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Induction of AML cell differentiation using HOXA9/DNA binding inhibitors as a potential therapeutic option for HOXA9-dependent AML 使用 HOXA9/DNA 结合抑制剂诱导急性髓细胞分化,作为治疗 HOXA9 依赖性急性髓细胞白血病的一种潜在方法
IF 6.6 2区 医学 Q2 Medicine Pub Date : 2024-05-06 DOI: 10.1002/hem3.77
Mélanie Lambert, Samy Jambon, Mohamed A. Bouhlel, Sabine Depauw, Julie Vrevin, Samuel Blanck, Guillemette Marot, Martin Figeac, Claude Preudhomme, Bruno Quesnel, David W. Boykin, Marie-Hélène David-Cordonnier

The mainstay of acute myeloid leukemia (AML) treatment still relies on traditional chemotherapy, with a survival rate of approximately 30% for patients under 65 years of age and as low as 5% for those beyond. This unfavorable prognosis primarily stems from frequent relapses, resistance to chemotherapy, and limited approved targeted therapies for specific AML subtypes. Around 70% of all AML cases show overexpression of the transcription factor HOXA9, which is associated with a poor prognosis, increased chemoresistance, and higher relapse rates. However, direct targeting of HOXA9 in a clinical setting has not been achieved yet. The dysregulation caused by the leukemic HOXA9 transcription factor primarily results from its binding activity to DNA, leading to differentiation blockade. Our previous investigations have identified two HOXA9/DNA binding competitors, namely DB1055 and DB818. We assessed their antileukemic effects in comparison to HOXA9 knockdown or cytarabine treatment. Using human AML cell models, DB1055 and DB818 induced in vitro cell growth reduction, death, differentiation, and common transcriptomic deregulation but did not impact human CD34+ bone marrow cells. Furthermore, DB1055 and DB818 exhibited potent antileukemic activities in a human THP-1 AML in vivo model, leading to the differentiation of monocytes into macrophages. In vitro assays also demonstrated the efficacy of DB1055 and DB818 against AML blasts from patients, with DB1055 successfully reducing leukemia burden in patient-derived xenografts in NSG immunodeficient mice. Our findings indicate that inhibiting HOXA9/DNA interaction using DNA ligands may offer a novel differentiation therapy for the future treatment of AML patients dependent on HOXA9.

急性髓性白血病(AML)的主要治疗手段仍然是传统化疗,65 岁以下患者的生存率约为 30%,65 岁以上患者的生存率则低至 5%。这种不利的预后主要源于频繁的复发、对化疗的耐药性以及针对特定急性髓细胞白血病亚型的获批靶向疗法有限。在所有急性髓细胞性白血病病例中,约70%的病例显示转录因子HOXA9过度表达,这与预后不良、化疗耐药性增加和复发率升高有关。然而,临床上尚未实现直接靶向 HOXA9。白血病HOXA9转录因子引起的失调主要源于其与DNA的结合活性,从而导致分化受阻。我们之前的研究发现了两种 HOXA9/DNA 结合竞争者,即 DB1055 和 DB818。我们评估了它们与HOXA9基因敲除或阿糖胞苷治疗相比的抗白血病效果。利用人类急性髓细胞模型,DB1055和DB818诱导体外细胞生长减少、死亡、分化和常见的转录组失调,但不影响人类CD34+骨髓细胞。此外,在人 THP-1 AML 体内模型中,DB1055 和 DB818 表现出强大的抗白血病活性,导致单核细胞分化为巨噬细胞。体外实验也证明了 DB1055 和 DB818 对来自患者的急性髓细胞白血病病灶的疗效,其中 DB1055 成功地减少了来自患者的异种移植在 NSG 免疫缺陷小鼠体内的白血病负荷。我们的研究结果表明,利用DNA配体抑制HOXA9/DNA相互作用可能为未来治疗依赖HOXA9的急性髓细胞性白血病患者提供一种新型分化疗法。
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引用次数: 0
The evolving pattern of the monoclonal protein improves the IMWG 2/20/20 classification for patients with smoldering multiple myeloma 单克隆蛋白的演变模式改进了 IMWG 2/20/20 型多发性骨髓瘤患者的分类方法
IF 6.6 2区 医学 Q2 Medicine Pub Date : 2024-05-06 DOI: 10.1002/hem3.76
Anna de Daniel, Luis Gerardo Rodríguez-Lobato, Natalia Tovar, M. Teresa Cibeira, David F. Moreno, Aina Oliver-Caldés, Ignacio Isola, Ester Lozano, Joan Bladé, Laura Rosiñol, Carlos Fernández de Larrea

The 2/20/20 International Myeloma Working Group (IMWG) score is the most employed risk score in clinical practice to evaluate the risk of progression from smoldering multiple myeloma (SMM) to symptomatic multiple myeloma. However, it faces a serious limitation: The risk score is applied at diagnosis and cannot be reapplied. Since a dynamic accurate patient risk assessment for progression is necessary, we aimed to investigate whether the detection of an evolving pattern in serum M-protein (SMP) improves the identification of high-risk patients. Eighty-three patients diagnosed with SMM between 2011 and 2020 were included. Patients were initially classified applying the 2/20/20 IMWG score at baseline and later reclassified depending on the presence of an SMP evolving pattern into six groups. We regrouped the patients into three final risk groups: low-risk, intermediate-risk, and high-risk. The risk of progression at two years for the high-risk group was 88% and all patients had progressed at 4 years. The performance measurements were superior for the new 2/20/20-Evolving score independently for the detection of high-risk patients. We show that the sequential measurement of the SMP is a noninvasive and widely available test that improves the 2/20/20 IMWG risk score.

2/20/20 国际骨髓瘤工作组(IMWG)评分是临床实践中最常用的风险评分,用于评估从烟雾型多发性骨髓瘤(SMM)发展为无症状多发性骨髓瘤的风险。然而,它也面临着严重的局限性:该风险评分在诊断时应用,不能再次应用。由于有必要对患者病情进展进行动态准确的风险评估,我们旨在研究检测血清 M 蛋白(SMP)的演变模式是否能提高高危患者的识别率。我们纳入了2011年至2020年间确诊的83名SMM患者。根据基线时的2/20/20 IMWG评分对患者进行初步分类,然后根据是否存在SMP演变模式将患者重新分为六组。我们将患者重新分为三个最终风险组:低风险组、中风险组和高风险组。高风险组患者两年后病情恶化的风险为 88%,所有患者四年后病情恶化。新的 2/20/20-Evolving 评分在独立检测高危患者方面的性能测量结果更优。我们的研究表明,SMP 的连续测量是一种非侵入性且可广泛使用的检测方法,可改善 2/20/20 IMWG 风险评分。
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引用次数: 0
Proximally biased V(D)J recombination in the clonal evolution of IGH alleles in KMT2A::AFF1 BCP-ALL of all age classes 各年龄段 KMT2A::AFF1 BCP-ALL 中 IGH 等位基因克隆进化过程中的近端偏向 V(D)J 重组
IF 6.6 2区 医学 Q2 Medicine Pub Date : 2024-04-22 DOI: 10.1002/hem3.71
Heiko Müller, Frank Dicker, Constance Bär, Wencke Walter, Stephan Hutter, Niroshan Nadarajah, Manja Meggendorfer, Qingsong Gao, Ilaria Iacobucci, Charles G. Mullighan, Wolfgang Kern, Torsten Haferlach, Claudia Haferlach

We report the analysis of 379 cases of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) using whole-transcriptome sequencing data (Table S1 and Supporting Information S1: Methods). In 48 adult, 36 pediatric, and 37 infant cases of BCP-ALL carrying t(4;11)(q21;q23)/KMT2A::AFF1 rearrangements (KMT2A-r), we observed strongly favored usage of proximal IGHV genes in V(D)J recombination and more abundant de novo DJH recombination than in other BCP-ALL subtypes. This finding has implications for the detection of measurable residual disease (MRD) in clinical practice as MRD-guided treatment choices have proved to provide valuable guidance in a disease that is still associated with poor prognosis in all age categories.

