American Journal of Hematology最新文献_第7页

Long-Term Outcomes of a Stratified Treatment Regimen Based on Etoposide and Glucocorticoids in Children With Hemophagocytic Lymphohistiocytosis (CCHG-HLH-2018): A Multicenter, Single-Arm Clinical Study 基于依托泊苷和糖皮质激素分层治疗儿童噬血细胞淋巴组织细胞增多症（CCHG-HLH-2018）的长期结局：一项多中心、单组临床研究。

IF 9.9 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2025-12-12 DOI: 10.1002/ajh.70158

Zishi Fang, Jie Yu, Wei Liu, Ang Wei, Qing Zhang, Jianpei Fang, Shaoyan Hu, Xiaoyan Wu, Jian Wang, Weihong Zhao, Aiguo Liu, Shilin Liu, Xuerong Li, Yongjun Fang, Jingshi Wang, Yuan Sun, Rong Liu, Leping Zhang, Yongmin Tang, Dongsheng Huang, Xiaojun Yuan, Liming Sun, Jian Ge, Yunze Zhao, Dong Wang, Wenqian Wang, Chenxin Zhou, Zhigang Li, Tianyou Wang, Rui Zhang, for the Chinese Children's Histiocyte Group

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyperinflammatory syndrome. The widely used HLH-1994/2004 protocols are primarily designed for primary HLH (pHLH). However, in Asia, particularly in China, secondary HLH (sHLH) is more prevalent, which may limit the efficacy of these protocols and increase treatment-related toxicity. To address this, we conducted a multicenter, prospective, single-arm clinical study to evaluate the CCHG-HLH-2018 protocol, a stratified treatment regimen based on glucocorticoids and etoposide, for pediatric HLH patients in China. A total of 286 patients from 20 centers were included, with a median follow-up of 64 months. Based on HLH-related indicators at onset, 64 patients (22.4%) were classified as low-risk group and 222 (77.6%) as high-risk group. The 5-year overall survival (OS) for all patients was 86.3% (95% CI, 81.7–89.8), with 96.9% (95% CI, 88.1–99.2) in low-risk group and 83.2% (95% CI, 77.6–87.5) in high-risk group (Holm-Bonferroni adjusted p = 0.006). The 5-year OS for pHLH patients was 72.9% (95% CI, 58.0–83.3), significantly lower than the 89.0% (95% CI, 84.3–92.4) for sHLH patients (Holm-Bonferroni adjusted p = 0.008). Among all patients, 54 (18.9%) achieved sustained remission without chemotherapy. No significant differences in OS and EFS were observed between high-risk patients receiving CSA-containing regimens and those receiving non-CSA regimens (p = 0.148, p = 0.107). However, exploratory subgroup analysis of idiopathic HLH patients suggested a trend toward improved survival with the CSA-containing regimen. The safety profile of the CCHG-HLH-2018 protocol was acceptable, with fewer adverse events in the low-risk group. Our findings suggest this stratified protocol is effective in reducing chemotherapy intensity for Chinese children with HLH.

Trial Registration: http://www.chictr.org.cn, identifier: ChiCTR1800017267

噬血细胞性淋巴组织细胞增多症（HLH）是一种危及生命的全身性高炎症综合征。广泛使用的HLH-1994/2004协议主要是为原发性HLH （pHLH）设计的。然而，在亚洲，特别是在中国，继发性HLH （sHLH）更为普遍，这可能限制了这些方案的疗效并增加了治疗相关的毒性。为了解决这个问题，我们进行了一项多中心、前瞻性、单臂临床研究，以评估CCHG-HLH-2018方案，这是一种基于糖皮质激素和依托泊苷的分层治疗方案，用于中国儿科HLH患者。共纳入来自20个中心的286例患者，中位随访时间为64个月。根据发病时hlh相关指标，低危组64例（22.4%），高危组222例（77.6%）。所有患者的5年总生存率（OS）为86.3% (95% CI, 81.7 ~ 89.8)，其中低危组为96.9% (95% CI, 88.1 ~ 99.2)，高危组为83.2% (95% CI, 77.6 ~ 87.5) （Holm-Bonferroni校正p = 0.006）。pHLH患者的5年OS为72.9% (95% CI, 58.0 ~ 83.3)，显著低于sHLH患者的89.0% (95% CI, 84.3 ~ 92.4) （Holm-Bonferroni校正p = 0.008）。在所有患者中，54例（18.9%）在没有化疗的情况下获得持续缓解。高危患者接受含csa方案和不接受csa方案的OS和EFS无显著差异（p = 0.148, p = 0.107）。然而，对特发性HLH患者的探索性亚组分析表明，含csa方案有提高生存率的趋势。CCHG-HLH-2018方案的安全性是可接受的，低风险组的不良事件较少。我们的研究结果表明，这种分层方案在降低中国儿童HLH化疗强度方面是有效的。试验注册：http://www.chictr.org.cn，标识符：ChiCTR1800017267。

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引用次数: 0

Extending the Biological Axis Linking CHIP to Cancer Emergence. 扩展芯片与癌症发生的生物学轴。

IF 12.8 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2025-12-09 DOI: 10.1002/ajh.70162

Tiziano Barbui,Arianna Ghirardi,Valerio De Stefano

引用次数: 0

Iptacopan for Immune Thrombocytopenia and Cold Agglutinin Disease: A Global Phase 2 Basket Clinical Trial Iptacopan用于免疫性血小板减少症和冷凝集素病：一项全球2期一揽子临床试验。

IF 9.9 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2025-12-09 DOI: 10.1002/ajh.70147

Alexander Röth, Wilma Barcellini, Christine Ademokun, Junho Jang, Maria Luisa Lozano, David Valcarcel Ferreiras, Cristina Pascual-Izquierdo, Shripad Chitnis, Sofiya Matviykiv, Alessandra Vitaliti, Chi Chen, Vasiliki Katsanou, Raghav Chawla, Hanny Al-Samkari

