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30-Minute infusion of isatuximab in patients with newly diagnosed multiple myeloma: Results of a Phase 1b study analysis 对新诊断的多发性骨髓瘤患者进行 30 分钟伊沙妥昔单抗输注：1b期研究分析结果。

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-11-05 DOI: 10.1002/hem3.70041

Enrique M. Ocio, Aurore Perrot, Philippe Moreau, Maria-Victoria Mateos, Sara Bringhen, Joaquín Martínez-López, Lionel Karlin, Song-Yau Wang, Corina Oprea, Yi Li, Ercem Kodas, Jesus San-Miguel

The addition of an anti-CD38 antibody to standard treatment regimens, in combination with an immunomodulatory drug or a proteasome inhibitor and dexamethasone, provides benefit to multiple myeloma (MM) patients in the relapsed/refractory setting (RRMM), as well as at an earlier disease stage in quadruplet combinations for transplant-eligible or non-eligible patients with newly diagnosed MM (NDMM).1-3 Isatuximab (Isa) is approved in various countries in combination with pomalidomide-dexamethasone or carfilzomib-dexamethasone for the treatment of RRMM patients.4-6Study findings in transplant-eligible NDMM patients demonstrated significant efficacy of Isa in quadruplet combinations with bortezomib-lenalidomide-dexamethasone (VRd) for induction therapy in the Phase 3 GMMG-HD7 trial (minimal residual disease [MRD] negativity: 50% with Isa-VRd vs 36% with VRd; p = 0.00017), and with carfilzomib-lenalidomide-dexamethasone (KRd) for induction/consolidation treatment in the Phase 3 IsKia/EMN24 trial (MRD negativity after consolidation: 77% with Isa-KRd vs 67% with KRd; p = 0.049), without new safety signals.7, 8In transplant-ineligible NDMM patients, significant PFS benefit (hazard ratio [HR], 0.60; 98.5% confidence interval [CI], 0.41–0.88; p < 0.001) and deep, sustained responses were reported with Isa in combination with VRd followed by Isa-Rd versus VRd followed by Rd, in a prespecified interim analysis of the Phase 3 IMROZ trial, with a manageable safety profile.9 In the Phase 3 BENEFIT trial, the addition of weekly bortezomib to Isa-Rd (reduced-dose VRd) induced a significant improvement in MRD negativity at 18 months versus Isa-Rd (53% vs. 26%, p < 0.0001).10The evaluation of Isa with either bortezomib-cyclophosphamide-dexamethasone (VCd) or VRd has shown safety and efficacy of these quadruplet regimens in the Phase 1b trial TCD13983 (NCT02513186) in transplant-ineligible NDMM patients (all cohorts) or patients with no immediate intent for autologous stem cell transplantation included in Isa-VRd/Part-B, as previously reported.11, 12To enhance the convenience of long-term treatment with IV Isa for patients and healthcare providers, by improving the current duration of Isa infusion (75 min), we prospectively evaluated the feasibility, safety, and tolerability of a novel, fast, 30-min infusion method for Isa in patients who were on maintenance therapy in the TCD13983 study.All patients on maintenance treatment, regardless of treatment cohort, were switched to 30-min infusion with Isa at 10 mg/kg (250-mL fixed-volume infusion). Details on study treatments before switching, premedications, and patient characteristics are provided in Supporting Information and Supporting Information S1: Figure S1. To accelerate the infusions to a target durat

在标准治疗方案中加入抗CD38抗体，与免疫调节药物或蛋白酶体抑制剂和地塞米松联合使用，可使复发/难治性多发性骨髓瘤（MM）患者获益，也可使符合移植条件或不符合移植条件的新诊断MM（NDMM）患者在四联疗法的早期疾病阶段获益。1-3 伊沙妥昔单抗（Isa）与泊马度胺-地塞米松或卡非佐米-地塞米松联合治疗 RRMM 患者已在多个国家获得批准。对符合移植条件的 NDMM 患者进行的研究结果表明，在 GMMG-HD7 3 期试验中，Isa 与硼替佐米-来那度胺-地塞米松（VRd）四联用进行诱导治疗具有显著疗效（最小残留病[MRD]阴性率：Isa-VRd 为 50%，VRd 为 36%；P = 0.00017），以及在 IsKia/EMN24 3 期试验中使用卡非佐米-来那度胺-地塞米松（KRd）进行诱导/巩固治疗（巩固治疗后 MRD 阴性：Isa-KRd 77% vs VRd 36%；P = 0：Isa-KRd为77%，KRd为67%；p = 0.049），没有出现新的安全性信号、8 在 IMROZ 3 期试验的预设中期分析中，符合移植条件的 NDMM 患者使用 Isa 联合 VRd 后再使用 Isa-Rd 与 VRd 后再使用 Rd 相比，获得了显著的 PFS 益处（危险比 [HR]，0.60；98.5% 置信区间 [CI]，0.41-0.88；p < 0.001）和深度、持续的应答，且安全性可控。在 3 期 BENEFIT 试验中，Isa-Rd（减量 VRd）与 Isa-Rd 相比，在 18 个月时每周添加硼替佐米可显著改善 MRD 阴性率（53% 对 26%，p < 0.0001）。10 在TCD13983（NCT02513186）的1b期试验中，对Isa与硼替佐米-环磷酰胺-地塞米松（VCd）或VRd联合治疗不符合移植条件的NDMM患者（所有组别）或Isa-VRd/Part-B中无立即进行自体干细胞移植意向的患者进行了评估，结果显示这些四联疗法具有安全性和有效性、12为了提高患者和医护人员长期静脉输注Isa治疗的便利性，改善目前Isa输注的持续时间（75分钟），我们对TCD13983研究中正在接受维持治疗的患者采用30分钟快速输注Isa的新型方法的可行性、安全性和耐受性进行了前瞻性评估。所有接受维持治疗的患者，无论治疗队列如何，均改用30分钟输注10 mg/kg的Isa（250 mL固定容量输注）。有关切换前的研究治疗、预处理和患者特征的详细信息，请参阅《佐证资料》和《佐证资料 S1：图 S1》。为了加快输液速度，使目标输液时间达到 30 分钟，第一次输液时将伊萨 10 mg/kg 稀释在 250 毫升的 0.9% 氯化钠输液袋中，以 250 毫升/小时的速度输注 30 分钟，然后以 500 毫升/小时的速度输注 15 分钟（佐证资料 S1：表 S1）。如果没有出现输液反应（IR），随后的输液将在约 30 分钟内以 500 毫升/小时的速度进行。没有基于健康状况或既往输注反应的患者转换排除标准；但是，最后一次 Isa 剂量应在转换前 1 个月（±7 天）给药。2023 年 1 月至 2024 年 1 月 5 日期间，45 名接受维持治疗的患者改用了新的 30 分钟输注方法：在 2023 年 1 月至 2024 年 1 月 5 日期间，45 名接受维持治疗的患者改用了新的 30 分钟输注方法：4 人接受 Isa-VCd，13 人接受 Isa-VRd/Part-A ，28 人接受 Isa-VRd/Part-B 。在进行本分析时（最后一名患者的最后一次就诊时间为 2024 年 1 月 22 日），Isa-VCd 组群的中位随访时间为 71.1 个月（n = 15），Isa-VRd/Part-A 组群的中位随访时间为 55.1 个月（n = 26），Isa-VRd/Part-B 组群的中位随访时间为 38.1 个月。在评估期间，45名患者在不同组别间进行了210次快速输注：45例首次输注采用中速输注（从250毫升/小时开始，持续30分钟，然后500毫升/小时，持续15分钟），165例后续输注采用快速输注（500毫升/小时）（佐证资料S1：表S2）。数据截止时，30 分钟输注周期的中位数为 4 次（范围为 2-11）；45 名患者接受了首次中速输注和首次 30 分钟输注；44 名患者接受了≥2 次 30 分钟输注，切换后的中位暴露持续时间为 16 周（8.0-46.1）。所有 45 例患者的中位转换周期为 45 个周期（38-88），Isa-VCd、Isa-VRd/Part-A 和 Isa-VRd/Part-B 组的中位转换周期分别为 80、64 和 41 个周期（佐证资料 S1：表 S3）。

