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IFN-α treatment may enable discontinuation of TKIs in NK cell-licensed patients with CML-CP IFN-α治疗可使NK细胞许可的CML-CP患者停用TKIs。
Pub Date : 2024-11-26 DOI: 10.1002/jha2.1053
Hiroshi Ureshino, Kazuharu Kamachi, Keisuke Kidoguchi, Shinya Kimura

The magnitude of the natural killer (NK) cell response contributes to the achievement of treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML) and is regulated by the interaction between killer immunoglobulin-like receptors (KIRs) on NK cells and human leukocyte antigen (HLA) class I molecules on target cells. The abundant combination between KIR and HLA through genetic polymorphisms determines the functional diversity of NK cells. We previously reported that KIR3DL1-HLA-Bw status is associated with achievement of TFR by reflecting NK cell potential. Patients with strong interaction between KIR3DL1/HLA-Bw were identified as having a higher molecular relapse risk, based on the “missing self” hypothesis which suggests that the lack of cognate ligands for KIRs may induce target cell lysis. However, all the patients with strong interaction between KIR3DL1/HLA-Bw who received prior IFN-α therapy achieved TFR (p = 0.007), explained by the “NK cell licensing” concept, whereby NK cells become more functional through the recognition “self” HLA class I molecules by KIRs. NK cell licensing may contribute to the potential efficacy of IFN-α treatment in patients with CML. We defined high-risk molecular relapse patients and suggest that KIR3DL1/HLA-Bw status may help detect patients who could benefit from IFN-α for maintaining TFR.

自然杀伤(NK)细胞反应的强度有助于慢性髓性白血病(CML)患者实现无治疗缓解(TFR),并受NK细胞上的杀伤免疫球蛋白样受体(KIRs)和靶细胞上的人白细胞抗原(HLA) I类分子之间的相互作用调节。KIR与HLA通过遗传多态性的丰富结合决定了NK细胞功能的多样性。我们之前报道过KIR3DL1-HLA-Bw状态通过反映NK细胞电位与TFR的实现相关。KIR3DL1/HLA-Bw之间相互作用强的患者被认为具有更高的分子复发风险,基于“缺失自我”假说,该假说表明缺乏KIRs的同源配体可能导致靶细胞裂解。然而,所有接受过IFN-α治疗的KIR3DL1/HLA- bw之间强相互作用的患者均实现了TFR (p = 0.007),这可以用“NK细胞许可”概念来解释,即NK细胞通过KIRs识别“自身”HLA I类分子而变得更有功能。NK细胞许可可能有助于IFN-α治疗CML患者的潜在疗效。我们定义了高危分子复发患者,并建议KIR3DL1/HLA-Bw状态可能有助于检测可能受益于IFN-α维持TFR的患者。
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引用次数: 0
Incidence and risk factors of graft failure in allogeneic hematopoietic stem cell transplantation for mucopolysaccharidosis in a nationwide pediatric cohort. A study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy 在一项全国儿童队列中,治疗粘多糖病的异基因造血干细胞移植移植失败的发生率和危险因素。代表法语国家骨髓移植和细胞治疗协会进行的一项研究。
Pub Date : 2024-11-26 DOI: 10.1002/jha2.1056
Laura Danhardt, Arnaud Wiedemann, Gerard Michel, Jean-Hugues Dalle, Fanny Rialland, Cécile Renard, Charlotte Jubert, Johan Maertens, Anne Sirvent, Nimrod Buchbinder, Christine Devalck, Bénédicte Brichard, Catherine Paillard, Stephanie Nguyen, Angelo Paci, David Combarel, Martin Castelle, Simona Pagliuca, Cecile Pochon

Context

Mucopolysaccharidosis (MPS) requires urgent treatment to prevent neurological damage. While gene therapy holds promise for effectively treating these diseases with minimal toxicity, access remains limited for most patients. Consequently, advancing allogeneic hematopoietic stem cell transplantation (HSCT) for young children is crucial. Since the 2010s, cord blood (CB) transplants with reduced-toxicity conditioning (RTC) have become the standard of care.

Patients and methods

Recent reports in France indicate a significant incidence of graft failures (GF), prompting a large-scale retrospective study from the French-speaking bone marrow transplantation society's registry, to understand GF risks, guide clinicians in selecting transplant platforms, and describe outcomes of second HSCT in young patients.

Results

This report analyses 93 children who underwent HSCT for MPS between 2000 and 2020. The GF rate was notably high (22.6% at day 100), primarily associated with the donor's HLA compatibility and the recipient's age. Well-matched CB and RTC were not found to be risk factors for GF. This study also details the procedures for second and third transplants in patients who rejected their first HSCT.

Conclusion

In the era of RTC, CB remains a viable and expedient option for MPS transplantation.

