HemaSphere最新文献

{"title":"Chimeric antigen receptor T-cell therapy in diffuse large B-cell lymphoma: Evaluating axicabtagene ciloleucel in the ZUMA-7 trial","authors":"Vadim Lesan, Cristian Munteanu","doi":"10.1002/hem3.70119","DOIUrl":"https://doi.org/10.1002/hem3.70119","url":null,"abstract":"<p>Chimeric antigen T-cell (CAR-T) therapy is the new standard of therapy in patients with refractory or early relapsed diffuse large B-cell lymphoma (r/r DLBCL).<span><sup>1</sup></span> Axicabtagene ciloleucel (Axi-cel) was one of the first therapies to show superior event free survival (primary endpoint of the study) and significant overall survival (OS) benefit in this context.<span><sup>2</sup></span> Recently published data on subsequent anti-lymphoma therapies after second-line axicabtagene ciloleucel (Axi-Cel) imply that outcomes are better when Axicel is given in earlier lines of therapies.<span><sup>3</sup></span> Further, reanalysis of the ZUMA-7 trial outcome data regarding the metabolic tumor volume (MTV) revealed that Axicel improved event-free survival and progression-free survival over the standard of care irrespective of MTV.<span><sup>4</sup></span> Although we acknowledge the positive impact of Axicel in the treatment of patients with DLBCL, we raise some concerns about moving Axicel further in the frontline therapies.</p><p>Analyzing the outcome results for subsequent therapies after Axi-cel and SOC in the context of the previous reports from the ZUMA-7 trial, we observed some important discrepancies. First, the median time to third-line therapy was lower in the SOC arm compared to the Axi-Cel arm (2.8 vs. 4.4 months). This difference could be either due to higher proportion of aggressive disease and/or poor prognostic factors in SOC arm or due to greater investigator's willingness to declare refractory and/or progressive disease in the SOC arm compared to Axi-Cel arm. Although, the absence of bridging therapy has precluded the enrollment of patients with aggressive disease in the initial report of the ZUMA-7 trial, only two patients had progressive disease before Axi-Cel infusion. At a median of 29 days from leukapheresis to infusion without bridging therapy, this results in a progression rate of 0.06 patients per day. On the other side, seventy patients progressed in the SOC arm before autologous stem cell transplantation (ASCT). Since data on the duration between the start of the salvage chemotherapy and ASCT was not reported, estimating it at about 60 days (corresponding to two cycles of salvage chemotherapy at a duration of 21 days per cycle and adding time for leukapheresis and pre-ASCT screening) will result in a progression rate of 1.1 patients per day. Altogether, these results point to a higher proportion of aggressive disease in the SOC arm and potential survivorship bias in the Axi-Cel arm. The role of investigator's willingness to declare more refractory and/or progressive disease in the SOC arm should be minimal, since the responses in the initial report were assessed per-blinded central review. Still, ZUMA-7 is an open-label study, and assessment bias might have occurred. Blinded outcome assessment alone is not sufficient to overcome the information bias upon which the response assessment is based.<span><sup>5</","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 3","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70119","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143689916","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 results of the FIL MCL0208 trial of lenalidomide maintenance versus observation after ASCT in MCL patients","authors":"Rita Tavarozzi, Simone Ferrero, Andrea Evangelista, Elisa Genuardi, Daniela Drandi, Michael Mian, Manuela Zanni, Federica Cavallo, Alice Di Rocco, Vittorio Stefoni, Chiara Pagani, Alessandro Re, Barbara Botto, Monica Balzarotti, Vittorio R. Zilioli, Maria Gomes da Silva, Luca Arcaini, Anna L. Molinari, Filippo Ballerini, Andrés J. M. Ferreri, Benedetta Puccini, Carlo Visco, Piero M. Stefani, Mario Luppi, Ivana Casaroli, Caterina Stelitano, Giovannino Ciccone, Umberto Vitolo, Maurizio Martelli, Sergio Cortelazzo, Marco Ladetto","doi":"10.1002/hem3.70102","DOIUrl":"https://doi.org/10.1002/hem3.70102","url":null,"abstract":"<p>Mantle cell lymphoma (MCL) is an uncommon subtype of B-cell non-Hodgkin lymphoma (NHL) not easily manageable due to chemotherapy resistance and tendency to relapse.