On July 2, 2025, the FDA approved Lynozyfic (linvoseltamab-gcpt) for the treatment of relapsed or refractory multiple myeloma (RRMM) in patients who have received at least four prior lines of therapy, including a proteasome inhibitor (PI), immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody. Lynozyfic is administered intravenously and represents the first bispecific antibody targeting both BCMA and CD3 to be approved in this setting. Unlike autologous CAR-T cell therapy, linvoseltamab requires no lymphodepletion or personalized manufacturing, offering an off-the-shelf immunotherapeutic option that engages the patient's T cells in real-time to eliminate malignant plasma cells.
Multiple myeloma (MM) is a malignant neoplasm of plasma cells characterized by clonal proliferation within the bone marrow and the production of monoclonal immunoglobulins (M-protein). This leads to organ dysfunction involving bone destruction, renal impairment, anemia, and immunosuppression. MM typically evolves from precursor conditions such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), progressing through a multistep transformation that is driven by accumulating genetic mutations and interactions with the bone marrow microenvironment [1]. Globally, MM accounts for approximately 1% of all cancers and around 10% of hematologic malignancies. It is predominantly a disease of the elderly, with a median age at diagnosis of around 69 years [2]. Standard induction for newly diagnosed patients includes a triplet regimen like bortezomib + lenalidomide + dexamethasone (VRd), followed by autologous stem cell transplantation (ASCT) and maintenance lenalidomide [3]. However, the updated EHA–EMN 2024 Guidelines now recommend quadruplet-based induction as the preferred frontline approach for transplant-eligible patients. These include anti-CD38 monoclonal antibody–containing regimens such as daratumumab + VRd (Dara-VRd) or isatuximab + VRd (Isa-VRd), both of which have demonstrated higher rates of measurable residual disease (MRD) negativity and longer progression-free survival compared with triplet regimens. For transplant-ineligible or frail patients, the guidelines endorse daratumumab + lenalidomide + dexamethasone (Dara-Rd) or daratumumab + bortezomib + melphalan + prednisone (Dara-VMP) as frontline standards due to their favorable tolerability and sustained responses [4]. In the relapsed or refractory setting, the EHA–EMN 2024 consensus expands treatment options to include early use of BCMA-directed cellular and immune therapies. CAR-T cell products such as ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel) are now considered appropriate from first relapse, especially in patients with high-risk cytogenetics or relapse within 18 months of initial therapy. In addition, off-the-shelf bispecific antibodies s
2025年7月2日，FDA批准Lynozyfic （linvoseltamab-gcpt）用于治疗复发或难治性多发性骨髓瘤（RRMM）患者，这些患者先前至少接受过四种治疗，包括蛋白酶体抑制剂（PI）、免疫调节剂（IMiD）和抗cd38单克隆抗体。Lynozyfic是静脉注射给药，是首个在这种情况下被批准的针对BCMA和CD3的双特异性抗体。与自体CAR-T细胞疗法不同，linvoseltamab不需要淋巴细胞消耗或个性化制造，提供了一种现成的免疫治疗选择，实时利用患者的T细胞来消除恶性浆细胞。多发性骨髓瘤（MM）是一种恶性浆细胞肿瘤，其特征是骨髓内的克隆增殖和单克隆免疫球蛋白（m蛋白）的产生。这导致器官功能障碍，包括骨破坏、肾损害、贫血和免疫抑制。骨髓性骨髓瘤通常由未确定意义的单克隆γ病（MGUS）和阴熏型多发性骨髓瘤（SMM）等前体疾病演变而来，在积累基因突变和与骨髓微环境[1]相互作用的驱动下，经过多步骤转化。在全球范围内，MM约占所有癌症的1%，约占血液恶性肿瘤的10%。它主要是老年人的疾病，诊断时的中位年龄约为69岁。新诊断患者的标准诱导包括硼替佐米+来那度胺+地塞米松（VRd）等三联方案，随后是自体干细胞移植（ASCT）和维持来那度胺bbb。然而，更新后的EHA-EMN 2024指南现在推荐将基于四联体的诱导作为符合移植条件的患者首选的一线方法。其中包括含有抗cd38单克隆抗体的方案，如达拉单抗+ VRd （Dara-VRd）或isatuximab + VRd (Isa-VRd)，与三重方案相比，这两种方案均显示出更高的可测量残余疾病（MRD）阴性率和更长的无进展生存期。对于不符合移植条件或身体虚弱的患者，指南认可达拉单抗+来那度胺+地塞米松（Dara-Rd）或达拉单抗+硼替佐米+美法兰+强的松（Dara-VMP）作为一线标准，因为它们具有良好的耐受性和持续的反应。在复发或难治性情况下，EHA-EMN 2024共识扩大了治疗选择，包括早期使用bcma定向细胞和免疫治疗。CAR-T细胞产品，如cilta-cel和idedecabtagene vicleucel （ide-cel）现在被认为适用于首次复发，特别是高危细胞遗传学或首次治疗18个月内复发的患者。此外，现成的双特异性抗体，如teclistamab、elranatamab和linvoseltamab，可以作为桥接或二线治疗，在疾病过程的早期纳入，提供快速可及性，而不受自体CAR-T制造的后勤限制。老年/体弱患者通常接受来那度胺+地塞米松（Rd）或硼替佐米联合治疗。对于3级难治性MM， selinexor和belantamab mafodotin等治疗方案的疗效有限，反应时间较短，毒性明显。尽管诸如ide-cel和cilta-cel等CAR-T疗法可以提供深度缓解，但它们的使用受到制造延迟和需要淋巴细胞清除的限制。鉴于CAR-T治疗物流带来的挑战和现有药物在三级难治性疾病中的有限疗效，迫切需要一种结合有效t细胞重定向和即时可用性的治疗方法。Linvoseltamab通过提供一种现成的双特异性方法来实现这一目标，该方法可提供深入，持久的反应，而无需淋巴细胞消耗或个性化制造。Linvoseltamab是一种双特异性T细胞接合剂（BiTE），可同时结合MM细胞上的b细胞成熟抗原（BCMA）和T细胞上的CD3。这种双重作用使细胞毒性T细胞接近骨髓瘤细胞，触发T细胞活化，免疫突触形成，并靶向杀死恶性浆细胞。与CAR-T疗法不同，linvoseltamab不需要体外细胞操作，提供了一种有效的、现成的免疫治疗策略，即使在大量预处理的三级难治性MM患者[7]中也能诱导深度反应。在发表于《临床肿瘤学杂志》（Journal of Clinical Oncology）的一项关键I/II期试验中，linvoseltamab （200 mg）的总缓解率（ORR）为64.5%，47.3%的患者达到至少非常好的部分缓解（≥VGPR）， 23.6%的患者达到完全缓解或严格完全缓解（CR/sCR）。值得注意的是，中位反应持续时间（DOR）为29。 4个月，反映了在这个经过大量预处理的人群中有持久的益处。反应发生迅速，平均反应时间为1.2个月。Linvoseltamab是一种双特异性抗体，靶向骨髓瘤细胞上的BCMA和T细胞上的CD3，可触发T细胞介导的强效细胞毒性，而无需淋巴细胞清除或个体化细胞制造。安全性是可控的，细胞因子释放综合征（CRS）仅限于早期周期，主要是1-2级。这些结果确立了linvoseltamab作为一种高效的、现成的t细胞参与剂用于治疗三级难治性MM患者。图1显示了linvoseltamab 200mg治疗的患者在预先指定的临床亚组中的ORR，显示出跨越年龄、种族、疾病分期和难治性状态的一致疗效。在早期研究和新兴的比较分析中，Linvoseltamab已经证明了有利和可管理的安全性。在关键的I/II期试验中，48.6%的患者发生了CRS，所有病例仅限于1-2级，主要局限于初始给药周期[8]。Kaplon等人（2024）强调，与其他BCMA x CD3双特异性药物相比，linvoseltamab的神经毒性发生率较低，同时也注意到其现成形式的好处，即无需淋巴细胞清除[9]。同样，Reynolds等人（2023）报道了linvoseltamab与teclistamab或talquetamab相比，≥3级感染的发生率更低，这归因于免疫抑制减少和缺乏桥接治疗bbb。总的来说，这些数据表明，linvoseltamab平衡了t细胞重定向和低严重不良事件发生率，为重度预处理mm患者提供了更安全的免疫治疗选择。raza Ur Rehman：构思研究，进行文献综述，进行数据分析和解释，撰写手稿，严格修改手稿，批准最终版本发表，监督研究，并提供行政支持。作者没有什么可报道的。这篇社论不需要伦理批准。本社论不需要征得同意，因为它不包括患者个人数据或可识别信息。作者声明无利益冲突。数据共享不适用于本社论，因为本研究没有创建或分析新数据。