背景:粘多糖病(MPS)需要紧急治疗以防止神经损伤。虽然基因疗法有望以最小的毒性有效治疗这些疾病,但对大多数患者来说,获得这些疾病的途径仍然有限。因此,推进幼儿同种异体造血干细胞移植(HSCT)至关重要。自2010年代以来,带有低毒性调节(RTC)的脐带血(CB)移植已成为护理标准。患者和方法:法国最近的报道表明移植失败(GF)的发生率很高,促使法语骨髓移植协会登记处进行了大规模的回顾性研究,以了解GF风险,指导临床医生选择移植平台,并描述年轻患者第二次HSCT的结果。结果:本报告分析了2000年至2020年期间93名因MPS接受HSCT治疗的儿童。GF率显著高(第100天22.6%),主要与供者的HLA相容性和受体的年龄有关。匹配良好的CB和RTC未被发现是GF的危险因素。本研究还详细介绍了拒绝第一次移植的患者进行第二次和第三次移植的程序。结论:在RTC时代,CB仍然是MPS移植的一种可行和方便的选择。
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引用次数: 0
Real-world practitioner perceptions of CARTITUDE-4 results for patients with previously treated multiple myeloma 从业人员对曾接受过治疗的多发性骨髓瘤患者的 CARTITUDE-4 结果的真实看法。
Pub Date : 2024-11-25 DOI: 10.1002/jha2.1047
Alexandrina Balanean, Samuel Baird, Brooke Dulka, Luke Jennings-Zhang, Robert N. Bone, Yolaine Jeune-Smith, Bruce Feinberg, Muhamed Baljevic

Introduction

Initially approved for the fifth-line or later therapeutic setting, the chimeric antigen receptor (CAR) T-cell regimen ciltacabtagene autoleucel (cilta-cel) was recently approved for second-line (2L) treatment in relapsed/refractory multiple myeloma (RRMM). Oncology practitioners use clinical trials to inform treatment, but real-world impressions and impact on practice are lacking. We aimed to determine whether presenting CARTITUDE-4 clinical trial data would impact real-world preferences/perceptions around CAR T-cell therapy.

Methods

Recruiting from the Cardinal Health Oncology Provider Extended Network (OPEN), we surveyed hematologists/oncologists to investigate fourth-line (4L) preferences in a hypothetical patient with triple-class–refractory MM. We posed the same questions and answers before and after the trial presentation and compared pre-/post-preferences toward cilta-cel and sequencing relative to bispecific antibodies (BsAbs). Using the same methodology as described above, we also performed a secondary analysis comparing pre-/post-perceptions on the use of CAR T-cell therapy in earlier lines for patients with triple-class–refractory MM.

Results

Among 50 respondents, decision-making factors before the trial presentation included CAR T-cell center availability (58%), comorbidities (52%), and center locations (34%). Additionally, 48% of 46 respondents chose 4L cilta-cel. Among 47, 40% wanted more real-world/long-term CAR T-cell therapy outcomes in any line, 38% wanted more 2L data, and 34% favored 2L/third-line (3L) use. After the presentation, the preference for cilta-cel doubled from 48% to 88% (< 0.001) among 50 respondents and rose from 34% to 55% (= 0.001) for earlier-line CAR T-cell therapy among 49. Moreover, 55% of 49 respondents preferred CAR T-cell therapy prior to BsAbs.

Discussion

We have shown that making oncology practitioners aware of trials precipitated decision-making factors and led to notable, significant shifts in future intended practice patterns. Being aware of trial data enables practitioners to make more informed decisions, tailor therapies to individual patients, and ultimately improve outcomes.

嵌合抗原受体(CAR) t细胞方案ciltacabtagene autoeucel (cilta-cel)最初被批准用于第五线或更晚的治疗环境,最近被批准用于复发/难治性多发性骨髓瘤(RRMM)的二线(2L)治疗。肿瘤学从业者使用临床试验来告知治疗,但缺乏现实世界的印象和对实践的影响。我们的目的是确定提交CARTITUDE-4临床试验数据是否会影响现实世界对CAR - t细胞治疗的偏好/看法。方法:从红衣主教健康肿瘤提供者扩展网络(OPEN)招募,我们调查了血液学家/肿瘤学家,调查了一名假设的三级难治性MM患者的第四线(4L)偏好。我们在试验报告前后提出了相同的问题和答案,并比较了相对于双特异性抗体(BsAbs), cilta- cell和测序的前后偏好。使用与上述相同的方法,我们还进行了二次分析,比较了在早期治疗中对三级难治性mm患者使用CAR - t细胞治疗的前后看法。结果:在50名受访者中,试验提出前的决策因素包括CAR - t细胞中心可用性(58%)、合并症(52%)和中心位置(34%)。此外,46名受访者中有48%选择了4L cilta-cel。在47名患者中,40%希望在任何一线获得更多真实世界/长期CAR -t细胞治疗结果,38%希望获得更多2L数据,34%支持使用2L/三线(3L)。在报告之后,49名早期CAR - t细胞治疗中,cilta- cell的偏好从48%增加到88% (p p = 0.001)。此外,49名受访者中55%的人更倾向于在bsab之前进行CAR - t细胞治疗。讨论:我们已经表明,让肿瘤学从业者意识到试验可以促成决策因素,并导致未来预期的实践模式发生显著的重大变化。了解试验数据使从业者能够做出更明智的决定,为个体患者量身定制治疗方法,并最终改善结果。
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引用次数: 0
Successful treatment of low-risk myelodysplastic syndrome-related anemia in patients with chronic kidney disease with daprodustat: A report of two cases 使用达泊司他(daprodustat)成功治疗慢性肾病患者的低风险骨髓增生异常综合征相关贫血:两个病例的报告。
Pub Date : 2024-11-25 DOI: 10.1002/jha2.1057
Hiroyoshi Kunimoto, Takayuki Sakuma, Takuma Ohashi, Mayoko Shirafuta, Hiroshi Teranaka, Hideaki Nakajima