<span><sup>1</sup></span> Current treatment for young, fit patients with MCL consists of induction treatment with rituximab and ARA-C-based chemotherapy, followed by consolidation with autologous stem cell transplantation (ASCT) and immunotherapy maintenance.<span><sup>2-4</sup></span> More recently, the potential value of immunomodulatory agents and Bruton tyrosine kinase inhibitors during induction and maintenance has been investigated, and the role of consolidation ASCT is now debated.<span><sup>5-7</sup></span></p><p>The FIL MCL0208 (clinicaltrials.gov no. 02354313) phase III trial evaluated the efficacy of lenalidomide maintenance (LEN) versus observation (OBS) after ASCT in younger, fit patients (18–65 years) with untreated advanced-stage MCL. Further details are provided in Supporting Information. The trial enrolled 303 patients across 38 centers (37 in Italy, 1 in Portugal). At the primary endpoint analysis, with a median follow-up of 38 months, LEN demonstrated a progression-free survival (PFS) benefit but no overall survival (OS) advantage.<span><sup>6</sup></span> Minimal residual disease (MRD) monitoring in peripheral blood (PB) and bone marrow (BM), conducted via nested and real-time PCR (RQ-PCR) at 10 predefined time points, highlighted MRD's prognostic value for time to progression (TTP).<span><sup>8</sup></span></p><p>This report presents long-term clinical and molecular outcomes with a median follow-up of 74 months, including four additional late MRD assessments at 18, 24, 30, and 36 months, expanding insights into LEN's impact and the prognostic role of MRD over time.</p><p>The sample size determination and the statistical plan analyses were described previously.<span><sup>6</sup></span> Further details are provided in Supporting Information.<span><sup>9, 10</sup></span></p><p>From May 4, 2010 to August 24, 2015, a total of 303 patients entered the study. Clinical characteristics at enrollment were published previously.<span><sup>6</sup></span> The PFS and OS of both the enrolled and randomized populations are described in the original report.<span><sup>6</sup></span></p><p>At the time of the present long-term analysis, the median follow-up was 84 months from enrollment and 73 months for the randomized population. The median PFS of the enrolled population was 64 (95% confidence interval [CI] 56–85) months, and the median OS of the enrolled population was not reached. The 72-month PFS was 48% (95% CI 42–54) and the 72-month OS 75% (95% CI 70–80). At the time of the present long-term analysis, 44 of 104 patients in the LEN arm had a PFS event compared to 51 of 101 patients in the OBS arm. The median PFS from randomization was 76 (95% CI 56-not reached) months in the LEN arm versus 73 (95% CI 46–90) months in the OBS arm. The 72-month PFS rates were 55% (95% CI 44–65)","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 3","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70102","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143689565","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":"Low-risk MDS—A spotlight on precision medicine for SF3B1-mutated patients","authors":"Shoshana Burke,&nbsp;Onima Chowdhury,&nbsp;Kevin Rouault-Pierre","doi":"10.1002/hem3.70103","DOIUrl":"https://doi.org/10.1002/hem3.70103","url":null,"abstract":"<p>A deep understanding of the biological mechanisms driving the pathogenesis of myelodysplastic neoplasms (MDS) is essential to develop comprehensive therapeutic approaches that will benefit patient's disease management and quality of life. In this review, we focus on MDS harboring mutations in the splicing factor <i>SF3B1</i>. Clones harboring this mutation arise from the most primitive hematopoietic compartment and expand throughout the entire myeloid lineage, exerting distinct effects at various stages of differentiation. Supportive care, particularly managing anemia, remains essential in <i>SF3B1</i>-mutated MDS. While <i>SF3B1</i> mutations are frequently linked with ring sideroblasts and iron overload due to impaired erythropoiesis, the current therapeutic landscape fails to adequately address the underlying disease biology, particularly in transfusion-dependent patients, where further iron overload contributes to increased morbidity and mortality. Novel agents such as Luspatercept and Imetelstat have shown promise, but their availability remains restricted and their long-term efficacy is to be investigated. Spliceosome modulators have failed to deliver and inhibitors of inflammatory pathways, including TLR and NF-κB inhibitors, are still under investigation. This scarcity of effective and disease-modifying therapies highlights the unmet need for new approaches tailored to the molecular and genetic abnormalities in <i>SF3B1</i>-mutated MDS. Emerging strategies targeting metabolic mis-splicing (e.g., <i>COASY</i>) with vitamin B5, pyruvate kinase activators, and inhibitors of oncogenic pathways like MYC and BCL-2 represent potential future avenues for treatment, but their clinical utility remains to be fully explored. The current limitations in treatment underscore the urgency of developing novel, more effective therapies for patients with <i>SF3B1</i>-mutated MDS.