BCP-ALL carrying KMT2A-r is an aggressive leukemia with poor prognosis characterized by the sudden occurrence of very high white blood cell counts, a slight preference for female patients, rapid progression, and significantly shorter survival than KMT2A-r-negative patients.1, 2 Treatment options that significantly prolong the survival of affected patients are limited to allogeneic stem cell transplantation.2 The incidence of KMT2A-r BCP-ALL is estimated between 4% and 10% in adults and 3% and 4% in childhood.3

KMT2A is a histone methyl transferase of the trithorax group involved in the establishment of epigenetic memory. It catalyzes H3K4 methylation of a large number of physiological targets including HOX genes, supporting activation of their expression.4, 5 In leukemogenic fusions, the N-terminal portion of KMT2A is fused in frame to more than 100 fusion partners.6 In the fusion product, the catalytic SET domain of KMT2A is lost. The most frequently observed fusion partners favor the interaction of the fusion product with another histone methyl transferase (DOT1L) that catalyzes H3K79 methylation. As a consequence, proper regulation of target genes activated in this aberrant fashion appears to be disturbed in cells carrying KMT2A-r.4, 5, 7, 8

Proximally biased V(D)J recombination was first described in pre-B-cell lines9 and later shown to depend on Pax5 function.10 It is now understood that the generation of a randomized immunoglobulin repertoire depends on chromatin modifications at the IGH locus controlled by PAX5 and its target, WAPL.11, 12 In addition to classical V(D)J recombination,13 B-cell receptors (BCRs) are known to be modified by direct VH to VHDJH recombination (VH replacement)14, 15 and this process is known to occur also in BCP-ALL cells.16-18 Whether the relative contribution of V(D)J recombination and VH replacem

我们利用全转录组测序数据分析了 379 例 B 细胞前体急性淋巴细胞白血病(BCP-ALL)病例(表 S1 和辅助信息 S1:方法)。在携带t(4;11)(q21;q23)/KMT2A::AFF1重排(KMT2A-r)的48例成人、36例儿科和37例婴儿BCP-ALL病例中,我们观察到与其他BCP-ALL亚型相比,近端IGHV基因在V(D)J重组中的使用受到强烈青睐,而新生DJH重组则更为丰富。携带 KMT2A-r 的 BCP-ALL 是一种侵袭性白血病,预后较差,其特点是突然出现极高的白细胞计数,女性患者略占优势,病情进展迅速,生存期明显短于 KMT2A-r 阴性患者、2 据估计,KMT2A-r BCP-ALL 在成人中的发病率为 4% 至 10%,在儿童中的发病率为 3% 至 4%。3KMT2A 是一种三轴组蛋白甲基转移酶,参与表观遗传记忆的建立。它催化包括 HOX 基因在内的大量生理靶标的 H3K4 甲基化,从而支持这些靶标的表达激活。4, 5 在致白血病融合中,KMT2A 的 N 端部分与 100 多个融合伙伴进行框架融合。在融合产物中,KMT2A 的催化 SET 结构域消失了。最常见的融合伙伴有利于融合产物与催化 H3K79 甲基化的另一种组蛋白甲基转移酶(DOT1L)相互作用。因此,在携带 KMT2A-r 的细胞中,以这种异常方式激活的靶基因的正常调控似乎受到了干扰。4、5、7、8近端偏向的 V(D)J 重组首先在前 B 细胞系中被描述9 ,后来被证明依赖于 Pax5 的功能10 。现在的理解是,随机免疫球蛋白复合物的产生依赖于由 PAX5 及其靶标 WAPL 控制的 IGH 基因座的染色质修饰11、12 除经典的 V(D)J 重组13 外,已知 B 细胞受体(BCR)可通过 VH 与 VHDJH 的直接重组(VH 置换)14、15 进行修饰,而且已知 BCP-ALL 细胞中也会发生这一过程。在分析 BCP-ALL 样本 RNA 序列(RNA-Seq)数据中的 BCR 重排时,我们注意到在携带 KMT2A-r 融合基因的样本中,涉及 IGHV6-1 的重排异常丰富。为了量化这一观察结果,我们对 RNA-Seq 读数进行了 MiXCR 分析(图 1)。通过MiXCR分析映射到特定IGHV基因的RNA-Seq读数数量可用于量化样本中单个IGHV基因的表达水平。图1中的热图显示了这一分析的结果。在该热图中,IGHV 基因按其与 IGH 基因座中 DJH 片段群的基因组距离远近排序。虽然对大多数样本来说,IGHV基因的表达水平似乎与其基因组位置无关,但在KMT2A-r样本中,最邻近的IGHV基因IGHV6-1的表达水平明显高于远端基因。我们对重排的IGH等位基因的MiXCR衍生核苷酸序列进行了连接分析,以检验V(D)J重组是否存在BCP-ALL亚型特异性差异。IMGT-V-QUEST用于这一目的,它将编码CDR3区域锚位置(C104-W118)氨基酸的核苷酸识别为连接点,并将这些核苷酸映射到CDR3区域的VH-N-D-N-JH成分上(表S2)。结果如图 2 所示。我们观察到,所有年龄段的 KMT2A-r 样本中,每个样本都有三个 DNJH 茎(图 2A)。每个样本的 DNJH 茎中位数相似的唯一亚型是 t(1;19)/TCF3::PBX1。另一端是 DUX4 亚型,该亚型每个样本未检测到多个 DNJH 茎。此外,在 KMT2A-r 样本中发现的核苷酸水平的 CDR3 区域比大多数其他 BCP-ALL 亚型的 CDR3 区域短(图 2B)。近端偏向的V(D)J重组导致IGHV6-1在BCR重排中的优先使用。事实上,多达50%的KMT2A-r样本都含有涉及IGHV6-1的BCR。
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引用次数: 0
New therapies for relapsed or refractory aggressive B-cell lymphoma increase survival: Analysis from the RELINF registry of the GELTAMO group 治疗复发或难治性侵袭性 B 细胞淋巴瘤的新疗法提高了生存率:GELTAMO 小组的 RELINF 登记分析
IF 6.6 2区 医学 Q2 Medicine Pub Date : 2024-04-22 DOI: 10.1002/hem3.70
Mariana Bastos-Oreiro, Pau Abrisqueta, Antonio Gutierrez, Ana Jiménez Ubieto, Maria Poza, Paula Fernanez-Caldas, María José LLacer, Sonia Gonzalez de Villambrosia, Raúl Córdoba, Alberto López, Elena Ceballos, Belen Navarro, Ana Muntañola, Eva Donato, Eva Diez-Baeza, Lourdes Escoda, Hugo Luzardo, María José Peñarrubia, Daniel García Belmonte, Emilia Pardal, Claudia Lozada, Alejandro Martín García-Sancho

Aggressive B-cell lymphomas (ABCL) represent a heterogeneous group of biologically different diseases with variable clinical outcomes.1, 2 Around one-third of patients are not cured with frontline treatment, and outcomes for this relapse/refractory (R/R) group are extremely poor with conventional treatments.3-5 However, during the last years, several promising new therapies (NTs) have been progressively incorporated into the treatment arsenal, such as new monoclonal antibodies (MAs), cellular therapy with T cells with chimeric antigen receptor (CAR-T cells), or, in a lesser extent, bispecific antibodies (BiMAs). Polatuzumab vedotin–bendamustine–rituximab6 was approved in Europe since 2019 and funded in Spain since September 2019. Tafasitamab–lenalidomide7 was approved for European Medicines Agency (EMA) in August 2021 and funded in Spain in 2023. CAR-T cell was approved for EMA in 2018,8-10 and funded in Spain in 2019. BiMAs are still only available in clinical trials.11, 12

Our study aims to assess to what extent these new treatments have been incorporated into the clinical practice and how this has impacted patient survival.