Anemia is a major clinical manifestation seen in myelodysplastic syndromes (MDS). Treatment options for anemia in low-risk MDS are limited. Especially, oral medication which is uniformly effective for anemia in low-risk MDS is required. Hypoxia-inducible factor (HIF) prolyl hydroxylase (HIF-PH) inhibitors, such as daprodustat, are oral tablets effective for renal anemia. Pharmacological restoration of HIF activity by HIF-PH inhibitors may be beneficial for MDS-related anemia as well. Yet, their efficacy and safety against low-risk MDS are unclear. Here, we report two cases of low-risk MDS complicated with chronic kidney disease whose anemia responded to daprodustat treatment.

贫血是骨髓增生异常综合征(MDS)的主要临床表现。低风险MDS患者贫血的治疗选择有限。特别是需要口服药物,这种药物对低风险MDS患者的贫血一致有效。低氧诱导因子(HIF)脯氨酰羟化酶(HIF- ph)抑制剂,如达普达司他,是治疗肾性贫血有效的口服片剂。HIF- ph抑制剂对HIF活性的药理学恢复可能对mds相关性贫血也有益。然而,它们对低风险MDS的疗效和安全性尚不清楚。在这里,我们报告了两例低风险MDS合并慢性肾脏疾病,其贫血对达生产司他治疗有反应。
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引用次数: 0
Safety and efficacy of ketamine use in patients with vaso-occlusive crisis: A systematic review and meta-analysis 在血管闭塞性危象患者中使用氯胺酮的安全性和有效性:系统回顾和荟萃分析。
Pub Date : 2024-11-25 DOI: 10.1002/jha2.1050
Ernesto Calderon Martinez, Stephin Zachariah Saji, Thomas Campos Carmona, Vaidarshi Abbagoni, Mohammad Salman, Mishell Estefanía Llerena Vargas, Suchita Mylavarapu, Druvini Fernando, Lakshmi Sheethal Arvapalli, Nathalia Schettino Samad, Nithin Karnan, Camila Sanchez Cruz

Introduction

Sickle cell disease (SCD) is characterized by acute episodes called vaso-occlusive crises (VOC). VOC is marked by severe pain due to blocked blood vessels by sickled cells. Ketamine has been reported to be effective and safe in managing VOC in SCD patients.

Objectives/methods

This review aims to determine ketamine's safety and efficacy through analysis of clinical trials and observational studies.

Methods

Adhering to PRISMA guidelines, this systematic review and meta-analysis systematically searched seven databases on May 20, 2024 for randomized control trials (RCT), cohorts, and case–control studies.

Results

Five studies with 689 participants met the inclusion criteria. A meta-analysis of two studies (518 observations) for the Numerical Rating Scale (NRS) pain score showed no significant difference, with a standardized mean difference (MD) of 0.23 (95% CI: −0.13 to 0.59, p = 0.21, I2 = 0%). For morphine milligram equivalent (MME), a meta-analysis of two studies (344 observations) resulted in an MD of −0.03 (95% CI: −0.09 to 0.04, p = 0.45, I2 = 97%). However, the side effects analysis from four studies (608 observations) showed a significantly higher relative risk (RR) of 5.74 (95% CI: 2.80–11.79, p < 0.0001, I2 = 0%) for mild side effects, including nausea, vomiting, and dizziness.

Conclusion

Ketamine qualitative synthesis shows potential for improving pain management in SCD patients during VOC, but without statistically significant differences in pain reduction. It is associated with increased mild side effects, though no severe adverse events were reported. Further research is needed to increase the sample size and power of the analysis to clarify optimal dosing and administration protocols for ketamine in this context.