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 3","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70103","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143689455","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":"Brentuximab vedotin monotherapy is a feasible and effective treatment for older patients with classical Hodgkin lymphoma unsuitable for curative chemotherapy: Results from the prospective GHSG–NLG phase II BVB trial","authors":"Alexander Fosså,&nbsp;Daniel Molin,&nbsp;Paul J. Bröckelmann,&nbsp;Gundolf Schneider,&nbsp;Ulf Schnetzke,&nbsp;Johan Linderoth,&nbsp;Peter M. H. Kamper,&nbsp;Sirpa M. Leppä,&nbsp;Julia Meissner,&nbsp;Valdete Schaub,&nbsp;Kjersti Lia,&nbsp;Michael Fuchs,&nbsp;Peter Borchmann,&nbsp;Boris Böll","doi":"10.1002/hem3.70099","DOIUrl":"https://doi.org/10.1002/hem3.70099","url":null,"abstract":"&lt;p&gt;Despite progress over the last decades, the treatment of patients with classical Hodgkin lymphoma (cHL) over the age of 60 years remains challenging.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Biological age, degree of frailty, and severity of underlying diseases may hamper the administration of curative chemotherapy-based approaches developed for younger patients.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; Furthermore, older patients more often have B-symptoms, advanced-stage disease, or other factors known to affect prognosis negatively.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; To improve outcomes for elderly patients with cHL, treatment approaches need to accommodate greater heterogeneity of patients.&lt;/p&gt;&lt;p&gt;In aggressive non-Hodgkin lymphoma (NHL), progress has been made in identifying older patients with impaired health who may need adapted treatment approaches.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Efforts to identify vulnerable older patients are currently also underway for elderly patients with cHL.&lt;span&gt;&lt;sup&gt;1, 3&lt;/sup&gt;&lt;/span&gt; Meanwhile, novel drugs hold promise as effective and better-tolerated options compared to traditional chemotherapy in older individuals.&lt;span&gt;&lt;sup&gt;1, 5&lt;/sup&gt;&lt;/span&gt; The antibody-drug conjugate brentuximab vedotin (BV) contains the tubulin-acting drug monomethyl auristatin E and targets CD30 expressing malignant Hodgkin and Reed&lt;i&gt;–&lt;/i&gt;Sternberg cell characteristic of cHL. Single-agent BV has relatively low toxicity with neuropathy being a common dose-limiting adverse effect, and is also tolerated by relapsed or refractory cHL patients over the age of 60 years.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;We started a prospective phase II trial in 2015, evaluating single-agent BV in patients considered unsuitable for available curative combination chemotherapy. The BVB trial (BV or BV with cyclophosphamide, doxorubicin, and prednisolone in the treatment of older patients with newly diagnosed cHL) was an international two-armed open-label intergroup multicentre phase II trial by the German Hodgkin Study Group (GHSG) and the Nordic Lymphoma Group (NLG) (NCT02191930). The main inclusion criteria were histologically proven cHL, no previous treatment, and age ≥60 years. Patients at any stage were eligible for BV monotherapy if scored ≥7 by the cumulative illness rating scale for geriatrics (CIRS-G) or not considered candidates for curative combination chemotherapy at the investigator's judgment irrespective of performance status. Patients with pre-existing peripheral neuropathy grade ≥1 were excluded. Staging of cHL was done with contrast-enhanced computed tomography (CT) from neck to pelvis and bone marrow biopsy (Supporting Methods). All patients gave written informed consent.