HemaSphere最新文献

{"title":"First-line ibrutinib treatment in patients with chronic lymphocytic leukemia is associated with overall survival rates similar to those of an age-matched general population: A pooled post hoc analysis","authors":"Paolo Ghia, Carolyn Owen, John N. Allan, Jacqueline C. Barrientos, Paul M. Barr, Chunxue Shi, Anita Szoke, Christopher Abbazio, Gabriel S. Krigsfeld, Jan A. Burger","doi":"10.1002/hem3.74","DOIUrl":"https://doi.org/10.1002/hem3.74","url":null,"abstract":"<p>Currently, there are no targeted agents that can cure chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), which is the most common leukemia among older adults.<span><sup>1</sup></span> In the absence of a curative regimen, the therapeutic goal is to maximize patients' life span while effectively managing disease symptoms.</p><p>Ibrutinib, a covalent, once-daily Bruton's tyrosine kinase inhibitor, has been shown to have survival superiority to chemotherapy (CT) and chemoimmunotherapy (CIT) in the first-line setting, including older adults and those with high-risk characteristics, and has demonstrated overall survival (OS) improvements in multiple pivotal trials.<span><sup>2-4</sup></span> In a long-term follow-up from RESONATE-2 of up to 8 years, first-line treatment with ibrutinib was associated with superior progression-free survival and OS compared with standard-of-care CT. Based on the results from the same study, adverse events (AEs) associated with ibrutinib can be managed effectively with dose reductions or dose holds, which results in AE resolution in most patients (85% and 90%, respectively), allowing them to remain on treatment and continue benefiting from ibrutinib.<span><sup>5</sup></span> The relatively long survival of patients with CLL/SLL treated with ibrutinib raises the question of whether the initiation of first-line ibrutinib could remove the survival hazard associated with CLL/SLL compared with the general population. The aims of this pooled analysis were to compare OS estimates of previously untreated patients with CLL/SLL who received ibrutinib or CT/CIT across three phase 3 studies with the OS estimates for an age-matched general population.</p><p>This post hoc analysis included data pooled from three randomized (1:1) controlled studies in patients with previously untreated CLL/SLL: RESONATE-2 (NCT01722487),<span><sup>2</sup></span> iLLUMINATE (NCT02264574),<span><sup>4</sup></span> and ECOG-ACRIN E1912 (NCT02048813).<span><sup>3</sup></span> Patients were separated into two groups: ibrutinib cohort (patients treated with ibrutinib, ibrutinib with rituximab, or ibrutinib with obinutuzumab); and CT/CIT cohort (patients receiving rituximab plus fludarabine plus cyclophosphamide, chlorambucil plus obinutuzumab, or single-agent chlorambucil). Details of the treatments and populations have been previously published for each study, and brief descriptions are included in the Supporting Information.</p><p>OS data from the time of initial CLL/SLL diagnosis for the ibrutinib-treated cohort or CT/CIT-treated cohort were compared with survival estimates for an age-matched US population in 2019 published by the Centers for Disease Control and Prevention (CDC).<span><sup>6</sup></span> Age-matched (1:1 match) simulated databases were generated based on the age distribution of patients treated with ibrutinib or CT/CIT from the three phase 3 clinical studies. OS probabilities were estimated using the Kaplan–Meier methodol","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 5","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.74","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156486","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":"Remission after CAR T-cell therapy: Do lymphoma patients recover a normal life?","authors":"Alya Perthus,&nbsp;Fanny Colin,&nbsp;Emilie Charton,&nbsp;Amélie Anota,&nbsp;Faustine Lhomme,&nbsp;Guillaume Manson,&nbsp;Sophie De Guibert,&nbsp;Pierre Daufresne,&nbsp;Adeline Bellec,&nbsp;Laetitia Le Bars,&nbsp;Sandra De Barros,&nbsp;Loïc