HemaSphere最新文献

{"title":"Chemoimmunotherapy-associated CD20 (MS4A1) resistance mutations in Waldenström macroglobulinemia: Epitope disruption independent of expression with implications for CD20-directed cellular therapies","authors":"Alberto Guijosa, Nickolas Tsakmaklis, Sirano Dhe-Paganon, Filip Garbicz, Ruben Carrasco, John Hatcher, Andres Ramirez-Gamero, Dominic Pizzarella, Amanda Kofides, Shirong Liu, Hao Sun, Xia Liu, María L. Guerrera, Andrew R. Branagan, Gottfried von Keudell, Shayna R. Sarosiek, Jorge J. Castillo, Zachary R. Hunter, Steven P. Treon","doi":"10.1002/hem3.70468","DOIUrl":"10.1002/hem3.70468","url":null,"abstract":"<p>CD20, encoded by <i>MS4A1</i>, is one of the earliest and most extensively used immunotherapeutic targets in B-cell malignancies. In Waldenström macroglobulinemia (WM), rituximab administered alone or with chemotherapy or BTK inhibitors is a mainstay of frontline therapy.<span><sup>1</sup></span> Acquired resistance to rituximab is common, though the mechanisms underlying resistance remain poorly understood. This knowledge gap is particularly relevant as novel CD20 therapies (e.g., T-cell engagers [TCE], chimeric antigen receptor [CAR] T-cell therapy) are entering clinical trials for previously treated WM patients.<span><sup>2-6</sup></span> We therefore performed a large multi-omic analysis to characterize <i>MS4A1</i> alterations in previously treated WM.</p><p>We performed whole-exome sequencing (WES) in CD19+ sorted bone marrow mononuclear cells with matched CD19-depleted peripheral blood mononuclear cells as germline control in 247 previously treated patients with WM. <i>MS4A1</i> mutations (<i>MS4A1</i><sup><i>MUT</i></sup>) were structurally mapped onto the CD20 crystal structure (PDB: 6Y90). Functional impact was evaluated using in silico prediction tools with predefined deleteriousness thresholds for point mutations (CADD > 20) and splice-site mutations (Splice AI > 0.7). RNA sequencing with rRNA depletion was performed to assess CD20 transcript levels, isoforms, and mutation expression. Flow cytometry (L27 clone) and CD20 immunohistochemistry (IHC) (L26 clone) were used to assess CD20 expression and localization (Supporting Information Methods).</p><p>We restricted our analysis to 164 patients who had a >5% <i>MYD88</i><sup><i>L265P</i></sup> variant allele fraction (VAF) to ensure adequate tumor content (median VAF, 36%; range, 5.4%–98%). The median age for these patients was 65 (37–89 years) and 61% were male. The median time from diagnosis and first therapy to study sample was 6.2 (95% CI 4.3–7.1) and 4.4 (95% CI 2.7–5.8) years, respectively. Patients received a median of 1.5 prior lines (range 1–9); 63 (38%) received CD20-containing CIT, 81 (49%) anti-CD20 without chemotherapy, and 20 (12%) no prior anti-CD20 therapy. At the time of study biopsy, 95/164 (58%) patients were progressing. A total of 9 (5%) patients harbored somatic <i>MS4A1</i><sup><i>MUT</i></sup> (Supporting Information S1: Table 1).</p><p><i>MS4A1</i><sup><i>MUT</i></sup> was observed exclusively in patients who were previously exposed to CD20-containing CIT (9/63; 14%) and was absent among those treated with anti-CD20 antibody without chemotherapy (0/81) or never exposed to an anti-CD20 antibody (0/20; P < 0.001 for three-way comparison; Figure 1A). However, compared with patients treated with anti-CD20 without chemotherapy, those receiving CIT had more prior therapy lines (median, 3 vs. 1; P < 0.001) and were more often progressing at biopsy (73% vs. 48%; P = 0.008) (Supporting Information S1: Table 2).</p><p>All nine patients with <i>MS4A1</i><s","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 10","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13626146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108685","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":"Quality of life with nivolumab and AVD first-line treatment of Hodgkin lymphoma in the Phase II GHSG NIVAHL trial","authors":"Christian Peter Jaworek, Ina Bühnen, Peter Herhaus, Julia Meissner, Karolin Trautmann-Grill, Teresa Halbsguth, Andrea Kerkhoff, Valdete Schaub, Michael Fuchs, Bastian von Tresckow, Peter Borchmann, Karolin Behringer, Paul Jan Bröckelmann","doi":"10.1002/hem3.70485","DOIUrl":"https://doi.org/10.1002/hem3.70485","url":null,"abstract":"<p>First-line treatment of classic Hodgkin lymphoma (HL) is undergoing a shift towards early incorporation of targeted agents. The anti-PD1-based regimen nivolumab plus doxorubicin, vinblastine and dacarbazine (N-AVD) is now approved for patients with advanced-stage disease and also considered a treatment option for intermediate-stage HL.