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Long-term genetic and clinical remissions after cessation of azacitidine treatment in patients with VEXAS syndrome VEXAS 综合征患者停止阿扎胞苷治疗后的长期遗传和临床缓解。

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-07-30 DOI: 10.1002/hem3.129

Anna M. Aalbers, Paul L. A. van Daele, Virgil A. S. H. Dalm, Peter J. M. Valk, Marc H. G. P. Raaijmakers

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an inflammatory syndrome caused by acquired mutations in the gene encoding ubiquitin like modifier activating enzyme 1 (UBA1) that is often fatal.1, 2 Allogeneic hematopoietic stem cell transplantation is currently considered the only curative treatment modality.3-6 We were the first to report eradication of virtually all UBA1-mutated cells by the hypomethylating agent azacitidine, reflected in clinical and genetic remissions,7 a finding confirmed in a recent phase II clinical trial.8Here, we report persistent, long-term (11–84 months) genetic and clinical remissions in VEXAS patients responding to treatment with the hypomethylating agent azacitidine, after cessation of therapy. The data indicate that azacitidine treatment may be an attractive alternative to stem cell transplant for disease eradication in VEXAS syndrome patients and reveal long-term clonal stability of UBA1-mutated cells under homeostatic and inflammatory conditions.Since its first description in December 2020,1 a UBA1 variant-confirmed diagnosis of VEXAS syndrome was made in 11 patients at our institution until February 2024 (all male, median age at diagnosis 67 years, range 57–77 years). UBA1 mutation detection and panel-based sequencing in these patients was performed as previously reported7 and as described in the Supporting Information Methods section. Of these 11 patients, eight have been exposed to azacitidine (administered at a dose of 75 mg/m2 subcutaneously once daily for 7 days in a 4-weekly schedule). Of the three patients that were not exposed to azacitidine, two patients were treated with corticosteroids and deceased due to infectious complications, and one patient was considered not a candidate for azacitidine treatment due to psychosocial circumstances. In two patients, azacitidine was used as a last resort on an in-house basis, after failure of multiple other lines of treatment, at the time that patients were critically ill (WHO performance status 4) due to VEXAS-related (respiratory) pathology. Both patients died shortly after administration of the first cycle of azacitidine with clinically active disease, and before genetic assessment of response after the first cycle. Six patients received multiple cycles of azacitidine (range, 3–8 cycles) on an out-patient basis with genetic monitoring of disease response. The characteristics of these six patients are listed in Table 1. Patients 1 and 2 carried a concurrent DNMT3A mutation at diagnosis with a variant allele frequency (VAF) of 59% and 30%, respectively, and patient 3 carried a TET2 mutation with a VAF of 4%. In patients 4, 5, and 6 no other mutations were detected by panel-based sequencing. Three of these six patients have bee

遗传学缓解表明 UBA1 突变细胞的数量急剧减少，与临床完全缓解有关，临床完全缓解的定义是疾病完全没有炎症复发，这体现在这些患者血浆中的 C 反应蛋白（CRP）长期恢复正常，以及所有患者的血红蛋白水平都有所提高（图 1）。所有应答患者均可停用所有其他免疫调节药物（如皮质类固醇、DMARDs 和/或托西珠单抗）。在临床和基因应答后进行骨髓评估的三名患者中，红细胞和髓系前体细胞的特征性空泡化以及红细胞、髓系和/或巨核细胞系的发育不良均已消失。被认为对阿扎胞苷无反应的患者（患者 3）共接受了三个周期的阿扎胞苷治疗，之后骨髓中的突变 UBA1 VAF 仍然很高（VAF 84%）。TET2 VAF 在治疗前后保持相似（分别为 4% 和 3%）。生活质量和贫血没有改善。当时，VEXAS 的临床症状相对较轻，因此停止了治疗，现在回想起来，这可能对实现基因缓解来说为时过早。在五名有应答的患者中，阿扎胞苷治疗在实现基因应答（任意定义为突变 UBA1 VAF <5%）后停止。1号患者在8个周期后因结肠癌治疗而停止治疗，另外两名患者在4个周期后出现应答，决定中断/停止治疗的原因是2-3级不良反应（疲劳和中性粒细胞减少），以及在1号患者中观察到停药后基因缓解仍可维持。其余两名有反应的患者在最近（2024 年 5 月提交本稿件时）五个周期后获得了临床和基因定义的反应（患者 5 突变 UBA1 的 VAF 从 75% 降至 0%，患者 6 突变 UBA1 的 VAF 从 56% 降至 0%），根据临床和基因反应以及之前其他患者停用阿扎胞苷的经验，在第五个周期后停止了阿扎胞苷治疗。在停止阿扎胞苷治疗后，前三例应答患者（停止治疗后进行了随访）的临床和遗传学症状均得到缓解，目前的中位随访时间为阿扎胞苷治疗最后一个周期后的31个月（11-84个月）（图1）。患者仍无任何与 VEXAS 相关的炎症表现，血药浓度保持稳定正常。在多年的中位随访期间，所有患者血液中的突变 UBA1 VAF 均保持相对稳定（范围为 0%-7%）。在 7 年的随访过程中，我们确实观察到患者 1 的突变 UBA1 VAF 逐渐增加（从 1%增至 7%）。更令人感兴趣的是，突变型 UBA1 VAF 并没有受到炎症发作的明显影响，炎症发作包括空肠弯曲杆菌 PCR 阳性的胃肠炎（患者 1）和晶体证明的痛风发作（患者 2），前者需要住院治疗（图 1）。总之，这些研究结果证实，正如我们和其他人之前所报道的那样，VEXAS 综合征患者对阿扎胞苷治疗的反应率相对较高7-10 ，更重要的是，这些研究结果表明，在获得基因应答后，可以安全地停用阿扎胞苷，从而获得长期的基因和临床缓解。这具有重要的临床意义，因为这将使阿扎胞苷治疗成为干细胞移植的一种有吸引力的替代疗法，而干细胞移植是目前唯一可用于VEXAS综合征患者的长期根除疾病的治疗方法。此外，停止阿扎胞苷治疗将保护患者免受该药物经常出现的不良反应，包括疲劳、骨髓抑制和感染并发症，从而影响生活质量。这些数据表明，在今后研究阿扎胞苷治疗 VEXAS 综合征价值的前瞻性临床试验中，应采用药物中断（"假日"）设计。迄今为止，阿扎胞苷根除UBA1突变细胞的机制尚不清楚，但可以假设泛素蛋白酶体系统的缺陷使细胞对这种药物敏感。最后，研究结果可能会对疾病的生物学特性和突变UBA1克隆的长期动力学产生新的启示，证明它们可以保持稳定多年，甚至在老年患者中也是如此。