Iptacopan is a first-in-class, oral, selective inhibitor of complement factor B that has demonstrated positive efficacy across several complement-driven diseases. Here we evaluate the efficacy and safety of iptacopan monotherapy in adult patients with primary immune thrombocytopenia (ITP) and primary cold agglutinin disease (CAD). We performed a global, multicenter, phase 2 basket study enrolling patients with primary ITP or CAD after failure of ≥ 1 unique prior therapies. Primary endpoints were platelet response (≥ 50 × 10⁹/L) for ITP and hemoglobin response (≥ 1.5 g/dL increase) for CAD sustained for ≥ 2 consecutive weeks during the first 12 weeks of iptacopan treatment, without the use of rescue therapy. Other endpoints included time to first response, duration of response, pharmacokinetics, safety/tolerability, and FACIT-Fatigue. Nineteen patients were treated with iptacopan (9 ITP, 10 CAD). Among patients with CAD, most showed improvements in hemoglobin levels, with a mean increase of 2.2 g/dL from baseline to week 12; five (50%) patients achieved the primary endpoint. Improvements were also observed for other outcomes in CAD, including lactate dehydrogenase, bilirubin, reticulocytes, and FACIT-Fatigue. Conversely, no patients with ITP met the primary endpoint. Most treatment-emergent adverse events (TEAEs) were mild, the most common being headache (21%), asthenia (16%), fatigue (16%), and petechiae (16%). Iptacopan monotherapy demonstrated encouraging preliminary efficacy in primary CAD, while no protocol-defined responses were observed in primary ITP. Iptacopan may represent a promising oral option for CAD and was well tolerated in both ITP and CAD with no unexpected safety signals.

Trial Registration: ClinicalTrials.gov identifier: NCT05086744

Iptacopan是补体因子B的首选口服选择性抑制剂，已被证明对多种补体驱动型疾病具有积极疗效。在这里，我们评估了伊他科潘单药治疗原发性免疫性血小板减少症（ITP）和原发性冷凝集素病（CAD）的成人患者的疗效和安全性。我们进行了一项全球、多中心、2期篮子研究，纳入了在既往治疗失败≥1种独特疗法后原发性ITP或CAD患者。主要终点是ITP的血小板反应（≥50 × 109/L）和CAD的血红蛋白反应（≥1.5 g/dL增加）在伊他科潘治疗的前12周内持续≥2周，未使用抢救治疗。其他终点包括首次反应时间、反应持续时间、药代动力学、安全性/耐受性和facit -疲劳。19例患者接受伊他科潘治疗（9 ITP, 10 CAD）。在冠心病患者中，大多数血红蛋白水平有所改善，从基线到第12周平均增加2.2 g/dL；5例（50%）患者达到了主要终点。CAD的其他结果也有改善，包括乳酸脱氢酶、胆红素、网织红细胞和facit -疲劳。相反，没有ITP患者达到主要终点。大多数治疗中出现的不良事件（teae）是轻微的，最常见的是头痛（21%）、乏力（16%）、疲劳（16%）和瘀点（16%）。伊他科泮单药治疗在原发性CAD中显示出令人鼓舞的初步疗效，而在原发性ITP中没有观察到协议定义的反应。伊普他泮可能是一种很有希望的CAD口服治疗方案，在ITP和CAD中都有良好的耐受性，没有意外的安全信号。试验注册：ClinicalTrials.gov标识符：NCT05086744。

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引用次数: 0

Reversal of Echocardiographic Alterations Following Hematopoietic Stem Cell Transplantation in Children With Sickle-Cell Anemia. 镰状细胞性贫血儿童造血干细胞移植后超声心动图改变的逆转。

IF 12.8 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2025-12-07 DOI: 10.1002/ajh.70163

Clémence Riez,Anne Leroux,Marie-Emilie Lopes,Annie Kamdem,Cécile Arnaud,Isabelle Hau,Mony Fahd,Jean-Hugues Dalle,Nathalie Dhedin,Catherine Paillard,Bassem Khazem,Ekaterina Belozertsteva,Céline Délestrain,Stéphane Bechet,Claire Falguière,Carine Vastel,Corinne Pondarré

引用次数: 0

Clinical Spectrum of Noonan Syndrome–Associated Myeloproliferative Disorder 努南综合征相关骨髓增生性疾病的临床谱。

IF 9.9 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2025-12-07 DOI: 10.1002/ajh.70150

Shinsuke Hirabayashi, Manabu Wakamatsu, Masataka Hasegawa, Takahiro Imaizumi, Kaori Fujiwara, Hiroyoshi Watanabe, Makiko Mori, Kyogo Suzuki, Shoji Saito, Nao Yoshida, Yoko Mizoguchi, Mizuka Miki, Yuko Honda, Shuichi Ozono, Kazuo Sakashita, Yoko Aoki, Hideki Muramatsu

Clinical spectrum of 27 patients with Noonan syndrome–associated myeloproliferative disorder.

努南综合征相关骨髓增生性疾病27例临床分析。

引用次数: 0

Non-T-Depleted Haploidentical Transplantation Compared to Allogeneic Transplantation From Matched Siblings or Unrelated Donors in Patients With Secondary AML in First Complete Remission: A Study From the ALWP/EBMT 来自ALWP/EBMT的一项研究：与首次完全缓解的继发性AML患者非t -耗尽单倍体移植相比，来自匹配兄弟姐妹或无血缘供体的同种异体移植

IF 9.9 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2025-12-06 DOI: 10.1002/ajh.70164

Arnon Nagler, Sarah Kayser, Allain Thibeault Ferhat, Nicolaus Kröger, Matthias Eder, Gérard Socié, Didier Blaise, Thomas Schroeder, Hélène Labussière-Wallet, Johan Maertens, Alessandro Busca, Edouard Forcade, Tobias Gedde-Dahl, Alessandro Rambaldi, Claude Eric Bulabois, Gesine Bug, Ali Bazarbachi, Eolia Brissot, Bipin Savani, Mohamad Mohty, Fabio Ciceri