<span><sup>1-3</sup></span> Because cure rates are high and many HL patients are young, longitudinal quality of life (QoL), fatigue, and return to work are central to shared decision-making. To this end, the QoL impact of anti-PD1-based first-line treatment remains poorly described.<span><sup>4, 5</sup></span></p><p>To address this knowledge gap, we herein report the preplanned longitudinal QoL analysis of the randomized Phase II GHSG NIVAHL trial (NCT03004833). In NIVAHL, 109 patients aged 18–60 years with intermediate-stage HL received cumulatively four cycles of N-AVD (concomitant, Group A; or sequential, Group B), each followed by 30 Gy involved-site radiotherapy (IS-RT).<span><sup>1, 2</sup></span> Patients providing separate informed consent completed the validated EORTC QLQ-C30 and QLQ-FA12 questionnaires at enrollment, after systemic treatment, after IS-RT, and at 1- and 3-year follow-up (FU).<span><sup>6, 7</sup></span> Functional, symptom, and global health status (GHS) scores were age- and sex-standardized to German general population reference values, with zero indicating no difference from the reference population.<span><sup>8</sup></span> As previously established, fatigue scores of 30 or higher were considered clinically relevant.<span><sup>9</sup></span> Differences from the reference population and changes over time were considered statistically significant if the corresponding 95% CI excluded zero. Time to recovery from fatigue (TTR-F; interval from end of treatment [EOT] to the first assessment with a fatigue score below 30) and time to return to work (TTR-W; interval from EOT to the first documented return to work or education among patients reporting employment or education before diagnosis) were analyzed using time-to-event methods, with multivariable Cox models adjusted for age and sex. In an exploratory analysis, the impact of immune-related hypothyroidism (irHypothyroidism), the most frequent chronic immune-related adverse event (irAE), on QoL domains was assessed. Analyses were performed in SAS 9.4 (SAS Institute, Cary, NC, USA).</p><p>Of 109 patients, 98 (90%) were evaluable for the present analysis, contributing 397 questionnaires (median 4 per patient) with high completion (QLQ-C30 93%, QLQ-FA12 97%) and declining availability over time (Figures S1 and S2). The median age was 27 years (range 18–60), 60% were female, 74% had an ECOG of 0, and 77% presented with Stage IIA disease. As expected in this trial for patients with intermediate-stage HL, at least one of the GHSG risk factors was present in all patients, with ≥3 nodal areas most common (Table S1). Baseline life situation, includ","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 10","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70485","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072630","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":"Generic versus branded imatinib in frontline chronic myeloid leukemia: A systematic review and meta-analysis","authors":"Shankar Biswas, Yashasvi Srivastava, Nayanika Tummala, Ayman Hamadttu","doi":"10.1002/hem3.70479","DOIUrl":"https://doi.org/10.1002/hem3.70479","url":null,"abstract":"<p>Chronic myeloid leukemia (CML) affects approximately 1 to 2 per 100,000 adults annually, and imatinib has transformed the disease into a chronic condition with near-normal life expectancy.<span><sup>1, 2</sup></span> Branded imatinib exceeded $100,000 per year in the United States prior to patent expiry, and more than 100 CML experts called these prices unsustainable.<span><sup>3</sup></span> The European LeukemiaNet 2020 recommendations endorsed generic imatinib as the cost-effective initial treatment for chronic-phase (CP) CML.