{"title":"Lynozyfic (Linvoseltamab): A First-in-Class Off-the-Shelf T-Cell Redirector for Refractory Multiple Myeloma","authors":"Raza Ur Rehman","doi":"10.1002/jha2.70182","DOIUrl":"https://doi.org/10.1002/jha2.70182","url":null,"abstract":"<p>Letter to the Editor</p><p>On July 2, 2025, the FDA approved Lynozyfic (linvoseltamab-gcpt) for the treatment of relapsed or refractory multiple myeloma (RRMM) in patients who have received at least four prior lines of therapy, including a proteasome inhibitor (PI), immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody. Lynozyfic is administered intravenously and represents the first bispecific antibody targeting both BCMA and CD3 to be approved in this setting. Unlike autologous CAR-T cell therapy, linvoseltamab requires no lymphodepletion or personalized manufacturing, offering an off-the-shelf immunotherapeutic option that engages the patient's T cells in real-time to eliminate malignant plasma cells.</p><p>Multiple myeloma (MM) is a malignant neoplasm of plasma cells characterized by clonal proliferation within the bone marrow and the production of monoclonal immunoglobulins (M-protein). This leads to organ dysfunction involving bone destruction, renal impairment, anemia, and immunosuppression. MM typically evolves from precursor conditions such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), progressing through a multistep transformation that is driven by accumulating genetic mutations and interactions with the bone marrow microenvironment [<span>1</span>]. Globally, MM accounts for approximately 1% of all cancers and around 10% of hematologic malignancies. It is predominantly a disease of the elderly, with a median age at diagnosis of around 69 years [<span>2</span>]. Standard induction for newly diagnosed patients includes a triplet regimen like bortezomib + lenalidomide + dexamethasone (VRd), followed by autologous stem cell transplantation (ASCT) and maintenance lenalidomide [<span>3</span>]. However, the updated EHA–EMN 2024 Guidelines now recommend quadruplet-based induction as the preferred frontline approach for transplant-eligible patients. These include anti-CD38 monoclonal antibody–containing regimens such as daratumumab + VRd (Dara-VRd) or isatuximab + VRd (Isa-VRd), both of which have demonstrated higher rates of measurable residual disease (MRD) negativity and longer progression-free survival compared with triplet regimens. For transplant-ineligible or frail patients, the guidelines endorse daratumumab + lenalidomide + dexamethasone (Dara-Rd) or daratumumab + bortezomib + melphalan + prednisone (Dara-VMP) as frontline standards due to their favorable tolerability and sustained responses [<span>4</span>]. In the relapsed or refractory setting, the EHA–EMN 2024 consensus expands treatment options to include early use of BCMA-directed cellular and immune therapies. CAR-T cell products such as ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel) are now considered appropriate from first relapse, especially in patients with high-risk cytogenetics or relapse within 18 months of initial therapy. In addition, off-the-shelf bispecific antibodies s","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"6 6","pages":""},"PeriodicalIF":1.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jha2.70182","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145581106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benjamin Chin-Yee, Benjamin D. Hedley, Rui Su, Barbra de Vrijer, Facundo Garcia-Bournissen, Sarah Parkinson, Cyrus C. Hsia, Matthew Nichols, Ian Chin-Yee, Christopher J. Patriquin
There is an unmet clinical need for effective treatment of paroxysmal nocturnal hemoglobinuria (PNH) in pregnancy for patients with inadequate response to C5 inhibitors. We report the first case of pegcetacoplan use in pregnancy with accompanying pharmacokinetic analysis. In a patient with transfusion-dependent anemia on eculizumab, third-trimester initiation of pegcetacoplan led to hematological stabilization, transfusion independence, and an uncomplicated term cesarean delivery of a healthy infant. Pegcetacoplan was undetectable in cord blood and breast milk despite therapeutic maternal levels, suggesting fetal and neonatal safety due to lack of significant placental and lactational transfer, and advancing evidence for pegcetacoplan use in pregnancy.
Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.
{"title":"Paroxysmal Nocturnal Hemoglobinuria in Pregnancy Treated With Pegcetacoplan: Case Report and Pharmacokinetic Analysis","authors":"Benjamin Chin-Yee, Benjamin D. Hedley, Rui Su, Barbra de Vrijer, Facundo Garcia-Bournissen, Sarah Parkinson, Cyrus C. Hsia, Matthew Nichols, Ian Chin-Yee, Christopher J. Patriquin","doi":"10.1002/jha2.70179","DOIUrl":"10.1002/jha2.70179","url":null,"abstract":"<p>There is an unmet clinical need for effective treatment of paroxysmal nocturnal hemoglobinuria (PNH) in pregnancy for patients with inadequate response to C5 inhibitors. We report the first case of pegcetacoplan use in pregnancy with accompanying pharmacokinetic analysis. In a patient with transfusion-dependent anemia on eculizumab, third-trimester initiation of pegcetacoplan led to hematological stabilization, transfusion independence, and an uncomplicated term cesarean delivery of a healthy infant. Pegcetacoplan was undetectable in cord blood and breast milk despite therapeutic maternal levels, suggesting fetal and neonatal safety due to lack of significant placental and lactational transfer, and advancing evidence for pegcetacoplan use in pregnancy.</p><p><b>Trial Registration</b>: The authors have confirmed clinical trial registration is not needed for this submission.</p>","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"6 6","pages":""},"PeriodicalIF":1.2,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12628701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145566297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>A 73-year-old male presented with worsening exertional dyspnea. Transthoracic echocardiography showed normal left ventricular size, preserved left ventricular ejection fraction (55%–60%), severe biatrial enlargement, and a dense speckling pattern. The left ventricular posterior wall measured 2.1 cm and the intraventricular septum measured 2.6 cm during diastole. Given that diastolic wall thicknesses over 1.2 cm can be seen in cardiac amyloidosis [<span>1</span>], this raised suspicion for an infiltrative process rather than more common processes such as hypertensive cardiomyopathy. Indeed, cardiac magnetic resonance imaging (top left) showed late gadolinium enhancement consistent with cardiac amyloidosis.</p><p>The patient denied any neuropathy and no pedal edema was noted on examination. While serum protein electrophoresis (SPEP) and serum immunofixation were unremarkable, serum kappa free light chain (FLC) was elevated at 54.4 milligrams per liter (mg/L, upper limit of normal [ULN] 19.4 mg/L). The serum lambda FLC was 8.5 mg/L (ULN 26.3 mg/L), yielding an abnormally elevated FLC ratio of 6.4 (reference range: 0.26–1.65). Troponin I was 0.041 nanograms per milliliter (ng/mL, ULN 0.110 ng/mL), but N-terminus pro B-type natriuretic peptide (nt-proBNP) was significantly elevated at 4510 picograms per milliliter (pg/mL, ULN 125 pg/mL). Immunohistochemistry for kappa light chain on a trephine bone marrow (BM) core biopsy revealed that the majority of plasma cells and small lymphocytes were kappa-restricted (top right). Congo red staining of the same specimen was positive with green birefringence in periosteal tissue (bottom left). Flow cytometry showed an abnormal kappa-restricted population (bottom right) of CD5-variable CD10-negative B cells phenotypically consistent with marginal zone lymphoma (MZL). No <i>MYD88</i> or <i>CXCR4</i> mutations were noted.</p><p>Given the presence of Congo red positivity with a presumed causative clone within the same biopsy sample, a diagnosis of AL amyloidosis secondary to MZL was made. While rare, this entity has been reported [<span>2</span>]. The patient was immediately scheduled to begin rituximab and bendamustine, given his worsening symptoms; however, he opted to defer treatment to seek a second opinion at our center. We performed amyloid typing using liquid chromatography with tandem mass spectrometry (using methods described previously) [<span>3</span>], which demonstrated ATTR (transthyretin)-type amyloidosis. The patient was instead started on the transthyretin stabilizer tafamidis and experienced gradual improvement in his dyspnea.</p><p>This case reinforces the importance of typing amyloidosis in virtually all cases. Late gadolinium enhancement and an FLC ratio over 5.0 are collectively quite suggestive of AL amyloidosis [<span>4</span>], especially when a lymphoproliferative clone is identified simultaneously. However, over 10% of cases of cardiac amyloidosis with abnormal SPEP/FLC results and BM am
{"title":"Amyloid Deposits in a Bone Marrow Biopsy Alongside a Presumed Causative Clone","authors":"Rahul Banerjee, Marie K. Das, Kelly D. Smith","doi":"10.1002/jha2.70180","DOIUrl":"10.1002/jha2.70180","url":null,"abstract":"<p>A 73-year-old male presented with worsening exertional dyspnea. Transthoracic echocardiography showed normal left ventricular size, preserved left ventricular ejection fraction (55%–60%), severe biatrial enlargement, and a dense speckling pattern. The left ventricular posterior wall measured 2.1 cm and the intraventricular septum measured 2.6 cm during diastole. Given that diastolic wall thicknesses over 1.2 cm can be seen in cardiac amyloidosis [<span>1</span>], this raised suspicion for an infiltrative process rather than more common processes such as hypertensive cardiomyopathy. Indeed, cardiac magnetic resonance imaging (top left) showed late gadolinium enhancement consistent with cardiac amyloidosis.</p><p>The patient denied any neuropathy and no pedal edema was noted on examination. While serum protein electrophoresis (SPEP) and serum immunofixation were unremarkable, serum kappa free light chain (FLC) was elevated at 54.4 milligrams per liter (mg/L, upper limit of normal [ULN] 19.4 mg/L). The serum lambda FLC was 8.5 mg/L (ULN 26.3 mg/L), yielding an abnormally elevated FLC ratio of 6.4 (reference range: 0.26–1.65). Troponin I was 0.041 nanograms per milliliter (ng/mL, ULN 0.110 ng/mL), but N-terminus pro B-type natriuretic peptide (nt-proBNP) was significantly elevated at 4510 picograms per milliliter (pg/mL, ULN 125 pg/mL). Immunohistochemistry for kappa light chain on a trephine bone marrow (BM) core biopsy revealed that the majority of plasma cells and small lymphocytes were kappa-restricted (top right). Congo red staining of the same specimen was positive with green birefringence in periosteal tissue (bottom left). Flow cytometry showed an abnormal kappa-restricted population (bottom right) of CD5-variable CD10-negative B cells phenotypically consistent with marginal zone lymphoma (MZL). No <i>MYD88</i> or <i>CXCR4</i> mutations were noted.