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for secondary acute myeloid leukemia (sAML). This study compared haploidentical donor (Haplo), matched sibling donor (MSD), and matched unrelated donor (MUD) HSCT in patients with sAML in first complete remission (CR1). Data from 3862 patients (Haplo = 643, MSD = 715, MUD = 2504) transplanted between 2010 and 2022 were analyzed, with a median follow-up of 3.3 years. Groups differed in patient and donor age, conditioning regimen, stem cell source, and graft-versus-host disease (GVHD) prophylaxis. Multivariate analysis showed that MSD-HSCT had a higher relapse risk than Haplo-HSCT (hazard ratio [HR]: 1.64) but lower non-relapse mortality (NRM, HR: 0.32) and acute GVHD risk (HR: 0.54 for grade II–IV), leading to an overall survival (OS) benefit (HR: 0.76). MUD-HSCT had lower NRM than Haplo-HSCT (HR: 0.63) but there were no significant differences in OS or GVHD risk. Donor type did not impact leukemia-free survival (LFS) or GVHD-free and relapse-free survival (GRFS). Adverse cytogenetics and reduced-intensity conditioning were associated with increased relapse risk, while lower Karnofsky scores, older age, and adverse cytogenetics independently predicted worse NRM, LFS, OS, and GRFS outcomes. Female-to-male donor-recipient pairs had an increased risk of chronic GVHD. In this registry-based analysis, MSD offered the best outcomes for sAML in CR1. Haplo-HSCT was comparable to MUD-HSCT, despite a higher NRM, and achieved long-term disease control in 60% of patients due to a low relapse incidence. In the absence of an MSD, both Haplo and MUD are viable alternatives.

同种异体造血干细胞移植（HSCT）是继发性急性髓系白血病（sAML）的一种治疗选择。本研究比较了首次完全缓解（CR1）的sAML患者的单倍相同供体（Haplo）、匹配的兄弟姐妹供体（MSD）和匹配的非亲属供体（MUD） HSCT。本研究分析了2010年至2022年间3862例移植患者（Haplo = 643, MSD = 715, MUD = 2504）的数据，中位随访时间为3.3年。各组在患者和供体年龄、调理方案、干细胞来源和移植物抗宿主病（GVHD）预防方面存在差异。多因素分析显示，MSD-HSCT的复发风险高于haplol - hsct（风险比[HR]: 1.64），但非复发死亡率（NRM, HR: 0.32）和急性GVHD风险（II-IV级HR: 0.54）较低，导致总生存（OS）获益（HR: 0.76）。MUD-HSCT的NRM低于haplol - hsct (HR: 0.63)，但OS和GVHD风险无显著差异。供体类型不影响无白血病生存期（LFS）或无gvhd和无复发生存期（GRFS）。不良细胞遗传学和低强度调节与复发风险增加相关，而较低的Karnofsky评分、年龄较大和不良细胞遗传学独立预测较差的NRM、LFS、OS和GRFS结果。女性-男性供体-受体配对的慢性GVHD风险增加。在这个基于注册表的分析中，MSD为CR1中的sAML提供了最好的结果。Haplo-HSCT与MUD-HSCT相当，尽管NRM更高，并且由于复发率低，60%的患者实现了长期疾病控制。在没有MSD的情况下，Haplo和MUD都是可行的替代方案。

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引用次数: 0

DIA Regimen Versus IA Regimen for Induction Therapy in Younger Adults With Acute Myeloid Leukemia: A Multicenter Open-Label Randomized Controlled Trial DIA方案与IA方案诱导治疗年轻成人急性髓系白血病：一项多中心开放标签随机对照试验

IF 9.9 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2025-12-06 DOI: 10.1002/ajh.70157

Xiwen Tong, Bin Xu, Shiyuan Zhang, Mengyuan Li, Shuai Su, Yi Zhu, Zhenqian Huang, Yaya Wang, Yi Xiao, Liang Huang, Dengju Li, Wei Huang, Jia Wei, Mei Huang, Zhiping Huang, Yuanyan Tang, Hongbo Ren, Donghua Zhang

Anthracyclines and cytarabine remain the cornerstone of intensive chemotherapy for patients with newly diagnosed acute myeloid leukemia (ND AML), typically delivered as a “7 + 3” regimen, which involves cytarabine (Ara-C) for 7 days and anthracycline (idarubicin (IDA) or daunorubicin (DNR)) for 3 days [1]. Various studies have evaluated optimal anthracycline and Ara-C dosing and explored adding a third drug to improve long-term outcomes and enhance response rates.Azanucleoside DNA hypomethylating agents (HMAs) are cytidine analogs that epigenetically reactivate genes via DNA methyltransferase-1 inhibition through aberrant gene silencing reversal [2, 3]. Due to its favorable toxicity profile and anti-leukemic activity, decitabine (DAC) has become the standard treatment foundation for patients with AML who are older or unfit for intensive chemotherapy [4]. However, no prospective clinical studies have compared the efficacy of adding decitabine to the IA (DIA) regimen versus the IA regimen alone. Therefore, we conducted a multicenter, prospective, randomized, controlled trial to evaluate the effects of these two treatment approaches.We conducted a multicenter, open-label, randomized controlled clinical trial across four hospitals in China from September 2020 to March 2024, where eligible patients were randomly assigned (1:1) to receive either the DIA or IA regimen. A total of 130 participants were enrolled in the study for interim analysis 65 participants were assigned to receive the DIA induction regimen, while the remaining 65 were assigned to the IA induction regimen (Figure S1). Baseline data are shown in Table S1.In the DIA group, 56 patients (86.2%) achieved CR/CRi and eight patients (12.3%) achieved partial remission (PR), resulting in an overall response rate (ORR) of 98.5%. In the IA group, 51 patients (78.5%) achieved CR/CRi and five patients (7.7%) achieved PR, resulting in an ORR of 86.2%. Among those achieving CR, 39 patients (69.6%) in the DIA group achieved deep remission (CRMRD-), compared to 19 patients (37.3%) in the IA group (p < 0.006) (Table 1).Analysis of molecular abnormalities indicated that patients with methylation mutations (p = 0.030) or CEBPA mutations (p = 0.002) treated with the DIA regimen had significantly higher CRMRD- rates than those in the IA group. ELN genetic typing revealed that intermediate-risk (p = 0.038) and adverse-risk patients (p = 0.045) showed a significantly higher CRMRD- rate in the DIA group compared to the IA group (Table 2).The median follow-up time for the entire cohort was 1027 days (95% confidence interval [CI], 903–1151 days). At the end of follow-up, 35 patients (53.8%) in the DIA group and 43 (66.2%) patients in the IA group underwent allo-HSCT and 51 patients (78.5%) survived in each group. Among patients who achieved CR, relapse occurred in 12