简介:镰状细胞病(SCD)的特点是急性发作称为血管闭塞危象(VOC)。挥发性有机化合物的特点是由于镰状细胞阻塞血管而引起剧烈疼痛。据报道,氯胺酮在控制SCD患者的VOC方面是有效和安全的。目的/方法:本综述旨在通过临床试验和观察性研究的分析来确定氯胺酮的安全性和有效性。方法:本系统评价和荟萃分析遵循PRISMA指南,于2024年5月20日系统检索了7个数据库,包括随机对照试验(RCT)、队列和病例对照研究。结果:5项研究689名受试者符合纳入标准。数值评定量表(NRS)疼痛评分的两项研究(518项观察)的荟萃分析显示无显著差异,标准化平均差异(MD)为0.23 (95% CI: -0.13至0.59,p = 0.21, i2 = 0%)。对于吗啡毫克当量(MME),两项研究(344项观察)的荟萃分析得出MD为-0.03 (95% CI: -0.09至0.04,p = 0.45, i2 = 97%)。然而,来自4项研究(608项观察)的副作用分析显示,轻微副作用(包括恶心、呕吐和头晕)的相对风险(RR)显著较高,为5.74 (95% CI: 2.80-11.79, p 2 = 0%)。结论:氯胺酮定性合成有可能改善VOC期间SCD患者的疼痛管理,但在减轻疼痛方面无统计学意义。它与轻度副作用增加有关,但没有严重不良事件的报道。需要进一步的研究来增加样本量和分析的能力,以澄清在这种情况下氯胺酮的最佳剂量和给药方案。
{"title":"Safety and efficacy of ketamine use in patients with vaso-occlusive crisis: A systematic review and meta-analysis","authors":"Ernesto Calderon Martinez,&nbsp;Stephin Zachariah Saji,&nbsp;Thomas Campos Carmona,&nbsp;Vaidarshi Abbagoni,&nbsp;Mohammad Salman,&nbsp;Mishell Estefanía Llerena Vargas,&nbsp;Suchita Mylavarapu,&nbsp;Druvini Fernando,&nbsp;Lakshmi Sheethal Arvapalli,&nbsp;Nathalia Schettino Samad,&nbsp;Nithin Karnan,&nbsp;Camila Sanchez Cruz","doi":"10.1002/jha2.1050","DOIUrl":"10.1002/jha2.1050","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Sickle cell disease (SCD) is characterized by acute episodes called vaso-occlusive crises (VOC). VOC is marked by severe pain due to blocked blood vessels by sickled cells. Ketamine has been reported to be effective and safe in managing VOC in SCD patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives/methods</h3>\u0000 \u0000 <p>This review aims to determine ketamine's safety and efficacy through analysis of clinical trials and observational studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Adhering to PRISMA guidelines, this systematic review and meta-analysis systematically searched seven databases on May 20, 2024 for randomized control trials (RCT), cohorts, and case–control studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Five studies with 689 participants met the inclusion criteria. A meta-analysis of two studies (518 observations) for the Numerical Rating Scale (NRS) pain score showed no significant difference, with a standardized mean difference (MD) of 0.23 (95% CI: −0.13 to 0.59, <i>p</i> = 0.21, <i>I</i><sup>2</sup> = 0%). For morphine milligram equivalent (MME), a meta-analysis of two studies (344 observations) resulted in an MD of −0.03 (95% CI: −0.09 to 0.04, <i>p</i> = 0.45, <i>I</i><sup>2</sup> = 97%). However, the side effects analysis from four studies (608 observations) showed a significantly higher relative risk (RR) of 5.74 (95% CI: 2.80–11.79, <i>p</i> &lt; 0.0001, <i>I</i><sup>2</sup> = 0%) for mild side effects, including nausea, vomiting, and dizziness.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Ketamine qualitative synthesis shows potential for improving pain management in SCD patients during VOC, but without statistically significant differences in pain reduction. It is associated with increased mild side effects, though no severe adverse events were reported. Further research is needed to increase the sample size and power of the analysis to clarify optimal dosing and administration protocols for ketamine in this context.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"5 6","pages":"1312-1321"},"PeriodicalIF":0.0,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848097","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}
引用次数: 0
A GIMEMA survey on therapeutic use and response rates of FLT3 inhibitors in acute myeloid leukemia: Insights from Italian real-world practice 一项关于FLT3抑制剂在急性髓性白血病治疗使用和反应率的GIMEMA调查:来自意大利现实世界实践的见解。
Pub Date : 2024-11-22 DOI: 10.1002/jha2.1045
Monica Messina, Alfonso Piciocchi, Leonardo M. Siena, Stefano Soddu, Francesco Buccisano, Cristina Mecucci, Giovanni Martinelli, Antonio Curti, Roberto Cairoli, Paola Fazi, Marco Vignetti, Maria Teresa Voso, Adriano Venditti, Anna Candoni

Given the limited data on the real-life therapeutic use of feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) inhibitors in Italy, we surveyed investigators at 59 Italian hematology centers to gain insight into the proportion of acute myeloid leukemia (AML) patients receiving FLT3 inhibitors and we collected data on the efficacy and safety of these agents. The survey results showed that in the real-life setting the response rate of the 3/7 + midostaurin regimen in newly diagnosed FLT3-mutated AML and of gilteritinib in the relapsed/refractory AML were comparable to that reported in the registrative clinical trials. The 3/7 + midostaurin treatment resulted in a 63% of complete remission (CR) rates and gilteritinib in a 44% of CR rates. The discontinuation rate of gilteritinib for intolerance or toxicity was low (accounting for 4% of treated cases).