<span><sup>4</sup></span> Individual studies comparing generic and branded imatinib have reported conflicting results. The only prior systematic review, by Erçalışkan et al.,<span><sup>5</sup></span> narratively summarized 36 papers but performed no quantitative pooling. We conducted the first meta-analysis pooling frontline clinical outcomes of generic versus branded imatinib in CML-CP.</p><p>This systematic review followed PRISMA 2020 guidelines<span><sup>6</sup></span> and was registered with PROSPERO. PubMed, Embase, and Scopus were searched from inception through January 2025 (Supporting Information S5: Table 6). Comparative observational studies enrolling adults with CML-CP who received generic imatinib with at least one frontline outcome compared with branded imatinib were included. Two reviewers independently extracted data and assessed quality using the Newcastle-Ottawa Scale (NOS; 0–9; Supporting Information S5: Table 2). Random-effects meta-analyses used the Mantel–Haenszel method with DerSimonian–Laird estimation. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for binary outcomes; hazard ratios (HRs) were pooled for event-free survival using the inverse-variance method. Heterogeneity was assessed with <i>I</i><sup>2</sup> and Cochran <i>Q</i>. Pre-specified subgroup analyses were by geographic region and NOS quality. Leave-one-out sensitivity analyses were performed for both primary outcomes. Meta-regression examined publication year and NOS score as moderators. Publication bias was assessed with funnel plots and trim-and-fill. Certainty of evidence was assessed using GRADE (Supporting Information S5: Table 4). Switch response and detailed safety data from this systematic review will be reported separately.</p><p>A total of 696 records were identified; after removing 292 duplicates and screening 404 records, 30 full texts were assessed (Supporting Information S5: Table 5) and 21 studies were included (Supporting Information S1: Figure 1). The 21 studies<span><sup>7-15</sup></span> encompassed 5349 patients across 13 countries, published between 2013 and 2025 (Supporting Information S5: Table 1). NOS scores ranged from 2 to 9 (median, 7); 13 studies (62%) were rated good quality. Twelve frontline comparative studies contributed to at least one pooled analysis. Of the 16 studies included in quantitative pooling, fewer than half contributed to any individual endpoint, and several ","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 10","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70479","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072629","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":"Gene expression analysis after BTK and PI3Kδ inhibitor treatment in chronic lymphocytic leukemia identifies cell-surface CXCR4 as a synergistic target for combinatorial therapy","authors":"Gabriela Mladonicka Pavlasova, Veronika Sandova, Laura Ondrisova, Vaclav Seda, Petra Pavelkova, Daniel Filip, Krystof Hlavac, Josef Vecera, Sarka Pospisilova, Anna Panovska, Stacey M. Fernandes, Michael Doubek, Jennifer R. Brown, Marek Mraz","doi":"10.1002/hem3.70481","DOIUrl":"https://doi.org/10.1002/hem3.70481","url":null,"abstract":"<p>BTK and PI3Kδ inhibitors (BTKi/PI3Ki) targeting kinases associated with the B-cell receptor (BCR) pathway are highly effective in chronic lymphocytic leukemia (CLL), and BTKi represent a cornerstone of CLL therapy. BTKi are preferred in clinical practice over idelalisib due to lower toxicity, but idelalisib plus anti-CD20 antibodies remains relevant in the treatment of CLL cases resistant to BTKi and venetoclax, in BTKi-intolerant patients, and next-generation PI3Ki such as duvelisib or umbralisib are being developed. Notably, BTK and PI3K are involved in distinct parts of the BCR cascade, yet their inhibition produces similar effects, including disruption of CLL cell migration and adhesion, leading to peripheral blood lymphocytosis.<span><sup>1, 2</sup></span> To increase clinical efficacy, BTKi/PI3Ki are commonly used in combination with anti-CD20 antibodies and/or with the BH3 mimetic venetoclax. However, CD20 expression is significantly repressed by BTKi or PI3Ki therapy,<span><sup>3, 4</sup></span> which complicates the use of BCRi in combination with anti-CD20 antibodies. Moreover, CLL cells adapt to BCR inhibition by altering gene expression to support their survival.