&lt;/p&gt;&lt;p&gt;BV was administered intravenously every 3 weeks at 1.8 mg/kg (maximum 180 mg) for up to 16 cycles. The response was assessed with CT after two and six cycles and at the end of therapy. Fluorodeoxyglucose positron emission tomography with CT (PET-CT) was not mandatory at diagnosis or response evaluation. The primar","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 3","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70099","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143689456","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":"Ibrutinib, lenalidomide, and rituximab in relapsed mantle cell lymphoma: Long-term follow-up of the Nordic Lymphoma Group MCL6 Philemon trial","authors":"Elin Forsgren,&nbsp;Rasmus R. K. Jørgensen,&nbsp;Hans Bentzen,&nbsp;Jon Riise,&nbsp;Jacob Haaber,&nbsp;Annika Pasanen,&nbsp;Hanne Kuitunen,&nbsp;Karin F. Wader,&nbsp;Tarec C. El-Galaly,&nbsp;Martin Hutchings,&nbsp;Ingrid Glimelius,&nbsp;Mats Jerkeman","doi":"10.1002/hem3.70101","DOIUrl":"https://doi.org/10.1002/hem3.70101","url":null,"abstract":"<p>Relapsed or refractory mantle cell lymphoma (R/R MCL) remains difficult to treat, with outcomes dependent on the treatment regimen and remission duration after first-line therapy. Several non-chemotherapeutic regimens are under evaluation in R/R, but few studies report long-term outcomes. In this study, we present the long-term outcomes of the 50 patients treated with ibrutinib, lenalidomide, and rituximab (IR2) in the Nordic Lymphoma Group MCL6 Philemon phase 2 trial. Survival outcomes were compared with a matched cohort from the Swedish MCL<i>complete</i> study. After 5 years, 14 patients (28%) remained relapse-free, including one with a <i>TP53</i> mutation. The median progression-free survival (PFS) was 17.4 months, with the longest PFS of 8.1 years. Thirty-two patients had died, primarily from MCL (72%). Poorer survival was associated with intermediate or high-risk Mantle Cell Lymphoma International Prognostic Index and impaired health-related quality of life (HRQoL). While <i>TP53</i> mutations (<i>n</i> = 11) did not significantly impact survival, a trend toward poorer outcomes was observed in multivariable Cox regression analyses (PFS hazard ratio: 2.09, 95% confidence interval: 0.95–4.62, <i>p</i> = 0.068). The IR2 regimen demonstrated superior survival compared to the MCL<i>complete</i> cohort both before and after matching. In conclusion, this study highlights the role of non-chemotherapeutic agents in R/R MCL and demonstrates the prognostic impact of HRQoL on overall survival. Although IR2 showed initial activity in TP53-mutated patients, it did not completely overcome their poor prognosis. However, the IR2 regimen may serve as a bridge to allogeneic stem cell transplantation or chimeric antigen receptor T-cell therapy.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 3","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143638913","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":"Inhibition of the NLRP3 inflammasome using MCC950 reduces vincristine-induced adverse effects in an acute lymphoblastic leukemia patient-derived xenograft model","authors":"Hana Starobova,&nbsp;Hannah McCalmont,&nbsp;Svetlana Shatunova,&nbsp;Nicolette Tay,&nbsp;Christopher M. Smith,&nbsp;Avril Robertson,&nbsp;Ingrid Winkler,&nbsp;Richard B. Lock,&nbsp;Irina Vetter","doi":"10.1002/hem3.70092","DOIUrl":"https://doi.org/10.1002/hem3.70092","url":null,"abstract":"<p>Vincristine is one of the most important chemotherapeutic drugs used to treat acute lymphoblastic leukemia (ALL). Unfortunately, vincristine often causes severe adverse effects, including sensory–motor neuropathies, weight loss, and overall decreased well-being, that are difficult to control and that decrease the quality of life and survival of patients. Recent studies demonstrate that sensory–motor adverse effects of vincristine are driven by neuroinflammatory processes, including the activation of the Nod-like receptor 3 (NLRP3) inflammasome. In this study, we aimed to test the effects of MCC950, a specific NLRP3 inhibitor, on the prevention of vincristine-induced adverse effects as well as tumor progression and vincristine efficacy in NOD/SCID/interleukin-2 receptor <i>γ</i>-negative mice patient-derived xenografts of ALL. We demonstrate that co-administration of MCC950 effectively prevented the development of mechanical allodynia, motor impairment, and weight loss and significantly improved the overall well-being of the animals without negatively impacting the <i>in vivo</i> efficacy of vincristine as a single agent or in combination with standard-of-care drugs. These results provide proof of principle that the adverse effects of vincristine chemotherapy can be prevented using NLRP3 inflammasome inhibitors and provide new options for the development of effective treatment strategies.