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How to diagnose acid sphingomyelinase deficiency (ASMD) and Niemann–Pick disease type C from bone marrow and peripheral blood smears 如何通过骨髓和外周血涂片诊断酸性鞘磷脂酶缺乏症（ASMD）和尼曼-皮克病 C 型。

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-11-05 DOI: 10.1002/hem3.70042

Sandrine Girard, Magali Pettazzoni, Roseline Froissart, Cécile Pagan, Thomas Boyer, Stephanie Dulucq, Valérie Gonçalves Monteiro, Nicolas Lechevalier, Marie Loosveld, Camille Lours, Caroline Mayeur-Rousse, Mélanie Pannetier, Caroline Peillon, Maria-Alessandra Rosenthal, Sonnthida Sep Hieng, Catherine Trichet, Lucile Baseggio, on behalf the French-Speaking Cellular Haematology Group (GFHC)

Lysosomal storage diseases (LSD) are inborn errors of metabolism disorders characterized by a defect in a lysosomal enzyme, transporter, or cofactor. Niemann–Pick diseases are classified into two distinct disorders: acid sphingomyelinase deficiency (ASMD) historically known as Niemann–Pick disease types A, AB, and B, and Niemann-Pick disease type C (NPC).1 ASMD is a rare autosomal recessive LSD, caused by pathogenic variants in the ASM-encoding SMPD1 gene (OMIM#607608).2 It results in the accumulation of sphingomyelin and other lipids, primarily in the liver, spleen, lung, bone marrow, lymph nodes, and central nervous system.3 Depending on their clinical phenotype, three different subtypes have been reported: A (severe infantile neurovisceral form), AB (chronic neurovisceral form), and B (chronic visceral form), with a continuum spectrum.1-4 NPC is an autosomal recessive LSD caused by the defective function of one of two proteins, NPC1 or NPC2. It results from mutations in the corresponding genes (OMIM#257220 and OMIM#607625). These two proteins act in sequence to regulate the egress of endocytosed nonesterified cholesterol from the late endosomal/lysosomal compartment. NPC manifests as a neurovisceral disease with a highly heterogeneous clinical spectrum.5 The prognosis of NPC is correlated with the age of onset of neurological symptoms, with four neurological forms defined: early infantile, late infantile, juvenile, and adolescent-adult. The diagnosis of ASMD and NPC is difficult because these diseases are heterogeneous and may share clinical features with other LSD such as Gaucher disease, especially when splenomegaly is present.5 Some cytological abnormalities have been reported in bone marrow (BM) and peripheral blood (PB) smears from ASMD and NPC patients, which could help to guide the more specific analysis such as enzymatic activity, biomarkers measurement, and genetic testing.6 However, the cytological data available in the literature are rather limited, often described in single case reports, and do not distinguish the different forms of ASMD and NPC. This work aims to report the cytological features of BM and PB in a retrospective study of 30 French cases from 28 families with ASMD types A [n = 5], AB [n = 3], B [n = 16], and NPC [n = 6], to improve knowledge and define recommendations to assist in diagnosis.The diagnosis of cases was based on biochemical analysis, specifically either a deficiency in acid sphingomyelinase activity in blood and/or an abnormal plasma biomarkers profile (i.e., lysosphingomyelin, lysosphingomyelin509/N-palmitoyl-O-phosphocholineserine, and oxysterols), confirmed by specific gene analysis, except for two suspected NPC patients for whom the genetic study was inconclusive and identified a vari

溶酶体贮积病（LSD）是以溶酶体酶、转运体或辅助因子缺陷为特征的先天性代谢异常疾病。尼曼-皮克病分为两种不同的疾病：酸性鞘磷脂酶缺乏症（ASMD），历史上称为尼曼-皮克病 A、AB 和 B 型，以及尼曼-皮克病 C 型（NPC）。1 ASMD 是一种罕见的常染色体隐性遗传 LSD，由编码 ASM 的 SMPD1 基因（OMIM#607608）中的致病变体引起。2 ASMD 会导致鞘磷脂和其他脂质的积聚，主要积聚在肝、脾、肺、骨髓、淋巴结和中枢神经系统中。根据其临床表型，已报道有三种不同的亚型：A 型（严重的婴儿神经内脏型）、AB 型（慢性神经内脏型）和 B 型（慢性内脏型），具有连续谱。1-4 NPC 是一种常染色体隐性 LSD，由 NPC1 或 NPC2 两种蛋白之一的功能缺陷引起。它是由相应基因（OMIM#257220 和 OMIM#607625）的突变引起的。这两种蛋白依次调节内吞的非酯化胆固醇从晚期内体/溶酶体区室排出。5 NPC 的预后与神经系统症状的发病年龄相关，有四种神经系统形式：早期婴儿型、晚期婴儿型、青少年型和青少年-成人型。ASMD 和鼻咽癌的诊断比较困难，因为这些疾病具有异质性，可能与其他 LSD（如戈谢病）具有相同的临床特征，尤其是在出现脾肿大时。有报道称，ASMD 和鼻咽癌患者的骨髓（BM）和外周血（PB）涂片存在一些细胞学异常，这有助于指导更具体的分析，如酶活性、生物标志物测定和基因检测。本研究旨在报告一项回顾性研究中 30 例法国病例的 BM 和 PB 细胞学特征，这些病例来自 28 个 ASMD A 型 [n = 5]、AB 型 [n = 3]、B 型 [n = 16] 和 NPC 型 [n = 6]的家族、7 在 30 例病例中，18 例在诊断时进行了分析（10 例 BM 并伴有相应的 PB，4 例仅有 BM，4 例仅有 PB），12 例在随访期间进行了分析，其中包括 9 例接受过治疗的患者（11 例 PB 和 1 例 BM 并伴有相应的 PB）。ASMD A 诊断时的中位年龄为 8 个月（范围为 6.0-13.0），ASMD AB 为 18.0 岁，ASMD B 为 53 岁（范围为 20-87.0 个月），NPC 为 11.0 岁（范围为 2.0-17.0）。两名经验丰富的细胞学专家（SG、LB）在双盲条件下使用光学显微镜，在用 May Grünwald-Giemsa 染色后，对 BM 和 PB 涂片的细胞学特征进行了审查。他们评估了白细胞和组织细胞/巨噬细胞的特征以及造血组织的形态。对 14 份确诊的 BM 涂片（表 1A 和图 1A）进行检查后发现，所有病例（ASMD 和 NPC）中都有大量泡沫组织细胞（FH），这些组织细胞经常聚集在一起，有时也孤立存在。它们的核呈圆形或椭圆形，偶尔偏心，很少双核。细胞质丰富，含有许多大小不一的白色小空泡，呈蓝色或粉红色。在一些病例中，还观察到包膜和带有铁沉积物或碎屑（类似黑色或深蓝色小珠子）的组织细胞。7 例病例出现海蓝色组织细胞（SBH），主要是 ASMD B，1 例为 ASMD AB（图 1Aa）。在 3 个病例中观察到造血细胞空泡化，其中 1 个病例的 PB 中也出现了空泡化的淋巴细胞（VL）（图 1Ab）。在 6 个病例中，涂片中脂肪空泡较多，或在造血组织中观察到脂肪包裹体（图 1Ac）。对 26 份肺涂片（诊断时 14 份，随访时 12 份）（表 1A、B 和图 1B）的检查发现，6 例诊断病例的 VL 阳性率超过了 GFHC 建议的 5%阈值（5 例 ASMD A 和 1 例 NPC）。 6 VL 表现为少量空泡（2 至 10 个不等），轮廓规则，通常聚集在细胞的一极（鹅口疮样）或排列成珍珠串状；它们很少单独出现（图 1B）。在两个病例中，对相关的骨髓涂片进行了分析，只有一个病例出现了空泡细胞，包括淋巴细胞（图 1A 病例 5）。在诊断时病情较轻的患者（ASMD AB、B 和后来发病的 NPC）或距诊断较远的随访患者（ASMD AB 接受酶替代疗法（ERT）治疗[n = 2 个兄弟姐妹]，ASMD B 接受 ERT 治疗[n = 4]或未接受治疗[n = 3]，NPC 接受治疗[n = 3]）中均未发现 VL。对骨髓和肺涂片进行细胞学分析可为诊断血液病提供有价值的信息，并有助于鉴别某些罕见的 LSD。溶酶体内代谢副产物的异常积聚可能导致在 BM 和 PB 涂片以及产前渗出液中观察到贮存细胞（大组织细胞贮存细胞或 VL）。对于未经训练的观察者来说，识别这些储存细胞可能具有挑战性，因为它们可能与其他 LSD 的储存细胞相似，或者看起来与反应性细胞相似。在 BM 样本中，原发病变的特征是 FH 比例不一，偶尔也会出现 SBH，这在文献中已有描述。SBH 并非唯一，而且一直与非蓝色 FH 同时发现。这种独特的细胞学外观也可见于其他各种 LSD，包括神经节苷脂、类脑脂质沉着病和后天性疾病，如血红蛋白病（地中海贫血、镰状细胞贫血）、肿瘤（慢性粒细胞白血病、淋巴瘤）、免疫性疾病（特发性血小板减少性紫癜、慢性化脓性肉芽肿）或脂质贮存障碍（SBH 综合征、肠外营养）。有趣的是，在患者 2 和 3 中，FH 的存在引导了脾肿大背景下的 LSD 诊断。在这两个病例中，鼻咽癌生物标志物特征异常，但基因检测并未确诊鼻咽癌。这两名患者都被发现是NPC1基因中一个致病或可能致病变体和一个意义不明变体的复合杂合子。目前，文献和专家们对变异体 NPC1:p.Asn222Ser 和 p.Ser1004Leu 的临床意义还存在争议（见 ClinVar 数据库）。不过，这两个病例说明，当这些变异与致病变异或可能致病的变异结合在一起时，可能与血液病表现有关。SBH和FH的密度变化不定，与年龄无关；这种变化似乎与涂片的细胞密度更相关。此外，对骨髓涂片的分析表明，约50%的涂片显示脂质含量高，并伴有大量脂肪空泡。患者的血脂情况（如有）、年龄或疾病类型与含脂组织细胞的比例之间没有相关性。这方面与切片的质量关系更为密切，因为稀释的切片脂质含量较少。细胞减少症，尤其是血小板减少症，在 ASMD 或鼻咽癌患者中很常见。1, 5, 10 全血细胞计数结果显示，细胞减少症的深度或存在与储能组织细胞浸润 BM 的比例之间没有相关性。据我们所知，文献中还没有 ASMD B 型患者在 PB 中出现 VL 的报道。将这些 VL 与感染发作期间出现在肺泡中的反应性淋巴细胞区分开来至关重要12。后者也显示细胞质微空泡，可观察到少量分散的细小空泡（数量从一个到三个不等），或大量非常细小的空泡，不规则地分布在整个细胞质中，没有明显的顺序或结构。总之，在所有类型的 ASMD/NPC 中，带有白色和/或淡蓝色内含物的 FH 数量增加是 BM 涂片的一个特征。检测这些FH（不仅限于SBH）是ASMD/NPC细胞学诊断方法的一大进步。SBH 的鉴定强烈提示了 ASMD B 型的诊断，这需要结合 SMPD1 基因分析，通过酶活性测定来确认。相反，在 ASMD 和鼻咽癌病例中，PB 和 BM 中出现循环 VL 的情况并不常见。它们的出现应引起对 LSD 的考虑，尤其是神经系统受累的严