<span><sup>3, 5, 6</sup></span> We hypothesized that analyzing BCR inhibitor-induced gene expression changes could reveal (dis)similarities in the effects of both BTKi and PI3Ki and identify other cell-surface molecules that may serve as alternative targets for monoclonal antibodies in combination with BTKi/PI3Ki.</p><p>To understand the effects of BTKi and PI3Ki, we performed RNA profiling (Illumina TrueSeq, see Supporting Information S1: Supplemental Methods) in CLL cells obtained from peripheral blood of CLL patients before and during first weeks of treatment with ibrutinib or idelalisib as a single agent <i>in vivo</i> (ibrutinib <i>n</i> = 11 pairs of pretreatment and on therapy samples from the end of Weeks 1–12, idelalisib <i>n</i> = 9 pairs of pretreatment and on therapy samples from the end of Weeks 2–4; patient characteristics in Supporting Information S2: Table 1). This identified 225 and 340 mRNAs that were significantly changed after ibrutinib or idelalisib treatment, respectively (adjusted P < 0.05, fold change > 1.5, base mean > 100; Figure 1A,B; data deposited as EGAS50000000620 and EGAS50000000621 in the European Genome-Phenome Archive). BCRi induced similar gene expression changes irrespectively of patients' <i>IGHV</i> mutational status or the time of sampling during therapy (Supporting Information S1: Figure 1A–C). Both BCRi induced relatively similar gene expression changes with overlap of 105 mRNAs differentially expressed with both ibrutinib and idelalisib (86 downregulated and 19 upregulated mRNAs; Figure 1C,D, Supporting Information S2: Table 2). These results confirm that ibrutinib primarily leads mostly to repression of gene expression,<span><sup>7</sup></span> and, to our knowledge, for the first time demonstrate that PI3Kδ inhibition wi","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 9","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70481","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048459","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":"Decoding cancer-associated ribosomal protein mutations: A new frontier in cancer and ribosome biology","authors":"Mirsada Čaušević, Robbie Loewith, Siniša Volarević","doi":"10.1002/hem3.70493","DOIUrl":"https://doi.org/10.1002/hem3.70493","url":null,"abstract":"<p>For a long time, ribosomes were considered passive molecular machines that produced proteins under the direction of translation factors, but this view has changed relatively recently.<span><sup>1</sup></span> Emerging evidence positions the ribosome as an active player in protein synthesis, capable of shaping translation through changes in ribosome composition, modifications, and interactions with regulatory factors.<span><sup>1, 2</sup></span> This functional diversity enables ribosomes to fine-tune protein synthesis in response to cellular demands, while altered ribosome heterogeneity has been increasingly linked to human disease.<span><sup>1, 2</sup></span></p><p>Ribosomal proteins (RPs), together with ribosomal RNA, constitute the structural and functional foundation of the ribosome and are essential for ribosome biogenesis (RiBi) and protein synthesis; accordingly, complete loss of most RP genes is incompatible with mammalian cell survival.<span><sup>2</sup></span> In contrast, heterozygous loss-of-function mutations are tolerated but cause ribosomopathies, including Diamond–Blackfan anemia and 5q- syndrome, which are characterized by developmental abnormalities and bone marrow failure.<span><sup>2-4</sup></span> These disorders are associated with impaired RiBi, which reduces global translational capacity and activates the 5S RNP–MDM2–p53 ribosomal stress response, along with other cellular stress pathways, while also perturbing key regulators of cell growth and proliferation, including MYC.<span><sup>1, 5</sup></span> These stress responses restrain cell proliferation and, when sustained, can promote apoptosis.<span><sup>1, 5</sup></span> Reduced ribosome abundance can also selectively alter the translation of specific mRNAs in a cell type- and context-dependent manner, leading to dysregulation of lineage-critical factors and transcriptional programs. Erythroid cells may be particularly vulnerable because erythropoiesis requires high levels of coordinated RiBi and protein synthesis. Impaired globin translation can disrupt heme–globin balance and increase oxidative stress, further compromising erythroid proliferation and differentiation.