</p><p>Given the presence of Congo red positivity with a presumed causative clone within the same biopsy sample, a diagnosis of AL amyloidosis secondary to MZL was made. While rare, this entity has been reported [<span>2</span>]. The patient was immediately scheduled to begin rituximab and bendamustine, given his worsening symptoms; however, he opted to defer treatment to seek a second opinion at our center. We performed amyloid typing using liquid chromatography with tandem mass spectrometry (using methods described previously) [<span>3</span>], which demonstrated ATTR (transthyretin)-type amyloidosis. The patient was instead started on the transthyretin stabilizer tafamidis and experienced gradual improvement in his dyspnea.</p><p>This case reinforces the importance of typing amyloidosis in virtually all cases. Late gadolinium enhancement and an FLC ratio over 5.0 are collectively quite suggestive of AL amyloidosis [<span>4</span>], especially when a lymphoproliferative clone is identified simultaneously. However, over 10% of cases of cardiac amyloidosis with abnormal SPEP/FLC results and BM am","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"6 6","pages":""},"PeriodicalIF":1.2,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12624456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145558310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>A 73-year-old female patient was diagnosed with essential thrombocythemia (ET) with <i>CALR<sup>mut</sup></i> and <i>DNMT3A<sup>mut</sup></i> at diagnosis (Variant Allele Function [VAF] 14.3% and 31.2%, respectively). While receiving cytoreductive therapy with hydroxycarbamide for 6 years, she developed progressive respiratory failure, associated with discrete anaemia. During the diagnostic workup, she underwent positron emission tomography-computed tomography that showed extensive pleural and peri-hilum hypermetabolism (Figure 1, left panel). At that time, blood counts were subnormal (leukocytes, 3.46 g/L; haemoglobin, 110 g/L; platelets, 433 g/L). Bronchial fibroscopy showed a granulating infiltration at the left superior lobar bronchus entrance with biopsies showing extra-medullary myeloid blast cells (immunohistochemistry showed CD34 [higher right image], MPO [lower right image], CD4 and CD56 expression; Figure 1, right panel; objective ×40). Bone marrow aspiration confirmed post-ET acute myeloid leukaemia (AML) with 44% myeloid blasts and a complex karyotype including monosomy 7 and a del(5q) deletion. Next Generation Sequencing (NGS) showed persistent <i>CALR</i> and <i>DNMT3A</i> mutations, but with lower VAF (2.3% and 1.3%, respectively), while two pathogenic mutations on <i>NRAS</i> and <i>SETBP1</i> genes were observed (VAF 31% and 33%, respectively), suggesting that the leukaemic transformation evolved at the expense of a different clone than the one associated with the myeloproliferative neoplasm (MPN). Due to technical issues, we could not assess the mutational profile in the bronchial biopsy.</p><p>The patient was included in a clinical trial evaluating induction therapy with CPX-351, a liposomal formulation of encapsulated cytarabine and daunorubicin, in patients with post-MPN AML (NCT04992949) [<span>1</span>]. After one cycle, she achieved complete morphologic and cytogenetic remission but no extra-medullary response with persistent bronchial myeloid blast cells. After one cycle of second-line therapy with azacitidine and venetoclax [<span>2-4</span>], bone marrow aspiration showed very poor marrow attributable to treatment toxicity, with no excess blast; a chest scan showed partial regression of pleural effusion and clinical improvement was observed. While receiving a second cycle of azacitidine–venetoclax, she presented to the emergency room with confusion, with a brain scan and cerebrospinal fluid examination confirming tumoral meningitis. The patient declined any further therapy and eventually died from AML.</p><p>Extramedullary localization of AML (or myeloid sarcoma) is a rare presentation of post-MPN AML that can occur without clear evidence of peripheral blood involvement by AML, as presented in this case [<span>5</span>]. This suggests that histopathological documentation of suspicious extramedullary lesions should be obtained in patients with MPN, even(Figure 1) with normal blood count.</p><p>Conception and design: C
{"title":"Pleural Infiltration Revealing Post-Essential Thrombocythemia Acute Myeloid Leukaemia","authors":"Clémentine Muron, Damien Luque Paz, Marie-Christine Copin, Corentin Orvain","doi":"10.1002/jha2.1108","DOIUrl":"10.1002/jha2.1108","url":null,"abstract":"<p>A 73-year-old female patient was diagnosed with essential thrombocythemia (ET) with <i>CALR<sup>mut</sup></i> and <i>DNMT3A<sup>mut</sup></i> at diagnosis (Variant Allele Function [VAF] 14.3% and 31.2%, respectively). While receiving cytoreductive therapy with hydroxycarbamide for 6 years, she developed progressive respiratory failure, associated with discrete anaemia. During the diagnostic workup, she underwent positron emission tomography-computed tomography that showed extensive pleural and peri-hilum hypermetabolism (Figure 1, left panel). At that time, blood counts were subnormal (leukocytes, 3.46 g/L; haemoglobin, 110 g/L; platelets, 433 g/L). Bronchial fibroscopy showed a granulating infiltration at the left superior lobar bronchus entrance with biopsies showing extra-medullary myeloid blast cells (immunohistochemistry showed CD34 [higher right image], MPO [lower right image], CD4 and CD56 expression; Figure 1, right panel; objective ×40). Bone marrow aspiration confirmed post-ET acute myeloid leukaemia (AML) with 44% myeloid blasts and a complex karyotype including monosomy 7 and a del(5q) deletion. Next Generation Sequencing (NGS) showed persistent <i>CALR</i> and <i>DNMT3A</i> mutations, but with lower VAF (2.3% and 1.3%, respectively), while two pathogenic mutations on <i>NRAS</i> and <i>SETBP1</i> genes were observed (VAF 31% and 33%, respectively), suggesting that the leukaemic transformation evolved at the expense of a different clone than the one associated with the myeloproliferative neoplasm (MPN). Due to technical issues, we could not assess the mutational profile in the bronchial biopsy.</p><p>The patient was included in a clinical trial evaluating induction therapy with CPX-351, a liposomal formulation of encapsulated cytarabine and daunorubicin, in patients with post-MPN AML (NCT04992949) [<span>1</span>]. After one cycle, she achieved complete morphologic and cytogenetic remission but no extra-medullary response with persistent bronchial myeloid blast cells. After one cycle of second-line therapy with azacitidine and venetoclax [<span>2-4</span>], bone marrow aspiration showed very poor marrow attributable to treatment toxicity, with no excess blast; a chest scan showed partial regression of pleural effusion and clinical improvement was observed. While receiving a second cycle of azacitidine–venetoclax, she presented to the emergency room with confusion, with a brain scan and cerebrospinal fluid examination confirming tumoral meningitis. The patient declined any further therapy and eventually died from AML.