Ysebaert,&nbsp;Marianne Merceur,&nbsp;Mélanie Cogné,&nbsp;Thierry Lamy De La Chapelle,&nbsp;Roch Houot,&nbsp;Aline Moignet","doi":"10.1002/hem3.72","DOIUrl":"https://doi.org/10.1002/hem3.72","url":null,"abstract":"<p>Chimeric antigen receptor T cells (CAR T cells) can induce prolonged remission in a substantial subset of patients with relapse/refractory lymphoma. However, little is known about patients' life after CAR T-cell therapy. We prospectively assessed the multidimensional recovery of lymphoma patients in remission, before leukapheresis, before CAR T-cell infusion, and 3, 6, and 12 months thereafter. Validated tools were used to measure lymphoma-related and global health-related quality of life (HRQoL; Functional Assessment of Cancer Therapy-Lymphoma [FACT-Lym] and EQ-5D-5L), cognitive complaint (FACT-Cognition), fatigue (FACIT-Fatigue subscale), psychological status (Hospital Anxiety and Depression Scale, Post-Traumatic Check List Scale), and sexuality (Relationship and Sexuality Scale). Beyond 12 months of remission, we also surveyed physical, professional, sexual, and general life status. At 3, 6, and 12 months, 53, 35, and 23 patients were evaluable, respectively. Improvement in lymphoma-related HRQoL was clinically relevant at 3, 6, and 12 months with a mean change from baseline of 10.9 (95% confidence interval [CI]: 5.8; 16.1), 12.2 (95% CI: 4.2; 20.1), and 11.72 (95% CI: 2.06; 21.38), respectively. Improvement in global HRQoL, fatigue, and anxiety was clinically relevant, but 20%–40% of patients experienced persistent fatigue, psychological distress, and cognitive complaints over time. Beyond 12 months after CAR T cells, 81.8% of 22 evaluable patients were satisfied with their daily life. Physical activity, professional, sexual, and global well-being had returned to prediagnosis levels in nearly half of the patients. We found an improvement in HRQoL after CAR T-cell therapy including anxiety, depression, sexual satisfaction, and general well-being. However, not all patients recover a “normal life.” Further research is needed to determine which patients are at risk of quality-of-life impairment to improve recovery after CAR T-cell infusion.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 5","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.72","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156487","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":"Influence of donor–recipient sex on engraftment of normal and leukemia stem cells in xenotransplantation","authors":"Syed A. Mian,&nbsp;Linda Ariza-McNaughton,&nbsp;Fernando Anjos-Afonso,&nbsp;Remisha Guring,&nbsp;Sophie Jackson,&nbsp;Aytug Kizilors,&nbsp;John Gribben,&nbsp;Dominique Bonnet","doi":"10.1002/hem3.80","DOIUrl":"https://doi.org/10.1002/hem3.80","url":null,"abstract":"<p>Immunodeficient mouse models are widely used for the assessment of human normal and leukemic stem cells. Despite the advancements over the years, reproducibility, as well as the differences in the engraftment of human cells in recipient mice remains to be fully resolved. Here, we used various immunodeficient mouse models to characterize the effect of donor–recipient sex on the engraftment of the human leukemic and healthy cells. Donor human cells and recipient immunodeficient mice demonstrate sex-specific engraftment levels with significant differences observed in the lineage output of normal CD34⁺ hematopoietic stem and progenitor cells upon xenotransplantation. Intriguingly, human female donor cells display heightened sensitivity to the recipient mice's gender, influencing their proliferation and resulting in significantly increased engraftment in female recipient mice. Our study underscores the intricate interplay taking place between donor and recipient characteristics, shedding light on important considerations for future studies, particularly in the context of pre-clinical research.