This is a multicentre retrospective study based on the GELTAMO RELINF platform, which has been active since January 2014 and includes only essential variables such as histological subtype, age, gender, and current situation. From 60 centers actively registering on the platform invited to participate, 17 centers accepted. All of these centers are university hospitals, and five are CAR-T cell therapy providers. Participating centers completed a short questionnaire on disease relapse and the use of NTs in their registered patients. Conventional treatments only include chemotherapy ± anti-CD20 antibodies ± autologous transplant. Investigators in each center were required to report relapses with histological confirmation of large B-cell lymphoma (LBCL). For refractory patients, histological confirmation was not mandatory. The histologies included were diffuse LBCL (DLBCL) and high-grade B-cell lymphoma (HGBCL) not otherwise specified (NOS) and double hit. Early relapse was defined as within 12 months of completion of induction therapy, and late relapse was defined as more than 12 months.

The present analysis was based on a January 2023 data cut-off. Overall survival (OS) and progression-free survival (PFS) were determined from diagnosis. OS was also calculated since the date of the first relapse (OS2). All reported p values were two-sided, and statistical significance was set at p < 0.05. Analyses were performed using SPSS version 29 (SPSS).

From 3270 patients with ABCL registered, 2853 patients were included in the present analysis; exclusion reasons are described in Supporting Information S1: Table 1.

Supporting Information S1: Table 2

如佐证资料 S1:表 4 所示,接受常规治疗的患者与接受 NT 治疗的患者在复发时间(早期与晚期)上没有差异。中位随访时间为 49 个月(95% 置信区间:47-51),整个队列的中位 PFS 为 54 个月(95% 置信区间:48-61),中位 OS 为 82 个月(95% 置信区间:74-90)(佐证资料 S1:图 1A)。在多变量分析中,早期复发(危险比,HR 2.91 [95% CI: 2.35-3.6];p &lt;0.001)、总线数(HR 1.4 [95% CI: 1.14-1.71];p = 0.018)、65 岁以上(HR 1.83 [95% CI: 1.17-2.86];p = 0.008)、75 岁以上(HR 2.86 [95% CI: 1.84-4.46];p &lt;0.仅考虑738例R/R患者,中位随访时间为40个月,中位OS(mOS2)为16.8个月(95% CI:14.5-19)(佐证资料S1:图1B)。接受两线以上治疗的患者组(19 个月 [95% CI:16-22])的中位OS2长于仅接受两线治疗的患者组(11 个月 [95% CI:6-17];p &lt;0.001)(图 1A)。早期复发组(13.5 个月 [95% CI:11.5-15.5])的中位 OS2 明显短于晚期复发组(31.1 个月 [95% CI:22.5-39.8];p &lt;0.001)(图 1B)。接受NT治疗的复发患者的中位OS2为31.1个月(95% CI:22.5-39.7),而标准治疗组为11.9个月(95% CI:9.2-14.6)(p &lt;0.001)(图1C)。接受CAR-T细胞治疗的患者的OS2优于未接受治疗的患者(p &lt;0.001)(图1D)。在早期复发患者中,接受 CAR-T 细胞治疗的患者的中位 OS2 为 32.2 个月(95% CI:16-48.4),而未接受治疗的患者的中位 OS2 为 10.5 个月(95% CI:7.6-13.4)(p &lt; 0.001)(图 1E)。当分析患者最初是否属于 CAR-T 提供者中心时,我们发现来自 CAR-T 细胞中心的患者的 mOS2 优于非 CAR-T 提供者中心的患者,在早期复发患者中都是如此(25 个月 [95% CI:20.6-29.3] vs. 14.9 个月 [95% CI: 12.2-17.5]; p &lt; 0.001)和晚期复发(80.7 个月 [95% CI: 60.1-101.4] vs. 57.7 个月 [95% CI: 42.4-72.9]; p = 0.011)(佐证资料 S1:图 2)。两组患者的特征见佐证资料 S1:表 6。有趣的是,NT在CAR-T提供者中心明显更常用,尤其是CAR-T细胞疗法。与OS2相关的因素见表1。多变量分析确定了早期复发(HR 1.68 [95% CI: 1.37-2.06]; p &lt; 0.001)、65 岁以上(HR 1.91 [95% CI: 1.23-2.98]; p = 0.004)、CAR-T 细胞治疗(HR 0.68 [95% CI: 0.51-0.90];p = 0.007)和属于 CAR-T 细胞中心(HR 0.7 [95% CI: 0.58-0.85];p &lt;0.001)是与 OS2 独立相关的变量、关于首次复发前的时间,如前所述,诱导治疗后第一年内的早期复发明显增多15、16,占复发的67%。同样,HGBCL 和富含 T 细胞的 B 细胞淋巴瘤等不良组织学的早期复发率也高于 DLBCL NOS。虽然这些组织学的侵袭性更强是众所周知的17、18 ,但据我们所知,这些数据以前从未报道过。此外,我们还发现早期复发与晚期复发患者的生存期存在显著差异,mOS2 分别为 13 个月和 31 个月。正如之前在 CORAL 和 ORCHARRD 试验15、16 中所述,这一事实众所周知,但在这里,通过中位数超过 4 年的随访,我们在真实的登记人群中证实了这一点。尽管如此,如前所述19 ,75 岁以上患者的 OS 不如年轻患者,原因之一是他们在大多数情况下接受的调整治疗强度较低。20 在我们的系列研究中,全球有 32% 的患者接受了 NT 治疗。在首次复发的患者中,NT 的使用并不常见。然而,必须考虑到只有波拉珠单抗和他法西他单抗可用于这一适应症。如图1A所示,与只接受两线治疗的患者相比,这些患者的OS2有所改善,这反映了NT的使用从三线治疗开始更为广泛的影响。 考虑到 NT 在这一人群中的关键试验结果8-12 以及真实世界的数据21-23,这一结果在意料之中。从这个意义上讲,我们发现 BiMA 和 CAR-T 与更好的预后有关。最后,我们发现,与在非 CAR-T 细胞中心接受治疗的患者相比,在 CAR-T 细胞中心接受治疗的患者生存率更高,这也是多变量分析中的一个自变量。这些结果可能与多种因素有关。这可能代表了更容易或更快获得 CAR-T 细胞疗法的优势,但也可能与临床试验中新药的快速获得有关,这在复杂程度高的中心更为常见。不过,根据现有数据,我们不能排除在 CAR 中心接受治疗的患者是经过更严格筛选的群体,其生物学特性更好,这也是该群体 OS 改善的原因。作为一项登记研究,我们没有关于患者特征或生物学特征的详细数据。总复发率低于预期,这与患者被确诊有关,尤其是在大中心,他们最终在其他中心接受治疗。另一方面,我们没有关于复发特征或所接受的完整治疗的详细信息。总之,我们的分析证实,在现实世界中,年龄和复发时间对 ABCL 患者的生存有负面影响。在这方面,HGBCL 等组织学类型的早期复发更为频繁。此外,根据我们的研究结果,近年来NT疗法的引入明显改善了患者的生存率,尤其是CAR-T细胞疗法。Pau Abrisqueta、Ana Jiménez Ubieto、Maria Poza、María José LLacer、Sonia Gonzalez de Villambrosia、Raúl Córdoba、Alberto López、Elena Ceballos、Belen Navarro、Ana Muntañola、Eva Donato、Eva Diez-Baeza、Lourdes Escoda、Hugo Luzardo、María José Peñarrubia、Daniel García Belmonte、Emilia Pardal 和 Claudia Lozada 收集数据并进行研究。安东尼奥-古铁雷斯(Antonio Gutierrez)收集数据、开展研究并进行统计分析。亚历杭德罗-马丁-加西亚-桑乔(Alejandro Martín García-Sancho )设计研究、分析和解释数据,并撰写论文。
{"title":"New therapies for relapsed or refractory aggressive B-cell lymphoma increase survival: Analysis from the RELINF registry of the GELTAMO group","authors":"Mariana Bastos-Oreiro,&nbsp;Pau Abrisqueta,&nbsp;Antonio Gutierrez,&nbsp;Ana Jiménez Ubieto,&nbsp;Maria Poza,&nbsp;Paula Fernanez-Caldas,&nbsp;María José LLacer,&nbsp;Sonia Gonzalez de Villambrosia,&nbsp;Raúl Córdoba,&nbsp;Alberto López,&nbsp;Elena Ceballos,&nbsp;Belen Navarro,&nbsp;Ana Muntañola,&nbsp;Eva Donato,&nbsp;Eva Diez-Baeza,&nbsp;Lourdes Escoda,&nbsp;Hugo Luzardo,&nbsp;María José Peñarrubia,&nbsp;Daniel García Belmonte,&nbsp;Emilia Pardal,&nbsp;Claudia Lozada,&nbsp;Alejandro Martín García-Sancho","doi":"10.1002/hem3.70","DOIUrl":"https://doi.org/10.1002/hem3.70","url":null,"abstract":"<p>Aggressive B-cell lymphomas (ABCL) represent a heterogeneous group of biologically different diseases with variable clinical outcomes.<span><sup>1, 2</sup></span> Around one-third of patients are not cured with frontline treatment, and outcomes for this relapse/refractory (R/R) group are extremely poor with conventional treatments.<span><sup>3-5</sup></span> However, during the last years, several promising new therapies (NTs) have been progressively incorporated into the treatment arsenal, such as new monoclonal antibodies (MAs), cellular therapy with T cells with chimeric antigen receptor (CAR-T cells), or, in a lesser extent, bispecific antibodies (BiMAs). Polatuzumab vedotin–bendamustine–rituximab<span><sup>6</sup></span> was approved in Europe since 2019 and funded in Spain since September 2019. Tafasitamab–lenalidomide<span><sup>7</sup></span> was approved for European Medicines Agency (EMA) in August 2021 and funded in Spain in 2023. CAR-T cell was approved for EMA in 2018,<span><sup>8-10</sup></span> and funded in Spain in 2019. BiMAs are still only available in clinical trials.<span><sup>11, 12</sup></span></p><p>Our study aims to assess to what extent these new treatments have been incorporated into the clinical practice and how this has impacted patient survival.</p><p>This is a multicentre retrospective study based on the GELTAMO RELINF platform, which has been active since January 2014 and includes only essential variables such as histological subtype, age, gender, and current situation. From 60 centers actively registering on the platform invited to participate, 17 centers accepted. All of these centers are university hospitals, and five are CAR-T cell therapy providers. Participating centers completed a short questionnaire on disease relapse and the use of NTs in their registered patients. Conventional treatments only include chemotherapy ± anti-CD20 antibodies ± autologous transplant. Investigators in each center were required to report relapses with histological confirmation of large B-cell lymphoma (LBCL). For refractory patients, histological confirmation was not mandatory. The histologies included were diffuse LBCL (DLBCL) and high-grade B-cell lymphoma (HGBCL) not otherwise specified (NOS) and double hit. Early relapse was defined as within 12 months of completion of induction therapy, and late relapse was defined as more than 12 months.</p><p>The present analysis was based on a January 2023 data cut-off. Overall survival (OS) and progression-free survival (PFS) were determined from diagnosis. OS was also calculated since the date of the first relapse (OS2). All reported <i>p</i> values were two-sided, and statistical significance was set at <i>p</i> &lt; 0.05. Analyses were performed using SPSS version 29 (SPSS).</p><p>From 3270 patients with ABCL registered, 2853 patients were included in the present analysis; exclusion reasons are described in Supporting Information S1: Table 1.</p><p>Supporting Information S1: Table 2 ","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140632047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Precision hematology: Navigating the evolution of diagnostic classifications in the era of globalized medicine 精准血液学:驾驭全球化医学时代诊断分类的演变
IF 6.6 2区 医学 Q2 Medicine Pub Date : 2024-04-04 DOI: 10.1002/hem3.65
Elizabeth Macintyre, Konstanze Döhner, Kirsten Grønbæk, Martin Dreyling, Brian Huntly, Antonio Almeida, John Gribben, for the EHA Board