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引用次数: 0

Disease-burden-adapted immunotherapy protocol for primary refractory or high-risk relapsed pediatric acute lymphoblastic leukemia 针对原发性难治性或高危复发儿科急性淋巴细胞白血病的疾病负担适应性免疫疗法方案。

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-07-29 DOI: 10.1002/hem3.111

Sanaa Khan, Krishnan VP, Yamini Krishnan, Gazel Sainulabdin, Somdipa Pal, Rincy Mathews, Darshan Kataria, Kunal Sehgal, Purva Kanvinde, Lashkari Harshaprasad, Minnie Bodhanwala, Bharat Agarwal, Ambreen Pandrowala, Prashant Hiwarkar

The survival rates for pediatric patients with primary refractory or high-risk relapsed B-cell acute lymphoblastic leukemia (r/r B-ALL), treated with chemotherapy-based protocols and followed by allogeneic hematopoietic cell transplantation (HCT), range from 15% to 30%.1 These outcomes are even more unfavorable in countries with evolving healthcare insurance systems due to treatment-related mortality and financial toxicity.2 The long-term event-free survival for such high-risk relapse of B-ALL is dependent on achieving minimal residual disease (MRD) negativity prior to HCT.3In the past decade, there have been significant advancements in targeted antibody-based immunotherapies for managing r/r B-ALL.4-11 Blinatumomab (Blina) is a T-cell engager that provides an antileukemic effect by targeting cytotoxic T cells to CD19-expressing cancer cells. Several studies have revealed the excellent efficacy of Blina in low-burden disease.4-8 However, recipients of Blina with high tumor burden have low response rates and are at risk of severe cytokine release syndrome (CRS).9 Whereas, Inotuzumab ozogamicin (InO) targets CD22, which is conjugated to calicheamicin, a potent cytotoxic agent and works well even for high-burden disease with response rates as high as 80%.10, 11To optimize the use of these novel immunotherapies in r/r B-cell ALL, we designed a disease-burden-adapted protocol of InO followed by Blina for high-burden (minimal residual disease (MRD) > 5%) CD22+ CD19+ disease and Blina only for low-burden (MRD ≤ 5%) CD19+ disease.This is a retrospective analysis of 39 patients with r/r B-cell ALL patients aged 1–18 years treated in three centers from January 2018 to August 2023. Patients were treated with a chemotherapy-based protocol from January 2018 to April 2021 and on a disease-burden-adapted immunotherapy protocol from May 2021 to August 2023.End-of-induction (EOI) MRD of >5% with high-risk cytogenetics or age >16 years and all patients with end-of-consolidation (EOC) MRD > 0.1% irrespective of age or cytogenetics were considered primary refractory. Very early relapse (<18 months from diagnosis; marrow or isolated extramedullary), early relapse (18–36 months from diagnosis or until 6 months off therapy; marrow or isolated extramedullary), and late relapse (≥36 months from diagnosis or >6 months off therapy; marrow or isolated extramedullary) with postrelapse induction MRD of ≥0.1% and second relapse with any level of disease were considered as high-risk.A fractionated dose of InO as 1.8 mg/m2 per course was administered intravenously over 1 h on Days 1, 8, and 15 of 28-day cycle as previously described.10, 11 Blina was given as a 28-day continuous intravenous infusion. The first 7 days of the f

表 1 列出了患者的人口统计学特征、白血病特征和治疗细节。8 名患者为初治难治（4 = 诱导失败，4 = 巩固治疗失败）。11名患者为高危复发白血病患者（2＝极早期，4＝早期复发，2＝晚期复发且复发后诱导MRD≥0.1%，3＝二次复发）。复发白血病患者之前接受过三种化疗方案（5 例）、两种化疗方案（5 例）或一种化疗方案（1 例）。19名患者中有5人（26%）患有髓外疾病，3人中枢神经系统阳性，2人睾丸受累。12名患者（5人=原发性难治性；7人=复发性）的MRD从0.008%到4.21%不等（图1A），均接受了Blina单药治疗。Blina周期的中位数为2个（范围：1-3）。7例患者（3例为原发性难治性患者；4例为复发性患者）的疾病负担率从5.34%到78%不等；他们接受了一个周期的InO治疗（图1A）。六名患者对 InO 有反应；三名患者 MRD 阴性，三名患者反应良好。所有六名患者都接受了布利纳巩固治疗，并达到了MRD阴性状态。18名患者（95%）在采用适应疾病负担的方案后达到了MRD阴性状态。16名患者（84%）接受了异基因造血干细胞移植。七名患者接受了单倍体捐献者的移植物，六名患者接受了匹配的非亲属捐献者的造血干细胞移植，三名患者接受了匹配的同胞捐献者的造血干细胞移植。一名患者由于移植前存在慢性副病毒血症、肠道腺病毒脱落和肥胖等高风险因素，没有HLA匹配供体，接受了自体移植。另一名患者同样没有 HLA 匹配的供体，但由于慢性副病毒血症和肠道腺病毒脱落而选择了维持性化疗。免疫治疗后中位随访424天（范围：117-914；图1B,C），有15名患者（77%；95% CI：49.5-90.6）存活并持续处于MRD阴性CR状态。相比之下，在免疫治疗前高风险复发白血病队列中，20 名患者中有一人（5%）无病，中位生存期为 93 天（图 1D；P &lt；0.0001）。免疫治疗前队列与疾病负担适应方案治疗队列的比较见佐证资料 S1：图 1。两名患者（12%）出现 1 级神经毒性，但在短暂停用 Blina 后恢复。一名接受 InO 治疗的患者出现了 1 级 CRS。迄今为止，接受 InO 治疗的六名患者接受了 HCT，只有一名患者在 HCT 期间出现了轻度 VOD，但对液体限制和利尿剂有反应。没有患者出现免疫疗法相关的3级或4级毒性。一名患者死于急性呼吸窘迫综合征，另一名患者死于早期播散性腺病毒血症。以抗体为基础的免疫疗法靶向 B 细胞抗原的替代机制为精准医疗提供了更多机会。临床试验表明，将Blina作为复发B细胞ALL HCT前的桥接方案可提高无病生存率。4-8 在中位随访2年时，接受Blina治疗的患者的无病生存率为55%-65%。我们的方案是用Blina巩固InO反应，这样可以在InO给药和移植之间留出更多时间，从而降低VOD风险。此外，在低负担疾病中完全使用 Blina 可能会降低严重 CRS 或神经毒性的风险。