</p><p>Extramedullary localization of AML (or myeloid sarcoma) is a rare presentation of post-MPN AML that can occur without clear evidence of peripheral blood involvement by AML, as presented in this case [<span>5</span>]. This suggests that histopathological documentation of suspicious extramedullary lesions should be obtained in patients with MPN, even(Figure 1) with normal blood count.</p><p>Conception and design: C","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"6 6","pages":""},"PeriodicalIF":1.2,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12610944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145514804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Phil Choi, Alberta Hoi, Rong Fu, Jun-ho Jang, Yok Lam Kwong, Yoshitaka Miyakawa, Chi-Chiu Mok, Hiroaki Niiro, Yasutaka Ueda, Robert Bagnall, Petya Kodjamanova, Da Eun Ahn, Nakul Saxena, Bryan Wahking, Shin-Seok Lee
Objective
This study aimed to assess the burden of warm autoimmune haemolytic anaemia (wAIHA) and treatment practices in the Asia-Pacific (APAC) region.
Methods
A systematic literature review (SLR) of observational studies in adult patients with wAIHA was conducted. Based on these findings, a Delphi panel was convened to develop consensus recommendations on diagnosis, treatment goals and algorithms by subtypes, unmet needs and research priorities.
Results
The SLR included 37 publications. Clinical guidelines consistently recommend direct antiglobulin testing for diagnosis and corticosteroids as first-line treatment. Real-world data showed corticosteroid use in over 80% of patients, with response rates of 81%–96%, and relapse rates of 18%–45%. The Delphi panel recommended routine screening for underlying conditions and early therapeutic interventions. Key challenges identified included restricted access to rituximab in parts of the APAC region and gaps in physician awareness. Research priorities included optimising therapy, assessing long-term outcomes and improving disease awareness.
Conclusion
This research emphasises the need for evidence-based, regionally adaptable treatment algorithms for wAIHA in the APAC region. Ongoing data gaps related to epidemiology, outcomes and quality of life must be addressed to enhance patient care.
Trial Registration
The authors have confirmed clinical trial registration is not needed for this submission.
{"title":"Warm Autoimmune Haemolytic Anaemia Management in Asia-Pacific: A Delphi Panel Expert Consensus and Systematic Literature Review","authors":"Phil Choi, Alberta Hoi, Rong Fu, Jun-ho Jang, Yok Lam Kwong, Yoshitaka Miyakawa, Chi-Chiu Mok, Hiroaki Niiro, Yasutaka Ueda, Robert Bagnall, Petya Kodjamanova, Da Eun Ahn, Nakul Saxena, Bryan Wahking, Shin-Seok Lee","doi":"10.1002/jha2.70174","DOIUrl":"https://doi.org/10.1002/jha2.70174","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study aimed to assess the burden of warm autoimmune haemolytic anaemia (wAIHA) and treatment practices in the Asia-Pacific (APAC) region.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A systematic literature review (SLR) of observational studies in adult patients with wAIHA was conducted. Based on these findings, a Delphi panel was convened to develop consensus recommendations on diagnosis, treatment goals and algorithms by subtypes, unmet needs and research priorities.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The SLR included 37 publications. Clinical guidelines consistently recommend direct antiglobulin testing for diagnosis and corticosteroids as first-line treatment. Real-world data showed corticosteroid use in over 80% of patients, with response rates of 81%–96%, and relapse rates of 18%–45%. The Delphi panel recommended routine screening for underlying conditions and early therapeutic interventions. Key challenges identified included restricted access to rituximab in parts of the APAC region and gaps in physician awareness. Research priorities included optimising therapy, assessing long-term outcomes and improving disease awareness.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This research emphasises the need for evidence-based, regionally adaptable treatment algorithms for wAIHA in the APAC region. Ongoing data gaps related to epidemiology, outcomes and quality of life must be addressed to enhance patient care.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial Registration</h3>\u0000 \u0000 <p>The authors have confirmed clinical trial registration is not needed for this submission.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"6 6","pages":""},"PeriodicalIF":1.2,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jha2.70174","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145469751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abdullah M. Khan, Glenn S. Kroog, Tito Roccia, Kate Knorr, Anita Boyapati, Naresh Bumma
Pseudoprogression is characterised by an increase in tumour size, driven by an influx of inflammatory cells, followed by regression. This phenomenon has rarely been reported in multiple myeloma (MM), despite increased use of immunotherapy approaches that have been associated with pseudoprogression in other malignancies. We report a case of pseudoprogression in a female in her early seventies with relapsed/refractory MM who was treated with the BCMA×CD3 bispecific antibody linvoseltamab. At study Day 28, she was hospitalised with acute bone pain and a new fracture, and a positron emission tomography/computed tomography scan suggested disease progression. However, biochemical markers of disease burden (serum M-protein, kappa light chain) had decreased from baseline, and therefore linvoseltamab was continued. At Day 77, M-protein was absent and the patient had achieved complete biochemical response, but she had to discontinue linvoseltamab due to infectious complications. A subsequent scan on Day 86 demonstrated marked improvement in osseous lesions. Despite being off therapy, the disease did not progress for 2 years. Assessment of T-cell activation and proinflammatory cytokine production indicated increased T-cell activation concurrent with onset of radiologic pseudoprogression. To our knowledge, this is the first description of radiologic pseudoprogression in MM with anti-BCMA bispecific antibody therapy.