鉴于意大利猫麦克多诺肉瘤(FMS)样酪氨酸激酶3 (FLT3)抑制剂在现实生活中的治疗应用数据有限,我们调查了意大利59个血液学中心的研究人员,以了解接受FLT3抑制剂的急性髓性白血病(AML)患者的比例,并收集了这些药物的疗效和安全性数据。调查结果显示,在现实环境中,3/7 + midoin方案对新诊断的flt3突变AML的反应率和吉特替尼方案对复发/难治性AML的反应率与注册临床试验报告的反应率相当。3/7 + midoin治疗导致63%的完全缓解(CR)率,吉特替尼导致44%的CR率。吉特替尼因不耐受或毒性而停药的比率很低(占治疗病例的4%)。
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引用次数: 0
Impact of secondary-type mutations in acute myeloid leukemia with CEBPA mutation 继发性突变对急性髓系白血病伴CEBPA突变的影响。
Pub Date : 2024-11-22 DOI: 10.1002/jha2.1055
Davidson Zhao, Musani Rumina, Mojgan Zarif, Cuihong Wei, Hong Chang
<p>To the Editor,</p><p>Secondary-type mutations (STM: <i>ASXL1</i>, <i>BCOR</i>, <i>EZH2</i>, <i>SF3B1</i>, <i>SRSF2</i>, <i>STAG2</i>, <i>U2AF1</i>, and <i>ZRSR2</i>) in acute myeloid leukemia (AML) were reported to be highly specific for secondary disease and associated with inferior event-free survival (EFS) [<span>1, 2</span>]. In light of these findings, the newly-revised 5th edition of the WHO Classification of Haematolymphoid Tumours (WHO-HAEM5) includes STM in the criteria defining AML, myelodysplasia-related (AML-MR) [<span>3</span>]. In the newly-published International Consensus of Classification of myeloid neoplasms and acute leukemia (ICC), <i>RUNX1</i> mutation together with STM as described by WHO-HAEM5 define the entity of AML with myelodysplasia-related gene mutations [<span>4</span>]. To date, several studies have examined the impact of STM in other molecularly defined entities of AML such as <i>NPM1</i>+ AML [<span>5-9</span>]. However, the impact of STM in AML with <i>CEBPA</i> mutation has not been studied extensively and remains unclear. Thus, we sought to investigate the clinical impact of STM in AML with <i>CEBPA</i> mutation.</p><p>We conducted a retrospective analysis with a single center cohort of 38 cases of AML with <i>CEBPA</i> mutation diagnosed at our institution from 2015 to 2024. Patients were included if they met WHO-HAEM5 criteria of blasts ≥ 20% and either biallelic <i>CEBPA</i> mutation or single <i>CEBPA</i> mutation in the basic leucine zipper (bZIP) domain. Cytogenetic testing, molecular genetic testing, and variant calling in next-generation sequencing were performed according to previously described procedures [<span>10</span>]. Gene panel for targeted sequencing and exon coverage for hotspot genes are listed in Tables S1 and S2.</p><p>The baseline clinicopathological characteristics and co-mutation landscape of the study cohort are summarized in Table 1 and Figure 1A. Of the 38 patients with AML with <i>CEBPA</i> mutation, 11 (29%) had STM. <i>SRSF2</i> and <i>STAG2</i> were the most common STMs (both 8/38, 21%), followed by <i>ASXL1</i> (6/38, 16%), <i>BCOR</i> (2/38, 5%), and <i>U2AF1</i> (1/38, 3%). <i>RUNX1</i> mutations were found in two (5%) patients, both of whom had concurrent WHO-HAEM5-defined STMs. <i>EZH2</i>, <i>ZRSR2</i>, and <i>SF3B1</i> mutations were not detected. The most common recurrent (>10%) co-mutated genes in the cohort were <i>TET2</i> (10/38; 26%), <i>GATA2</i> (9/38, 24%), <i>WT1</i> (8/38, 21%), <i>NRAS</i> (6/38, 16%) and <i>FLT3</i>-ITD (4/38, 11%). Compared to patients without STM, patients with STM were older, had less proliferative disease, had lower hemoglobin levels, and had significantly lower variant allele frequency of mutant <i>CEBPA</i> and infrequent in-frame bZIP <i>CEBPA</i> mutation.</p><p>Consistent with the older age of the STM+ group, only five (46%) patients received intensive chemotherapy compared to all 27 (100%) patients in the STM-ve group. Of note,
未来需要更大队列的前瞻性研究来证实STM或框架内bZIP突变是否对并发STM和CEBPA突变的AML患者具有预后意义。总之,我们的数据表明,WHO-HAEM5定义的伴有CEBPA突变并并发STM的AML患者可能更适合归类为AML- mr。根据ICC分类,它只选择帧内bZIP CEBPA突变,识别无STM的同质队列,并有效排除可能更好地归类为AML-MR的患者。Davidson Zhao收集并分析了数据并撰写了手稿。Musani Rumina收集数据并撰写手稿。Mojgan Zarif和Cuihong Wei收集了数据。洪昌设计了这项研究并分析了数据。所有作者阅读,严格审查,并批准了手稿。作者声明无利益冲突。作者没有得到这项工作的特别资助。作者已确认本次提交不需要伦理批准声明。作者已确认本次提交不需要患者同意声明。作者已确认该提交不需要临床试验注册。