<span><sup>3</sup></span></p><p>Paradoxically, despite reduced translational capacity and activation of robust tumor-suppressive responses, including p53 upregulation and MYC downregulation, these disorders confer a substantial predisposition to malignancies, particularly myeloid neoplasms and selected solid tumors.<span><sup>6</sup></span> Consistent with this paradox, recurrent somatic heterozygous loss-of-function mutations in RP genes are found across a broad spectrum of acquired human cancers.<span><sup>1, 6</sup></span> In this context, <i>TP53</i> inactivation is thought to represent a particularly important permissive event, enabling cells harboring heterozygous loss-of-function RP mutations to evade the p53-dependent ribosomal stress checkpoint and acquire malignant potential.<span><sup>6</sup></","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 9","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70493","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149047884","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":"Dynamic risk stratification in smoldering multiple myeloma: Integrating evolving biomarkers with the 2/20/20 Model","authors":"Theresia Akhlaghi,&nbsp;David Nemirovsky,&nbsp;Kylee H. Maclachlan,&nbsp;Ross S. Firestone,&nbsp;Neha Korde,&nbsp;Sham Mailankody,&nbsp;Alexander M. Lesokhin,&nbsp;Hani Hassoun,&nbsp;Dhwani Patel,&nbsp;Urvi A. Shah,&nbsp;Carlyn R. Tan,&nbsp;Heather J. Landau,&nbsp;Gunjan L. Shah,&nbsp;Michael Scordo,&nbsp;Anish K. Simhal,&nbsp;Ola Landgren,&nbsp;Sergio A. Giralt,&nbsp;Saad Z. Usmani,&nbsp;Andriy Derkach,&nbsp;Malin Hultcrantz","doi":"10.1002/hem3.70473","DOIUrl":"10.1002/hem3.70473","url":null,"abstract":"<p>Smoldering multiple myeloma (SMM) is a heterogeneous precursor with variable risk of progression to multiple myeloma (MM). Current risk models rely on baseline features, limiting predictive accuracy. We aimed to define evolving risk factors and integrate them with the 2/20/20 model to improve risk stratification. We analyzed 323 SMM patients diagnosed per IMWG 2014 criteria at Memorial Sloan Kettering Cancer Center (2002-2019). Serial M-protein and free light chain-ratio (FLCr) measurements were assessed during the first year following diagnosis. Using a multivariable Cox proportional hazards model adjusted for baseline 2/20/20 risk, age, and sex, we defined optimal cut-offs for evolving M-protein (eMP) as an increase of ≥0.4 g/dL and evolving FLCr (eFLCr) as an increase of ≥40% within the first year. Both eMP and eFLCr were independently associated with progression to MM (hazard ratio [HR] 2.8, 95% confidence interval [CI] 1.5–5.5; and HR 2.9, 95% CI 1.8–4.8). Median time to progression was 18 months for eMP and 41 months for eFLCr, compared to 130 versus 201 months without eMP and eFLCr, respectively. Integrating evolving biomarkers into the 2/20/20 model improved performance (c-index 0.79 vs. 0.70). Patients with both high baseline risk and evolving markers had 2- and 5-year progression rates of 41% and 83%, respectively, while low-risk patients without evolving disease exhibited a stable course resembling monoclonal gammopathy of undetermined significance (MGUS) with a 5-year progression rate of 8%. These findings support incorporating dynamic biomarkers into existing models to improve risk stratification and inform clinical decision-making in SMM.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 9","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13598806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038315","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":"Second-line axicabtagene ciloleucel in large B-cell lymphoma ineligible for transplantation: ALYCANTE final analysis","authors":"Roch Houot,&nbsp;Jean Lemoine,&nbsp;Alexis Claudel,&nbsp;Emmanuel Bachy,&nbsp;Guillaume Cartron,&nbsp;François-Xavier Gros,&nbsp;Franck Morschhauser,&nbsp;Lucie Oberic,&nbsp;Thomas Gastinne,&nbsp;Pierre Feugier,&nbsp;Rémy Duléry,&nbsp;Catherine Thieblemont,&nbsp;Magalie Joris,&nbsp;Fabrice Jardin,&nbsp;Sylvain Choquet,&nbsp;Olivier Casasnovas,&nbsp;Gabriel Brisou,&nbsp;Morgane