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引用次数: 0

GPRASP protein deficiency triggers lymphoproliferative disease by affecting B-cell differentiation GPRASP 蛋白缺乏会影响 B 细胞分化，从而引发淋巴组织增生性疾病。

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-10-30 DOI: 10.1002/hem3.70037

Antonio Morales-Hernández, Emilia Kooienga, Heather Sheppard, Gabriela Gheorghe, Claire Caprio, Ashley Chabot, Shannon McKinney-Freeman

Gprasp1 and Gprasp2 encode proteins that control the stability and cellular trafficking of CXCR4, a master regulator of hematopoiesis whose dynamic regulation is required for appropriate trafficking of B-cells in the germinal center (GC). Here, we report that Gprasp1 and Gprasp2-deficient B-cells accumulate in the GC and show transcriptional abnormalities, affecting the mechanisms controlling Aicda expression and exposing them to excessive somatic hypermutation. Consequently, about 30% of mice transplanted with Gprasp-deficient hematopoietic stem and progenitor cells developed a biologically aggressive and fatal B-cell hyperproliferative disease by 20–50 weeks posttransplant. Histological and molecular profiling reveal that Gprasp1- and Gprasp2-deficient neoplasms morphologically resemble human high-grade B-cell lymphomas of germinal center origin with shared morphologic features of both Burkitt Lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), and molecular features consistent with DLBCL, as well as elevated mutational burden and heterogenous transcriptional and mutational signature. Thus, reduced Gprasp1 and Gprasp2 gene expression perturbs B-cell maturation and increases the risk of B-cell neoplasms of germinal center origin. As this model recapitulates the essential features of the heterogenous group of human hematopoietic malignancies, it could be a powerful tool to interrogate the mechanisms of lymphomagenesis for these cancers.

Gprasp1和Gprasp2编码控制CXCR4稳定性和细胞贩运的蛋白质，CXCR4是造血的主调节因子，B细胞在生殖中心（GC）的适当贩运需要它的动态调节。在这里，我们报告了 Gprasp1 和 Gprasp2 缺陷的 B 细胞在 GC 中聚集并显示出转录异常，影响了控制 Aicda 表达的机制，并使它们面临过度的体细胞超突变。因此，在移植了Gprasp缺陷造血干细胞和祖细胞的小鼠中，约有30%的小鼠在移植后20-50周出现了生物侵袭性和致命的B细胞过度增殖性疾病。组织学和分子谱分析显示，Gprasp1和Gprasp2缺陷型肿瘤在形态上类似于人类生殖中心起源的高级别B细胞淋巴瘤，具有伯基特淋巴瘤（BL）和弥漫大B细胞淋巴瘤（DLBCL）的共同形态特征，分子特征与DLBCL一致，以及突变负荷增加和异源转录与突变特征。因此，Gprasp1 和 Gprasp2 基因表达的减少会扰乱 B 细胞的成熟，并增加生殖中心来源 B 细胞肿瘤的风险。由于该模型再现了人类异质性造血恶性肿瘤的基本特征，因此它可以成为研究这些癌症淋巴致病机制的有力工具。

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引用次数: 0

Mitochondrial retention in mature red blood cells from patients with sickle cell disease is associated with stress erythropoiesis but not with proinflammatory state 镰状细胞病患者成熟红细胞中的线粒体滞留与红细胞生成压力有关，但与促炎状态无关

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-10-28 DOI: 10.1002/hem3.70030

Marc Romana, Sandrine Laurance, Marie-Dominique Hardy-Dessources, Laetitia Claer, Sylvie Ravion, Karim Dorgham, Yohann Garnier, Lea Kuznicki, Vanessa Tarer, Benoit Tressières, Sophie D. Lefevre, Veronique Baccini, Mariano A. Ostuni, Caroline Le Van Kim, Maryse Etienne-Julan