{"title":"Impact of secondary-type mutations in acute myeloid leukemia with CEBPA mutation","authors":"Davidson Zhao,&nbsp;Musani Rumina,&nbsp;Mojgan Zarif,&nbsp;Cuihong Wei,&nbsp;Hong Chang","doi":"10.1002/jha2.1055","DOIUrl":"10.1002/jha2.1055","url":null,"abstract":"&lt;p&gt;To the Editor,&lt;/p&gt;&lt;p&gt;Secondary-type mutations (STM: &lt;i&gt;ASXL1&lt;/i&gt;, &lt;i&gt;BCOR&lt;/i&gt;, &lt;i&gt;EZH2&lt;/i&gt;, &lt;i&gt;SF3B1&lt;/i&gt;, &lt;i&gt;SRSF2&lt;/i&gt;, &lt;i&gt;STAG2&lt;/i&gt;, &lt;i&gt;U2AF1&lt;/i&gt;, and &lt;i&gt;ZRSR2&lt;/i&gt;) in acute myeloid leukemia (AML) were reported to be highly specific for secondary disease and associated with inferior event-free survival (EFS) [&lt;span&gt;1, 2&lt;/span&gt;]. In light of these findings, the newly-revised 5th edition of the WHO Classification of Haematolymphoid Tumours (WHO-HAEM5) includes STM in the criteria defining AML, myelodysplasia-related (AML-MR) [&lt;span&gt;3&lt;/span&gt;]. In the newly-published International Consensus of Classification of myeloid neoplasms and acute leukemia (ICC), &lt;i&gt;RUNX1&lt;/i&gt; mutation together with STM as described by WHO-HAEM5 define the entity of AML with myelodysplasia-related gene mutations [&lt;span&gt;4&lt;/span&gt;]. To date, several studies have examined the impact of STM in other molecularly defined entities of AML such as &lt;i&gt;NPM1&lt;/i&gt;+ AML [&lt;span&gt;5-9&lt;/span&gt;]. However, the impact of STM in AML with &lt;i&gt;CEBPA&lt;/i&gt; mutation has not been studied extensively and remains unclear. Thus, we sought to investigate the clinical impact of STM in AML with &lt;i&gt;CEBPA&lt;/i&gt; mutation.&lt;/p&gt;&lt;p&gt;We conducted a retrospective analysis with a single center cohort of 38 cases of AML with &lt;i&gt;CEBPA&lt;/i&gt; mutation diagnosed at our institution from 2015 to 2024. Patients were included if they met WHO-HAEM5 criteria of blasts ≥ 20% and either biallelic &lt;i&gt;CEBPA&lt;/i&gt; mutation or single &lt;i&gt;CEBPA&lt;/i&gt; mutation in the basic leucine zipper (bZIP) domain. Cytogenetic testing, molecular genetic testing, and variant calling in next-generation sequencing were performed according to previously described procedures [&lt;span&gt;10&lt;/span&gt;]. Gene panel for targeted sequencing and exon coverage for hotspot genes are listed in Tables S1 and S2.&lt;/p&gt;&lt;p&gt;The baseline clinicopathological characteristics and co-mutation landscape of the study cohort are summarized in Table 1 and Figure 1A. Of the 38 patients with AML with &lt;i&gt;CEBPA&lt;/i&gt; mutation, 11 (29%) had STM. &lt;i&gt;SRSF2&lt;/i&gt; and &lt;i&gt;STAG2&lt;/i&gt; were the most common STMs (both 8/38, 21%), followed by &lt;i&gt;ASXL1&lt;/i&gt; (6/38, 16%), &lt;i&gt;BCOR&lt;/i&gt; (2/38, 5%), and &lt;i&gt;U2AF1&lt;/i&gt; (1/38, 3%). &lt;i&gt;RUNX1&lt;/i&gt; mutations were found in two (5%) patients, both of whom had concurrent WHO-HAEM5-defined STMs. &lt;i&gt;EZH2&lt;/i&gt;, &lt;i&gt;ZRSR2&lt;/i&gt;, and &lt;i&gt;SF3B1&lt;/i&gt; mutations were not detected. The most common recurrent (&gt;10%) co-mutated genes in the cohort were &lt;i&gt;TET2&lt;/i&gt; (10/38; 26%), &lt;i&gt;GATA2&lt;/i&gt; (9/38, 24%), &lt;i&gt;WT1&lt;/i&gt; (8/38, 21%), &lt;i&gt;NRAS&lt;/i&gt; (6/38, 16%) and &lt;i&gt;FLT3&lt;/i&gt;-ITD (4/38, 11%). Compared to patients without STM, patients with STM were older, had less proliferative disease, had lower hemoglobin levels, and had significantly lower variant allele frequency of mutant &lt;i&gt;CEBPA&lt;/i&gt; and infrequent in-frame bZIP &lt;i&gt;CEBPA&lt;/i&gt; mutation.&lt;/p&gt;&lt;p&gt;Consistent with the older age of the STM+ group, only five (46%) patients received intensive chemotherapy compared to all 27 (100%) patients in the STM-ve group. Of note,","PeriodicalId":72883,"journal":{"name":"EJHaem","volume":"5 6","pages":"1370-1372"},"PeriodicalIF":0.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848583","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}
引用次数: 0
Immediate improvement in patient care: Auditing adherence to the British Society for Haematology guidelines on screening and management of the long-term consequences of multiple myeloma and treatment 患者护理的即时改善:审计遵守英国血液病学会关于多发性骨髓瘤和治疗的长期后果的筛查和管理指南。
Pub Date : 2024-11-15 DOI: 10.1002/jha2.999
Kerrie Sweeney, Aaron Niblock, Diana Greenfield, John Snowden