Cheminant,&nbsp;Jacques-Olivier Bay,&nbsp;Jules Coville,&nbsp;Francisco Llamas-Gutierrez,&nbsp;Karin Tarte,&nbsp;Cédric Portugues,&nbsp;Emmanuel Itti,&nbsp;Xavier Palard-Novello,&nbsp;Paul Blanc-Durand,&nbsp;Yassine Al Tabaa,&nbsp;Clément Bailly,&nbsp;Camille Laurent,&nbsp;François Lemonnier","doi":"10.1002/hem3.70472","DOIUrl":"10.1002/hem3.70472","url":null,"abstract":"&lt;p&gt;Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, is a standard-of-care (SOC) second-line option for patients with refractory/relapsed (R/R) large B-cell lymphoma (LBCL). In the ZUMA-7 trial, axi-cel demonstrated superior efficacy compared to chemoimmunotherapy followed by high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT), in transplant-eligible patients. However, in clinical practice, approximately half the patients with R/R LBCL are transplant-ineligible, due to advanced age or comorbidities, and have a poor prognosis with standard chemoimmunotherapy.&lt;span&gt;&lt;sup&gt;1-4&lt;/sup&gt;&lt;/span&gt; This prompted the ALYCANTE trial to evaluate axi-cel as a second-line therapy in patients with high-risk R/R LBCL deemed ineligible for transplantation. At the interim analysis, the study met its primary endpoint, achieving a 3-month complete metabolic response (CMR) rate of 71.0%.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; With a median follow-up of 12.0 months, median progression-free survival (PFS) was 11.8 months, while median overall survival (OS) was not reached (NR).&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; The final analysis of ALYCANTE, reported here after a median follow-up of 37.4 months, confirms the durable efficacy of axi-cel across age and comorbidity subgroups, with no new safety signals. Causes of death and outcome of patients who relapsed after axi-cel treatment are also reported.&lt;/p&gt;&lt;p&gt;In this Phase 2, prospective, single-arm, open-label study (ALYCANTE; NCT04531046), patients were enrolled across 18 centers. Study design and procedures were previously reported.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Briefly, patients aged ≥18 years with high-risk R/R LBCL after a first-line of chemoimmunotherapy were considered ineligible for HDCT/ASCT based on physician assessment and at least one of the following criteria: age ≥ 65 years, hematopoietic cell transplantation-comorbidity index (HCT-CI) score ≥ 3, or prior ASCT. ALYCANTE was conducted in accordance with the Declaration of Helsinki and International Good Clinical Practice guidelines. All patients provided written informed consent.&lt;/p&gt;&lt;p&gt;Patients underwent leukapheresis, optional bridging therapy (rituximab plus gemcitabine and oxaliplatin, and/or corticosteroids), and lymphodepleting chemotherapy (cyclophosphamide 500 mg/m&lt;sup&gt;2&lt;/sup&gt;/day and fludarabine 30 mg/m&lt;sup&gt;2&lt;/sup&gt;/day for 3 days), 5 days prior to axi-cel infusion (2 × 10&lt;sup&gt;6&lt;/sup&gt; CAR T-cells/kg). Disease assessments, survival, and safety were evaluated in patients who received axi-cel. Study endpoints and assessments are described in Supplemental Data. Efficacy outcomes were also analyzed by age (&lt;70 vs. ≥70 years) and HCT-CI score (&lt;3 vs. ≥3). The final analysis occurred when the last patient deceased, withdrew consent, completed follow-up, or was lost to follow-up (data cutoff date [DCO], June 13, 2025). Response rates were calculated using the Clopper–Pearson method. Time-to-event endpoints we","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 9","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024777","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":"A functional prognostic model predicts progression-free survival in patients with relapsed chronic lymphocytic leukemia treated with ibrutinib + venetoclax","authors":"Johanne U. Hermansen,&nbsp;Weikaixin Kong,&nbsp;Andrea M. Brodersen,&nbsp;Yanping Yin,&nbsp;Aleksandra Urban,&nbsp;Idun D. Rein,&nbsp;Liye He,&nbsp;Rudi Agius,&nbsp;Rebecca S. Teglgaard,&nbsp;Juho Rousu,&nbsp;Christian Brieghel,&nbsp;Sabina Kersting,&nbsp;Mark-David Levin,&nbsp;Hoa T. T. Tran,&nbsp;Mattias Mattsson,&nbsp;Juha Ranti,&nbsp;Gerrit-Jan Veldhuis,&nbsp;Caspar da Cunha-Bang,&nbsp;Rogier Mous,&nbsp;Julie Dubois,&nbsp;Arnon P. Kater,&nbsp;Jorrit