In the era of precision medicine, hematology stands at the forefront of medical disciplines. Indeed, our enduring commitment to employing molecular techniques for disease characterization, coupled with their application in individual patient management at diagnosis and during treatment monitoring, places hematology in a pivotal position. We continue to seamlessly integrate an ever-expanding array of diagnostic techniques, developed and crafted by a variety of medical and scientific specialists. These experts have collaborated in a multidisciplinary fashion to define and communicate the most appropriate diagnosis and treatment for patients with hematological cancers and nonmalignant disorders. However, this increasingly demands progressively specialized training tracks and skill sets.

The archetypical hematologist, who historically personally saw the patient, biopsied the bone marrow or even spleen, stained the cells, and then made a morphological/cytological diagnosis before starting and accompanying treatment, has become a relic of the past. At a minimum, achieving precision diagnosis of tumors of hematopoietic and lymphoid tissues requires hematologists (diagnostic and therapeutic), pathologists, geneticists, biomedical scientists/technicians/engineers, and radiologists/nuclear medicine specialists.

In any community, rules and regulations are imperative for peaceful, constructive coexistence. These regulations must be clear, concise, and up-to-date and then be communicated to and understood by all actors involved in their execution. This is a formidable challenge in a globalized world with exponentially evolving technological and informatic/data capabilities. Classifications must be provided by experts, who should be free of conflict of interest and capable of providing guidelines for the treatment of all patients across a gradient of increasingly disparate access to health.

The World Health Organization (WHO) tumor classification system, available at https://www.iarc.who.int, has long served as the accepted standard reference. This classification has undergone multiple updates over the years, reflecting our evolving knowledge of tumor biology and advancements in diagnostic and therapeutic approaches. At a more specialized level, national and international medical specialist societies have become important actors, initially in organizing scientific meetings and supporting research, and subsequently expanding into education, training, mentorship, advocacy, and support for postgraduate practice, including guideline production/endorsement. Indeed, in the latest survey of European Hematology Association (EHA) members, with replies from 4966 individuals in six continents, on the EHA services they appreciate, guidelines came second on the list, just after high-quality education. Collaboration between WHO/IARC (International Agency for Research on Cancers) and specialist societies, therefore, remains crucial.

In 2008, the co

所有作者都参与了手稿的撰写,特别是编辑(Elizabeth Macintyre 和 John Gribben)、骨髓增刊(Konstanze Döhner、Kirsten Grønbæk、Brian Huntly、Antonio Almeida)和淋巴增刊(Elizabeth Macintyre、Martin Dreyling、John Gribben)。我们感谢 Elias Campos 和 German Ott 提供的建设性意见。K. Döhner曾获得诺华、Celgene/BMS、安斯泰来、Agios、Abbvie和JAZZ的研究资助;曾获得诺华和葛兰素史克的酬金;并曾担任诺华、Celgene/BMS、Abbvie、葛兰素史克、AOP和MSD的顾问委员会成员。K. Grønbæk 曾获得杨森制药公司的研究资助,并曾在葛兰素史克、Evaxion 和 Nanexa 的顾问委员会任职。M. Dreyling 曾获得艾伯维、拜耳、BMS/Celgene、吉利德/Kite、杨森、礼来和罗氏的机构研究资助;曾获得阿斯利康、拜耳、吉利德/Kite、杨森、礼来、诺华和罗氏的演讲酬金;曾在艾伯维、阿斯利康、拜耳、BMS/Celgene、吉利德/Kite、杨森、礼来/乐施、诺华和罗氏的科学顾问委员会任职。B. Huntly 曾担任 Exscientia、Stelexis Therapeutics 和 Appollo Therapeutics 的顾问,并从 Astra-Zeneca 和 Sysmex 获得研究经费。A. Almeida 曾担任艾伯维、BMS、杨森和诺华的演讲人;曾在艾伯维、BMS 和诺华的顾问委员会任职。J. Gribben从阿斯利康和杨森获得研究经费;从安进、吉利德和阿斯利康获得酬金;从杨森、Genmab和艾伯维获得研究所的临床试验研究经费。
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引用次数: 0
Ponalfil trial for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia: Long-term results 针对费城染色体阳性急性淋巴细胞白血病成人患者的 Ponalfil 试验:长期结果
IF 6.6 2区 医学 Q2 Medicine Pub Date : 2024-04-02 DOI: 10.1002/hem3.67
Josep-Maria Ribera, Mireia Morgades, Jordi Ribera, Pau Montesinos, Isabel Cano-Ferri, Pilar Martínez, Jordi Esteve, Daniel Esteban, María García-Fortes, Natalia Alonso, José González-Campos, Arancha Bermúdez, Anna Torrent, Eulàlia Genescà, Clara Maluquer, Joaquín Martínez-López, Ramón García-Sanz