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 5","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.80","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141073710","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":"Toward a more patient-centered drug development process in clinical trials for patients with myelodysplastic syndromes/neoplasms (MDS): Practical considerations from the International Consortium for MDS (icMDS)","authors":"Fabio Efficace,&nbsp;Rena Buckstein,&nbsp;Gregory A. Abel,&nbsp;Johannes M. Giesinger,&nbsp;Pierre Fenaux,&nbsp;Jan Philipp Bewersdorf,&nbsp;Andrew M. Brunner,&nbsp;Rafael Bejar,&nbsp;Uma Borate,&nbsp;Amy E. DeZern,&nbsp;Peter Greenberg,&nbsp;Gail J. Roboz,&nbsp;Michael R. Savona,&nbsp;Francesco Sparano,&nbsp;Jacqueline Boultwood,&nbsp;Rami Komrokji,&nbsp;David A. Sallman,&nbsp;Zhuoer Xie,&nbsp;Guillermo Sanz,&nbsp;Hetty E. Carraway,&nbsp;Justin Taylor,&nbsp;Stephen D. Nimer,&nbsp;Matteo Giovanni Della Porta,&nbsp;Valeria Santini,&nbsp;Maximilian Stahl,&nbsp;Uwe Platzbecker,&nbsp;Mikkael A. Sekeres,&nbsp;Amer M. Zeidan","doi":"10.1002/hem3.69","DOIUrl":"https://doi.org/10.1002/hem3.69","url":null,"abstract":"<p>Notable treatment advances have been made in recent years for patients with myelodysplastic syndromes/neoplasms (MDS), and several new drugs are under development. For example, the emerging availability of oral MDS therapies holds the promise of improving patients' health-related quality of life (HRQoL). Within this rapidly evolving landscape, the inclusion of HRQoL and other patient-reported outcomes (PROs) is critical to inform the benefit/risk assessment of new therapies or to assess whether patients live longer and better, for what will likely remain a largely incurable disease. We provide practical considerations to support investigators in generating high-quality PRO data in future MDS trials. We first describe several challenges that are to be thoughtfully considered when designing an MDS-focused clinical trial with a PRO endpoint. We then discuss aspects related to the design of the study, including PRO assessment strategies. We also discuss statistical approaches illustrating the potential value of time-to-event analyses and their implications within the estimand framework. Finally, based on a literature review of MDS randomized controlled trials with a PRO endpoint, we note the PRO items that deserve special attention when reporting future MDS trial results. We hope these practical considerations will facilitate the generation of rigorous PRO data that can robustly inform MDS patient care and support treatment decision-making for this patient population.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 5","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.69","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141073749","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":"An integrated classification of tumor suppressor IKZF1 inactivation and oncogenic activation in Philadelphia chromosome-like acute lymphoblastic leukemia","authors":"Zicong Huang,&nbsp;Ling Zhang,&nbsp;Xiaoyuan Gong,&nbsp;Jia Li,&nbsp;Shiyu Deng,&nbsp;Zihong Cai,&nbsp;Bingqing Tang,&nbsp;Kangyu Huang,&nbsp;Xin Li,&nbsp;Weihua Zhao,&nbsp;Yang Xu,&nbsp;Li Xuan,&nbsp;Qifa Liu,&nbsp;Ying Wang,&nbsp;Suning Chen,&nbsp;Hongsheng Zhou","doi":"10.1002/hem3.82","DOIUrl":"https://doi.org/10.1002/hem3.82","url":null,"abstract":"<p>Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is recognized for its genetic and clinical diversity. In this study, we identified a novel high-risk subset of Ph-like ALL, characterized by the activation of oncogenic signaling and the inactivation of the tumor suppressor gene <i>IKZF1</i>, resulting in a dismal outcome. The association between cytogenetic aberrations and clinical features was assessed on a cohort of 191 patients with Ph-like ALL. Our findings revealed that patients with inactivation of <i>IKZF1</i> combined with activation of oncogenic signaling (<i>CRLF2/EPOR/JAK2</i> rearrangements or <i>p-CRKL/p-STAT5</i> high expression) had the worst outcome (3-year overall survival [OS] of 28.8% vs. 80.1% for others, <i>p</i> &lt; 