M. Enserink,&nbsp;Carsten U. Niemann,&nbsp;Tero Aittokallio,&nbsp;Sigrid S. Skånland","doi":"10.1002/hem3.70467","DOIUrl":"10.1002/hem3.70467","url":null,"abstract":"<p>Targeted therapies have improved outcomes for patients with chronic lymphocytic leukemia (CLL); yet, not all achieve durable responses. Existing prognostic models, developed for chemoimmunotherapy, have limited predictive value for newer targeted combinations. Here, we used data from a randomized phase II clinical trial to identify predictors of progression-free survival (PFS) in response to Bruton tyrosine kinase (BTK) + B-cell lymphoma 2 (Bcl-2) inhibitor combination therapy. We studied the functional, genetic, and clinical characteristics of patients with relapsed/refractory (R/R) CLL treated with ibrutinib + venetoclax in the VISION/HO141 clinical trial (NCT03226301). Ex vivo drug sensitivity testing, (phospho)protein profiling, and immunophenotyping were performed on baseline peripheral blood mononuclear cells from 177 patients. Ex vivo drug sensitivity correlated with clinical responses to single-agent therapies. (Phospho)protein patterns reflected intracellular pathway activity and predicted ex vivo drug sensitivity. Using stringent feature selection and regularized ridge regression to prevent overfitting, we integrated functional, genetic, and clinical data sets and identified six features—sensitivity to VEGFR-2-, JAK1/2 + Bcl-2-, and BTK + PI3K-inhibitors; phosphorylation ratios of Bcl-2:BTK and p90RSK:PLCγ2; and frequency of CD8⁺ T cells—that together outperformed the International Prognostic Index for CLL (CLL-IPI) and other clinical scores in predicting PFS. These findings demonstrate that a prognostic model based on the functional features of CLL cell signaling and interaction with the microenvironment has the potential to improve upon conventional prognostic scores, warranting further clinical validation also in the frontline setting.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 9","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13585436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148989694","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":"Identification of favorable subgroups of pediatric high-hyperdiploid acute lymphoblastic leukemia—A retrospective multinational study","authors":"Andishe Attarbaschi,&nbsp;Amir Enshaei,&nbsp;Saskia Sonnenberg,&nbsp;Chloé Arfeuille,&nbsp;Draga Barbaric,&nbsp;Lena Behrman,&nbsp;Anke Bergmann,&nbsp;Nicole Bodmer,&nbsp;Judith M. Boer,&nbsp;Myriam Campbell,&nbsp;Gunnar Cario,&nbsp;Hélène Cavé,&nbsp;Lydia Champezou,&nbsp;Sarah Elitzur,&nbsp;Gabriele Escherich,&nbsp;Hester A. de Groot-Kruseman,&nbsp;Monique L. den Boer,&nbsp;Csongor Kiss,&nbsp;Jelena Lazic,&nbsp;Anja Möricke,&nbsp;Hannah Muhle,&nbsp;Karin Nebral,&nbsp;Rob Pieters,&nbsp;Pierre Rohrlich,&nbsp;Martin Schrappe,&nbsp;Lucie Srámková,&nbsp;Ajay Vora,&nbsp;Emese Zsigrai,&nbsp;Arndt Borkhardt,&nbsp;Martin Zimmermann,&nbsp;Anthony V. Moorman,&nbsp;International Berlin-Frankfurt-Münster (i-BFM) Study Group","doi":"10.1002/hem3.70477","DOIUrl":"10.1002/hem3.70477","url":null,"abstract":"&lt;p&gt;B-cell acute lymphoblastic leukemia (B-ALL) with high-hyperdiploidy (HHD) represents the most prevalent genetic subtype of childhood ALL and is associated with favorable outcome measures.&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; HHD occurs in 25%–30% of B-ALL and is largely defined by a modal chromosome number (MCN) ranging from 51 up to 67.&lt;span&gt;&lt;sup&gt;1, 2, 4&lt;/sup&gt;&lt;/span&gt; Although several study groups have proposed HHD-definitions to identify patients with particularly favorable outcome, there is no consensus regarding the use of HHD as a whole group or its subgroups for risk stratification. This issue is clinically relevant because HHD-ALL still accounts for a substantial proportion of relapses, but it also requires renewed consideration because modern treatment, including blinatumomab-based chemoimmunotherapy, is likely to change the prognostic contribution of genetic classifiers derived from chemotherapy-based cohorts.