{"title":"Radiologic Pseudoprogression Associated With a Positive Response in a Patient With Multiple Myeloma Treated With a BCMA×CD3 Bispecific Antibody: A Case Report","authors":"Abdullah M. Khan, Glenn S. Kroog, Tito Roccia, Kate Knorr, Anita Boyapati, Naresh Bumma","doi":"10.1002/jha2.70168","DOIUrl":"https://doi.org/10.1002/jha2.70168","url":null,"abstract":"<p>Pseudoprogression is characterised by an increase in tumour size, driven by an influx of inflammatory cells, followed by regression. This phenomenon has rarely been reported in multiple myeloma (MM), despite increased use of immunotherapy approaches that have been associated with pseudoprogression in other malignancies. We report a case of pseudoprogression in a female in her early seventies with relapsed/refractory MM who was treated with the BCMA×CD3 bispecific antibody linvoseltamab. At study Day 28, she was hospitalised with acute bone pain and a new fracture, and a positron emission tomography/computed tomography scan suggested disease progression. However, biochemical markers of disease burden (serum M-protein, kappa light chain) had decreased from baseline, and therefore linvoseltamab was continued. At Day 77, M-protein was absent and the patient had achieved complete biochemical response, but she had to discontinue linvoseltamab due to infectious complications. A subsequent scan on Day 86 demonstrated marked improvement in osseous lesions. Despite being off therapy, the disease did not progress for 2 years. Assessment of T-cell activation and proinflammatory cytokine production indicated increased T-cell activation concurrent with onset of radiologic pseudoprogression. To our knowledge, this is the first description of radiologic pseudoprogression in MM with anti-BCMA bispecific antibody therapy.</p>","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"6 6","pages":""},"PeriodicalIF":1.2,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jha2.70168","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145469987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Caterina Cristinelli, Michele Merli, Marco Lucioni, Manuel Gotti, Roberta Sciarra, Sara Rattotti, Federico Carpi, Gianmarco Favrin, Benedetta Bianchi, Giuseppe Neri, Marta Coscia, Marcello Gambacorta, Francesco Passamonti, Marco Paulli, Luca Arcaini
Background
Castleman disease (CD) encompasses a range of heterogeneous non-clonal lymphoproliferative disorders, including unicentric (UCD), and multicentric (MCD) forms. The latter is subdivided into HHV-8+ MCD, POEMS-MCD, and idiopathic-MCD, not otherwise specified (iMCD-NOS).
Methods
Here we report the clinical characteristics and outcomes of 28 consecutive CD patients, diagnosed in two centers of northern Italy according to recently published diagnostic criteria.
Results
UCD was reported in 12 cases (43%) and MCD in 16 (57%). Among these, 6 (21%) were HHV-8 positive (1 HIV-positive and 5 HIV-negative), and 10 (36%) had iMCD-NOS. Treatment of UCD consisted of surgical excision in 10/12 cases, resulting in ongoing complete remission in all cases. Single nodal localization favorably affected overall survival (OS) and progression-free survival (PFS) (p < 0.05). Out of 16 MCD patients, 10 had iMCD-NOS and 6 had HHV-8+MCD. Anti-IL-6 monoclonal antibody was used as first-line treatment in 5/10 iMCD-NOS patients, 3 of whom relapsed, although none died. Two out of 6 patients with HHV-8+ MCD were treated with single-agent rituximab and one with rituximab plus chemotherapy. UCD patients had significantly better OS and PFS compared to iMCD and HHV-8+MCD groups (p < 0.001).
Conclusions
Our report confirms that UCD, iMCD-NOS, and HHV-8+MCD represent distinct clinical entities with different outcomes requiring specific treatment approaches.
Trial Registration
The authors have confirmed clinical trial registration is not needed for this submission.
{"title":"Clinical Presentation, Treatment, and Outcomes of 28 Patients With Castleman Disease: A Retrospective Analysis of an Italian Cohort","authors":"Caterina Cristinelli, Michele Merli, Marco Lucioni, Manuel Gotti, Roberta Sciarra, Sara Rattotti, Federico Carpi, Gianmarco Favrin, Benedetta Bianchi, Giuseppe Neri, Marta Coscia, Marcello Gambacorta, Francesco Passamonti, Marco Paulli, Luca Arcaini","doi":"10.1002/jha2.70158","DOIUrl":"https://doi.org/10.1002/jha2.70158","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Castleman disease (CD) encompasses a range of heterogeneous non-clonal lymphoproliferative disorders, including unicentric (UCD), and multicentric (MCD) forms. The latter is subdivided into HHV-8+ MCD, POEMS-MCD, and idiopathic-MCD, not otherwise specified (iMCD-NOS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here we report the clinical characteristics and outcomes of 28 consecutive CD patients, diagnosed in two centers of northern Italy according to recently published diagnostic criteria.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>UCD was reported in 12 cases (43%) and MCD in 16 (57%). Among these, 6 (21%) were HHV-8 positive (1 HIV-positive and 5 HIV-negative), and 10 (36%) had iMCD-NOS. Treatment of UCD consisted of surgical excision in 10/12 cases, resulting in ongoing complete remission in all cases. Single nodal localization favorably affected overall survival (OS) and progression-free survival (PFS) (<i>p</i> < 0.05). Out of 16 MCD patients, 10 had iMCD-NOS and 6 had HHV-8+MCD. Anti-IL-6 monoclonal antibody was used as first-line treatment in 5/10 iMCD-NOS patients, 3 of whom relapsed, although none died. Two out of 6 patients with HHV-8+ MCD were treated with single-agent rituximab and one with rituximab plus chemotherapy. UCD patients had significantly better OS and PFS compared to iMCD and HHV-8+MCD groups (<i>p</i> < 0.001).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our report confirms that UCD, iMCD-NOS, and HHV-8+MCD represent distinct clinical entities with different outcomes requiring specific treatment approaches.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial Registration</h3>\u0000 \u0000 <p>The authors have confirmed clinical trial registration is not needed for this submission.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"6 6","pages":""},"PeriodicalIF":1.2,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jha2.70158","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145469988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>A 72-year-old lady presented to the emergency department with extreme pallor and exertional dyspnoea. Her medical history was unremarkable, and she was not on any regular medications.