0.001; 2-year event-free survival [EFS] of 6.5% vs. 57.0% for others, <i>p</i> &lt; 0.001). Multivariable analysis demonstrated that this high-risk feature was an independent inferior prognostic factor (adjusted hazard ratio for OS = 4.55, 95% confidence interval [CI]: 2.35–8.81, <i>p</i> &lt; 0.001; adjusted hazard ratio for EFS = 3.27, 95% CI: 1.99–5.39, <i>p</i> &lt; 0.001). Allogeneic hematopoietic stem cell transplantation was associated with improved prognoses in patients within the high-risk subgroup. In conclusion, this study identified a clinically distinct entity that possesses effective prognostic features and provides potential guidance for refining risk stratification in Ph-like ALL.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 5","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.82","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141073751","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":"Treatment outcomes in patients with large B-cell lymphoma after progression to chimeric antigen receptor T-cell therapy","authors":"Gloria Iacoboni,&nbsp;Josu Iraola-Truchuelo,&nbsp;Maeve O'Reilly,&nbsp;Víctor Navarro,&nbsp;Tobias Menne,&nbsp;Mi Kwon,&nbsp;Ana África Martín-López,&nbsp;Sridhar Chaganti,&nbsp;Javier Delgado,&nbsp;Claire Roddie,&nbsp;Ariadna Pérez,&nbsp;Jane Norman,&nbsp;Manuel Guerreiro,&nbsp;Adam Gibb,&nbsp;Ana Carolina Caballero,&nbsp;Caroline Besley,&nbsp;Nuria Martínez-Cibrián,&nbsp;Alberto Mussetti,&nbsp;Robin Sanderson,&nbsp;Hugo Luzardo,&nbsp;Sunil Iyengar,&nbsp;Jose Maria Sánchez,&nbsp;Ceri Jones,&nbsp;Juan-Manuel Sancho,&nbsp;Pere Barba,&nbsp;Anne-Louise Latif,&nbsp;Lucia López-Corral,&nbsp;Rafael Hernani,&nbsp;Juan Luis Reguera,&nbsp;Anna Sureda,&nbsp;Alejandro Martin Garcia-Sancho,&nbsp;Mariana Bastos,&nbsp;Pau Abrisqueta,&nbsp;Andrea Kuhnl","doi":"10.1002/hem3.62","DOIUrl":"https://doi.org/10.1002/hem3.62","url":null,"abstract":"<p>Over 60% of relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients who receive chimeric antigen receptor (CAR) T cells will experience disease progression. There is no standard next line of therapy and information in this setting is scarce and heterogeneous. We analyzed 387 R/R LBCL patients who progressed after CAR T cells from July 2018 until March 2022 in Spain and the United Kingdom. Median overall survival (OS) was 5.3 months, with significant differences according to the interval between infusion and progression (&lt;2 months [1.9 months], 2–6 months [5.2 months], and &gt;6 months [not reached]). After progression, 237 (61%) patients received treatment. Focusing on the first subsequent therapy, overall (complete) response rates were 67% (38%) for polatuzumab–bendamustine–rituximab (POLA), 51% (36%) for bispecific antibodies (BsAb), 45% (35%) for radiotherapy (RT), 33% (26%) for immune checkpoint inhibitors (ICIs), 25% (0%) for lenalidomide (LENA), and 25% (14%) for chemotherapy (CT). In terms of survival, 12-month progression-free survival and OS was 36.2% and 51.0% for POLA, 32.0% and 50.1% for BsAb, 30.8% and 37.5% for RT, 29.9% and 27.8% for ICI, 7.3% and 20.8% for LENA, and 6.1% and 18.3% for CT. Thirty-two (14%) patients received an allogeneic hematopoietic cell transplant with median OS not reached after a median follow-up of 15.1 months. In conclusion, patients with R/R LBCL who progress within the first 2 months after CAR T-cell therapy have dismal outcomes. Novel targeted agents, such as polatuzumab and BsAbs, can achieve prolonged survival after CAR T-cell therapy failure.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 5","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.62","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141073750","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":"News on sickle cell disease: Heme-driven disordered erythropoiesis","authors":"Francesca Vinchi","doi":"10.1002/hem3.75","DOIUrl":"https://doi.org/10.1002/hem3.75","url":null,"abstract":"&lt;p&gt;Sickle cell disease (SCD) is a hemolytic disorder caused by a point mutation in the β-globin gene leading to the expression of an abnormal hemoglobin (HbS) that has the tendency to polymerize under hypoxic conditions, thus driving red cell sickling. Because of the propensity of sickle red blood cells (RBCs) to break into the circulation and be cleared at a faster rate by reticulo-endothelial macrophages, hemolysis is a hallmark of SCD.