Advances in myeloma have resulted in improved prognosis for patients. However complications of the disease and treatment, pose a risk of specific long-term consequences. An audit tool was adapted to assess adherence to the British Society for Haematology guidelines for screening and management of long-term myeloma consequences. Thereafter a screening checklist was developed to prompt the implementation of guideline recommendations, followed by a re-audit evaluating the effectiveness of the checklist.

Good baseline practice was identified relating to vaccinations, herpes prophylaxis, dental assessment, bisphosphonates, calcium/ vitamin D supplementation and holistic needs assessments. However gaps in practice included monitoring of lipids, HBA1C, NT-pro-BNP/ BNP, BMI, calcium/ vitamin D and parathyroid hormone in kidney disease, endocrine screening and geriatric assessments. Re-audit demonstrated that geriatric assessment remains a gap in practice, however other standards now scored between 80 to 100% compliance, highlighting the benefits of a screening checklist, to increase adherence to recommendations.

骨髓瘤的进展改善了患者的预后。然而,该病的并发症和治疗可能造成特定的长期后果。采用一种审计工具来评估英国血液病学会筛查和管理骨髓瘤长期后果指南的依从性。此后,制定了一份筛选清单,以促进指南建议的实施,随后进行了重新审核,评估清单的有效性。确定了与疫苗接种、疱疹预防、牙科评估、双膦酸盐、钙/维生素D补充和整体需求评估有关的良好基线做法。然而,实践中的差距包括监测血脂、HBA1C、NT-pro-BNP/ BNP、BMI、钙/维生素D和甲状旁腺激素在肾脏疾病、内分泌筛查和老年评估中的作用。重新审计表明,老年评估在实践中仍然存在差距,但其他标准的符合性现在在80%至100%之间,突出了筛查清单的好处,以增加对建议的遵守。
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引用次数: 0
Association between microenvironment-related genes and prognosis of primary central nervous system lymphoma 微环境相关基因与原发性中枢神经系统淋巴瘤预后的关系
Pub Date : 2024-11-14 DOI: 10.1002/jha2.1046
Keiichiro Hattori, Kenichi Makishima, Sakurako Suma, Yoshiaki Abe, Yasuhito Suehara, Tatsuhiro Sakamoto, Naoki Kurita, Ryota Ishii, Ryota Matsuoka, Masahide Matsuda, Takao Tsurubuchi, Ryo Nishikawa, Shota Tanaka, Akitake Mukasa, Yoshitaka Narita, Koichi Ichimura, Motoo Nagane, Shingo Takano, Bryan J. Mathis, Eiichi Ishikawa, Daisuke Matsubara, Shigeru Chiba, Mamiko Sakata-Yanagimoto

Background

Primary central nervous system lymphoma (PCNSL) is a rare lymphoid malignancy. Systemic profiling of the PCNSL tumor microenvironment (TME) was previously conducted through gene expression analysis. We investigated the prognostic impact of TME on survival to establish novel prognostic biomarkers in PCNSL patients.

Methods

We analyzed expression levels of 770 neuroinflammation-related (NFR) genes via NanoString nCounter technology in tumor samples from 30 PCNSL patients. Genes related to the “recurrence group (RG)” or “non-recurrence group (NRG)” were identified and validated using whole transcriptomic analysis of an independent PCNSL cohort (n = 30).

Results

Forty-five of 770 NFR genes were highly expressed in the RG (3-year overall survival (OS, 22.2%), compared with the NRG group (3-year OS 66.7%). Signatures related to glial cells were enriched in the RG-associated gene set. Multivariate analysis revealed that high expressions of TUBB4A (p = 0.028, HR: 3.88), S100B (p = 0.046, HR: 3.093), and SLC6A1 (p = 0.034, HR: 3.765) were significantly related to death. Expression levels of these three genes were also significantly associated with poor OS in the validation cohort. Immunohistochemical staining against TUBB4A, S100B, and proteins specific to glial cells (GFAP, OLIG2, and CD68) revealed significantly higher positivity in RG glial cells.

Conclusion

These data suggest that TME-related genes play a crucial role in the pathogenesis of PCNSL, complementing the well-known involvement of the NF-kB signaling pathway. TME targeting, especially glial cell-specific proteins, may thus open new and complementary avenues of therapy for all stages of PCNSL.