</p><p>Initial full blood count (FBC) revealed a haemoglobin of 50 g/L (reference range: 120–155 g/L), a mean cell volume of 126.5 fL (reference range: 79.0–90.6 fL), a borderline reticulocyte count of 20 × 10<sup>9</sup>/L (reference range: 20–79 × 10<sup>9</sup>/L) and thrombocytopenia of 49 × 10<sup>9</sup>/L (reference range: 132–345 × 10<sup>9</sup>/L). Total white cell count and differential were within normal limits. The patient was admitted for investigation of these cytopenias.</p><p>The peripheral blood film received in the laboratory was regrettably obtained post-transfusion, demonstrating a dimorphic picture (Figure 1). Features of megaloblastic anaemia were observed, such as macro-ovalocytes and hypersegmented neutrophils (Panel A), macropolycytes (Panel B) and occasional apoptotic neutrophils (Panel C) [<span>1</span>]. In addition, there was an unexpected number of circulating nucleated red cell precursors with left shift, an atypical finding on peripheral blood in the context of megaloblastic anaemia [<span>2</span>]. These precursors consisted of occasional basophilic erythroblasts, characterized by basophilic cytoplasm and a perinuclear halo (Panels A and D); polychromatic erythroblasts, with less intense basophilic cytoplasm and a more condensed chromatin pattern (Panels E and F); and numerous abnormal orthochromatic erythroblasts (Panel G).</p><p>Haematinic assessment confirmed severe vitamin B12 deficiency (< 111 pmol/L; reference range: 142–725 pmol/L), with normal folate levels (8.75 nmol/L; reference range: 6–39 nmol/L). Iron studies, ferritin and serum protein electrophoresis were unremarkable. Haemolytic anaemia was excluded based on a low reticulocyte count, normal bilirubin and LDH, and absence of schistocytes, red cell agglutinates or spherocytes on blood film.</p><p>The patient did not have neurological features of vitamin B12 deficiency, such as ataxia, paresthesia and neuropsychiatric changes. She followed an omnivorous diet and did not have a history of gastrointestinal surgery or malabsorption. Tissue transglutaminase levels were normal, and a CT scan revealed no abnormalities that could account for the vitamin B12 deficiency.</p><p>Treatment with intramuscular hydroxocobalamin injections was initiated, along with regular monitoring of the complete blood count and potassium levels. Due to the unusual presence of early red cell precursors, repeat peripheral blood films were advised during hydroxocobalamin therapy. Persistence of these precursors would have prompted consideration of a bone marrow biopsy to exclude diagnoses such as acute leukemia.</p><p>The patient achieved near normalization of her counts within 2 weeks, with a haemoglobin of 105 g/L, and a platelet count of 123 × 10<sup>9</sup>/L. A repeat blood film at this po
{"title":"An Unusual Case of Severe Vitamin B12 Deficiency With Early Erythroblasts on Peripheral Blood Film","authors":"Jessica Muscat, Alexander Gatt","doi":"10.1002/jha2.70178","DOIUrl":"10.1002/jha2.70178","url":null,"abstract":"<p>A 72-year-old lady presented to the emergency department with extreme pallor and exertional dyspnoea. Her medical history was unremarkable, and she was not on any regular medications.</p><p>Initial full blood count (FBC) revealed a haemoglobin of 50 g/L (reference range: 120–155 g/L), a mean cell volume of 126.5 fL (reference range: 79.0–90.6 fL), a borderline reticulocyte count of 20 × 10<sup>9</sup>/L (reference range: 20–79 × 10<sup>9</sup>/L) and thrombocytopenia of 49 × 10<sup>9</sup>/L (reference range: 132–345 × 10<sup>9</sup>/L). Total white cell count and differential were within normal limits. The patient was admitted for investigation of these cytopenias.</p><p>The peripheral blood film received in the laboratory was regrettably obtained post-transfusion, demonstrating a dimorphic picture (Figure 1). Features of megaloblastic anaemia were observed, such as macro-ovalocytes and hypersegmented neutrophils (Panel A), macropolycytes (Panel B) and occasional apoptotic neutrophils (Panel C) [<span>1</span>]. In addition, there was an unexpected number of circulating nucleated red cell precursors with left shift, an atypical finding on peripheral blood in the context of megaloblastic anaemia [<span>2</span>]. These precursors consisted of occasional basophilic erythroblasts, characterized by basophilic cytoplasm and a perinuclear halo (Panels A and D); polychromatic erythroblasts, with less intense basophilic cytoplasm and a more condensed chromatin pattern (Panels E and F); and numerous abnormal orthochromatic erythroblasts (Panel G).</p><p>Haematinic assessment confirmed severe vitamin B12 deficiency (< 111 pmol/L; reference range: 142–725 pmol/L), with normal folate levels (8.75 nmol/L; reference range: 6–39 nmol/L). Iron studies, ferritin and serum protein electrophoresis were unremarkable. Haemolytic anaemia was excluded based on a low reticulocyte count, normal bilirubin and LDH, and absence of schistocytes, red cell agglutinates or spherocytes on blood film.</p><p>The patient did not have neurological features of vitamin B12 deficiency, such as ataxia, paresthesia and neuropsychiatric changes. She followed an omnivorous diet and did not have a history of gastrointestinal surgery or malabsorption. Tissue transglutaminase levels were normal, and a CT scan revealed no abnormalities that could account for the vitamin B12 deficiency.</p><p>Treatment with intramuscular hydroxocobalamin injections was initiated, along with regular monitoring of the complete blood count and potassium levels. Due to the unusual presence of early red cell precursors, repeat peripheral blood films were advised during hydroxocobalamin therapy. Persistence of these precursors would have prompted consideration of a bone marrow biopsy to exclude diagnoses such as acute leukemia.</p><p>The patient achieved near normalization of her counts within 2 weeks, with a haemoglobin of 105 g/L, and a platelet count of 123 × 10<sup>9</sup>/L. A repeat blood film at this po","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"6 6","pages":""},"PeriodicalIF":1.2,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12584156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145454187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frederik Christensen, Deniz Kenan Kılıç, Alexander Djupnes Fuglkjær, Jesper Petersen, Tarec Christoffer El-Galaly, Andreas Glenthøj, Jens Helby, Izabela Ewa Nielsen
Background
Haemoglobin S (HbS) and C (HbC) are the most important sickling variants on the African continent, imposing major health burdens. Early detection of carrier status is crucial but often hindered by resource limitations.