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引用次数: 0

Impact of second autologous stem-cell transplantation at relapsed multiple myeloma: A French multicentric real-life study 第二次自体干细胞移植对复发多发性骨髓瘤的影响：法国多中心真实生活研究。

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-07-29 DOI: 10.1002/hem3.106

Axel André, Lydia Montes, Damien Roos-Weil, Laurent Frenzel, Marguerite Vignon, Thomas Chalopin, Pierre-Edouard Debureaux, Alexis Talbot, Agathe Farge, Fabrice Jardin, Karim Belhadj, Bruno Royer, Jean-Pierre Marolleau, Bertrand Arnulf, Pierre Morel, Stéphanie Harel

A second autologous stem-cell transplantation (ASCT2) is considered for relapsed multiple myeloma (RMM) patients showing prolonged response after a first ASCT. However, given breakthrough treatments like anti-CD38 and immunotherapy, its role remains debated. We conducted a real-life study in 10 French centers (1996–2017) involving 267 RMM patients receiving ASCT2. The median age was 61 years, with 49% females. Most patients received melphalan 200 mg/m² before ASCT2, with low early mortality (1%). Very good partial response or better (VGPR+) rate post ASCT2 was 78%. Post ASCT2, 48% received consolidation therapy and 40% maintenance therapy. Median event-free survival (EFS) after ASCT2 was 2.6 years (95% confidence interval [CI]: 2.3–2.8), and 2-year EFS estimate was 63% (95% CI: 57–70). Median overall survival (OS) was 8.1 years (95% CI: 5.9–NA), and 2-year OS estimate was 92% (95% CI: 88–95). Multivariate analysis revealed that VGPR+ status and maintenance therapy post ASCT2 were associated with better EFS (hazard ratio [HR]: 0.6; 95% CI: 0.3–0.9, p = 0.012 and HR: 0.4; 95% CI: 0.3–0.6, p < 0.001, respectively) and OS (HR: 0.4; 95% CI: 0.2–0.9, p = 0.017 and HR: 0.2; 95% CI: 0.1–0.4, p < 0.001, respectively), while male sex correlated with poorer outcomes for EFS (HR: 2.5; 95% CI: 1.7–3.7, p < 0.001) and OS (HR: 2.7; 95% CI: 1.4–4.9, p = 0.002). Overall, ASCT2 appeared efficient with low toxicity in RMM. Maintenance therapy was associated with extended EFS and OS, particularly in patients with VGPR+ status post ASCT2. These findings underscore ASCT2's potential in RMM when coupled with maintenance therapy in selected patients.

复发多发性骨髓瘤（RMM）患者在第一次自体干细胞移植（ASCT）后出现长期反应，可考虑进行第二次自体干细胞移植（ASCT2）。然而，鉴于抗CD38和免疫疗法等突破性治疗方法，其作用仍存在争议。我们在法国的10个中心开展了一项实际研究（1996-2017年），共有267名RMM患者接受了ASCT2。中位年龄为61岁，女性占49%。大多数患者在ASCT2前接受了美法仑200 mg/m²治疗，早期死亡率较低（1%）。ASCT2后的部分反应非常好或更好（VGPR+）率为78%。ASCT2后，48%的患者接受了巩固治疗，40%接受了维持治疗。ASCT2后的中位无事件生存期（EFS）为2.6年（95%置信区间[CI]：2.3-2.8），2年EFS估计值为63%（95% CI：57-70）。中位总生存期（OS）为8.1年（95% CI：5.9-NA），2年OS估计值为92%（95% CI：88-95）。多变量分析显示，VGPR+ 状态和 ASCT2 后的维持治疗与较好的 EFS 相关（危险比 [HR]：HR：0.6；95% CI：0.3-0.9，P = 0.012；HR：0.4；95% CI：0.3-0.6，P = 0.017；HR：0.2；95% CI：0.1-0.4，P = 0.002）。总体而言，ASCT2在RMM患者中疗效显著，毒性较低。维持治疗与延长 EFS 和 OS 相关，尤其是在 ASCT2 后 VGPR+ 状态的患者中。这些发现强调了ASCT2在RMM中的潜力，如果在选定的患者中配合维持治疗的话。

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引用次数: 0

Prospective study of complement activation and thromboinflammation within sickle cell disease and its complications 镰状细胞病及其并发症中补体激活和血栓性炎症的前瞻性研究。

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-07-25 DOI: 10.1002/hem3.135

Christos Varelas, Efthymia Vlachaki, Philippos Klonizakis, Despoina Pantelidou, Fani Minti, Michael Diamantidis, Nikolaos Sabanis, Evdoxia Koravou, Ioanna Christodoulou, Despina Papadopoulou, Stamatia Theodoridou, Tasoula Touloumenidou, Apostolia Papalexandri, Ioanna Sakellari, Sofia Vakalopoulou, Vasilis Perifanis, George Vassilopoulos, Ioannis Mitroulis, Eleni Gavriilaki

Sickle cell disease (SCD) results from mutations in the β-globin gene, producing abnormal hemoglobin S (HbS) and leading to complications causing significant morbidity and mortality.1 One of the hallmark consequences of SCD is the occurrence of vaso-occlusive crises (VOCs), which arise from the interplay of factors in the disease's pathophysiology, involving abnormal hemoglobin polymerization, inflammation, endothelial dysfunction, and activation of the immune system, culminating in the painful obstruction of blood vessels by sickled red blood cells, that tend to obstruct blood vessels, leading to reduced blood flow and oxygen supply. This vicious cycle of ischemia followed by reperfusion constitutes the ischemia-reperfusion model.2The complement system, a complex defense mechanism, is implicated in various diseases through unregulated activation.3 However, diagnostic challenges hinder patient selection for complement inhibition.4 Preliminary data from our group using novel assays indicate complement activation even at a steady state in a limited patient population.5Limited information exists on additional markers in the complement activation and endothelial dysfunction cycle in SCD. Neutrophil extracellular traps (NETs), indicative of thromboinflammation, are elevated in SCD patients, even during steady state.6 ADAMTS13 (A Disintegrin and Metalloproteinase with Thrombospondin motifs), studied for its role in SCD vasculopathy, shows conflicting results as a potential biomarker.7, 8 Genetic variants and autoantibodies leading to unregulated complement activation are implicated in the pathogenesis of various human diseases.9Despite the lack of specific biomarkers or targeted treatments for crises, our hypothesis posits the presence of complement activation and thromboinflammation in SCD, particularly during complications, with distinct yet unexplored clinical or genetic features in these patients.Our study's methods regarding patient population, observation period, functional assays, and genetic, bioinformatic, and statistical analysis are demonstrated in supplementary materials. Our study included 81 adult SCD patients who are treated in different Hemoglobinopathies Units across Northern Greece. Their median age was 41 years, and 50 were female (61.7%). As expected in our population, the majority had the S/beta genotype (62), while 19 patients had the S/S genotype. Twenty-three presented SCD complications during the observation period (17 vaso-occlusive crises and six proteinuria/nephropathy) and were studied during this complication. Importantly, none of the patients that presented with renal damage, was on deferasirox, or other iron chelation therapy. The remaining 58 patients were studied at the end of the observation period.