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 3","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70092","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143638914","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":"Who owns that blood? Recontacting donors with results from genetic testing after allogeneic hematopoietic cell transplantation","authors":"Mirjam E. Belderbos,&nbsp;Marc Bierings,&nbsp;Noa van Bergeijk,&nbsp;Ghislaine J. W. M. van Thiel","doi":"10.1002/hem3.70107","DOIUrl":"https://doi.org/10.1002/hem3.70107","url":null,"abstract":"&lt;p&gt;Chris Dobson, a 17-year-old male, was transplanted for acute lymphoid leukemia (ALL) from a female matched unrelated donor. Eight years post-transplant, Chris presents with progressive pallor and fatigue and is diagnosed with acute myeloid leukemia. Clinical genomic testing reveals 100% donor chimerism and a likely pathogenic &lt;i&gt;BRCA1&lt;/i&gt; mutation, presumably donor-derived. This finding is significant for his female donor, as &lt;i&gt;BRCA1&lt;/i&gt; mutations increase breast and ovarian cancer risk, warranting early screening and preventive options. However, her preference for receiving such information is unknown.&lt;/p&gt;&lt;p&gt;Alba Beyaz, a 23-year-old female, joins a cancer survivor genomics study. Ten years ago, she received hematopoietic cell transplantation (HCT) from her younger sister, who is now 18. Alba, currently healthy, donates a blood sample for whole exome sequencing of clonal hematopoieis (CH). Results reveal a likely pathogenic &lt;i&gt;DNMT3a&lt;/i&gt; mutation in 30% of reads. While having this mutation does not change Alba's current health, CH is linked to several long-term health risks in the general population. While Alba opted to receive her results, the preference of her sister, the HCT donor, is unclear.&lt;/p&gt;&lt;p&gt;Recent advances in next-generation sequencing and bioinformatics have significantly expanded our understanding of normal and malignant hematopoiesis. Within the context of clinical allogenic hematopoietic cell transplantation (allo-HCT), genetic tests provide a sensitive means to monitor post-transplant donor chimerism and minimal residual disease and analyze the mutational drivers of relapse or donor-derived malignancy after transplantation. Some of these tests, such as sequencing-based evaluation of HCT donor chimerism, are already standard clinical practice in many centers, with others rapidly approaching clinical application. Additionally, advances in (single-cell) genomic technologies are increasingly being used in scientific research aimed at dissecting the mechanisms of post-transplant hematopoieis.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;While holding significant clinical and scientific potential, genomic tests can yield both expected and unexpected results beyond the target information. Following HCT, genetic testing may uncover genetic information of donor origin, including germline and somatic mutations. While the majority of genetic aberrations are non-functional, some may contribute to an increased risk of disease. Depending on the specific aberration, whether it is germline or somatic, and whether it occurred before or after HCT, its identification may be relevant for the HCT recipient, the donor, or both. For example, germline variants associated with hematologic malignancies (e.g., &lt;i&gt;ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1&lt;/i&gt;, and &lt;i&gt;UBA1&lt;/i&gt;) are relevant for both parties. In contrast, germline variants associated with non-hematologic cancers, such as &lt;i&gt;BRCA1&lt;/i&gt;, primarily impact the HCT donor. Finally, somatic clonal mutation","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 3","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70107","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632829","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":"Mitigation of atrial fibrillation-related complications with antithrombotic and cytoreductive therapy in patients with Myeloproliferative Neoplasms: Implications from the GSG-MPN bioregistry","authors":"Hyunyee Rosa Cho,&nbsp;Susanne Isfort,&nbsp;Kim Kricheldorf,&nbsp;Frank