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; As a consequence, SCD patients present with elevated circulating heme levels and almost complete exhaustion of the hemoglobin and heme scavengers, haptoglobin, and hemopexin.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; The saturation of these scavengers leaves heme in a “free” form, loosely bound to other plasma proteins and thus, more prone to accumulate in cells and tissue and promote cell oxidative damage due to its reactive iron moiety.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Besides hemolysis, disordered erythropoiesis is a feature of hemoglobinopathies, such as β-thalassemia and SCD. Whereas β-thalassemia is hallmarked by ineffective erythropoiesis, less is known about alterations in SCD erythropoiesis, which is likely more effective than in β-thalassemia. A severe misbalance between the expansion of early-stage erythroid progenitor cells and disrupted differentiation of late-stage erythroid precursors drive ineffective erythropoiesis in β-thalassemia.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Although cell death during the Hb synthesis phase of terminal differentiation has been described to contribute to a certain extent to disordered erythropoiesis in SCD,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; this mechanism is less pronounced than in β-thalassemia. Erythroid progenitors in SCD have a better ability to terminally differentiate compared to β-thalassemia, and peripheral hemolysis of RBCs due to polymerization of deoxygenated sickle hemoglobin is the major cause of anemia in this disease.&lt;/p&gt;&lt;p&gt;The mechanisms of disordered erythropoiesis in SCD, and whether and how hemolysis and free heme contribute to them remained in large part unknown to date. Recently, Xiuli An and group investigated sickle erythropoiesis to better dissect potential alterations in the erythroid activity that could further contribute to anemia, besides the hemolytic process.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Taking advantage of a mouse model of SCD, the authors analyzed bone marrow erythropoiesis and compared it to erythropoiesis in a murine model of β-thalassemia. Despite similar induction of erythropoietin (EPO) levels, SCD mice exhibited a modest increase in early progenitors and failed to adequately respond to the hormone compared to β-thalassemia mice, whose erythroblast increase was two-fold higher than in SCD.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; This suggests impaired bone marrow erythropoietic activity, which was confirmed by the observation that SCD erythroid progenitor cells showed decreased erythroid colony-forming ability and diminished response to EPO in vitro.&lt;span&gt;&lt;sup&gt;4&lt;/su","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 5","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.75","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953077","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":"Immune-monitoring of myelodysplastic neoplasms: Recommendations from the i4MDS consortium","authors":"Cristina A. Tentori,&nbsp;Lin P. Zhao,&nbsp;Benedetta Tinterri,&nbsp;Kathryn E. Strange,&nbsp;Katharina Zoldan,&nbsp;Konstantinos Dimopoulos,&nbsp;Xingmin Feng,&nbsp;Elena Riva,&nbsp;Benjamin Lim,&nbsp;Yannick Simoni,&nbsp;Vidhya Murthy,&nbsp;Madeline J. Hayes,&nbsp;Antonella Poloni,&nbsp;Eric Padron,&nbsp;Bruno A. Cardoso,&nbsp;Michael Cross,&nbsp;Susann Winter,&nbsp;Aida Santaolalla,&nbsp;Bhavisha A. Patel,&nbsp;Emma M. Groarke,&nbsp;Daniel H. Wiseman,&nbsp;Katy Jones,&nbsp;Lauren Jamieson,&nbsp;Charles Manogaran,&nbsp;Naval Daver,&nbsp;Laura Gallur,&nbsp;Wendy