The introduction of tyrosine kinase inhibitors (TKI) has significantly changed the outcome of children and adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).1 Several phase 2 trials have shown improved outcomes with the incorporation of ponatinib to first-line therapy, either in combination with chemotherapy or with blinatumomab,2-4 and a matching adjusted indirect comparison of ponatinib versus imatinib as frontline treatment for Ph+ ALL showed a significant survival advantage for ponatinib over imatinib containing regimens.5 A phase 3 trial comparing imatinib versus ponatinib in combination with attenuated chemotherapy has shown a significantly higher measurable residual disease (MRD)-negative rate at the end of induction in adults with newly diagnosed Ph+ ALL treated with ponatinib.6 The phase 2 PONALFIL trial from the Spanish PETHEMA (Programa Español de Tratamientos en Hematología) group combined ponatinib with standard induction and consolidation chemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHSCT) in 30 adult patients (18–60 years, median age 49 years) with newly diagnosed Ph+ ALL.7 End-induction and postconsolidation complete molecular response (CMR) rates were 47% and 71%, respectively. With a median follow-up of 2.1 years, the 2-year event-free survival (EFS, considering molecular relapse as an event) and overall survival (OS) rates were 70% and 96%, respectively. Only pre-emptive administration of TKI (30 mg/d for the first year and 15 mg/d during the second year) was prescribed by the trial, and 18 out of the 26 transplanted patients did not receive any TKI after the transplant. We hereby report the follow-up of the study, with a median of 4 years.

Figure 1 shows the updated flowchart of the study. All patients (n = 30) achieved complete cytologic response (CCR), although two abandoned the trial due to retina artery thrombosis and severe gastrointestinal infection requiring partial intestinal resection (one patient each). Both patients received dasatinib and remain alive and in CMR. End-induction CMR was attained in 14/30 patients (47%), 5/30 (17%) achieved MMR, and the remaining 11 patients did not achieve molecular response. Two patients discontinued the trial after consolidation. The first showed molecular relapse and due to specific circumstances had to be treated with vincristine, steroids, and dasatinib; this patient is currently alive and in CMR under maintenance with ponatinib. The second patient was removed from the trial by physician criteria because of the lack of molecular response, being treated with blinatumomab and alloHSCT, and is currently under maintenance with dasatinib. AlloHSCT was performed in 26 patients, two of whom died due to the procedure (severe graft versus host disease—GVHD, and severe cytomegalovirus inf

酪氨酸激酶抑制剂(TKI)的问世极大地改变了费城染色体阳性急性淋巴细胞白血病(Ph+ ALL)儿童和成人患者的治疗效果。1 多项 2 期试验显示,将波纳替尼与化疗或 blinatumomab 联合应用于一线治疗后,疗效有所改善2-4,一项将波纳替尼与伊马替尼作为 Ph+ ALL 一线治疗方案的匹配调整间接比较显示,与含有伊马替尼的方案相比,波纳替尼具有显著的生存优势5。一项比较伊马替尼与泊纳替尼联合减毒化疗的3期试验显示,在接受泊纳替尼治疗的新诊断Ph+ ALL成人患者中,诱导治疗结束时可测量的残留疾病(MRD)阴性率明显高于伊马替尼。西班牙 PETHEMA(Programa Español de Tratamientos en Hematología)小组进行的 PONALFIL 2 期试验将波纳替尼与标准诱导和巩固化疗相结合,然后进行异基因造血干细胞移植(alloHSCT)治疗 30 例新诊断 Ph+ ALL 的成人患者(18-60 岁,中位年龄 49 岁)7。中位随访 2.1 年,2 年无事件生存率(EFS,将分子复发视为一个事件)和总生存率(OS)分别为 70% 和 96%。试验只规定了TKI的先期治疗(第一年30毫克/天,第二年15毫克/天),26例移植患者中有18例在移植后未接受任何TKI治疗。图 1 是该研究的最新流程图。所有患者(n = 30)都获得了完全细胞学应答(CCR),但有两名患者因视网膜动脉血栓和严重胃肠道感染而放弃了试验,需要进行部分肠道切除(各一名患者)。这两名患者都接受了达沙替尼治疗,目前仍然存活并进行了 CMR。14/30(47%)名患者获得了诱导末CMR,5/30(17%)名患者获得了MMR,其余11名患者未获得分子反应。两名患者在巩固治疗后中止了试验。第一位患者出现分子学复发,由于特殊情况,不得不接受长春新碱、类固醇和达沙替尼治疗;这位患者目前还活着,正在接受CMR治疗,并使用泊纳替尼维持治疗。第二名患者由于缺乏分子反应,根据医生标准被从试验中剔除,接受了blinatumomab和alloHSCT治疗,目前正在接受达沙替尼的维持治疗。26名患者接受了异体HSCT治疗,其中两人分别在移植后3个月和24个月因该治疗而死亡(严重移植物抗宿主疾病-GVHD和严重巨细胞病毒感染各一名患者)。在其余 23 名移植患者中,有 6 名患者出现了临床或分子复发。复发患者的同工酶为p190(3例)、p210(2例)和p230(1例)。一名患者在移植 25 个月后出现孤立性胸膜复发,再次接受相同的诱导化疗,然后从不同的供体进行了第二次异体造血干细胞移植。该患者目前存活,在第二次异体供体移植 3 个月后进行了 CMR,并接受了泊纳替尼维持治疗。五名患者出现分子性复发(距alloHSCT的中位时间为9个月,范围为4-20),并成功接受了泊纳替尼(30毫克/天)治疗。其中一名患者因出现四级肝毒性而停药,该患者目前处于分子缓解期。两名患者出现骨髓复发。第一位患者接受了 CD19 CAR T 治疗,术后 3 个月,在帕纳替尼(30 毫克/天)的维持下,目前在 CMR 中存活。第二名患者接受了 FLAG Ida 和泊纳替尼(30 毫克/天)的抢救性化疗,治疗 37 个月后仍在 CMR 中存活。其余 17 名患者在最后一次随访时仍未接受治疗。目前在世患者的中位随访时间为 4.1 年(范围为 0.2-6.2 年),4 年 OS 概率为 92%(95% 置信区间 [CI],72%-98%)(图 2A)。PONALFIL试验的随访结果证实了2年中位随访观察到的初步结果,并表明在造血干细胞移植后抢先服用泊纳替尼的政策下,相当一部分患者可以在alloHSCT后获得长期生存。迄今为止,还没有一项对照研究探讨过移植后抢先使用与预防性使用泊纳替尼的问题。在我们的试验中,只有一名患者出现了孤立的髓外复发,而移植后的常规骨髓分子随访并未预计到这一情况。
{"title":"Ponalfil trial for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia: Long-term results","authors":"Josep-Maria Ribera,&nbsp;Mireia Morgades,&nbsp;Jordi Ribera,&nbsp;Pau Montesinos,&nbsp;Isabel Cano-Ferri,&nbsp;Pilar Martínez,&nbsp;Jordi Esteve,&nbsp;Daniel Esteban,&nbsp;María García-Fortes,&nbsp;Natalia Alonso,&nbsp;José González-Campos,&nbsp;Arancha Bermúdez,&nbsp;Anna Torrent,&nbsp;Eulàlia Genescà,&nbsp;Clara Maluquer,&nbsp;Joaquín Martínez-López,&nbsp;Ramón García-Sanz","doi":"10.1002/hem3.67","DOIUrl":"https://doi.org/10.1002/hem3.67","url":null,"abstract":"<p>The introduction of tyrosine kinase inhibitors (TKI) has significantly changed the outcome of children and adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).<span><sup>1</sup></span> Several phase 2 trials have shown improved outcomes with the incorporation of ponatinib to first-line therapy, either in combination with chemotherapy or with blinatumomab,<span><sup>2-4</sup></span> and a matching adjusted indirect comparison of ponatinib versus imatinib as frontline treatment for Ph+ ALL showed a significant survival advantage for ponatinib over imatinib containing regimens.<span><sup>5</sup></span> A phase 3 trial comparing imatinib versus ponatinib in combination with attenuated chemotherapy has shown a significantly higher measurable residual disease (MRD)-negative rate at the end of induction in adults with newly diagnosed Ph+ ALL treated with ponatinib.<span><sup>6</sup></span> The phase 2 PONALFIL trial from the Spanish PETHEMA (Programa Español de Tratamientos en Hematología) group combined ponatinib with standard induction and consolidation chemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHSCT) in 30 adult patients (18–60 years, median age 49 years) with newly diagnosed Ph+ ALL.<span><sup>7</sup></span> End-induction and postconsolidation complete molecular response (CMR) rates were 47% and 71%, respectively. With a median follow-up of 2.1 years, the 2-year event-free survival (EFS, considering molecular relapse as an event) and overall survival (OS) rates were 70% and 96%, respectively. Only pre-emptive administration of TKI (30 mg/d for the first year and 15 mg/d during the second year) was prescribed by the trial, and 18 out of the 26 transplanted patients did not receive any TKI after the transplant. We hereby report the follow-up of the study, with a median of 4 years.</p><p>Figure 1 shows the updated flowchart of the study. All patients (<i>n</i> = 30) achieved complete cytologic response (CCR), although two abandoned the trial due to retina artery thrombosis and severe gastrointestinal infection requiring partial intestinal resection (one patient each). Both patients received dasatinib and remain alive and in CMR. End-induction CMR was attained in 14/30 patients (47%), 5/30 (17%) achieved MMR, and the remaining 11 patients did not achieve molecular response. Two patients discontinued the trial after consolidation. The first showed molecular relapse and due to specific circumstances had to be treated with vincristine, steroids, and dasatinib; this patient is currently alive and in CMR under maintenance with ponatinib. The second patient was removed from the trial by physician criteria because of the lack of molecular response, being treated with blinatumomab and alloHSCT, and is currently under maintenance with dasatinib. AlloHSCT was performed in 26 patients, two of whom died due to the procedure (severe graft versus host disease—GVHD, and severe cytomegalovirus inf","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.67","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140340472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A new mouse model highlights the need for better JAK inhibitors in myeloproliferative neoplasms 一种新的小鼠模型凸显了骨髓增殖性肿瘤对更好的 JAK 抑制剂的需求
IF 6.6 2区 医学 Q2 Medicine Pub Date : 2024-04-02 DOI: 10.1002/hem3.66
Charles E. de Bock