蒽环类药物和阿糖胞苷仍然是新诊断的急性髓性白血病（ND AML）患者强化化疗的基础，通常以“7 + 3”方案给予，其中包括阿糖胞苷（Ara-C） 7天，蒽环类（阿达霉素（IDA）或柔红霉素（DNR）） 3天。各种研究已经评估了蒽环类药物和Ara-C的最佳剂量，并探索添加第三种药物以改善长期疗效和提高反应率。氮杂核苷DNA低甲基化剂（HMAs）是胞苷类似物，通过异常基因沉默逆转，通过DNA甲基转移酶-1抑制，在表观遗传学上重新激活基因[2,3]。由于其良好的毒性和抗白血病活性，地西他滨（decitabine， DAC）已成为年龄较大或不适合强化化疗的AML患者的标准治疗基础。然而，没有前瞻性临床研究比较在IA （DIA）方案中添加地西他滨与单独IA方案的疗效。因此，我们进行了一项多中心、前瞻性、随机对照试验来评估这两种治疗方法的效果。我们于2020年9月至2024年3月在中国的四家医院进行了一项多中心、开放标签、随机对照临床试验，其中符合条件的患者被随机分配（1:1）接受DIA或IA方案。本研究共纳入130名受试者进行中期分析，其中65名受试者接受DIA诱导方案，其余65名受试者接受IA诱导方案（图S1）。基线数据见表S1。在DIA组中，56例（86.2%）患者达到CR/CRi， 8例（12.3%）患者达到部分缓解（PR），总缓解率（ORR）为98.5%。IA组有51例（78.5%）患者达到CR/CRi， 5例（7.7%）患者达到PR， ORR为86.2%。在达到CR的患者中，DIA组有39例患者（69.6%）达到深度缓解（CRMRD-）， IA组为19例患者（37.3%）（p < 0.006）（表1）。分子异常分析表明，接受DIA方案治疗的甲基化突变（p = 0.030）或CEBPA突变（p = 0.002）患者的CRMRD-率显著高于IA组。ELN基因分型显示，DIA组中危（p = 0.038）和危（p = 0.045）患者的CRMRD-率明显高于IA组（表2）。整个队列的中位随访时间为1027天（95%可信区间[CI]， 903-1151天）。随访结束时，DIA组35例（53.8%）、IA组43例（66.2%）行同种异体造血干细胞移植，两组分别有51例（78.5%）存活。在达到CR的患者中，DIA组复发12例（21.4%），IA组复发11例（21.6%）（表1）。DIA组的3年OS为74.2%，IA组为76.5% (p = 0.912)，而DIA组的3年EFS为65.8%，IA组为58.6% (p = 0.206)（图1A，B）。我们将所有患者分为移植或非移植亚组进行生存分析。在移植患者中，与接受IA方案的患者相比，接受DIA诱导方案的患者有更好的EFS趋势，差异接近统计学意义（p = 0.053）（图1D）。在接受移植的高危AML患者中，接受DIA诱导方案的患者表现出更好的EFS (p = 0.027)（图1H）。两组均出现III-IV级血液学毒性，包括白细胞减少、中性粒细胞减少和血小板减少（表S2）。虽然DIA组和IA组的CR率相似，但DIA组mrd阴性患者的比例明显更高（69.6%对37.3%）。达到CR但mrd阳性的患者保留了具有高增殖潜力的残留白血病细胞，与mrd阴性患者相比，往往导致复发和预后较差。通常，实现mrd阴性缓解与改善的生存结果相关，并且越来越被认为是强化诱导治疗的关键终点，因为它与移植前后复发风险降低相关[5,6]。DIA方案可以提高MRD阴性率，减少复发率，为后续的同种异体造血干细胞移植创造有利条件。我们的研究结果表明，甲基化突变患者和CEBPA突变患者的CRMRD发生率更高，并且可能从DIA方案中获益更多。甲基化相关基因突变（如DNMT3A、TET2、IDH1、IDH2）显著影响DNA甲基化模式。TET2和IDH1/2的突变诱导肿瘤抑制基因[7]的全基因组高甲基化和启动子特异性高甲基化。继发性遗传性病变(如：（FLT3-ITD、NPM1或IDH1突变）在这些表观遗传启动的细胞中驱动恶性转化[8]。总的来说，这些与甲基化相关的基因突变对DNA甲基化动力学产生不同但协同的影响，最终通过表观遗传失调驱动疾病进展。这一机制可以解释为什么甲基化突变患者在DIA方案中实现CRMRD-。在表观遗传调控因子突变的AML患者和CEBPA突变[9]患者中，甲基化模式发生显著变化。甲基化沉默基因CEBPA已被鉴定为t (8;21) AML[10]的关键地西他滨敏感基因。这些因素可能解释了为什么与IA方案相比，DIA方案中CEBPA突变患者的MRD率更高。然而，这些解释必须严格地视为探索性的。该分析本身受到中期样本量和基线不平衡（IA组中DNMT3A突变频率较高）的限制，这可能会混淆观察到的关联。因此，这些发现应谨慎解释，并等待更大的前瞻性设计队列验证。值得注意的是，我们的研究结果显示，与IA方案相比，DIA方案显著提高了中度和不良风险AML患者的CRMRD率。除了DNA甲基转移酶抑制作用外，地西他滨在AML细胞中显示出显著的化疗增敏活性，增强了它们对传统化疗药物的反应性，包括阿糖胞苷和柔红霉素[11]。不良细胞遗传学显著影响地西他滨的疗效。在接受地西他滨诱导的AML患者中，与没有这些异常的患者相比，17p缺失（17p-）和复杂核型的患者获得了显著更高的应答率（71%对36%，p = 0.010）[12]。这些发现可以解释为什么DIA方案导致中度和不良风险AML患者mrd阴性缓解率更高。在我们的前瞻性研究中，DIA方案的CR率与其他DAC研究中报道的相似或更高。一项回顾性研究比较了DIA和IA方案治疗伴有MDS特征的ND AML患者的有效性，发现DIA方案的CR率更高（85.2% vs. 68.5%, p = 0.040），显示出对中高危患者[13]的特别益处。一项开放标签I期研究联合地西他滨和DA方案在ND AML患者中实现了57%的CR率。一项前瞻性多中心研究评估了DAC与低剂量IA方案联合治疗MDS演变的AML的疗效，报告了63.6%的CR率。在治疗ND AML患者的诱导方案中，DAC有时被合并到传统的“7 + 3”方案中，其他药物也会联合使用。在47例ND AML患者中，克拉德里滨联合IA （CLIA）方案的CR率达到81%，其中55%达到MRD阴性，估计1年OS率为75%。在接受索拉非尼联合IA方案的ND AML患者中，54例（87%）达到CR[16]。此外，一项II期研究报告称，在ND - AML患者中，CLIA方案的CR率为77%，MRD阴性率为70%。我们的治疗方案的效果等于甚至超过这些方案。对人类白血病细胞系的研究表明，地西他滨后给予Ara-C增强细胞毒性，阿糖胞苷优先杀死低甲基化细胞。这些发现表明地西他滨诱导的低甲基化增加了白血病细胞系对阿糖胞苷细胞毒性作用的敏感性。先前的一项研究也证实了DAC和IDA之间的协同抗白血病作用。地西他滨与依达柔比星和阿糖胞苷表现出协同作用，增强了其抗白血病作用，这可能是DIA方案MRD转化率高于IA方案的原因。DIA方案安全、可耐受（轻度、可控的药物相关AE），与IA方案相比，血液/非血液AE发生率无显著差异。虽