Ingram,&nbsp;P. Brent Ferrell,&nbsp;Katja Sockel,&nbsp;Nicolas Dulphy,&nbsp;Nicolas Chapuis,&nbsp;Anne S. Kubasch,&nbsp;Astrid M. Olsnes,&nbsp;Austin Kulasekararaj,&nbsp;Hugues De Lavellade,&nbsp;Wolfgang Kern,&nbsp;Mieke Van Hemelrijck,&nbsp;Dominique Bonnet,&nbsp;Theresia M. Westers,&nbsp;Sylvie Freeman,&nbsp;Uta Oelschlaegel,&nbsp;David Valcarcel,&nbsp;Marco G. Raddi,&nbsp;Kirsten Grønbæk,&nbsp;Michaela Fontenay,&nbsp;Sanam Loghavi,&nbsp;Valeria Santini,&nbsp;Antonio M. Almeida,&nbsp;Jonathan M. Irish,&nbsp;David A. Sallman,&nbsp;Neal S. Young,&nbsp;Arjan A. van de Loosdrecht,&nbsp;Lionel Adès,&nbsp;Matteo G. Della Porta,&nbsp;Catherine Cargo,&nbsp;Uwe Platzbecker,&nbsp;Shahram Kordasti,&nbsp;i4MDS consortium","doi":"10.1002/hem3.64","DOIUrl":"https://doi.org/10.1002/hem3.64","url":null,"abstract":"<p>Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal role of immune dysregulation within the bone marrow milieu during MDS evolution. Nonetheless, immunotherapy for MDS has not experienced breakthroughs seen in other malignancies, partly attributable to the absence of an immune classification that could stratify patients toward optimally targeted immunotherapeutic approaches. A pivotal obstacle to establishing “immune classes” among MDS patients is the absence of validated accepted immune panels suitable for routine application in clinical laboratories. In response, we formed International Integrative Innovative Immunology for MDS (i4MDS), a consortium of multidisciplinary experts, and created the following recommendations for standardized methodologies to monitor immune responses in MDS. A central goal of i4MDS is the development of an immune score that could be incorporated into current clinical risk stratification models. This position paper first consolidates current knowledge on MDS immunology. Subsequently, in collaboration with clinical and laboratory specialists, we introduce flow cytometry panels and cytokine assays, meticulously devised for clinical laboratories, aiming to monitor the immune status of MDS patients, evaluating both immune fitness and identifying potential immune “risk factors.” By amalgamating this immunological characterization data and molecular data, we aim to enhance patient stratification, identify predictive markers for treatment responsiveness, and accelerate the development of systems immunology tools and innovative immunotherapies.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 5","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.64","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140949120","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":"Interplay between α-thalassemia and β-hemoglobinopathies: Translating genotype–phenotype relationships into therapies","authors":"Jim Vadolas,&nbsp;Tiwaporn Nualkaew,&nbsp;Hsiao P. J. Voon,&nbsp;Shahla Vilcassim,&nbsp;George Grigoriadis","doi":"10.1002/hem3.78","DOIUrl":"https://doi.org/10.1002/hem3.78","url":null,"abstract":"<p>α-Thalassemia represents one of the most important genetic modulators of β-hemoglobinopathies. During this last decade, the ongoing interest in characterizing genotype–phenotype relationships has yielded incredible insights into α-globin gene regulation and its impact on β-hemoglobinopathies. In this review, we provide a holistic update on α-globin gene expression stemming from DNA to RNA to protein, as well as epigenetic mechanisms that can impact gene expression and potentially influence phenotypic outcomes. Here, we highlight defined α-globin targeted strategies and rationalize the use of distinct molecular targets based on the restoration of balanced α/β-like globin chain synthesis. Considering the therapies that either increase β-globin synthesis or reactivate γ-globin gene expression, the modulation of α-globin chains as a disease modifier for β-hemoglobinopathies still remains largely uncharted in clinical studies.