Stegelmann,&nbsp;Martine Klausmann,&nbsp;Florian H. Heidel,&nbsp;Martin Griesshammer,&nbsp;Holger Schulz,&nbsp;Andreas Hochhaus,&nbsp;Joachim Göthert,&nbsp;Rudolf Schlag,&nbsp;Wiebke Hollburg,&nbsp;Lino Teichmann,&nbsp;Katja Sockel,&nbsp;Stefan Wilop,&nbsp;Deniz Gezer,&nbsp;Martin Kirschner,&nbsp;Konstanze Döhner,&nbsp;Tim H. Brümmendorf,&nbsp;Steffen Koschmieder,&nbsp;for the German Study Group for Myeloproliferative Neoplasms (GSG-MPN)","doi":"10.1002/hem3.70090","DOIUrl":"https://doi.org/10.1002/hem3.70090","url":null,"abstract":"&lt;p&gt;Vascular complications such as thromboembolic events (TEs) and severe bleeding events (BEs) are the major causes of morbidity and mortality in patients (pts) with Myeloproliferative Neoplasms (MPNs).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; TEs are promoted by the hypercoagulable state in MPN, caused by elevated blood counts, activation of platelets, leukocytes, and endothelial cells, the presence of the JAK2V617F mutation, and increased circulating procoagulant microparticles and the occurrence of acquired activated protein C resistance. Disease-associated bleeding may occur via acquired von Willebrand syndrome, platelet dysfunction, antiplatelet agents (APAs), and thrombocytopenia.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; In addition, hemostasis can be disturbed by anticoagulation therapy, acquired hemophilia,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; or complications such as liver dysfunction or disseminated intravascular coagulopathies due to infection.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Atrial fibrillation (AF) is the most common sustained arrhythmia, with increasing prevalence with age.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; The incidence of AF has rarely been studied in MPN, but was suggested to be higher compared to the general population.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; The same study found that MPN pts with AF had a higher frequency of cardiovascular risk factors (CVRFs) and thrombotic complications and a shorter thrombosis-free survival than MPN pts without AF.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; However, in a separate study comparing 63 pts with polycythemia vera (PV) and AF to 124 control pts with AF only, no increased incidence of thrombosis was found.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Both studies found no increase in major BE. However, none of the two studies reported the use and effects of cytoreductive therapy (CRT) in their cohorts, a critical means to decrease the risk of both initial and recurrent thrombosis in high-risk MPN pts.&lt;/p&gt;&lt;p&gt;Therefore, we conducted this retrospective analysis of 2,780 MPN pts enrolled in the GSG-MPN bioregistry, in order to identify the characteristics of AF in MPN pts and to assess the benefit–risk profile of antithrombotic therapies (ATTs) alone or in combination with MPN-specific CRT. The German Study Group MPN bioregistry (GSG-MPN bioregistry) is an ambispective observational study of MPN pts, with over 70 centers participating. Recruitment started in August 2012, with a data cut-off date of January 2020.&lt;/p&gt;&lt;p&gt;As in the general population,&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; the median age of AF pts in our MPN cohort was higher than those without AF (Supporting Information S1: Table S3). The prevalence of AF in pts older than 80 years of age in our MPN cohort was higher than that in the general population (18.2% [Supporting Information S1: Figure S1] vs. 8.8% in the FRAMINGHAM study&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt;).&lt;/p&gt;&lt;p&gt;Since the incidence and complication rate of MPN pts increase with age and since CRT is recommended in an age-adapted manner, we performed a case–control analysis following a 1:1","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 3","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70090","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632830","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":"Loss of CYLD promotes splenic marginal zone lymphoma","authors":"Athanasios Pseftogas,&nbsp;Jessica Bordini,&nbsp;Silvia Heltai,&nbsp;Ferdinando Bonfiglio,&nbsp;Georgios Gavriilidis,&nbsp;Vasileios Vasileiou,&nbsp;Sofoklis Keisaris,&nbsp;Daniela Belloni,&nbsp;Caterina Taccetti,&nbsp;Pamela Ranghetti,&nbsp;Eleonora Perotta,&nbsp;Michela Frenquelli,&nbsp;Uday Aditya Sarkar,&nbsp;Elisa Albi,&nbsp;Francesca Martini,&nbsp;Emmanuela