镰状细胞病（SCD）是由β-球蛋白基因突变引起的，会产生异常的血红蛋白S（HbS），并导致并发症，造成严重的发病率和死亡率。SCD 的标志性后果之一是血管闭塞性危象（VOCs）的发生，这种危象是由疾病病理生理学中的各种因素相互作用引起的，其中包括血红蛋白聚合异常、炎症、内皮功能障碍和免疫系统激活，最终导致血管被镰状红细胞阻塞，使患者痛苦不堪，而镰状红细胞往往会阻塞血管，导致血流量和供氧量减少。这种缺血后再灌注的恶性循环构成了缺血-再灌注模型。2 补体系统是一种复杂的防御机制，它通过不规则的激活与各种疾病有牵连。6ADAMTS13（A Disintegrin and Metalloproteinase with Thrombospondin motifs）在 SCD 血管病变中的作用研究显示，其作为潜在生物标志物的结果相互矛盾。尽管缺乏针对危象的特异性生物标志物或靶向治疗，但我们的假设认为补体激活和血栓栓塞性炎症存在于 SCD 中，尤其是在并发症期间，这些患者具有独特的临床或遗传学特征，但尚未得到探讨。我们的研究在患者人群、观察期、功能检测以及遗传学、生物信息学和统计学分析方面的方法见补充材料。我们的研究包括 81 名成年 SCD 患者，他们在希腊北部不同的血红蛋白病单位接受治疗。他们的中位年龄为 41 岁，50 人为女性（61.7%）。正如我们预期的那样，大多数患者的基因型为 S/beta（62 例），19 例患者的基因型为 S/S。23 名患者在观察期间出现了 SCD 并发症（17 例血管闭塞性危象和 6 例蛋白尿/肾病），并在并发症期间接受了研究。重要的是，这些出现肾损害的患者中没有人在接受地拉羅司或其他铁螯合疗法。其余 58 名患者在观察期结束时接受了研究。首先，我们测量了稳定状态和观察期间的可溶性 C5b-9 和改良哈姆试验。在稳定状态下，出现 SCD 并发症的患者中，可溶性 C5b-9 超过正常值的比例明显高于未出现 SCD 并发症的患者（7/23，30%，P = 0.028）。同样，出现并发症的患者在稳定状态下进行改良哈姆试验的比例也明显较高（5/23，21%，p = 0.001，图 1A）。在观察期间，我们发现可溶性 C5b-9 明显增加（p = 0.001）。在出现并发症的患者中，这一增幅明显更高（p = 0.046，图 1B）。一名未出现并发症的患者 Ham 试验和 sC5b-9 均呈阳性，而 42 名未出现并发症的患者仅有 C5b-9 升高。由于 VOC 是最常见的并发症，因此在有 VOC 的患者中也出现了显著的结果（数据未显示）。ADAMTS13 与之相似，在稳定状态和随访时均在正常范围内（图 2B）。我们能够测量 81 例患者中 60 例的 NETS。在出现疾病并发症的患者中，稳定状态下的 NETs 明显增加。此外，与稳定状态相比，随访时测量的 NETs 也有显著增加（p < 0.001，图 2B）。改良哈姆试验阳性患者的 C5b9 增加（p < 0.001）。在我们的研究人群中，没有发现NET与C5b-9之间有明显的关联。我们从小等位基因频率（MAF）小于1%的罕见变体开始进行基因分析，因为罕见变体在补体相关疾病患者中已被普遍描述10。我们检测到 23 个罕见变异，详见佐证资料 S1：表 1。几乎所有的罕见变异都记录在独特的患者中。只有两名患者发现了 CFH 中的 rs35836460、CFHR1 中的 rs186530184、THBD 中的 rs183647515 和 ADAMTS13 中的 rs202206149，三名患者发现了 THBD 中的 rs3176136。

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引用次数: 0

Parkinson-like neurotoxicity in female patients treated with idecabtagene-vicleucel 接受 idecabtagene-vicleucel 治疗的女性患者的帕金森样神经毒性。

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-07-25 DOI: 10.1002/hem3.131

Audrey Couturier, Martine Escoffre, Frédérique Leh, Anne-Sophie Villoteau, Xavier Palard, Florence Le Jeune, Olivier Decaux, Thierry Lamy, Roch Houot

Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are two BCMA-directed CAR T-cells approved for the treatment of relapsed or refractory multiple myeloma. Similar to CD19-directed CAR T-cells, acute adverse events may occur after BCMA-directed CAR T-cells, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). However, a new type of neurotoxicity has been recently reported in patients treated with BCMA-directed CAR T-cells, the so-called movement and neurocognitive toxicity (MNT). Common features include late onset of Parkinson-like symptoms such as tremor, bradykinesia, and neurocognitive disorder. Only 10 cases of MNT occurring after BCMA-directed CAR T-cells have been reported so far (Table 1). The symptoms appeared with a median time of 36 days (range, 14–914 days). Interestingly, all cases occurred in male patients and after cilta-cel except for one patient who had been treated with ide-cel.4 MNT has been associated with high expansion and persistence of circulating CAR T-cells, cerebrospinal fluid infiltration by CAR T-cells, and no clear response to levodopa. Autopsy report from a patient who died shortly after presenting with MNT showed a T-cell infiltrate in the periventricular region of the basal ganglia as well as BCMA expression in the basal ganglia, suggesting an on-target off-tumor toxicity.1 BCMA expression was also found on basal ganglia cells of healthy subjects.1 Potential risk factors of MNT include high tumor burden at baseline before the start of lymphodepletion, grade ≥2 CRS, occurrence of ICANS, high CAR T-cell expansion, and prolonged persistence.1 Management of this new and rare toxicity remains poorly defined. Corticosteroids, systemic chemotherapy, anakinra, intrathecal injections of cytarabine and steroids, IV Ig, and plasmaspharesis have been tested without clear benefit. Most patients experience mild or no improvement of their symptoms. In some patients, symptoms worsen and may lead to death.Here, we report the case of two female patients who developed parkinsonism after ide-cel infusion.Patient 1 is a 74-year-old woman who had been diagnosed with monoclonal gammopathy of unknown significance in 2003, which progressed to multiple myeloma in 2009. Before undergoing CAR T-cell therapy, she had received 11 prior lines of therapy including chemotherapy, IMIDs, proteasome inhibitors, daratumumab, and lastly talquetamab, a CD3/GPRC5D bispecific antibody. She was offered CAR T-cell therapy after developing lytic bone lesions while being treated with talquetamab. She received bridging therapy with Selinexor, which allowed partial metabolic response. After ide-cel infusion, she developed grade 1 CRS on Day 2 and no ICANS. She did not require treatment with tocilizumab nor dexamethasone. She was discharged on Day 10 postinfusion.I

医生应了解这种罕见的毒性，以便及早识别和快速干预，从而限制不可逆转的神经损伤风险。Xavier Palard、Florence Lejeune、Frédérique Leh、Anne-Sophie Villoteau、Martine Escoffre、Oliver Decaux和Thierry Lamy对文章进行了审阅和编辑。Roch Houot从Kite/Gilead公司、诺华公司、Incyte公司、杨森公司、MSD公司、武田公司和罗氏公司领取酬金；并在Kite/Gilead公司、诺华公司、百时美施贵宝/赛尔基因公司、ADC Therapeutics公司、Incyte公司和Miltenyi公司担任顾问。Olivier Decaux 从杨森、Celgene/BMS、安进、武田、葛兰素史克、赛诺菲、艾伯维、罗氏、The Binding Site、Sebia、Menarini-Stemline 和辉瑞获得酬金。其余作者声明不存在竞争性经济利益。

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引用次数: 0

Prophylactic tocilizumab reduces the incidence of cytokine release syndrome in relapsed/refractory myeloma patients treated with teclistamab: Implications for outpatient step-up dosing 预防性托珠单抗可降低接受替卡单抗治疗的复发/难治性骨髓瘤患者细胞因子释放综合征的发生率：对门诊病人阶梯用药的影响。

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-07-24 DOI: 10.1002/hem3.132

Charlotte L. B. M. Korst, Kaz Groen, Patricia W. C. Bosman, Fleur van der Valk, Christie P. M. Verkleij, Sandy Kruyswijk, Maaike E. M. de Ruijter, Dianne M. Heijink, Maria T. Kuipers, Sonja Zweegman, Niels W. C. J. van de Donk

Teclistamab, a T-cell redirecting bispecific antibody (BsAb) targeting B-cell maturation antigen (BCMA), has marked activity in heavily pretreated multiple myeloma (MM) patients (overall response rate: 63.0%; at least very good partial response [≥VGPR]: 59.4%; median progression-free survival [PFS]: 11.3 months).1, 2 Teclistamab treatment induces T-cell activation and production of proinflammatory cytokines such as interleukin-6 (IL-6).3 This increase in cytokines frequently results in a systemic inflammatory response syndrome (cytokine-release syndrome [CRS]), characterized by fever, and in more severe cases also hypotension and hypoxia.1, 2, 4, 5 CRS mitigation strategies include step-up dosing and premedication with steroids and antihistamines. The incidence of CRS in teclistamab-treated patients was 72.1% (grade 2: 21.2%; grade ≥3: 0.6%) with most CRS events occurring during step-up dosing.1, 2, 4 Recurrent CRS occurred in 33.3% of the patients.4 Patients are generally hospitalized for the administration of the step-up doses and first full dose to adequately monitor for early signs and symptoms of CRS (median hospital stay in a real-world setting: 10 days).1, 6 Treatment of CRS with steroids or the IL-6 receptor-blocking antibody tocilizumab is effective with rapid resolution of symptoms.3, 4 Patients who received tocilizumab for their first CRS event were less likely to experience a subsequent CRS event compared to those who did not receive tocilizumab (20.0% vs. 62.2%).4 A single dose of tocilizumab blocks the IL-6 receptor for approximately 10 days and covers the full step-up dosing period.7 Based on these data, we aimed to evaluate the efficacy of tocilizumab administered prior to the first step-up dose to prevent the development of CRS following the initiation of teclistamab therapy in 29 patients treated in our hospital.Teclistamab was administered according to the approved schedule with two step-up doses (0.06 and 0.3 mg/kg) followed by the full dose of 1.5 mg/kg every week (48–72 h between step-up doses and the first full dose). In patients undergoing hemodialysis, teclistamab was given directly after hemodialysis sessions. Prophylactic tocilizumab (8 mg/kg intravenously [IV]; maximum dose of 800 mg) was administered 1 h prior to the first step-up dose. Patients also received 16 mg dexamethasone, 2 mg clemastine, and 1000 mg acetaminophen 1 h prior to both step-up doses and the first full dose. All patients received herpes zoster (valacyclovir) and Pneumocystis jirovecii pneumonia prophylaxis (co-trimoxazole, or pentamidine in case of co-trimoxazole allergy). Granulocyte colony-stimulating factor was considered in cases of grade ≥3 neutropenia, and IgG replacement was given in cases with polyclonal IgG <