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引用次数: 0

Why We Do Not Recommend That People With High-Risk Smoldering Myeloma Receive Treatment 为什么我们不推荐高风险阴燃性骨髓瘤患者接受治疗

IF 9.9 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2025-12-04 DOI: 10.1002/ajh.70159

Ghulam Rehman Mohyuddin, Mackenzie Lemieux, Rajshekhar Chakraborty, Morie Gertz

Smoldering myeloma (SMM) affects approximately 1 in 200 individuals over age 40 and represents a precursor state to multiple myeloma [1]. The 2014 diagnostic reclassifications fundamentally altered SMM's natural history by moving the highest-risk patients into the myeloma category, while advances in imaging—particularly MRI and PET—now detect lesions that would have been missed by conventional radiography [2, 3]. These dual changes have rendered previous natural history studies and risk stratification systems obsolete. Notably in 2025, both the European Commission and the United States FDA approved the first ever treatment of high-risk SMM based on the Phase III AQUILA trial [4]. While recent trials have demonstrated statistically significant improvements in progression-free survival (PFS) with early intervention, we remain convinced that high-risk SMM should not be routinely treated.Identifying patients who might benefit from SMM treatment is still an unsolved problem. A frequently quoted study to describe the natural history of SMM (10% risk of progression in the first 5 years) included patients who were diagnosed between 1970 and 1995, much before the advent of advanced imaging and diagnostic reclassifications [5]. Several other risk stratification systems have been developed to try to identify these patients and guide disease management. These too have the limitation of inclusion of patients that have not undergone rigorous advanced imaging with MRI or PET and being derived from datasets prior to diagnostic reclassifications [6]. There is discordance between different criteria, with a study showing that the overall agreement between three models of SMM risk assessment (Old Mayo, IMWG 20/2/20 and PETHEMA) is only 16.6% [6]. A recent retrospective cohort study in which patients underwent advanced imaging also demonstrates that these conventional staging systems overestimate the risk of progression [7]. As a result, our current risk stratification systems fail to predict who progresses to myeloma, who will experience true morbidity at progression, and who may benefit from early intervention.Previous SMM randomized trials did not provide sufficient insights on what progression events were being prevented by therapy. It was thus unknown whether treatment was preventing laboratory abnormalities, or morbidity. The recent AQUILA trial, which was a randomized comparison of observation versus daratumumab for high-risk SMM provided this information, and the recent FDA Oncological Drugs Advisory Committee (ODAC) offered insights into progression events [8, 9].In the AQUILA trial, although overall progression events were more frequent in the observation arm compared to the daratumumab arm, these events were largely asymptomatic [8]. Among the 166 patients who experienced progression events across both arms, only thre