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 5","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.78","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140924891","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":"T-cell lymphoblastic lymphoma in constitutional mismatch repair deficiency (CMMRD): Exploring treatment opportunities","authors":"Emma Kroeze,&nbsp;Dilys D. Weijers,&nbsp;Michelle M. Kleisman,&nbsp;Uri Ilan,&nbsp;Reno S. Bladergroen,&nbsp;Rico Hagelaar,&nbsp;Jules P. P. Meijerink,&nbsp;Marjolijn C. J. Jongmans,&nbsp;Jan L. C. Loeffen,&nbsp;Roland P. Kuiper","doi":"10.1002/hem3.73","DOIUrl":"https://doi.org/10.1002/hem3.73","url":null,"abstract":"&lt;p&gt;Constitutional mismatch repair deficiency (CMMRD) is a high-risk childhood cancer predisposition syndrome caused by biallelic germline mutations in one of the four mismatch repair (MMR) genes &lt;i&gt;MLH1&lt;/i&gt;, &lt;i&gt;MSH2&lt;/i&gt;, &lt;i&gt;MSH6&lt;/i&gt;, or &lt;i&gt;PMS2&lt;/i&gt;. Defective MMR results in the rapid accumulation of mutations and the continuous development of malignancies from an early age. The tumor spectrum of CMMRD patients consists mostly of high-grade brain tumors, gastrointestinal (GI) tumors, and hematologic malignancies.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Hematologic malignancies in CMMRD patients are predominantly lymphomas, most of which are T-cell lymphoblastic lymphomas (T-LBLs).&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; T-LBL is a malignancy of immature T cells, characterized by infiltration of blasts in the mediastinum and lymph nodes, with fewer than 25% blasts in the bone marrow.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; Treatment of T-LBL generally consists of 2-year multiagent chemotherapy (LBL2018, NCT04043494).&lt;/p&gt;&lt;p&gt;Intensive surveillance protocols for CMMRD patients allow for early detection of brain tumors and GI tumors, providing additional treatment options besides chemotherapy, such as radical surgical resection or radiotherapy.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Moreover, hypermutated brain and GI tumors have shown a good response to PD-1 inhibitors, with hypermutated being defined as &gt;10 mutations/Mb (mut/Mb).&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt; Clinically relevant surveillance strategies for hematologic malignancies are not yet available and it has yet to be studied whether T-LBLs are hypermutated, like brain and GI tumors, and could therefore benefit from checkpoint inhibitors, such as PD-1 inhibitors, as well. Consequently, CMMRD-associated T-LBL is currently treated according to the standard of care treatment strategies for sporadic T-LBL. There are several reasons why standard-of-care treatment strategies might be suboptimal in CMMRD T-LBL patients. Since CMMRD T-LBL patients are often heavily pretreated for previous malignancies, they may have developed chemoresistance. Additionally, previous doses of intensive therapy make patients also more vulnerable to severe complications. Moreover, the current LBL chemotherapeutic backbone consists of a number of mutagenic agents that can cause additional mutations and contribute to the development of new malignancies in these patients.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Additionally, there are indications that MMR deficiency leads to inherent resistance to thiopurines,&lt;span&gt;&lt;sup&gt;8-10&lt;/sup&gt;&lt;/span&gt; an important component of T-LBL treatment strategies (LBL2018, NCT04043494). It could therefore be beneficial for CMMRD patients to adapt the LBL backbone by removing the partially toxic and ineffective chemotherapeutic agents and replacing them with other, more effective agents. Molecular characterization of CMMRD-associated T-LBL and sporadic T-LBL could provide insights into molecular similarities and differences between these malignancies, potentially res","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 5","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.73","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140914747","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}