此外，预防性托珠单抗有可能减少类固醇在CRS治疗中的使用，而类固醇与开始BsAb治疗后较高的感染性并发症风险有关15。我们的数据还支持进一步评估预防性托珠单抗，以实现门诊患者安全使用替卡单抗，这有可能减少医疗资源的使用并改善患者的生活质量。此外，这项分析的样本量太小，无法就预测托珠单抗预防后 CRS 的疾病或患者相关因素得出明确结论。然而，我们的结果和另一项研究12 的结果表明，尽管使用了托珠单抗预防治疗，但循环浆细胞的高频率可能与≥2 级 CRS 相关。需要对更多患者进行新的研究，以评估哪些基线特征可预测接受托西珠单抗预防治疗的患者的 CRS。此外，在 MajesTEC-1 的关键队列中，有一部分患者没有发生 CRS，4 这表明，在预防性使用托珠单抗的策略中，我们也让原本不需要使用托珠单抗的患者接触到了托珠单抗。遗憾的是，目前还无法可靠地确定哪些患者会发生 CRS。4 总之，在加大剂量 1 之前使用预防性托珠单抗明显降低了 CRS 的发生频率，而且不影响疗效。虽然递增剂量通常在住院环境中进行，但我们也证明了预防性使用托西珠单抗的低CRS率可能会提高门诊特克司他单抗递增剂量的安全性和可行性，同时降低入院治疗CRS的风险。Charlotte L. B. M. Korst、Kaz Groen、Patricia W. C. Bosman、Fleur van der Valk、Christie P. M. Verkleij、Sandy Kruyswijk、Maaike E. M. de Ruijter、Dianne M. Heijink、Maria T. Kuipers、Sonja Zweegman和Niels W. C. J. van de Donk招募患者、提供数据并解释数据。Charlotte L. B. M. Korst 和 Niels W. C. J. van de Donk 设计并进行了统计分析。Niels W. C. J. van de Donk 起草了手稿的第一版，所有作者均可获得研究中报告的所有数据，并修改和批准了手稿的最终版本。Sonja Zweegman 曾获得 Celgene、武田和杨森的研究资助，并在杨森、武田、BMS、Oncopeptides 和赛诺菲的顾问委员会任职，所有报酬均由该机构支付。Niels W. C. J. van de Donk 获得了杨森制药、AMGEN、Celgene、诺华、Cellectis 和 BMS 的研究资助，并在杨森制药、AMGEN、Celgene、BMS、武田、默克、罗氏、诺华、拜耳、Adaptive、辉瑞、艾伯维和赛维耶的顾问委员会任职，所有这些机构均向其支付报酬。其余作者声明没有利益冲突。泰克司他单抗同情使用计划和MajesTEC-1研究得到了杨森制药公司的支持。

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引用次数: 0

The role of trephine bone marrow biopsies in the era of measurable residual disease—Results from the CLL10 trial of the German CLL Study Group (GCLLSG) 可测量残留疾病时代穿刺骨髓活检的作用--德国 CLL 研究组 (GCLLSG) CLL10 试验的结果。

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-07-24 DOI: 10.1002/hem3.126

Nadine Kutsch, Sandra Robrecht, Anna Fink, Elisabeth Lange, Rudolf Weide, Michael G. Kiehl, Martin Sökler, Rudolf Schlag, Ursula Vehling-Kaiser, Georg Köchling, Christoph Plöger, Michael Gregor, Torben Plesner, Michael R. Clausen, Ilske Oschlies, Matthias Ritgen, Marco Herling, Kirsten Fischer, Hartmut Döhner, Clemens-Martin Wendtner, Karl-Anton Kreuzer, Stephan Stilgenbauer, Michael Hallek, Sebastian Böttcher, Wolfram Klapper, Barbara Eichhorst

The advent of BCL-2 inhibitor-based time-limited therapies has currently replaced chemoimmunotherapy as one standard of care in chronic lymphocytic leukemia (CLL). Despite many differences in efficacy and safety profile, both treatment approaches achieve similarly high rates of undetectable measurable residual disease (U-MRD).1, 2 U-MRD has been shown to correlate with progression-free survival (PFS) and even with overall survival (OS) within the MURANO trial,3 as well as in the CLL14 trial.4 Currently, U-MRD is accepted by the European Medicines Agency (EMA) as intermediate endpoint within clinical trials.5The iwCLL 2018 response criteria require a bone marrow (BM) aspirate and trephine biopsy for confirmation of complete remission, with immunohistochemistry (IHC) recommended as a tool to differentiate between CLL cells versus benign T- and B-cell infiltrates.6 While the prognostic value of measurable residual disease (MRD) in CLL has been extensively studied before,7-11 the role of BM assessments by IHC on trephine biopsies has not yet been evaluated. As both BM aspirations and trephine biopsies are collected using an invasive procedure, their added valued remained a matter of debate. Therefore, prognostic value of BM IHC and flow cytometry-based BM MRD assessments is analyzed herein. Moreover, we investigated whether or not sensitive MRD assessments in the peripheral blood (PB) might be able to completely replace the need for BM assessments. Finally, the impact of central versus local pathology investigations are evaluated.Patient data were derived from the prospective, randomized CLL10 trial of the GCLLSG, in which chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine and rituximab (BR) was administered. BM aspiration and biopsy were performed at final staging 2 months (+28 days) after end of therapy. Central assessment of BM trephine biopsy material for IHC was performed by the hematopathology department in Kiel in conjunction with the prior local pathology. To this end, pathologists aim to identify lymphoid cells with a CLL phenotype in aggregates of lymphoid cells according to the current WHO classification12 by superimposing B-cell distribution pattern detected by CD20, CD19, or CD79a with the staining for CD5 and CD23 on separate slides. B-cell markers were stained according to standard protocols on an automated stainer. MRD was assessed in the central laboratory in Kiel by four-color flow cytometry at a threshold of 10−4 as previously described.13, 14We compared the impact of MRD and IHC using Kaplan–Meier landmark analyses of PFS and OS from the time point of sample assessment with log-rank tests and Cox proportional hazards regression modeling. Independent prognostic baseline