阴燃型骨髓瘤（SMM）在40岁以上的人群中发病率约为1 / 200，是多发性骨髓瘤bbb的前兆。2014年的诊断重新分类从根本上改变了SMM的自然史，将风险最高的患者转移到骨髓瘤类别，而成像技术的进步，特别是MRI和pet，现在可以检测到传统x线摄影无法检测到的病变[2,3]。这些双重变化使得以前的自然历史研究和风险分层系统过时了。值得注意的是，在2025年，欧盟委员会和美国FDA都批准了基于AQUILA III期试验的首个高风险SMM治疗方案。虽然最近的试验显示早期干预对无进展生存期（PFS）有统计学上的显著改善，但我们仍然相信高风险的SMM不应该常规治疗。确定可能从SMM治疗中受益的患者仍然是一个未解决的问题。一项经常被引用的研究描述了SMM的自然史（前5年有10%的进展风险），其中包括1970年至1995年间诊断的患者，远早于先进影像学和诊断重分类bb0的出现。已经开发了其他几种风险分层系统，试图识别这些患者并指导疾病管理。这些也有局限性，包括没有经过严格的MRI或PET高级成像的患者，以及在诊断重分类之前的数据集。不同标准之间存在不一致性，一项研究表明，三种SMM风险评估模型（Old Mayo， IMWG 20/2/20和PETHEMA）之间的总体一致性仅为16.6%[6]。最近的一项回顾性队列研究，患者接受了先进的影像学检查，也表明这些传统的分期系统高估了进展的风险。因此，我们目前的风险分层系统无法预测谁会发展为骨髓瘤，谁会在进展中经历真正的发病率，以及谁可能从早期干预中受益。先前的SMM随机试验没有提供足够的见解，说明治疗可以预防哪些进展事件。因此，尚不清楚治疗是否能预防实验室异常或发病率。最近的AQUILA试验提供了这一信息，该试验是对观察和daratumumab治疗高风险SMM的随机比较，最近的FDA肿瘤药物咨询委员会（ODAC）提供了对进展事件的见解[8,9]。在AQUILA试验中，尽管与daratumumab组相比，观察组的总体进展事件更频繁，但这些事件大多是无症状的。在166名双臂均出现进展事件的患者中，只有3名患者出现了症状性骨痛，其中2名患者属于daratumumab治疗组[8]。所有其他骨骼事件似乎是无症状的影像学发现。在出现“贫血进展”的患者中，血红蛋白中位数下降为1.7 g/dL，没有相应的疲劳报告，也没有严重到需要输血的贫血。大多数进展事件代表通过强化监测发现的无症状发现：对照组16例患者和达拉单抗组5例患者仅通过协议规定的重复骨髓取样检测到≥60%的浆细胞。ECOG E3A06试验探讨来那度胺与观察，76%的对照组在2年无进展，这表明表面上的高风险患者过度治疗。这就提出了一个基本问题：我们是在治疗疾病还是治疗测试结果？最近对SMM患者的三个回顾性数据集的观察显示，SMM的发病率较低[10-12]，而先前的数据也表明，SMM患者的进展事件几乎总是不发病的[7,13]。此外，在AQUILA试验的观察组中，20%被诊断为骨髓瘤的患者没有开始治疗，这引发了对骨髓瘤目前定义的进展的临床意义的质疑，甚至在研究人员治疗该试验的患者中也是如此。对于已知对骨髓瘤有效的SMM药物的试验测试，对照组应在进展b[14]时接受结合该药物的有效治疗。不幸的是，并非所有的SMM随机试验都达到了这个标准。西班牙的试验显示，与观察组相比，来那度胺加地塞米松的总生存期（OS）有所改善。然而，该试验没有进行OS分析，在进展为骨髓瘤[15]的对照组中，只有28%的患者接受了来那度胺。因此，该试验比较了早期给予一组患者有效药物与不给予另一组大多数患者有效药物的情况。来那度胺与观察的ECOG试验尚未显示出OS优势，也没有提供进展后治疗的细节。鉴于该试验仅在美国进行，我们怀疑缺乏OS优势是由于当患者进展为b[16]骨髓瘤时提供了高质量的护理。daratumumab与观察的AQUILA试验并没有为OS提供支持，因此，任何关于OS的推论都必须在此背景下进行。这是一项全球试验，在进展为骨髓瘤的地区进行了广泛不同的治疗。尽管如此，该试验似乎已经显示出改善的OS，使用达拉单抗的5年OS为93.0%（与主动监测相比为86.9%）。该试验从2017年12月到2019年5月招募，但对照组的患者可能会在随后的几年中取得进展，当时daratumumab已显示出对新诊断的骨髓瘤的疗效。早在2018年5月，ALCYONE试验就已导致daratumumab被FDA批准用于新诊断的骨髓瘤。在我们看来，在骨髓瘤进展时，没有向对照组提供以daratumumab为基础的方案（或至少是当代三联疗法）是一个错失的机会。最能说明这一点的事实是，在105名继续接受治疗的对照组患者中，只有29名（27.8%）接受了硼替佐米/来那度胺/地塞米松治疗，只有18%接受了含有抗cd38治疗的方案。这篇论文的作者最近的通信报告说，在试验中的41例死亡中，只有12例发生在开始初始治疗后，其中9例在主动监测组，3例在达拉单抗组。试验中许多患者的死亡原因尚不清楚，除骨髓瘤外的其他原因导致的死亡人数存在不平衡（达拉单抗组12例，观察组17例）。我们假设看到的差异可能仅仅是偶然的，因为试验不是针对操作系统的。另一种可能性是，鉴于该试验的全球性质和各地护理标准的广泛差异，筛查不充分可能导致因AL淀粉样蛋白漏诊而猝死的可能性更高。因此，尽管在AQUILA试验中看到了OS结果，但没有证据表明在骨髓瘤诊断时提供高质量治疗的早期干预可以改善OS。在美国，Daratumumab治疗SMM的费用约为每位患者每年20万美元。在接受达拉单抗治疗的患者中出现明显低IgG的患者需要额外的IVIG费用。病人和社会都能感受到这种金融毒性。除了财务上的负面影响，身体上的负担也是实实在在的。在接受daratumumab治疗的患者中，80%发生了任何级别的感染，而在观察队列中，这一比例为45%，而3级或更高级别的感染分别发生在17%和5%的患者中。更多接受达拉单抗治疗的患者出现了治疗紧急不良事件（97%对83%）。在daratumumab组中，所有级别的疲劳发生率是前者的两倍（42%对21%），考虑到该药物是在无症状人群中使用的，并且直观地认为预防贫血作为螃蟹事件可以改善疲劳，这一点更令人担忧。其他SMM干预措施的毒性要大得多。GEM-CESAR试验评估了卡非佐米、来那度胺、地塞米松的延长疗程，并结合干细胞移植治疗SMM患者。在该试验中，4.4%的患者（90例中的4例）死于与骨髓瘤进展无关的原因，如中风、心脏骤停、肺癌和骨髓增生异常综合征[20]。没有同时进行的对照组来确定相似患者群体的基线死亡率和竞争风险，如果采用温和的方法观察或治疗，患者是否会活得更长，这是未知的。早期干预的前提是防止“不可逆转”的器官损伤。然而，先进的成像技术使这种观点变得过时。全身弥散加权MRI可以检测局灶性病变，其灵敏度远高于AQUILA中使用的PET/CT或低剂量CT[21-23]。最重要的是，正如SPOTLIGHT试验（NCT06212323）所评估的那样，定期监测可以在出现症状性并发症之前进行干预。在使用现代影像学的当代队列中，疾病进展事件非常罕见[10,11,24]。当症状事件确实发生时，它们通常被发现得

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引用次数: 0

When a Trait Becomes a Disease: A Rare Hematologic Overlap of Sickle Cell Trait and Hereditary Spherocytosis 当一个性状成为一种疾病：罕见的血液学重叠镰状细胞性状和遗传性球形红细胞增多症

IF 9.9 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2025-12-04 DOI: 10.1002/ajh.70154

Omar Ammari, Mina Shah, Yasmin Elgammal, Ammar Husami, Theodosia A. Kalfa, Jahnavi Gollamudi