Objectives
To develop machine learning (ML) models to accurately classify HbS and HbC carriers using readily available routine blood tests, facilitating cost-effective mass screening.
Methods
We utilised demographic and routine blood parameters from 469,248 individuals from the UK general population, including 1635 individuals with HbS and/or HbC variants identified by whole exome sequencing, to develop ML models for carrier detection based on standard blood tests. Three ML models (Logistic Regression [LR], Random Forest [RF] and XGBoost [XGB]) were trained using 32 different standard blood test results.
Results
All models demonstrated high discriminatory ability (ROC-AUC: LR 0.951; RF 0.943; XGB 0.956) in the UK general population. At a sensitivity of 95%, specificities were 77% (LR), 76% (RF) and 78% (XGB). SHAP analysis revealed consistent key features across models. When use was restricted to black individuals, performance fell considerably.
Conclusions
ML models based on routine blood tests effectively identify HbS and HbC carriers in a mixed general population. This approach has the potential to enhance screening efficiency by reducing reliance on specialised techniques.
背景：血红蛋白S （HbS）和C （HbC）是非洲大陆最重要的镰状红细胞变异体，造成了重大的健康负担。早期发现带菌者的状态是至关重要的，但往往受到资源限制的阻碍。目的：开发机器学习（ML）模型，使用现成的常规血液检查准确分类HbS和HbC携带者，促进具有成本效益的大规模筛查。方法：我们利用来自英国普通人群的469,248人的人口统计学和常规血液参数，包括1635名HbS和/或HbC变异的个体，通过全外显子组测序鉴定，建立基于标准血液检测的载体检测ML模型。使用32种不同的标准血液检测结果训练了三种ML模型（Logistic Regression [LR]， Random Forest [RF]和XGBoost [XGB]）。结果：所有模型在英国普通人群中表现出较高的区分能力（ROC-AUC: LR 0.951; RF 0.943; XGB 0.956）。灵敏度为95%，特异性为77% (LR), 76% （RF）和78% （XGB）。SHAP分析揭示了模型之间一致的关键特征。当使用仅限于黑人时，表现明显下降。结论：基于常规血液检查的ML模型可有效识别混合普通人群中的HbS和HbC携带者。这种方法有可能通过减少对专门技术的依赖来提高筛查效率。
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Jasmine Singh, Nancy Li, Elham Ashrafi, Le Thi Phuong Thao, David J. Curtis, Erica M. Wood, Zoe K. McQuilten
Introduction
Clonal haematopoiesis of indeterminate potential (CHIP) is a risk factor for blood cancers and non-haematological diseases. Understanding factors that lead to CHIP is essential in developing preventive strategies. We aimed to identify factors associated with risk of CHIP through a systemic literature review.
Methods
We searched MEDLINE and EMBASE for original studies reporting an age-adjusted risk measure for factors associated with an outcome of incident or prevalent CHIP. Random effects meta-analyses were performed for factors reported in at least three cohorts.
Results
From 3305 abstracts, 26 studies were included, ranging from 118 to 239,216 participants. Risk of CHIP was higher in those with hypertension (Odds Ratio [OR] 1.1, 95% confidence interval 1.03–1.16), HIV infection (OR 2.37; 1.68–3.34), and smoking (OR 1.13; 1.10–1.17). The risk of CHIP was lower in those of Asian compared to White ethnicity (OR 0.73; 0.56–0.94). Male sex was not associated with risk of CHIP overall (OR 0.94; 0.86–1.03), but was associated with reduced risk of DNMT3A-CHIP (OR 0.82; 0.78–0.86) and increased risk of ASXL1-CHIP (OR 2.00; 1.76–2.27) or spliceosome-CHIP (OR 2.51; 2.03–3.11). We demonstrated no association between CHIP and diabetes, body mass index, or cardiovascular disease.
Conclusion
Our findings highlight the heterogeneity of CHIP, and suggest that factors associated with risk of CHIP differ between genes.
Trial Registration
The authors have confirmed clinical trial registration is not needed for this submission.
{"title":"Factors Associated with Risk of Clonal Haematopoiesis of Indeterminate Potential: A Systematic Review and Meta-Analysis","authors":"Jasmine Singh, Nancy Li, Elham Ashrafi, Le Thi Phuong Thao, David J. Curtis, Erica M. Wood, Zoe K. McQuilten","doi":"10.1002/jha2.70173","DOIUrl":"https://doi.org/10.1002/jha2.70173","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Clonal haematopoiesis of indeterminate potential (CHIP) is a risk factor for blood cancers and non-haematological diseases. Understanding factors that lead to CHIP is essential in developing preventive strategies. We aimed to identify factors associated with risk of CHIP through a systemic literature review.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We searched MEDLINE and EMBASE for original studies reporting an age-adjusted risk measure for factors associated with an outcome of incident or prevalent CHIP. Random effects meta-analyses were performed for factors reported in at least three cohorts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>From 3305 abstracts, 26 studies were included, ranging from 118 to 239,216 participants. Risk of CHIP was higher in those with hypertension (Odds Ratio [OR] 1.1, 95% confidence interval 1.03–1.16), HIV infection (OR 2.37; 1.68–3.34), and smoking (OR 1.13; 1.10–1.17). The risk of CHIP was lower in those of Asian compared to White ethnicity (OR 0.73; 0.56–0.94). Male sex was not associated with risk of CHIP overall (OR 0.94; 0.86–1.03), but was associated with reduced risk of <i>DNMT3A</i>-CHIP (OR 0.82; 0.78–0.86) and increased risk of <i>ASXL1</i>-CHIP (OR 2.00; 1.76–2.27) or spliceosome-CHIP (OR 2.51; 2.03–3.11). We demonstrated no association between CHIP and diabetes, body mass index, or cardiovascular disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings highlight the heterogeneity of CHIP, and suggest that factors associated with risk of CHIP differ between genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial Registration</h3>\u0000 \u0000 <p>The authors have confirmed clinical trial registration is not needed for this submission.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"6 6","pages":""},"PeriodicalIF":1.2,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jha2.70173","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145406882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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