分析PB中存在U-MRD的患者，33名IHC+患者的估计3年PFS率为51.3%，而101名IHC-患者的估计3年PFS率为83.3%（HR = 2.646，95% CI：1.488-4.705，p <0.001）。29例IHC+和PB D-MRD患者的估计3年PFS率为30.7%，而9例IHC-/PB D-MRD患者的估计3年PFS率为55.6%（HR = 2.035，95% CI：0.772-5.368，p = 0.151）（图1B）。估计IHC+/PB U-MRD患者的3年OS率为100.0%，IHC-/PB U-MRD患者的3年OS率为98.0%（HR = 0.668，95% CI：0.146-3.050，p = 0.602）。IHC+/PB D-MRD患者的3年OS率估计为89.1%，IHC-/PB D-MRD患者为100.0%（HR = 0.364，95% CI：0.073-1.807，p = 0.216）（图1B）。在单变量分析中，治疗组、IHC的BM浸润、PB和BM中的MRD以及del(11q)状态、IGHV突变状态和基线时的血清胸苷激酶被确定为PFS的预后因素。当在多变量分析中考虑到所有这些变量时，BM中的血流MRD和IGHV突变状态被认为是PFS的独立预后因素。我们的结论是，为了更好地预测预后，仍有必要对抽取的骨髓进行基于血流的 MRD 评估。一旦知道了骨髓 MRD，穿刺活检似乎就没有附加价值了，因为穿刺活检可能会被省略。如果将MRD排除在多变量分析之外，治疗组、IGHV突变状态和IHC检测的骨髓浸润被认为是独立的预后因素。因此，如果无法进行MRD评估，那么对骨髓进行检查似乎有助于预后判断。在同时接受局部和中央 IHC 评估的 310 例患者中，我们发现作为单一参数评估的 IHC+ 与较短的 PFS 相关，因为从地标开始估计的 3 年 PFS 率为 39.3%，而 IHC- 为 77.5%（HR = 2.671，95% CI：1.942-3.674，p < 0.001）。随后，我们评估了在当地实验室与中心实验室进行评估时 IHC 的预后价值。有趣的是，与在中心实验室检测 IHC 的患者（估计 3 年 PFS 率为 82.2%，HR = 1.756，95% CI：1.108-2.782，p = 0.017）相比，在当地实验室评估 IHC 的患者（估计 3 年 PFS 率为 68.0%）预后较差。这一结果表明，参比实验室的 IHC 结果具有更好的特异性。IHC+患者从地标开始的3年PFS率，本地实验室为33.3%，而中心实验室为42.5%（HR = 1.160，95% CI：0.733-1.834；p = 0.527）（图1C）。当地实验室和中心实验室在 IHC 样本方面的差异可能是由于在评估当地样本时没有统一的标准。在根据 IHC 和当地实验室与中心实验室的基质浸润情况调查从样本评估的地标时间点开始的 OS 时，没有发现显著差异。这可能与后续治疗有效有关。如果由当地实验室评估，IHC-患者的估计3年OS-率为93.5%（HR = 1.983，95% CI：0.943-4.170，P = 0.071）；如果由中央实验室评估，则为98.5%（HR = 1.983，95% CI：0.943-4.170，P = 0.071）。总之，我们可以证实，MRD似乎是限时疗法PFS的一个有效预后参数，尽管这些数据仅包括化学免疫疗法，如果MRD和IHC的数据都可用，则应重新评估靶向药物。这与基于化学免疫疗法组合的 3 期试验（CLL8、CLL10、CLL11）的汇总分析结果一致，该分析也显示 PB 中的 MRD 与 PFS 之间存在显著关系。虽然流式 MRD 和 IHC 这两种方法都能为反应深度提供有价值的信息，但多变量分析的结果表明，BM 中的流式 MRD 能提供所需的预后信息，患者可以不必再进行活检。Nadine Kutsch、Sandra Robrecht、Sebastian Böttcher、Wolfram Klapper、Barbara Eichhorst构思并设计了这项分析。

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引用次数: 0

Long-term survival and safety of elranatamab in patients with relapsed or refractory multiple myeloma: Update from the MagnetisMM-3 study 艾拉他单抗对复发或难治性多发性骨髓瘤患者的长期生存率和安全性：MagnetisMM-3研究的最新进展。

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-07-24 DOI: 10.1002/hem3.136

Michael H. Tomasson, Shinsuke Iida, Ruben Niesvizky, Mohamad Mohty, Nizar J. Bahlis, Joaquin Martinez-Lopez, Guenther Koehne, Paula Rodriguez-Otero, H. Miles Prince, Andrea Viqueira, Eric Leip, Umberto Conte, Sharon T. Sullivan, Alexander M. Lesokhin

Targeting B-cell maturation antigen (BCMA) on myeloma cells has led to improved clinical benefit in heavily pretreated patients with relapsed or refractory multiple myeloma (RRMM), including those patients with triple-class exposed disease.1 Elranatamab, a humanized BCMA-CD3 bispecific antibody, was approved for the treatment of patients with RRMM based on the results from the registrational MagnetisMM-3 study, which enrolled patients previously treated with at least one immunomodulatory drug, one proteasome inhibitor, and one anti-CD38 monoclonal antibody.2, 3 Among BCMA-naive patients (n = 123), treatment with elranatamab led to an objective response rate (ORR) of 61.0%, with 35.0% of patients achieving a complete response (CR) or better.4 After a descriptive median follow-up of 14.7 months (data cutoff approximately 14 months after the last patient's initial dose), the median progression-free survival (PFS) and overall survival (OS) had not been reached, making it difficult to contextualize the survival outcomes in the treatment landscape for RRMM.4 Here, we report updated results, including Kaplan–Meier estimates of PFS and OS after a longer follow-up.As of the data cutoff of March 26, 2024 (approximately 26 months after the last patient's initial dose), with a median follow-up of 28.4 months (95% confidence interval [CI], 28.0–29.0; estimated by reverse Kaplan–Meier), the ORR was 61.0%, with 37.4% of patients achieving CR or better. Among responders, the median duration of response was not yet reached, and the probability of maintaining response at 24 months was 66.9% (95% CI, 54.4–76.7). The median PFS was 17.2 months (95% CI, 9.8–not-estimable [NE]) (Figure 1) and the median OS was 24.6 months (95% CI, 13.4–NE) (Figure 2).No new safety signals emerged with longer follow-up. Hematologic adverse events in ≥25% (any grade, maximum grade 3/4) of the patient population included neutropenia (49.6%, 49.6%), anemia (48.8%, 37.4%), thrombocytopenia (31.7%, 23.6%), and lymphopenia (26.8%, 25.2%). Other adverse events of interest observed in patients included infections (70.7%; 42.3% maximum grade 3/4; 6.5% grade 5), cytokine release syndrome (57.7%; all grade ≤2), and immune effector cell–associated neurotoxicity (4.9%; all grade ≤2).Elranatamab monotherapy continues to improve survival outcomes without new safety signals. Despite the refractory patient population with a high percentage of patients with poor prognostic features in MagnetisMM-3, the median PFS of 17.2 months and the median OS of 24.6 months observed with additional follow-up are promising among bispecific antibodies currently approved for RRMM. In an analysis of MajesTEC-1 with a median follow-up of 23 months, BCMA-naive patients treated with teclistamab had a median PFS of 11.3 months (95% CI, 8.8–16.4) and a median OS of 21.9 months (95% CI, 15.1–NE).