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;We therefore performed a retrospective multinational study within the international Berlin-Frankfurt-Munster (i-BFM) ALL Group to evaluate previously described HHD-subgroup definitions in European-based B-ALL trials. Our primary aim was not to compare the prognostic impact of HHD- versus non-HHD-B-ALL across trials. Rather, we aimed to determine, within each included study, which HHD-definition identified both the largest proportion of B-ALL cases and the most favorable outcome, followed by an assessment of consistency across studies. The study should thus be interpreted as a reference benchmark for ongoing and future HHD-ALL cohorts, rather than as a definitive guide for treatment de-intensification in contemporary protocols.&lt;/p&gt;&lt;p&gt;Data on basic characteristics, treatment, and outcome of non-Down syndrome B-ALL patients aged 1–18 years were collected from seven i-BFM ALL Group members. Overall, 11,530 B-ALL patients treated across nine multicenter trials were included (Supporting Information S3: Data Supplement), comprising 3231 patients with HHD- and 8299 with non-HHD-B-ALL.&lt;span&gt;&lt;sup&gt;6-15&lt;/sup&gt;&lt;/span&gt; Patients were treated in recruiting trials between 1998 and 2018. The median follow-up exceeded 5 years in all trials except ALL-IC BFM 2009.&lt;span&gt;&lt;sup&gt;15&lt;/sup&gt;&lt;/span&gt; Apart from the EORTC-CLG 58951 trial, HHD was not used for risk stratification.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; For the COALL Study Group, the two consecutive trials COALL-07-03 and COALL-08-09 were analyzed together because they shared the same diagnostic work-up and central cytogenetic review and used closely related treatment backbones, whereas DCOG ALL10 and ALL11 were kept separate as they represented distinct, prospectively defined treatment-reduction strategies. This resulted in eight trial cohorts.&lt;span&gt;&lt;sup&gt;8, 14&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;For this study, HHD was defined as a chromosome number between 51 and 67.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Diagnostic bone marrow and/or peripheral blood samples were analyzed by standard G-banded karyotyping. Apart from t","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 9","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13585435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148989747","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":"Inherited microcytic anemias due to disorders of iron and heme metabolism: An updated clinical review","authors":"Alexandros Makis,&nbsp;Ioanna Saougou,&nbsp;Eleftheria Hatzimichael","doi":"10.1002/hem3.70465","DOIUrl":"10.1002/hem3.70465","url":null,"abstract":"<p>Microcytic anemia is among the most common hematological abnormalities in clinical practice and is usually attributable to iron deficiency, thalassemia traits, or anemia of inflammation. A small but clinically important subset of patients, however, has inherited disorders of iron metabolism or heme synthesis presenting with persistent, unexplained, familial, or iron-refractory microcytosis. Over the past decade, advances in the understanding of the hepcidin–ferroportin axis, erythroid iron regulation, standardized hepcidin assays, and next-generation sequencing have substantially refined diagnosis, while expert guidance for iron-refractory iron deficiency anemia (IRIDA) has refined management, and hepcidin-targeted therapies in early development signal a shift towards mechanism-based treatment, though their role in IRIDA remains investigational. This review provides an updated, clinically oriented framework for inherited microcytic anemias caused by defects in systemic iron homeostasis, cellular iron transport, mitochondrial iron utilization, and heme biosynthesis. We propose a contemporary diagnostic algorithm integrating clinical features, iron biomarkers, hepcidin assessment, and molecular testing, and review current and emerging therapeutic strategies. Early recognition enables accurate diagnosis, avoids inappropriate investigations and treatment, facilitates genetic counselling, and helps prevent irreversible organ damage, particularly in iron-overload disorders.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 9","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148989718","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}