Sickle cell trait (SCT) is a heterozygous form of sickle cell disease (SCD) and occurs from a genetic mutation in one of two copies of the beta-globin gene, where valine replaces glutamic acid (HbS) [1]. The prevalence of SCT is around 5% in people of African ancestry in the United States [2]. Most individuals with SCT remain asymptomatic; complications typically occur only under extreme physiological stress, such as high altitude or dehydration [3]. Organ damage is rare, although the presence of SCT has been associated with chronic kidney disease (CKD) and venous thromboembolism (VTE) [3, 4]. Recent literature [2] attributes coinheritance of other red cell disorders as a risk factor for severe organ damage in individuals with SCT [5].Hereditary spherocytosis (HS) is a red blood cell (RBC) membranopathy due to a mutation in cytoskeletal proteins, lending RBCs a spherical shape, leading to increased RBC fragility and hemolysis [6]. While individuals with HS and SCT alone have a typically mild clinical course, the coinheritance of these two conditions can result in severe clinical sequalae [7]. Prior literature on HS and SCT coinheritance demonstrates splenic sequestration or infarct as a typical complication in association with stressors, but there are no cases that describe extra-splenic manifestations [7-9]. Herein, we present a case of a 54-year-old female with SCT, HS, and a heterozygous G6PD A-pathogenic variant who presented with avascular necrosis (AVN) and proliferative retinopathy.A 54-year-old woman of African ancestry with known SCT presented to our hematology office at the University of Cincinnati Medical Center after X-rays for right knee pain workup indicated medial femoral condyle subchondral lucency with increasing peripheral sclerosis, suggesting AVN. She had thigh and knee pain, fatigue, body aches, and left-sided abdominal pain following air travel and exercise. Labs revealed normal hemoglobin with evidence of chronic hemolysis (see Table 1). A CT scan completed 1 year prior showed normal spleen size. MRI of the right knee confirmed AVN in the lateral and medial femoral condyles.The usual causes of AVN were investigated. She denied prolonged steroid exposure, a history of thrombosis, or connective tissue disorders. Serum protein electrophoresis and hypercoagulability workup were negative (see Table 1). She had mildly positive anticardiolipin antibodies which did not meet the Sapporo criteria of antiphospholipid syndrome (APS) [10].Hemoglobin electrophoresis and subsequent beta-globin gene testing confirmed SCT [HBB c.20A>T, p.(Glu7Val)]. The incongruence between clinical symptoms and the SCT status led to testing for coinheritance of other RBC disorders. Briefly, hemoglobin-O2 affinity (p50) and viscosity testing were normal. G6PD level was found to