Bahlis：AbbVie、Amgen、Celgene、Genentech/Roche、GSK、Janssen、Karyopharm Therapeutics、Sanofi 和 Takeda 的酬金；Amgen、Celgene、Janssen、Karyopharm Therapeutics、Pfizer、Sanofi 和 Takeda 的咨询或顾问角色；来自艾伯维、安进、Celgene、基因泰克/罗氏、葛兰素史克、杨森、Karyopharm Therapeutics、赛诺菲和武田的个人酬金；以及 Celgene 和杨森的专利、特许权使用费和/或其他知识产权利益。Joaquin Martinez-Lopez：担任百时美施贵宝、杨森和诺华的顾问；获得安斯泰来和百时美施贵宝的研究资助；担任百时美施贵宝、杨森-Cilag 和罗氏的发言人。Paula Rodriguez-Otero：担任艾伯维、百时美施贵宝、葛兰素史克、杨森、辉瑞和赛诺菲的顾问；从艾伯维、Celgene、葛兰素史克、H3 Biomedicine、杨森、辉瑞和赛诺菲获得个人酬金；辉瑞支付差旅和住宿费用；担任百时美施贵宝、葛兰素史克、杨森和赛诺菲的发言人。亚历山大-M.Lesokhin：iTeos Therapeutics、杨森、Legend Biotech、辉瑞、赛诺菲和 Trillium Therapeutics 的酬金；辉瑞、Trillium Therapeutics 和 Arcellx 的咨询或顾问角色；iTeos Therapeutics、杨森、Legend Biotech、辉瑞、赛诺菲和 Trillium Therapeutics 的个人酬金；来自百时美施贵宝、基因泰克、杨森、辉瑞、赛诺菲和 Trillium Therapeutics 的研究经费；以及 Serametrix 的专利、特许权使用费和/或其他知识产权利益。Andrea Viqueira、Eric Leip、Umberto Conte 和 Sharon T. Sullivan：在辉瑞公司任职并持有股票。Guenther Koehne：无利益冲突。本研究根据国际协调委员会的《良好临床实践指南》和《赫尔辛基宣言》的原则进行。本研究由辉瑞公司资助。

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引用次数: 0

Correction to “Primary central nervous system lymphomas: EHA–ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up” 原发性中枢神经系统淋巴瘤：EHA-ESMO 诊断、治疗和随访临床实践指南》。

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-07-22 DOI: 10.1002/hem3.118

Ferreri AJM, Illerhaus G, Doorduijn JK, et al. Primary central nervous system lymphomas: EHA–ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. HemaSphere. 2024;8:e89.

In the author listing of this manuscript, the first name of the first author was misspelled. The correct spelling is Andrés JM Ferreri.

The original article has been corrected. We apologize for this error.

[此处更正了文章 DOI：10.1002/hem3.89.]。

引用次数: 0

Realizing precision medicine in chronic lymphocytic leukemia: Remaining challenges and potential opportunities 实现慢性淋巴细胞白血病的精准医疗：仍然存在的挑战和潜在机遇。

IF 7.6 2区医学 Q1 HEMATOLOGY

HemaSphere

Pub Date : 2024-07-21 DOI: 10.1002/hem3.113

Kostas Stamatopoulos, Sarka Pavlova, Othman Al-Sawaf, Thomas Chatzikonstantinou, Christina Karamanidou, Gianluca Gaidano, Florence Cymbalista, Arnon P. Kater, Andy Rawstron, Lydia Scarfò, Paolo Ghia, Richard Rosenquist

Patients with chronic lymphocytic leukemia (CLL) exhibit diverse clinical outcomes. An expanding array of genetic tests is now employed to facilitate the identification of patients with high-risk disease and inform treatment decisions. These tests encompass molecular cytogenetic analysis, focusing on recurrent chromosomal alterations, particularly del(17p). Additionally, sequencing is utilized to identify TP53 mutations and to determine the somatic hypermutation status of the immunoglobulin heavy variable gene. Concurrently, a swift advancement of targeted treatment has led to the implementation of novel strategies for patients with CLL, including kinase and BCL2 inhibitors. This review explores both current and emerging diagnostic tests aimed at identifying high-risk patients who should benefit from targeted therapies. We outline existing treatment paradigms, emphasizing the importance of matching the right treatment to the right patient beyond genetic stratification, considering the crucial balance between safety and efficacy. We also take into consideration the practical and logistical issues when choosing a management strategy for each individual patient. Furthermore, we delve into the mechanisms underlying therapy resistance and stress the relevance of monitoring measurable residual disease to guide treatment decisions. Finally, we underscore the necessity of aggregating real-world data, adopting a global perspective, and ensuring patient engagement. Taken together, we argue that precision medicine is not the mere application of precision diagnostics and accessibility of precision therapies in CLL but encompasses various aspects of the patient journey (e.g., lifestyle exposures and comorbidities) and their preferences toward achieving true personalized medicine for patients with CLL.

慢性淋巴细胞白血病（CLL）患者的临床结果多种多样。目前，越来越多的基因检测方法被用于识别高危患者，并为治疗决策提供依据。这些检测包括分子细胞遗传学分析，重点是复发性染色体改变，尤其是 del(17p)。此外，还利用测序来确定 TP53 突变和免疫球蛋白重变异基因的体细胞高突变状态。与此同时，靶向治疗的迅速发展也为 CLL 患者带来了新的治疗策略，包括激酶和 BCL2 抑制剂。本综述探讨了现有的和新出现的诊断测试，这些测试旨在确定应从靶向治疗中获益的高危患者。我们概述了现有的治疗范例，强调了在基因分层之外为合适的患者匹配合适的治疗方法的重要性，并考虑了安全性和有效性之间的关键平衡。我们还考虑了为每位患者选择治疗策略时的实际和后勤问题。此外，我们还深入探讨了耐药性的内在机制，并强调了监测可测量残留疾病以指导治疗决策的相关性。最后，我们强调了汇总真实世界数据、采用全球视角和确保患者参与的必要性。综上所述，我们认为精准医疗并不仅仅是在 CLL 中应用精准诊断和精准疗法，而是涵盖患者治疗过程中的各个方面（如生活方式暴露和合并症）及其偏好，为 CLL 患者实现真正的个性化医疗。

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引用次数: 0