Sickle cell disease (SCD) is a hemoglobinopathy characterized by the occurrence of vaso-occlusive events, severe chronic hemolytic anemia, and ultimately chronic complications and end-organ damages.1-3 SCD pathophysiology has been shown to be extremely complex, resulting from microcirculatory dysfunctions associated with altered vaso-regulation and activation of inflammation cascades responsible of sterile inflammatory state, endothelial and neutrophil activation, and release of neutrophil extracellular trap (NET).1, 4-6 More recently, a dysfunctional erythropoiesis has been described in SS patients characterized by high level of reticulocytes, increased apoptosis at the later stage of erythropoiesis, and abnormal retention of mitochondria in red blood cells (RBCs).7-13 It is noteworthy that the functionality of these mitochondria in mature sickle RBCs remains controversial11, 12 and mechanisms responsible for the mitochondrial retention during erythropoiesis have not been identified. Besides these unanswered points, several groups reported in vitro evidence that plasma mitochondrial DNA released by hemolysis of these abnormal RBCs could trigger type I interferon production12 and NET release in SCD patients.13 Altogether, these studies suggested that mitochondrial DNA from sickle mature RBCs could play a key role in the proinflammatory state associated with the disease.In the present study, we characterized mature RBCs retaining mitochondria in a large cohort of the two main SCD genotypes, that is, SS and SC adult patients (71 and 40 patients, respectively) compared to 21 AA control individuals. We analyzed associations between mitochondria retention and hemolysis as well as inflammation markers (see patients and methods in Supporting Information and Supporting Information S1: Table 1 for the biological and demographic parameters).Mitochondria presence in mature RBCs, total, and stress reticulocytes was assessed using flow cytometry (CD71/TO and/or MitoTracker Deep Red (MTKDR) staining) (Figure 1A). SS patients exhibited significant higher percentage of total circulating reticulocytes (5.0% ± 2.2%) compared to AA healthy donors (1.1% ± 0.4%), with a significant intermediate phenotype for SC patients (3.6% ± 1.7%) (Figure 1Bi). SS patients presented significant high levels of stress reticulocytes (2.6% ± 1.2%) compared to very low level observed in AA healthy donors (0.14 ± 0.09) while SC patients exhibited significant intermediate level (1.8% ± 1.0%) (Figure 1Bii). We did not observe significant difference of total and stress reticulocyte percentages between hydroxyurea (HU)-treated and nontreated SS patients (Figure 1Biii,iv). Percentage of mitochondria+-total reticulocytes was significantly higher in SS patients (25.0% ± 13.2%) compared to AA healthy donors (11.9% ± 8.

然而，cf 线粒体 DNA 的水平与红细胞中线粒体的保留无关，这表明检测到的 cf 线粒体 DNA 并不完全来自红细胞，而很可能来自中性粒细胞等其他循环细胞。这一假设得到了 Caielli 等人研究的支持，他们的研究表明中性粒细胞在体外释放 cf 线粒体 DNA 的能力与 NETs 的形成或坏死无关。我们认为线粒体的异常保留与患者的溶血状态有关，与炎症指标无关：概念化。Laetitia Claer、Karim Dorgham、Mariano A. Ostuni、Sandrine Laurance、Marc Romana、Maryse Etienne-Julan：概念化：方法论。Sandrine Laurance、Marc Romana、Mariano A. Ostuni、Caroline Le Van Kim、Maryse Etienne-Julan：方法：验证桑德琳-劳伦斯、马克-罗曼纳、马里亚诺-A-奥斯图尼、莱亚-库兹尼基、莱蒂西亚-克莱尔：形式分析：形式分析Lea Kuznicki、Laetitia Claer、Karim Dorgham、Marie-Dominique Hardy-Dessources、Sylvie Ravion、Yohann Garnier、Vanessa Tarer、Benoit Tressières、Sophie D. Lefevre：调查。Karim Dorgham、Maryse Etienne-Julan、Veronique Baccini：资源Sandrine Laurance、Marc Romana、Laetitia Claer、Lea Kuznicki、Mariano A. Ostuni、Caroline Le Van Kim、Maryse Etienne-Julan：数据整理桑德琳-劳伦斯、马克-罗曼纳：撰写原稿。Sandrine Laurance、Marc Romana、Mariano A. Ostuni、Caroline Le Van Kim、Maryse Etienne-Julan、Lea Kuznicki、Laetitia Claer：写作审阅和编辑。Sandrine Laurance、Marc Romana、Maryse Etienne-Julan：项目管理Sandrine Laurance、Marc Romana、Caroline Le Van Kim：项目管理：作者声明无利益冲突。这项工作得到了法国国家健康与医学研究院（Inserm）和GR-Ex卓越实验室的支持。

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引用次数: 0

Abstract Book 摘要手册

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-10-24 DOI: 10.1002/hem3.70012

Alex F. Herrera1, Michael Leblanc2, Sharon M. Castellino3, Hongli Li2, Sarah Rutherford4, Andrew Evens5, Kelly Davison6, Angela Punnett7, Susan K. Parsons8, Sairah Ahmed9, Carla Casulo10, Nancy L. Bartlett11, Joseph Tuscano12, Matthew Mei1, Brian Hess13, Ryan Jacobs14, Hayder Saeed15, Pallawi Torka16, Boyu Hu17, Craig H. Moskowitz18, Supreet Kaur19, Gaurav Goyal20, Christopher Forlenza16, Andrew Doan21, Adam Lamble22, Pankaj Kumar23, Saeeda Chowdury24, Brett Brinker25, Namita Sharma26, Avina Singh27, Kristie Blum28, Anamarija Perry29, Alexandra Kovach21, David Hodgson30, Louis Constine10, Lale Kostakoglu31, Anca Prica30, Hildy Dillon32, Richard F. Little33, Margaret A. Shipp34, Michael Crump30, Brad S. Kahl11, John Leonard4, Sonali Smith35, Kara M. Kelly36, Jonathan W. Friedberg101City of Hope, 2SWOG Statistics and Data Management Center, 3Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, 4Weill Cornell Medicine, 5Rutgers Cancer Institute of New Jersey, 6McGill University Health Center, 7SickKids Hospital, 8Tufts Medical Center, 9MD Anderson Cancer Center, 10University of Rochester, 11Washington University in St. Louis, 12UC Davis, 13Medical University of South Carolina, 14Levine Cancer Institute, 15Moffitt Cancer Center, 16Memorial Sloan Kettering Cancer Center, 17Huntsman Cancer Institute, University of Utah, 18University of Miami, 19University of Texas at San Antonio, 20University of Alabama at Birmingham, 21Children's Hospital of Los Angeles, 22Seattle Children's Hospital, 23Illinois Cancer Care, 24Prisma Health Cancer Institute, 25Cancer & Hematology Center, 26Geisinger Community Medical Center, 27Fairview Ridges Hospital, 28Emory University, Winship Cancer Institute, 29University of Michigan, 30Princess Margaret Cancer Centre, 31University of Virginia, 32SWOG Cancer Research Network, 33National Cancer Institute, 34Dana-Farber Cancer Institute, 35University of Chicago, 36Roswell Park Comprehensive Cancer CenterFigure 1: Progression-Free Survival in in Modified Intent-to-treat Analysis Set.<b