镰状细胞性状（SCT）是镰状细胞病（SCD）的一种杂合形式，发生于β -珠蛋白基因两个拷贝之一的基因突变，其中缬氨酸取代了谷氨酸（HbS）[1]。在美国，非洲裔人群中SCT的患病率约为5%。大多数SCT患者仍无症状；并发症通常只发生在极端的生理压力下，如高海拔或脱水。器官损害是罕见的，尽管SCT的存在与慢性肾脏疾病（CKD）和静脉血栓栓塞（VTE）有关[3,4]。最近的文献[2]将其他红细胞疾病的共遗传作为SCT患者[5]严重器官损伤的危险因素。遗传性球形红细胞增多症（HS）是一种由细胞骨架蛋白突变引起的红细胞（RBC）膜病变，使红细胞呈球形，导致红细胞易碎性增加和溶血。虽然单独患有HS和SCT的个体通常具有轻微的临床病程，但这两种情况的共同遗传可能导致严重的临床后遗症。先前关于HS和SCT共遗传的文献表明，脾隔离或梗死是与应激源相关的典型并发症，但没有描述脾外表现的病例[7-9]。在此，我们报告一例54岁女性SCT， HS和杂合G6PD - a致病变异，表现为血管坏死（AVN）和增殖性视网膜病变。一名54岁非洲血统女性，已知SCT，在辛辛那提大学医学中心的血液学办公室接受右膝疼痛x光检查后发现，股骨内侧髁软骨下透明伴周围硬化增加，提示AVN。她在航空旅行和运动后出现大腿和膝盖疼痛、疲劳、身体疼痛和左侧腹部疼痛。实验室显示血红蛋白正常，伴有慢性溶血（见表1）。1年前完成的CT扫描显示脾脏大小正常。右膝MRI证实股骨外侧和内侧髁有AVN。调查AVN的常见原因。她否认长期服用类固醇、有血栓病史或结缔组织疾病。血清蛋白电泳和高凝检查均为阴性（见表1）。她的抗心磷脂抗体轻度阳性，但不符合抗磷脂综合征（APS）的札幌标准。血红蛋白电泳和随后的β -珠蛋白基因检测证实了SCT [HBB c.20A&gt；T, p.(Glu7Val)]。临床症状和SCT状态之间的不一致导致检测其他红细胞疾病的共遗传。简单地说，血红蛋白- o2亲和力（p50）和粘度测试正常。G6PD水平为76%，略低于正常水平，与女性杂合G6PD缺乏症相符（见表1）。渗透梯度细胞计数法检测显示其曲线与轻度遗传性球形红细胞增多症相符（图1）。氧梯度ektacetry测量RBC在下降和上升的氧压梯度[11]上的变形能力，显示她的红细胞在氧压不典型的情况下开始镰状细胞。镰状细胞点（PoS）， HbS聚合加速的地方，定义为可变形性（由延伸指数显示）达到最大值95%的pO2，低于几乎所有镰状细胞性贫血患者的值，即使他们的胎儿血红蛋白水平高于35%[11]。因此，我们进行了全外显子组测序（见补充方法）并进行了分析，发现了导致HS的致病性SLC4A变异（c.1030C&gt；T, p.Arg344*）（见图S1），以及其G6PD基因（a - matera单倍型）[12]的杂合突变，解释了其G6PD活性轻度低的原因。随访期间，患者视力恶化，伴有scd相关视网膜病变等特征。排除糖尿病和高血压病理。鉴于恶化的临床表现，我们讨论了羟基脲（HU）、红细胞（RBC）交换和脾切除术治疗SCD和HS的选择。由于担心手术和药物副作用，患者倾向于红细胞交换。鉴于缺乏改善视网膜病变的可靠数据和后勤问题，这进一步修改为静脉切开术后的简单输血。在此通信时，她已经完成了六次治疗，将HbS从41%降低到28%，疲劳和膝关节疼痛明显改善（见表1）。需要长期随访来记录视网膜病变的改善情况。本例患者具有非典型SCT的临床特征，包括慢性溶血、AVN和增殖性视网膜病变。这些并发症是典型的SCD及其变异形式，如HbSC疾病。值得注意的是，慢性溶血并不是孤立SCT bb0的公认特征，这促使对共存的内在红细胞疾病进行评估。我们的检查导致诊断为共遗传遗传性球形红细胞增多症（HS），解释了她的慢性代偿性溶血和临床表现。此外，我们的病人G6PD水平稍低。由于G6PD水平高于60%很少导致溶血，因此这不太可能是其临床表型[12]的主要决定因素。大约有18例患者同时患有HS和SCT[7,8]，通常表现为脾隔离。我们的病人在飞机旅行后的左上腹疼痛史与这些报告相符。然而，她也有AVN和增生性视网膜病变。我们的病例表明，SCT和HS患者可能出现额外的脾并发症。迄今为止，由于缺乏筛查或发现其他原因，这些并发症可能尚未报告。从机制上讲，SCT和HS的共遗传产生了一种独特的红细胞病理生理，类似于在HbSC疾病中观察到的。在SCT存在的情况下，HS引起的细胞内黏度增加会增强HbS聚合和镰状反应[13,14]，增加缺血和微血管闭塞的风险，可能导致AVN和视网膜病变。在脾脏，由于其相对缺氧和酸性环境，这导致梗死甚至脾切除。关于HS和SCT共遗传的处理，特别是脾外并发症的数据很少。脾切除术已被用于HS和SCT共遗传的患者，以解决脾肿大和梗死相关疼痛[7-9]。该方法可解决脾并发症，但其对AVN或视网膜病变等并发症的影响尚不清楚。鉴于SCT和HS共遗传患者缺乏循证治疗，我们提出了三种治疗方案：脾切除术、羟基脲（HU）和红细胞交换输注。在HS中，脾切除术可减少贫血、红细胞胞内黏度和血管外溶血。因此，我们推断脾切除术可以减少她红细胞中的HbS聚合。然而，脾切除术也与全血粘度增加有关，因为球细胞的存在，这可能损害微血管灌注，增加血栓形成的风险。羟基脲（HU）用于SCD[17]的疾病修饰。我们推断，降低HbS和增加胎儿血红蛋白含量可以保护她免受进一步的并发症，尽管环境压力因素仍可能导致镰状病变。最后，我们推断，人工红细胞交换输注，也用于SCD的疾病改造，将用健康的供体细胞代替患者的红细胞，减少膜病和血红蛋白病的影响，以改善氧输送，减少镰状细胞和溶血[18,19]。在撰写本文时，患者完成了6次简单的红细胞交换，并证实疲劳和膝关节疼痛症状有所改善。总之，我们描述了一个病例的个人伴随HS和SCT，他们的临床表现，和管理方案。当临床表现与患者报告的基因型不匹配时，该病例强调需要进行替代诊断和扩大检查。通过一系列的实验室检查，我们最终诊断出她患有乙型肝炎样红细胞增生样疾病，并为她提供治疗，强调了通过倾听患者的担忧和在临床表现与患者的表现不一致时进行额外的实验室研究来获取完整的临床病史的重要性。， o.a.和J.G.参与了构思和设计，收集了数据，起草了手稿，并最终批准了出版版本。M.S.和O.A.对手稿的贡献相同。Y.E.进行红细胞表型检测，A.H.提供基因组分析；T.A.K.分析了红细胞表型基因检测。所有作者都进行了重要的修改，并批准了最终的手稿。作者没有什么可报告的。本病例报告是按照《赫尔辛基宣言》中概述的伦理原则进行的。患者已同意并知晓这份手稿。此外，患者还签署了一份有关基因检测的同意书。本报告的发表已获得患者的知情同意，包括相关临床细节和任何随附图像。所有的努力都是为了保持病人的匿名性，没有任何可识别的信息被披露。作者声明无利益冲突。支持本研究结果的数据可向通讯作者索取。由于隐私或道德限制，这些数据不会公开。

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引用次数: 0

A Novel, Ruxolitinib-Sensitive, CCDC6::JAK2 Fusion Gene in a Patient With Atypical, JAK2 Unmutated, Polycythemia Vera-Like, Myeloproliferative Neoplasm 一种新型Ruxolitinib敏感、CCDC6:: JAK2融合基因在非典型、JAK2未突变、真性红细胞增多症样骨髓增殖性肿瘤中的应用

IF 9.9 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2025-12-03 DOI: 10.1002/ajh.70156

Niccolò Bartalucci, Danilo Tarantino, Giuseppe G. Loscocco, Alessio Enderti, Daniele Colazzo, Raffaella Santi, Daniela Parrini, Manjola Balliu, Valentina Boldrini, Yasmine Abbassi, Elisabetta Pelo, Monia Marchetti, Paola Guglielmelli, Alessandro M. Vannucchi

In our study, we identified a novel, ruxolitinib-sensitive, CCDC6::JAK2 fusion gene as a driver of atypical JAK2-unmutated MPN with a polycythemic phenotype. The CCDC6::JAK2 chimeric protein retains the CCDC6 coiled-coil domain and the JAK2 kinase domain. Dimerization of chimeric proteins through coiled-coil domains promotes JAK2 autophosphorylation leading to constitutive activation of the JAK/STAT signaling pathway.

在我们的研究中，我们发现了一种新的，ruxolitinib敏感的，CCDC6::JAK2融合基因作为非典型JAK2未突变的MPN的驱动因子，具有多细胞表型。CCDC6::JAK2嵌合蛋白保留了CCDC6卷曲结构域和JAK2激酶结构域。通过卷曲结构域的嵌合蛋白二聚化促进JAK2自磷酸化，导致JAK/STAT信号通路的组成性激活。

引用次数: 0