudinal T-cell receptor sequencing and single-cell transcriptomics revealed diminished cytotoxic and interferon signaling, reduced T-cell clonality, and increased oxidative phosphorylation activity following CAR T-cell infusion. Our findings identify low SAT and sarcopenia as prognostic biomarkers that influence survival, therapeutic response, and immunometabolic profiles. Their quantification through standard imaging techniques offers a cost-effective strategy for early risk stratification and individualized management in CAR T-cell therapy.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 3","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70314","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147615029","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":"Casein kinase 1δ/ε inhibition suppresses CLL proliferation through cell-intrinsic and microenvironmental mechanisms","authors":"Antonia Mikulova,&nbsp;Hana Plesingerova,&nbsp;Michaela Chorvatova,&nbsp;Pavlina Kebkova,&nbsp;Jana Bartosikova,&nbsp;Petra Prochazkova,&nbsp;Jan Verner,&nbsp;Dominik Mulidran,&nbsp;Stepan Cada,&nbsp;Olga Vondalova-Blanarova,&nbsp;Nela Kolcakova,&nbsp;Tomas Loja,&nbsp;Terezia Kurucova,&nbsp;Eva Hoferkova,&nbsp;Boris Tichy,&nbsp;Jana Kotaskova,&nbsp;Marek Mraz,&nbsp;Lukas Kubala,&nbsp;Pavlina Janovska,&nbsp;Vitezslav Bryja","doi":"10.1002/hem3.70343","DOIUrl":"https://doi.org/10.1002/hem3.70343","url":null,"abstract":"<p>Chronic lymphocytic leukemia (CLL) is a consequence of pathological B-cell accumulation in blood and lymphoid organs. Due to high refractoriness, CLL is still incurable in many cases; therefore, there is an urgent need to develop novel therapeutic options. We have shown earlier that inhibition of casein kinase 1δ/ε (CK1δ/ε) is a promising CLL treatment strategy. Herein, we elucidate the molecular and cellular mechanisms mediating CK1δ/ε inhibition efficacy in CLL. Using an in vivo Eµ-TCL1 adoptive transfer model, we showed that CK1δ/ε inhibition caused CLL cell accumulation at the S/G2 phase in a cell-intrinsic mode. Furthermore, CK1δ/ε inhibition led to a T-cell decrease in lymph nodes (LNs). Using primary CLL cells and a system mimicking the LN microenvironment in vitro, we demonstrated that CK1δ/ε inhibition interfered with multiple pro-survival mechanisms provided by the microenvironment, most notably with the nuclear factor κ B (NFκB) pathway. NFκB acts downstream of the T-cell-mediated CD40L:CD40 stimulus, and indeed, CK1δ/ε inhibition efficiently blocked the proliferation of primary CLL triggered by CD40L across multiple patient groups, with lower efficacy in patients with <i>TP53</i> defects. We propose that CK1δ/ε inhibitors act in the multiple-hit mode, striking both intrinsically via direct interference with cell cycle machinery and extrinsically via inhibition of multiple pro-proliferative stimuli.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 3","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70343","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147615084","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":"Response to therapy and prognosis according to molecular characterization in CALR-mutated essential thrombocythemia","authors":"Marta Santaliestra,&nbsp;Marta Garrote,&nbsp;María Concepción Fernández-Rodríguez,&nbsp;Patricia Vélez,&nbsp;Alicia Senín,&nbsp;Eduardo Arellano-Rodrigo,&nbsp;Neus Garcia-Gisbert,&nbsp;Raquel Longarón,&nbsp;Manuel Pérez-Encinas,&nbsp;Gonzalo Caballero-Navarro,&nbsp;Maria Soledad Noya-Pereira,&nbsp;Beatriz Cuevas,&nbsp;María Teresa Gómez-Casares,&nbsp;Ruth Stuckey,&nbsp;Gonzalo Carreño-Tarragona,&nbsp;Francisca Ferrer-Marin,&nbsp;Miguel Angel Cortés,&nbsp;Elena Magro,&nbsp;Isabel Mata,&nbsp;Anna Angona,&nbsp;Raúl Pérez,&nbsp;María Laura Fox,&nbsp;Irene Pastor-Galán,&nbsp;Paula Sastre,&nbsp;Ana Triguero,&nbsp;Valentín García-Gutierrez,&nbsp;Juan Carlos Hernández-Boluda,&nbsp;Beatriz Bellosillo,&nbsp;Alberto Alvarez-Larran","doi":"10.1002/hem3.70325","DOIUrl":"https://doi.org/10.1002/hem3.70325","url":null,"abstract":"<p>Response to cytoreductive therapy according to <i>CALR</i> mutation type, <i>CALR</i> variant allele frequency (VAF), and additional mutations has not been previously studied in essential thrombocythemia (ET). The impact of the molecular profile on treatment response and the main clinical outcomes was analyzed in 557 <i>CALR</i> ET patients (<i>CALR</i> Type 1, <i>n</i> = 339, median VAF 36%; and <i>CALR</i> Type 2, <i>n</i> = 218, median VAF 35%). NGS data on additional mutations were available for 257 patients. <i>CALR</i> Type 2 showed a significantly higher rate of complete hematological response (CHR) to first-line cytoreduction. However, in the multivariate analysis, the effect of <i>CALR</i> mutation type in response rates was no longer significant once <i>CALR</i> VAF was considered, whereas high VAF remained independently associated with a lower likelihood of achieving CHR (hazard ratio [HR] = 0.482, 95% confidence interval (CI): 0.297–0.781; P = 0.003). Moreover, high VAF was also associated with an increased risk of arterial thrombosis (HR = 4.135, 95% CI: 1.093–15.645; P = 0.037), and progression to MF (HR = 2.631, 95% CI: 1.004–6.890; P = 0.049). Although allele burden affects overall survival (OS) in the entire population, its impact was surpassed by the presence of high molecular risk (HMR) mutations (HR = 2.114, 95% CI: 1.070–4.176; P = 0.031). Furthermore, the HMR profile was also associated with a higher risk of progression to acute leukemia, while it did not influence the probability of CHR or progression to MF. In conclusion, <i>CALR</i> VAF and HMR profile appear to be more important than <i>CALR</i> mutation type regarding treatment response and major clinical outcomes in ET.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 3","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70325","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147615050","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}