Sant'Antonio,&nbsp;Fabrizio Mavilia,&nbsp;Fotis Psomopoulos,&nbsp;Manasori Daibata,&nbsp;José Ángel Martínez Climent,&nbsp;George Mosialos,&nbsp;Davide Rossi,&nbsp;Alessandro Campanella,&nbsp;Lydia Scarfò,&nbsp;Kostas Stamatopoulos,&nbsp;Konstantinos Xanthopoulos,&nbsp;Paolo Ghia","doi":"10.1002/hem3.70098","DOIUrl":"https://doi.org/10.1002/hem3.70098","url":null,"abstract":"<p>Splenic marginal zone lymphoma (SMZL) is a distinct clinical and pathological entity among marginal zone lymphomas. Genetic and microenvironmental factors leading to aberrant activation of the NF-κB pathway have been implicated in SMZL pathogenesis. CYLD is a negative regulator of NF-κB and other signaling pathways acting as a deubiquitinase of regulatory molecules and has been reported as a tumor suppressor in different types of cancer, including B-cell malignancies. To assess whether CYLD is implicated in the natural history of SMZL, we profiled primary cells from patients with SMZL and SMZL cell lines for CYLD expression and functionality. We report that CYLD is downregulated in patients with SMZL and that <i>CYLD</i> ablation in vitro leads to NF-κB pathway hyperactivation, promoting the proliferation of SMZL cells. In addition, we found that CYLD deficiency was associated with increased migration of SMZL cells in vitro, through CCR7 receptor signaling, and with increased dissemination in vivo. <i>CYLD</i> loss was sufficient to induce BcR signaling, conferring increased resistance to ibrutinib treatment in vitro. In summary, our work uncovers a novel role of CYLD as a key regulator in SMZL pathogenesis, dissemination, and resistance to targeted agents. On these grounds, CYLD could be proposed as a novel target for patient stratification and personalized interventions.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 3","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70098","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632828","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":"Selecting patients with sickle cell disease for gene addition or gene editing-based therapeutic approaches: Report on behalf of a joint EHA Specialized Working Group and EBMT Hemoglobinopathies Working Party consensus conference","authors":"Lucia de Franceschi,&nbsp;Franco Locatelli,&nbsp;David Rees,&nbsp;Christian Chabannon,&nbsp;Jean-Hugues Dalle,&nbsp;Stefano Rivella,&nbsp;Achille Iolascon,&nbsp;Stephan Lobitz,&nbsp;Miguel R. Abboud,&nbsp;Josu de la Fuente,&nbsp;Pagona Flevari,&nbsp;Emanuele Angelucci,&nbsp;Mariane de Montalembert","doi":"10.1002/hem3.70089","DOIUrl":"https://doi.org/10.1002/hem3.70089","url":null,"abstract":"<p>Sickle cell disease (SCD) remains associated with reduced life expectancy and poor quality of life despite improvements observed in the last decades mostly related to comprehensive care, use of hydroxycarbamide, screening to identify patients at risk of strokes, and implementation of safe transfusion protocols. The course of the disease is highly variable, making it difficult to predict severity and response to therapy. Allogeneic hematopoietic stem cell transplantation potentially provides a cure with a relatively low rate of complications, but few patients have an HLA-identical sibling. The hopes of patients and healthcare providers have been raised after the initial excellent results of gene therapy studies. However, there is a strong contrast between the high expectations of families and patients and the limited availability of the product, which is technically complex and very expensive. In light of this consideration and of the limited data available on the long-term efficacy and toxicity of different gene therapy approaches, the European Hematology Association Red Cell &amp; Iron Specialized Working Group (EHA SWG) and the hemoglobinopathy working part of the European Blood &amp; Marrow Transplant (EBMT) Group have prioritized the development of recommendations for selection of patients with SCD who are good candidates for gene therapy. The decision-making algorithm was developed by a panel of experts in hemoglobinopathies and/or transplantation chosen by EHA SWG and EBMT, to discuss the selection of SCD patients for gene therapy and draw notes on the related clinical problems.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 3","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70089","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612361","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}