Alex F. Herrera1、Michael Leblanc2、Sharon M. Castellino3、Hongli Li2、Sarah Rutherford4、Andrew Evens5、Kelly Davison6、Angela Punnett7、Susan K. Parsons8、Sairah Ahmed9、Carla Casulo10、Nancy L. Bartlett11、Joseph Tuscano12、Matthew Mei1、Brian Hess13、Ryan Jacobs14、Hayder Saeed15、Pallawi Torka16、Boyu Hu17、Craig H. Moskowitz18、Supreet Kaur19、Gaurav Goyal20、Christopher Forlenza16、Andrew Doan21、Adam Lamble22、Pankaj Kum23、Saeeda Chowdd.莫斯科维茨18、Supreet Kaur19、Gaurav Goyal20、Christopher Forlenza16、Andrew Doan21、Adam Lamble22、Pankaj Kumar23、Saeeda Chowdury24、Brett Brinker25、Namita Sharma26、Avina Singh27、Kristie Blum28、Anamarija Perry29、Alexandra Kovach21、David Hodgson30、Louis Constine10、Lale Kostakoglu31、Anca Prica30、Hildy Dillon32、Richard F．Little33、Margaret A. Shipp34、Michael Crump30、Brad S. Kahl11、John Leonard4、Sonali Smith35、Kara M. Kelly36、Jonathan W. Friedberg101City of Hope.Friedberg101City of Hope、2SWOG 统计与数据管理中心、3Aflac 癌症与血液疾病中心、亚特兰大儿童医疗中心、4Weill Cornell Medicine、5Rutgers Cancer Institute of New Jersey、6McGill University Health Center、7SickKids Hospital、8Tufts Medical Center、9MD Anderson Cancer Center、10University of Rochester、11Washington University in St.12戴维斯大学、13南卡罗来纳医科大学、14莱文癌症研究所、15莫菲特癌症中心、16纪念斯隆-凯特琳癌症中心、17犹他大学亨茨曼癌症研究所、18迈阿密大学、19德克萨斯大学圣安东尼奥分校、20阿拉巴马大学伯明翰分校、21洛杉矶儿童医院、22西雅图儿童医院、23伊利诺伊癌症护理中心、24普利斯玛健康癌症研究所、25癌症与坎普；血液学中心、26Geisinger Community Medical Center、27Fairview Ridges Hospital、28Emory University, Winship Cancer Institute、29University of Michigan、30Princess Margaret Cancer Centre、31University of Virginia、32SWOG Cancer Research Network、33National Cancer Institute、34Dana-Farber Cancer Institute、35University of Chicago、36Roswell Park Comprehensive Cancer Center 图 1：图 1：修正意向治疗分析集中的无进展生存期。背景：在晚期（AS）典型霍奇金淋巴瘤（cHL）的一线治疗中纳入布仑妥昔单抗韦多汀（BV）可改善儿童和成人患者（pts）的预后。我们假设，在AS cHL治疗中，引入PD-1阻断与尼妥珠单抗联合多柔比星、长春新碱和达卡巴嗪（N-AVD）将比BV-AVD改善无进展生存期（PFS），并在随机3期S1826研究中评估了这种方法。早期结果表明，N-AVD 在无进展生存期方面具有优势；在此，我们提供了中位随访 2 年（y）的最新数据：符合条件的患者年龄≥12岁，患有3-4期cHL。根据年龄、国际预后评分（IPS）和放疗意向（RT），患者按1:1随机分配到6个周期的N-AVD或BV-AVD。BV-AVD需要使用G-CSF，而N-AVD则不需要。在预先指定的患者中，允许对治疗结束 PET 上残留的代谢活跃病灶进行 RT。研究人员采用2014年卢加诺分类法评估反应和疾病进展。主要终点是PFS；次要终点包括安全性、无事件生存期（EFS）、患者报告结果和总生存期：994例患者于19年9月7日至5月22日期间入组，随机接受N-AVD（496例）或BV-AVD（498例）治疗。符合条件的患者有 970 人，组成了修改后的意向治疗队列。中位年龄为 27 岁（范围为 12-83 岁），56% 的患者为男性，76% 为白人，12% 为黑人，13% 为西班牙裔。24%的患者年龄为 18 岁，10%的患者年龄为 60 岁，32%的患者 IPS 为 4-7。各组中只有 7 例（0.7%）患者接受了 RT 治疗。中位随访时间为 2.1 年，N-AVD 的 PFS 优势持续存在（HR 0.45，95% CI 0.3-0.65，双侧 p <0.001），N-AVD 治疗后 2 年的 PFS 为 92%，而 BV-AVD 治疗后为 83%。所有年龄、分期、IPS亚组的PFS获益情况一致。N-AVD 后的 EFS 也有所改善。BV-AVD 观察到 14 例死亡，而 N-AVD 观察到 7 例死亡。除中性粒细胞减少症和关节痛外，几乎所有不良事件在BV-AVD后都更常见，包括外周感觉神经病变（任何级别，29% N对56% BV）。两组患者的发热性中性粒细胞减少症和感染率相似，肺炎、结肠炎、胃炎和皮疹的发生率也相似：结论：与BV-AVD相比，N-AVD在青少年和成人AS cHL患者中的耐受性更好，PFS也有所改善。更长时间的随访证实了N-AVD在2年后的PFS获益，包括预先指定的亚组。N-AVD是治疗AS cHL的新标准。 Friedberg3、Andrea Gallamini4、Massimo Federico5、Eliza Hawkes6、David Hodgson7、Peter Johnson8、Eric Mou9、Kerry Savage10、Pier Luigi Zinzani11、Andrew Evens121美国明尼苏达州罗切斯特市梅奥诊所、2 美国马萨诸塞州波士顿塔夫茨医学中心，3 美国纽约罗切斯特大学医学中心，4 意大利尼斯安托万-拉卡萨涅癌症中心，5 意大

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引用次数: 0

Long-term outcome of 2-year survivors after allogeneic hematopoietic cell transplantation for acute leukemia 急性白血病异基因造血细胞移植后两年幸存者的长期预后。

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-10-22 DOI: 10.1002/hem3.70026

Marion Larue, Myriam Labopin, Thomas Schroeder, Xiao-jun Huang, Igor W. Blau, Johannes Schetelig, Arnold Ganser, Rose-Marie Hamladji, Wolfgang Bethge, Nicolaus Kröger, Gerard Socié, Urpu Salmenniemi, Henrik Sengeloev, Bhagirathbhai Dholaria, Bipin N. Savani, Arnon Nagler, Fabio Ciceri, Mohamad Mohty

Information on late complications in patients with acute leukemia who have undergone allogeneic hematopoietic cell transplantation (HCT) is limited. We performed a left-truncated analysis of long-term survival in patients with acute leukemia who were alive and disease-free 2 years after HCT. We included 2701 patients with acute lymphoblastic leukemia (ALL) and 9027 patients with acute myeloid leukemia (AML) who underwent HCT between 2005 and 2012. The 10-year overall survival (OS) rate was 81.3% for ALL and 76.2% for AML, with the main causes of late mortality being relapse (ALL-33.9%, AML-44.9%) and chronic graft-versus-host disease (ALL-29%, AML-18%). At 10 years, HCT-related mortality was 16.8% and 20.4%, respectively. Older age and unrelated donor transplantation were associated with a worse prognosis for both types of leukemia. In addition, transplantation in the second or third complete remission and peripheral blood HSC for ALL are associated with worse outcomes. Similarly, adverse cytogenetics, female donor to male patient combination, and reduced intensity conditioning in AML contribute to poor prognosis. We conclude that 2-year survival in remission after HCT for acute leukemia is encouraging, with OS of nearly 80% at 10 years. However, the long-term mortality risk of HCT survivors remains significantly higher than that of the age-matched general population. These findings underscore the importance of tailoring transplantation strategies to improve long-term outcomes in patients with acute leukemia undergoing HCT.