The discovery that the gain of function JAK2V617F mutation is present in myeloproliferative neoplasms (MPNs) has led to numerous clinical trials assessing the efficacy of JAK inhibitors. Most notably, ruxolitinib, a combined JAK1/2 selective inhibitor, has gained approval in patients with myeolofibrosis (MF), and additional JAK2 inhibitors including fedratinib, pacritinib, and momelotinib also under evaluation for patients with MF. However, while these inhibitors demonstrate some clinical benefit, they do not adequately reduce the mutant clone fraction.1, 2 Consequently, a critical question for the field has been whether the lack of a durable response is attributed to either (i) the inability of current JAK inhibitors to completely block the pathway or (ii) the possibility that mutant clones are not entirely dependent on this activated pathway.

To address these two possibilities, a new study from the laboratory of Ross Levine, published in Cancer Discovery,3 developed an innovative mouse model of Jak2V617F alone or in combination with Tet2 loss. The novel aspect of this mouse model lies in the ability to control the expression and genetic deletion of Jak2V617F allele from mutant clones upon development of MPN. To do so, it utilizes two orthogonal site-specific recombinases which exert precise control over the temporal expression and deletion of the Jak2V617F allele.

The mouse model uses the well-established Cre recombinase that recognises short nucleotide target sequences called Lox sites, in conjunction with the relatively new Dre recombinase which recognizes short nucleotide sequences called Rox sites. Importantly, the strategic arrangement and orientation of these sequences can lead to either flipping or deletion of the intervening DNA sequence. In this context, Dre recombinase is employed to initiate the expression of the Jak2V617F allele. Subsequently, a modified CreER recombinase, translocated to the nucleus upon tamoxifen treatment, can delete the Jak2V617F allele (Figure 1A). This intricate mouse model provided a powerful tool for comparing the durability of response between JAK inhibitors and the genetic loss of Jak2V617F in the context of MPNs.

To understand the role of Jak2V617F in the initiation and maintenance in MPNs in vivo, lineage-negative hematopoietic stem and progenitor cells were harvested from donor Ubc:CreER-Jak2Rox/Lox mice. These cells were then electroporated with Dre recombinase-encoding messenger RNA to induce Jak2V617F expression and then transplanted into lethally irradiated recipient mice, that all went on to develop MPNs, confirming that Jak2V617F is both sufficient and necessary for MPN development.

<
这些问题包括:(i) 酪氨酸激酶抑制水平是否能完全表征完全的基因缺失;(ii) 耐药机制(如获得性点突变)是否不可避免;(iii) 强效抑制剂是否会驱使除 JAK2V617F 外含有其他高风险突变的克隆生长?有趣的是,关于第三个问题,最近的一项研究发现,患者的克隆含有 TET2、DNMT3A 和 ASXL1 等基因的高危突变,但缺乏 JAK2V617F,这并不影响预后。它还很好地强调了精确再现血液恶性肿瘤的忠实动物模型的相关性。从历史上看,这些小鼠模型主要集中在单个转基因或病变(如 Jak2V617F)的表达上。然而,随着CRISPR/Cas9等技术在引入特定基因突变方面变得越来越有效,新模型的开发将继续帮助解决重要的临床问题。
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引用次数: 0
Comparison of whole-genome and immunoglobulin-based circulating tumor DNA assays in diffuse large B-cell lymphoma 弥漫大 B 细胞淋巴瘤全基因组检测与基于免疫球蛋白的循环肿瘤 DNA 检测的比较
IF 6.6 2区 医学 Q2 Medicine Pub Date : 2024-04-01 DOI: 10.1002/hem3.47
Reid W. Merryman, Justin Rhoades, Kan Xiong, Robert A. Redd, Katherine Antel, Hyun Hwan An, Mikaela McDonough, Liliana Guerrero, Andela Crnjac, Sainetra Sridhar, Timothy Blewett, Ju Cheng, Parastoo B. Dahi, Yago Nieto, Robin M. Joyce, Yi-Bin Chen, Alex F. Herrera, Philippe Armand, Mark Murakami, Viktor A. Adalsteinsson

Minimal residual disease (MRD) has emerged as a promising biomarker in diffuse large B-cell lymphoma (DLBCL). Both pretreatment levels and dynamic changes in circulating tumor DNA (ctDNA) have been associated with clinical outcomes, and in many studies, ctDNA outperforms traditional response assessment tools.1-3 Newer panel-based approaches (CAPP-Seq, PhasED-Seq) appear to have improved sensitivity compared to immunoglobulin-based high-throughput sequencing (IgHTS).4, 5 There is growing interest in using ctDNA to guide response-adapted treatment approaches in DLBCL and ctDNA techniques that maximize sensitivity while retaining excellent specificity are needed to optimally guide such strategies.