背景:原发性中枢神经系统淋巴瘤(PCNSL)是一种罕见的淋巴系统恶性肿瘤。PCNSL肿瘤微环境(TME)的系统分析以前是通过基因表达分析进行的。我们研究了TME对PCNSL患者生存的预后影响,以建立新的预后生物标志物。方法:通过NanoString nCounter技术分析了30例PCNSL患者肿瘤样本中770个神经炎症相关(NFR)基因的表达水平。通过独立PCNSL队列(n = 30)的全转录组分析,鉴定并验证了与“复发组(RG)”或“非复发组(NRG)”相关的基因。结果:770个NFR基因中有45个在RG组中高表达(3年总生存率为22.2%),而NRG组的3年总生存率为66.7%。rg相关基因集中富集了与胶质细胞相关的特征。多因素分析显示,TUBB4A (p = 0.028, HR: 3.88)、S100B (p = 0.046, HR: 3.093)、SLC6A1 (p = 0.034, HR: 3.765)的高表达与死亡显著相关。在验证队列中,这三个基因的表达水平也与不良OS显著相关。免疫组化对TUBB4A、S100B和胶质细胞特异性蛋白(GFAP、OLIG2和CD68)的免疫组化染色显示RG胶质细胞中明显较高的阳性。结论:这些数据表明,tme相关基因在PCNSL的发病机制中起着至关重要的作用,补充了众所周知的NF-kB信号通路的参与。因此,TME靶向,特别是胶质细胞特异性蛋白,可能为PCNSL的所有阶段开辟新的和互补的治疗途径。
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引用次数: 0
Congestive heart failure after anthracycline-containing treatment for Hodgkin lymphoma: A Swedish matched cohort study 含蒽环类药物治疗霍奇金淋巴瘤后充血性心力衰竭:瑞典匹配队列研究。
Pub Date : 2024-11-13 DOI: 10.1002/jha2.1048
Joachim Baech, Tarec Christoffer El-Galaly, Joshua P. Entrop, Ingrid Glimelius, Daniel Molin, Sissel Johanne Godtfredsen, Michael J. Crowther, Karin E. Smedby, Sandra Eloranta, Caroline E. Dietrich

Introduction

Congestive heart failure (CHF) is a known complication after anthracyclines and radiotherapy for classical Hodgkin lymphoma (cHL). Contemporary cHL treatment may be associated with less risk because radiotherapy use and techniques have changed substantially over time.

Methods

In this study, Swedish cHL patients diagnosed in 2000–2018, and treated with adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine (ABVD) or bleomycin, etoposide, Adriamycin [doxorubicin], cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), were matched 1:10 to the general population on birth year and sex to investigate relative rates and cumulative risks of CHF.

Results

A total of 1994 cHL patients were included, with a median age of 34 years. The median follow-up was 8.1 years. The CHF rate was higher for patients versus comparators (adjusted hazard ratio [HR] = 3.02, 95% confidence interval [CI]: 2.26–4.02). Patients treated with ≤200 mg/m2 of anthracyclines had HR of 2.89 (95% CI: 1.51–3.47) versus 3.91 (95% CI: 2.72–5.60) for >200 mg/m2. Treatment with ABVD was associated with a significantly higher CHF rate (adjusted HR = 3.25, 95% CI: 2.31–4.23), while BEACOPP was not (adjusted HR = 1.95, 95% CI: 0.91–4.16). The increase in relative rates translated to the absolute scale, with an increased risk persisting up to 18 years for low cumulative doses.

Conclusion

These findings highlight that cHL survivors still face a substantial excess risk of CHF in the modern treatment era and that focus on cardiovascular health remains relevant.

简介:充血性心力衰竭(CHF)是蒽环类药物和放射治疗经典霍奇金淋巴瘤(cHL)后的已知并发症。由于放疗的使用和技术随着时间的推移发生了很大的变化,当代cHL治疗的风险可能较低。方法:在本研究中,2000-2018年诊断为cHL并接受阿霉素[阿霉素]、博来霉素、长春碱和达卡巴嗪(ABVD)或博来霉素、乙泊苷、阿霉素[阿霉素]、环磷酰胺、长春新碱、丙卡嗪和泼尼松(BEACOPP)治疗的瑞典cHL患者,按出生年和性别与普通人群进行1:10匹配,调查CHF的相对发病率和累积风险。结果:共纳入cHL患者1994例,中位年龄34岁。中位随访时间为8.1年。患者的CHF发生率高于对照组(校正风险比[HR] = 3.02, 95%可信区间[CI]: 2.26-4.02)。≤200mg /m2蒽环类药物组患者的风险比为2.89 (95% CI: 1.51-3.47),而≤200mg /m2组患者的风险比为3.91 (95% CI: 2.72-5.60)。ABVD治疗与较高的CHF发生率相关(调整后的HR = 3.25, 95% CI: 2.31-4.23),而BEACOPP治疗与此无关(调整后的HR = 1.95, 95% CI: 0.91-4.16)。相对比率的增加转化为绝对规模,低累积剂量的风险增加可持续18年。结论:这些发现强调,在现代治疗时代,cHL幸存者仍然面临大量的CHF超额风险,关注心血管健康仍然是相关的。
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引用次数: 0
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