有关接受异基因造血细胞移植（HCT）的急性白血病患者晚期并发症的信息非常有限。我们对 HCT 术后 2 年存活且无病的急性白血病患者的长期生存情况进行了左截断分析。我们纳入了 2005 年至 2012 年期间接受 HCT 的 2701 名急性淋巴细胞白血病（ALL）患者和 9027 名急性髓性白血病（AML）患者。ALL患者的10年总生存率（OS）为81.3%，AML患者为76.2%，晚期死亡的主要原因是复发（ALL-33.9%，AML-44.9%）和慢性移植物抗宿主疾病（ALL-29%，AML-18%）。10年后，HCT相关死亡率分别为16.8%和20.4%。高龄和非亲缘供体移植与两种类型白血病的较差预后有关。此外，在第二次或第三次完全缓解时进行移植以及外周血造血干细胞用于 ALL 与较差的预后有关。同样，不良细胞遗传学、女性供者与男性患者的组合以及急性髓细胞白血病的减量调理也会导致预后不良。我们的结论是，急性白血病造血干细胞移植后的2年缓解期生存率令人鼓舞，10年的OS接近80%。然而，HCT 幸存者的长期死亡风险仍明显高于年龄匹配的普通人群。这些发现强调了调整移植策略以改善接受 HCT 的急性白血病患者长期预后的重要性。

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引用次数: 0

Casting light on the national mission to eliminate sickle cell disease in India 揭示印度消除镰状细胞病的国家使命

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-10-19 DOI: 10.1002/hem3.70033

Frédéric B. Piel, Roshan Colah, Dipty L. Jain

Sickle cell disease (SCD) is a neglected global public health burden.1 Although it primarily affects populations from sub-Saharan Africa,2 SCD is also prevalent across the Indian subcontinent, particularly among tribal (or scheduled) populations.3 India is the most populated country in the world. According to the latest population estimates of the United Nations World Population Prospects,4 its population includes 1.441 billion people, and it is expected to further increase to reach 1.697 billion in 2063. India ranks as the country with the third highest number of annual births affected by SCD, after Nigeria and the Democratic Republic of the Congo.2 Although SCD has long been considered to be mild across the Indian subcontinent, recent evidence has demonstrated that there was a much wider range of severity than previously thought.5 Finally, tribal populations tend to be largely over-represented in the low socio-economic groups across India, making them a vulnerable group for many communicable and non-communicable diseases.6Interventions to reduce SCD morbidity and mortality, such as newborn screening, vaccinations, penicillin prophylaxis, and hydroxyurea, have proven to be effective in large-scale studies in high- and upper-middle-income countries, including the United States,7 United Kingdom,8 Jamaica,9 and Brazil.10 Pilot studies of these interventions have been conducted in numerous low-income countries.11 Cost-benefit analyses conducted in sub-Saharan Africa12 and India13 suggested that these interventions would also be effective in these settings. Nevertheless, due to a lack of political and financial commitments, no national program has so far been launched in a low- or lower-middle-income country of high prevalence for SCD. Despite the curative promises of gene therapies,14 there is an urgent need to scale up interventions in the most affected countries to improve the quality of life of patients affected and reduce the global burden of SCD.11In July 2023, the Government of India launched the “National Sickle Cell Anaemia Elimination Mission.”15 Although this program was officially launched by Prime Minister Modi, it did not receive much attention internationally. The stated aims of the Mission are twofold: (i) to improve the care of all SCD patients for their better future and (ii) to lower the prevalence of the disease by 2047 through a multifaceted coordinated approach toward screening and awareness strategies. The ambitious plan at launch was to screen 70 million people across India over the first 3 years of the Missio

镰状细胞病（SCD）是一种被忽视的全球公共卫生负担。1 虽然镰状细胞病主要影响撒哈拉以南非洲地区的人口，2 但它在印度次大陆也很普遍，尤其是在部落（或在册人口）中。3 印度是世界上人口最多的国家。根据联合国《世界人口展望》4 的最新人口估计，印度人口为 14.41 亿，预计到 2063 年将进一步增至 16.97 亿。2 虽然长期以来人们一直认为印度次大陆的 SCD 病情较轻，但最近的证据表明，其严重程度的范围比以前想象的要大得多。5 最后，印度各地的部落人口往往在社会经济地位较低的群体中占很大比例，这使他们成为许多传染性和非传染性疾病的易感人群。在美国、7 英国、8 牙买加9 和巴西10 等高收入和中上收入国家进行的大规模研究证明，新生儿筛查、疫苗接种、青霉素预防和羟基脲等降低 SCD 发病率和死亡率的干预措施是有效的。然而，由于缺乏政治和财政承诺，迄今为止还没有一个国家在 SCD 高发的低收入或中低收入国家启动国家计划。11 2023 年 7 月，印度政府启动了 "消除镰状细胞性贫血国家使命"（National Sickle Cell Anaemia Elimination Mission）15 。尽管该计划由莫迪总理正式启动，但在国际上并未引起广泛关注。该计划的既定目标有两个：(i) 改善对所有镰状细胞性贫血患者的护理，让他们拥有更美好的未来；(ii) 到 2047 年，通过多方面协调的筛查和宣传策略，降低该疾病的患病率。启动之初的雄心勃勃的计划是在该计划的头 3 年对全印度 7000 万人进行筛查。该计划推荐的筛查方法是溶解度镰状试验（阳性病例需经黄金标准高效液相色谱法（HPLC）确认）或近十年来出现的快速护理点检测（POCT）设备。溶解度检测无法区分镰状细胞性病（SCD）的同基因型患者（SS）和镰状细胞性状（SCT）的异基因型患者（AS）。此外，在用于新生儿筛查时，由于存在大量胎儿血红蛋白（HbF），当 HbS 占总血红蛋白的比例低于 10%时，假阴性率很高。因此，在高收入国家，溶解度检测往往只用于紧急筛查。高效液相色谱法（HPLC）验证往往成本高昂，依赖于技术精湛的工作人员、需要定期维护的精密设备和可用试剂。因此，可能没有系统地进行确证试验来验证溶解度镰状试验的结果。POCT 设备有可能提供一种有前途的替代方法，尤其是在大城市以外的地区。16 目前的 POCT 通常可以区分 SCD 和 SCT，但不能鉴别镰状细胞-β地中海贫血。最近开发的 GazelleTM 设备旨在解决这一局限性。17 一些 POCT 设备（如 SickleScanTM 或 HemoTypeSCTM）的灵敏度和特异性已在严格的国内18、19 和国际研究中得到验证。虽然印度医学研究理事会 (ICMR) 已对几种筛查方法进行了正式验证，但样本量相对较小，而且有几种检测方法声称其敏感性和特异性均为 100%。目前迫切需要采用国际公认的标准协议对这些方法进行独立验证，特别是对 POCT 设备进行独立验证。鉴于已确认的 SCD 患者需要接受治疗，在当地生产羟基脲（目前用于预防 SCD 并发症的主要药物）也产生了类似的影响。截至 2024 年 9 月 17 日，印度全国共筛查了 42,139,843 人，其中 163,765 人被确定为 SCD（0.39%），1,144,274 人被确定为 SCT（2.72%）（表 1）。另有 398,628 人（0.95%）的筛查结果显示仍在确认过程中。该仪表板没有提供地区或种族细分，但这些初步数据为了解该计划在印度的规模提供了宝贵的信息。22 该计划启动仅 1 年多，筛查人数已超过 4200 万。相比之下，这一数字是美国新生儿普遍筛查计划每年检测人数（约 360 万）的 10 倍以上，是英国新生儿普遍筛查计划每年检测人数（约 60 万）的 70 倍。这项计划的规模意味着，平均每天都有将近 400 例新的 SCD 病例可能被特派团发现。这大致相当于英国一年中新发现的受影响新生儿数量。此外，每天还能发现约 2500 名携带者。虽然从临床角度来看，这些人并不值得关注，但他们与 SCD 的未来负担密切相关，因此应向他们介绍该疾病，并为他们提供婚前筛查23 和遗传咨询24。对撒哈拉以南非洲成人的调查发现，由于与 SCD 相关的婴儿死亡率较高，SCD 患者的人数往往比预期的要少得多。26 虽然在印度观察到的与预期的人数之间的差异可能是由一系列复杂的因素造成的，但在印度，尤其是在部落人群中，近亲结婚的程度很高。28 尽管调查团的初步数据表明，单单预防近亲结婚就有可能使印度每年的 SCD 新生儿人数大幅减少。这也将影响包括先天性畸形在内的其他各种健康后果的发生率。29 此外，在这样一个幅员辽阔、文化多样的国家，了解文化习俗和传统至关重要，尤其是在考虑到部落人口时，他们往往被边缘化，在社会经济地位较低的群体中所占比例过高。来自英国巴基斯坦社区的证据表明，即使是在原籍国以外的多民族社区，变化也往往是几代人慢慢发生的。30 同样，沙特阿拉伯实施的强制计划也凸显了在一个人口少得多且财力雄厚的国家采取此类干预措施的复杂性。31 筛查是识别 SCD 患者并管理他们及其并发症的必要第一步。31 筛查是识别 SCD 患者并处理他们及其并发症的必要的第一步。然而，教育材料、医疗保健设施、专科人员和治疗方案的可获得性和可及性对于成功随访已识别的 SCD 患者以及理想情况下的携带者也是至关重要的。作为 "使命 "的一部分，已经用印地语和英语编写了几份指南和培训材料32 ，但目前有关其使用情况的信息很少。目前还没有关于该计划影响的公开数据，但跟踪随访率、羟基脲的使用情况、并发症发生率的变化以及对该疾病的认识是否因这一全国性举措而有所改变，将是该计划能否取得成功的关键。可靠的数据对于证明该计划的益处和确保其可持续性至关重要。在该计划实施的头 3 年，印度只有 5%的人口接受了筛查。印度全国每年约有 2500 万新生儿，因此需要在全国范围内持续努力，才能实现与美国或英国目前实施的新生儿筛查计划相当的普及计划。如果这是长期目标，就需要持续的政治意愿和财政资源。在这样一个大规模倡议中使用的词汇非常重要，需要仔细斟酌。这项任务中使用的 "消除 "一词让人联想到用于包括疟疾在内的传染病的雄心勃勃的战略。33 考虑到 SCD 的遗传性质，这一术语是令人遗憾的。应将该计划作为一个契机，以减少影响印度人口的不平等现象，并减轻整个次大陆未来的 SCD 负担，而不是进一步污名化部落人口或可能助长优生学宣传。在印度这样一个幅员辽阔、人口众多的国家，能够如此迅速地实施如此大规模的计划，实在令人惊叹。在短短一年多的时间里，就有 4000 多万人接受了筛查，治疗一种在很大程度上被忽视的疾病，这是一项了不起的成就，值得庆祝。然而，还需要制定严格的程序，以确保筛查设备和方案符合国际标准，并在全国范围内始终如一地遵循指导方针，从而产生高质量的流行病学数据。特派团在国内和国际上的公信力有赖于可靠的数据。还需要进行成本效益分析，以证明这一举措的影响。最后，这项任务的成功对于证明在撒哈拉以南非洲国家实施大规模 SCD 计划的可行性具有重要意义。Frédéri