To improve sensitivity, whole-genome sequencing (WGS) has been used to identify patient-specific tumor fingerprints which can be assayed within plasma cell-free DNA (cfDNA). This approach increases the likelihood of detecting tumor mutations but is challenging due to the massive excess of normal cfDNA in plasma. To address this, we developed minor-allele-enriched sequencing through recognition oligonucleotides (MAESTRO) which uses short allele-specific probes to enrich thousands of prespecified mutations and enable their detection using Duplex Sequencing with up to 100-fold fewer sequencing reads.6 We subsequently described a new implementation of this test called MAESTRO-Pool, wherein personalized MRD tests from all patients in cohort studies are pooled into a single test.7 This enables both the detection of MRD in each patient's plasma cfDNA and the assessment of the specificity of each bespoke MRD test using unmatched samples from other patients. We have further described an improved “dynamic MRD caller” that accounts for varied numbers of mutations and cfDNA molecules assayed and reports a probability score for MRD detection.7 This safeguards against false detection and enables the identification of borderline-negative samples for follow-up testing.

Here, we applied MAESTRO-Pool and our dynamic MRD caller in a pilot study, analyzing ctDNA in plasma samples from nine patients with relapsed/refractory DLBCL undergoing autologous stem cell transplantation (ASCT) and comparing our results with those obtained using conventional IgHTS MRD testing.

The study was performed using formalin-fixed paraffin-embedded (FFPE) tissue biopsies and serial post-ASCT peripheral blood samples from patients enrolled in a phase II trial testing pembrolizumab maintenance therapy following ASCT (NCT02362997).8 All patients signed informed consent. Plasma samples were previously analyzed using the IgHTS ClonoSEQ® assay (Adaptive Biotechnologies), and ctDNA was found to be a significant predictor of progression-free survival (PFS).9 Among 31 enrolled patients, nine had leftover genomic DNA (gDN

在 9 位入选患者的 59 个样本中,有一个样本(DL-12 的样本 4)的 MRD 检测结果不一致--使用 MRD 追踪器检测到 4 ppm 的 ctDNA,但使用 MAESTRO-Pool 却检测不到(该样本的特定检测限 [LoD] 为 16 ppm)。使用 MRD Tracker 和 MAESTRO-Pool 估算的肿瘤组分是一致的(图 S1)。即使所需的测序读数减少了 13 倍,我们仍观察到 MRD Tracker(中位数 LoD 40 ppm,范围 1-4727)和 MAESTRO-Pool(中位数 LoD 30 ppm,范围 1-18243)的中位数 LoD 相似(图 S2)。MAESTRO-Pool 还能使用队列中其他患者的非匹配样本对每位患者定制 MRD 检测的特异性进行经验评估(图 S3)。对于九名患者中的七名患者的 MRD 检测,我们在中位数为 52 份(范围 51-54)的其他患者未匹配样本中观察到了 100% 的特异性。其余两名患者(DL-017 和 DL-045)的 MRD 检测在 55 份和 53 份未匹配样本中分别显示出 95% 和 98% 的特异性,在 1、23、3 和 3 ppm 的四个样本中出现了误检。值得注意的是,与之前的一项研究7 相比,我们在该队列中观察到的本底碱基错误率略高,这可能是我们观察到低水平误检的四个样本的原因(图 S4)。在证明 MAESTRO-Pool 能在 DLBCL 患者中鉴定并富集低频患者特异性突变等位基因后,我们接下来试图将 MAESTRO-Pool 与使用 ClonoSeq® 的 IgHTS 进行比较,ClonoSeq® 是一种经食品药品管理局批准的市售 MRD 检测方法(图 1C)。MAESTRO-Pool 在所有五名复发患者的复发前都检测到了ctDNA,包括五名复发患者中四名患者的最早时间点。与 IgHTS(中位数 44 天,范围从未被发现到 518 天)相比,MAESTRO-Pool 从检测到 ctDNA 到临床复发的时间(前导时间)更长(中位数 178 天,范围 69-518 天)(p = 0.37)。与 IgHTS 相比,MAESTRO-Pool 提高了灵敏度(MAESTRO-Pool 对所有样本的灵敏度为 80.6%,对有匹配 ClonoSEQ 结果的样本的灵敏度为 90.5%,而 ClonoSEQ 的灵敏度为 61.9%)(p = 0.006),同时保持了较高的特异性(MAESTRO-Pool 和 ClonoSeq 的特异性均为 100%)。与 ClonoSeq 相比,MAESTRO-Pool 的灵敏度更高,这主要是因为 MAESTRO-Pool 提高了对低于 1000 ppm 的 ctDNA 分馏物的检测能力。IgHTS在10/12个MAESTRO-Pool肿瘤分数≥1000 ppm的样本中检测到了ctDNA,但在3/7个MAESTRO-Pool肿瘤分数&lt;1000 ppm的样本中仅检测到了ctDNA(图1D)。利用复发 DLBCL 中常见突变基因的额外诱饵集,我们在复发患者中发现了多种新型突变。值得注意的是,一名在ASCT后18.5个月病情恶化的患者(DL-015)的血浆中出现了CREBBP R1446H突变,其等位基因频率从ASCT后的0.048%增加到复发时的30.53%(图2B)。在这项试验性研究中,我们发现使用MAESTRO-Pool鉴定的ctDNA是复发/难治性DLBCL患者复发的灵敏标志物。与 IgHTS 相比,MAESTRO-Pool 在保持高特异性的同时提高了灵敏度。通过富集低频患者特异性突变等位基因,MAESTRO-Pool得出了与正交测定(MRD Tracker)相似的结果,但所需的测序量减少了13倍。最后,我们的研究结果表明,这种方法还可以通过使用互补的靶向测序方法来跟踪基因演变。最大限度地提高灵敏度,同时保持近乎完美的特异性,对于开发适应DLBCL的MRD治疗策略至关重要。较新的基于面板的 MRD 方法已证明灵敏度有所提高,但仍可能不够灵敏。例如,III 期 POLARIX 试验中使用 AVENIO CAPP-Seq 检测法评估的早期 ctDNA 动态与 PFS 相关,但效应差异相对较小(2 年 PFS 差异为 -20%)。12 超灵敏 MRD 技术(如 MAESTRO-Pool)依赖于更多的肿瘤报告物,可能更适合 DLBCL 的反应适应性治疗方法,这种方法可以根据患者的个体风险升级或降级治疗。在这里,我们展示了 MAESTRO-Pool 方法可以通过添加相关基因面板来补充,以寻找治疗中出现的突变。即使在测试的小基因组中,我们也发现了复发时出现的新突变,包括 CREBBP 赖氨酸乙酰转移酶结构域中的一个热点突变,在之前的研究中,该突变与 MYC 表达增加13 和 MHC II 类表达减少14 相关。 个性化 MRD 方法确实给临床实施带来了独特的挑战。MAESTRO-Pool 需要 WGS 和个性化探针设计,但每种方法的成本都在持续下降。虽然这种方法需要前期成本,但MAESTRO-Pool能以明显较少的读数检测低丰度突变,而且前期成本可通过连续的MRD样本摊销。尽管如此,我们的研究结果表明,DLBCL 的定制 WGS 液体活检在优化 MRD 检测灵敏度、保持极高特异性和跟踪克隆演变方面具有独特的优势。我们的试点研究结果支持在DLBCL中使用MAESTRO-Pool进行更多研究。Justin Rhoades、Kan Xiong、Mark Murakami和Viktor A. Adalsteinsson设计了研究方案、进行了研究、分析了数据并编辑了论文。罗伯特-A-雷德(Robert A. Redd)分析了数据并审阅了论文。Katherine Antel、Hyun Hwan An、Mikaela McDonough、Liliana Guerrero、Andela Crnjac、Sainetra Sridhar、Timothy Blewett、Ju Cheng、Parastoo B. Dahi、Yago Nieto、Robin M. Joyce、Yi-Bin Chen、Alex F. Herrera和Philippe Armand进行了研究并审阅了论文:Genmab、Adaptive Biotechnologies、Bristol Myers Squibb、Abbvie、Inteillia、Epizyme;顾问:Alphasights;机构研究基金:默克(Merck)、百时美施贵宝(Bristol Myers Squibb)、基因工程公司(Genmab)、基因泰克/罗氏(Genentech/Roche)。Yago Nieto-顾问:Affimed、Novonordisk;研究经费:诺华、Biosecura、阿斯利康、Affimed、武田。Yi-Bin Chen-顾问:Incyte、Jasper、Gamida Cell、Daiichi、Celularity、Equilium、Actinium。Alex F. Herrera-顾问:Bristol Myers Squibb、Gen
{"title":"Comparison of whole-genome and immunoglobulin-based circulating tumor DNA assays in diffuse large B-cell lymphoma","authors":"Reid W. Merryman,&nbsp;Justin Rhoades,&nbsp;Kan Xiong,&nbsp;Robert A. Redd,&nbsp;Katherine Antel,&nbsp;Hyun Hwan An,&nbsp;Mikaela McDonough,&nbsp;Liliana Guerrero,&nbsp;Andela Crnjac,&nbsp;Sainetra Sridhar,&nbsp;Timothy Blewett,&nbsp;Ju Cheng,&nbsp;Parastoo B. Dahi,&nbsp;Yago Nieto,&nbsp;Robin M. Joyce,&nbsp;Yi-Bin Chen,&nbsp;Alex F. Herrera,&nbsp;Philippe Armand,&nbsp;Mark Murakami,&nbsp;Viktor A. Adalsteinsson","doi":"10.1002/hem3.47","DOIUrl":"https://doi.org/10.1002/hem3.47","url":null,"abstract":"<p>Minimal residual disease (MRD) has emerged as a promising biomarker in diffuse large B-cell lymphoma (DLBCL). Both pretreatment levels and dynamic changes in circulating tumor DNA (ctDNA) have been associated with clinical outcomes, and in many studies, ctDNA outperforms traditional response assessment tools.<span><sup>1-3</sup></span> Newer panel-based approaches (CAPP-Seq, PhasED-Seq) appear to have improved sensitivity compared to immunoglobulin-based high-throughput sequencing (IgHTS).<span><sup>4, 5</sup></span> There is growing interest in using ctDNA to guide response-adapted treatment approaches in DLBCL and ctDNA techniques that maximize sensitivity while retaining excellent specificity are needed to optimally guide such strategies.</p><p>To improve sensitivity, whole-genome sequencing (WGS) has been used to identify patient-specific tumor fingerprints which can be assayed within plasma cell-free DNA (cfDNA). This approach increases the likelihood of detecting tumor mutations but is challenging due to the massive excess of normal cfDNA in plasma. To address this, we developed minor-allele-enriched sequencing through recognition oligonucleotides (MAESTRO) which uses short allele-specific probes to enrich thousands of prespecified mutations and enable their detection using Duplex Sequencing with up to 100-fold fewer sequencing reads.<span><sup>6</sup></span> We subsequently described a new implementation of this test called MAESTRO-Pool, wherein personalized MRD tests from all patients in cohort studies are pooled into a single test.<span><sup>7</sup></span> This enables both the detection of MRD in each patient's plasma cfDNA and the assessment of the specificity of each bespoke MRD test using unmatched samples from other patients. We have further described an improved “dynamic MRD caller” that accounts for varied numbers of mutations and cfDNA molecules assayed and reports a probability score for MRD detection.<span><sup>7</sup></span> This safeguards against false detection and enables the identification of borderline-negative samples for follow-up testing.</p><p>Here, we applied MAESTRO-Pool and our dynamic MRD caller in a pilot study, analyzing ctDNA in plasma samples from nine patients with relapsed/refractory DLBCL undergoing autologous stem cell transplantation (ASCT) and comparing our results with those obtained using conventional IgHTS MRD testing.</p><p>The study was performed using formalin-fixed paraffin-embedded (FFPE) tissue biopsies and serial post-ASCT peripheral blood samples from patients enrolled in a phase II trial testing pembrolizumab maintenance therapy following ASCT (NCT02362997).<span><sup>8</sup></span> All patients signed informed consent. Plasma samples were previously analyzed using the IgHTS ClonoSEQ® assay (Adaptive Biotechnologies), and ctDNA was found to be a significant predictor of progression-free survival (PFS).<span><sup>9</sup></span> Among 31 enrolled patients, nine had leftover genomic DNA (gDN","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.47","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140333283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Circulating tumor plasma cells and peripheral blood measurable residual disease assessment in multiple myeloma patients not planned for upfront transplant 对未计划进行前期移植的多发性骨髓瘤患者进行循环肿瘤浆细胞和外周血可测量残留疾病评估
IF 6.6 2区 医学 Q2 Medicine Pub Date : 2024-04-01 DOI: 10.1002/hem3.63
Prashant R. Tembhare, Harshini Sriram, Twinkle Khanka, Sanghamitra Gawai, Bhausaheb Bagal, Sitaram G. Ghogale, Nilesh Deshpande, Karishma Girase, Jagruti Patil, Syed Khaizer Hasan, Dhanalaxmi Shetty, Kinjalka Ghosh, Gaurav Chatterjee, Sweta Rajpal, Nikhil V. Patkar, Hasmukh Jain, Sachin Punatar, Anant Gokarn, Lingaraj Nayak, Sumeet Mirgh, Nishant Jindal, Manju Sengar, Navin Khattry, Papagudi G. Subramanian, Sumeet Gujral