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引用次数: 0

Promoting and supporting leadership in hematology departments 促进和支持血液科的领导能力

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-10-17 DOI: 10.1002/hem3.70028

Roch Houot, Emmanuel Gyan

In recent years, the hospital system has faced tremendous pressure from economic and societal crises, which were further aggravated by the COVID-19 pandemic. Today, the European healthcare system is in a continuous crisis, primarily due to underinvestment and workforce shortages.1 In such a situation, management skills at all levels of hospital departments become critical, especially for heads of departments—a position historically driven in many countries, including France, by academic rather than managerial competencies.Challenges with medical staff retention have also exacerbated the workload of healthcare professionals.2 The shortage of healthcare workers in Europe is projected to reach 4.1 million by 2030, including 0.6 million physicians.3 Workforce shortages contribute to burnout among physicians and other healthcare workers, which renders the tasks of heads of departments extremely challenging.4, 5In the past two decades, the practice of hematology has experienced accelerated advancements in diagnostics and therapeutics, with notable prolongation of patient survival, albeit at the cost of intensified medical care due to the novel time-consuming therapeutic approaches. As such, the diversity of hematologic diagnoses and specialized treatments have created an expanding curriculum with ever more limited human resources.2, 6 The number of hematologic specialists and the competence of their training have become a concern in European countries.6The European Hematology Association (EHA) has created solutions for training in hematology, including the European Hematology curriculum, developed through a “bottom-up” process, which has inspired national educational initiatives.6 The European Working Time Directive (EWTD), introduced in 2004, aims to reduce long working hours to enhance patient safety. In this context, the European Commission urged member states to adopt the EWTD for hospital physicians.2 However, these initiatives create challenges for department heads, who must manage increased workloads with limited staffing and heightened awareness of the adverse effects of inadequate organization on workers' health.In a recent survey conducted with 2390 university hospital faculty members in France between October and December 2021, 40% of participants had severe burnout, 14% had suicidal ideation, and 12% had job strain.4 The factors associated with the unfavorable experiences included heavy work overload, work-life imbalance, and perceived lack of support from the institution.4, 7 Although the impact of stressful events on the risk of burnout and suicide is undeniable, many personality traits, such as emotional stability, extraversion, and social integration, play a role.<

法国血液科主任团体的目标是提高管理技能，从根本上重建医疗系统。这一举措符合法国政府的决定，即在医疗部门建立更多的自主权，使科室主任成为医院管理的核心。11 这反过来又意味着，受过管理培训的科室主任除了承担临床和学术职责外，还要准备好参与医院所需的多方利益相关者组织。科室主任对科室的内部结构和医疗团队的工作生活质量做出了巨大贡献，并在组织、相关性、医疗质量和安全、医疗和辅助医疗团队的本地管理以及研究员和医学生的管理等方面构成了参考水平。2 例如，靶向疗法和免疫疗法的成功彻底改变了各种血液病的治疗格局，改善了患者的预后，包括延长了生存期。因此，血液病学家面临着新的挑战，需要持续研究、多学科合作和专业知识，以优化患者预后，确保在临床实践中安全有效地使用这些疗法。考虑到新型疗法的复杂性和癌症幸存者人数的增加，医生的职业负担也在加重。13 随着优秀的医生离开公立医院，加入经济待遇更好、条件更优越的其他医院，血液科也面临着人员短缺的问题。2 有必要采取措施，增加对医疗系统或医院预算的投资，以留住并吸引医疗专业人员，从而抵消临床负担过重的影响。另一项举措包括将耗时的任务委托给非医务人员，包括实验室的生物医学科学家和临床护理专家，如英国国民健康服务所做的那样。专业协会和社区的干预措施在预防和管理个人负担加重方面发挥着重要作用。已发表的研究强调了职业倦怠在欧洲肿瘤学家中的普遍性，并在国家和国际大会上加强了宣传活动，13 欧洲血液学协会正在解决年轻血液学家中的这一问题。15 必须收集欧洲各年龄段血液学家中职业倦怠普遍性的数据，以呼吁投资采取措施，使血液学成为对年轻和资深医生都有吸引力的领域。然而，这与现实相去甚远。为此，有必要自下而上地重建医院系统，以适应行政管理的变化。参与支持性网络，如我们正在建立的社区，可以分享经验和学习机会。这个由血液科负责人组成的社区是提供管理支持的有力工具。鉴于这种社区的个人和组织主动性，我们鼓励其他专业科室的负责人积极参与社区建设，自下而上地为医院组织、结构和功能的重建做出贡献。同样，与欧洲其他国家的科室负责人进行这种交流，也必将有助于分享不同的护理和组织模式，从而相互启发。

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引用次数: 0

Overcoming a T-ALL order: A comprehensive study linking genomics to clinical outcomes 战胜 T-ALL 订单：将基因组学与临床结果联系起来的综合研究

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-10-13 DOI: 10.1002/hem3.70027

Yizhou Huang, Charles E. de Bock

Acute lymphoblastic leukemia (ALL) remains a leading success story of how modern therapies have improved patient outcomes from less than 10% survival rate in the 1950s to exceeding 90% today. This has been in part from the decades of research in the optimal use of chemotherapeutics, and, for B-cell ALL (B-ALL), the implementation of risk stratification based on clinical factors (e.g., age and peripheral blood cell counts), minimal/measurable residual disease (MRD), and cytogenetics (favorable, neutral, or unfavorable). However, for T-cell ALL (T-ALL), risk stratification is currently only based on MRD levels at the end of induction and again at the end of consolidation therapy with genomics and cytogenetics not considered prognostic factors in treatment decision-making.1 In an effort to include genomics into the risk stratification for T-ALL, a new study led by Charles Mullighan and David Teachey2 has now been published as a landmark analysis of 1300 uniformly treated T-ALL cases that, for the first time, not only defines a total of 15 discrete genetic subtypes but also links them to clinical outcomes.This new study integrates whole genome sequencing (WGS), whole exome sequencing (WES), and whole transcriptome sequencing data to expand the classification of T-ALL into a total of 15 different subtypes (Figure 1). The most significant variation from the current classification is the definition of two new subtypes, including a new early T-cell precursor (ETP)-like ALL subtype and an LMO2 γδ-like subtype—both of which have a diverse set of genetic alterations. Of the many genetic alterations, an interesting discriminator is the KMT2A fusions present in the ETP-like subtype being mostly KMT2A::AFDN fusion, while the non-ETP subtypes exclusively have KMT2A::MLLT1 fusion. The authors also compared the gene expression signatures of all 15 subtypes with normal hematopoietic and T-cell development cell stages. They found that the different T-ALL subtypes mapped across the entire continuum of T-cell development, supporting the hypothesis that each subtype represented a “frozen” stage of cellular differentiation. In the case of the ETP-like subtype, despite the heterogenous genetic drivers, the most likely cell of origin was found to be hematopoietic stem and progenitor cells (HSPC).It will come as no surprise that this study confirms the high frequency of recurrent NOTCH1 mutations (69% of cases) in T-ALL, second only to CDKN2A alterations (71% of cases), with the majority being coding sequence mutations that lead to activation of NOTCH1 signaling. However, this study also found rare single-nucleotide variants (SNV) within intron 28 of the NOTCH1 gene which generated a new splice acceptor site and resulted in a 43 amino acid insertion between the heterodimerization (HD) domain and the transmembrane (TM) domain of NOTCH1. Functionally, this new mutation

一个有趣的发现是，对于 KMT2A 基因重排的患者，亚型背景对临床结果和风险分组至关重要。例如，ETP 样和 KMT2A 亚型 T-ALL 患者被列为 "极高风险"，而非 ETP 样和 KMT2A 亚型患者则被列为 "低风险"。SPI1 亚型也很有趣，因为虽然被归类为 "极高风险"，但他们更有可能是 MRD 阴性。他们的不良预后部分是由于发生了同样携带 SPI1 融合体的继发性恶性肿瘤。最近发现，携带 SPI1 融合的 T-ALL 病例对达沙替尼高度敏感。因此，这项新研究显示，携带 SPI1 融合基因的患者极易发展为继发性恶性肿瘤，因此在治疗中可以考虑尽早使用达沙替尼，尽管激酶抑制剂的使用是否会改变 T-ALL 克隆和继发性恶性肿瘤的发展轨迹还有待观察。那么，这项新研究如何改变新诊断的 T-ALL 患者的管理，这种新的风险分层是否可以前瞻性地使用？令人欣慰的是，作者在开发这些风险模型时考虑到了临床转化，因此可以通过重点选择的特征对新的 T-ALL 患者进行分层。因此，如果前瞻性地应用这些模型，被归类为 "极高风险 "的患者可以快速进行骨髓移植。相反，对于 "低风险 "患者（如 MRD 阴性、非 ETP-like KMT2A 亚型），可以降低强化化疗的强度，或引入无治疗间隔期。这些方法可能有助于控制化疗的毒副作用，潜在地改善患者的生活质量，而不会对临床结果产生不利影响（图1）。这项研究为研究T-ALL生物学的研究人员提供了大量新信息，也为临床医生提供了大量新信息，有助于在获得下一代测序数据后管理患者。不久前的2017年，在比利时鲁汶的一次小型会议上，查尔斯-穆利根（Charles Mullighan）展示了总共264例T-ALL病例的转录组和WES数据。查尔斯的回答是："当然。我们的研究才刚刚起步。我们相信，如果再问主要作者同样的问题，他们的回答很可能不会改变。黄一舟和Charles E. de Bock都得到了国家健康与医学研究委员会（NHMRC）Ideas Grant 2029411的资助。本出版物未获得任何资助。

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引用次数: 0

Outcomes and prognostic factors in 3306 patients with relapsed/refractory chronic lymphocytic leukemia treated with ibrutinib outside of clinical trials: A nationwide study 在临床试验之外接受伊布替尼治疗的 3306 例复发/难治性慢性淋巴细胞白血病患者的疗效和预后因素：一项全国性研究。

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-10-08 DOI: 10.1002/hem3.70017

Gian Matteo Rigolin, Pier Paolo Olimpieri, Valentina Summa, Simone Celant, Lydia Scarfò, Maria Pia Ballardini, Antonio Urso, Silvia Gambara, Francesco Cavazzini, Paolo Ghia, Antonio Cuneo, Pierluigi Russo

We performed a cohort study that included all patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) who received ibrutinib in the Italian National Health Service. With a median follow-up of 42.2 months (IQR 30.8–54.6 months), the study involved 3306 patients with a median age of 72.1 years, of whom 42.6% had received ≥2 previous lines of treatment. The estimated 24-month probabilities of being on treatment and alive were 57.9% (95% confidence interval [CI]: 59.6–56.2) and 76.6% (95% CI: 75.2–78.1), respectively. The median time to treatment discontinuation (TTD) was 31.3 months (95% CI: 29.5–33.5). Out of 3306 patients, 2015 (60.9%) discontinued treatment, with 993 cases attributed to death or disease progression (30.0% of all cases). Among the 1022 patients who discontinued treatment for reasons other than progression or death, 564 (17.1%) patients did so due to toxicity or medical decision, while 458 patients (13.8%) were lost to follow-up. Multivariable analysis revealed that age, Eastern Cooperative Oncology Group Performance Status, the number of previous lines of therapy, refractoriness to the last treatment, and reduced renal function were associated with shorter TTD and overall survival (OS). The coexistence of 17p− and TP53 mutations had an independent unfavorable impact on TTD and OS. Nonstandard doses were associated with shorter TTD and advanced stage with shorter OS. The median OS postprogression and postdiscontinuation for other reasons were estimated at 12.9 (95% CI: 11.3–16.2) and 22.7 months (95% CI: 20.2–28.3), respectively. This large real-world study shows that ibrutinib is an effective treatment for R/R CLL. Baseline patient characteristics and double-hit TP53 aberrations were associated with inferior prognosis, and discontinuation due to CLL progression portended a poor outcome.

我们开展了一项队列研究，纳入了意大利国家医疗服务机构所有接受伊布替尼治疗的复发/难治性慢性淋巴细胞白血病（R/R CLL）患者。该研究的中位随访时间为 42.2 个月（IQR 30.8-54.6 个月），共涉及 3306 名患者，中位年龄为 72.1 岁，其中 42.6% 的患者曾接受过≥2 次治疗。估计24个月内接受治疗和存活的概率分别为57.9%（95%置信区间[CI]：59.6-56.2）和76.6%（95%置信区间：75.2-78.1）。停止治疗的中位时间（TTD）为 31.3 个月（95% 置信区间：29.5-33.5）。在 3306 例患者中，2015 例（60.9%）中止了治疗，其中 993 例是由于死亡或疾病进展（占所有病例的 30.0%）。在因病情进展或死亡以外的原因而中断治疗的 1022 例患者中，有 564 例（17.1%）患者是由于毒性或医疗决定而中断治疗，另有 458 例（13.8%）患者失去了随访机会。多变量分析显示，年龄、东部合作肿瘤学组（Eastern Cooperative Oncology Group）表现状态、既往治疗次数、对上次治疗的耐受性以及肾功能减退与较短的TTD和总生存期（OS）有关。17p基因突变和TP53基因突变同时存在对TTD和OS有不利影响。非标准剂量与较短的TTD有关，晚期与较短的OS有关。进展后和因其他原因停药后的中位OS估计分别为12.9个月（95% CI：11.3-16.2）和22.7个月（95% CI：20.2-28.3）。这项大型真实世界研究表明，伊布替尼是治疗R/R CLL的有效方法。基线患者特征和双击TP53畸变与不良预后有关，因CLL进展而停药预示着不良预后。

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引用次数: 0