Circulating tumor plasma cells (CTPCs) provide a noninvasive alternative for measuring tumor burden in newly diagnosed multiple myeloma (NDMM). Moreover, measurable residual disease (MRD) assessment in peripheral blood (PBMRD) can provide an ideal alternative to bone marrow MRD, which is limited by its painful nature and technical challenges. However, the clinical significance of PBMRD in NDMM still remains uncertain. Additionally, data on CTPC in NDMM patients not treated with transplant are scarce. We prospectively studied CTPC and PBMRD in 141 NDMM patients using highly sensitive multicolor flow cytometry (HS-MFC). PBMRD was monitored at the end of three cycles (PBMRD1) and six cycles (PBMRD2) of chemotherapy in patients with detectable baseline CTPC. Patients received bortezomib-based triplet therapy and were not planned for an upfront transplant. Among baseline risk factors, CTPC ≥ 0.01% was independently associated with poor progression-free survival (PFS) (hazard ratio [HR] = 2.77; p = 0.0047) and overall survival (OS) (HR = 2.9; p = 0.023) on multivariate analysis. In patients with detectable baseline CTPC, undetectable PBMRD at both subsequent time points was associated with longer PFS (HR = 0.46; p = 0.0037), whereas detectable PBMRD at any time point was associated with short OS (HR = 3.25; p = 0.004). Undetectable combined PBMRD (PBMRD1 and PBMRD2) outperformed the serum-immunofixation-based response. On multivariate analysis, detectable PBMRD at any time point was independently associated with poor PFS (HR = 2.0; p = 0.025) and OS (HR = 3.97; p = 0.013). Thus, our findings showed that CTPC and PBMRD assessment using HS-MFC provides a robust, noninvasive biomarker for NDMM patients not planned for an upfront transplant. Sequential PBMRD monitoring has great potential to improve the impact of the existing risk stratification and response assessment models.

循环肿瘤浆细胞(CTPCs)为测量新诊断多发性骨髓瘤(NDMM)的肿瘤负荷提供了一种无创替代方法。此外,外周血中可测量的残留疾病(MRD)评估(PBMRD)可作为骨髓MRD的理想替代方法,而骨髓MRD因其痛苦和技术难度而受到限制。然而,PBMRD在NDMM中的临床意义仍不确定。此外,关于未接受移植治疗的NDMM患者的CTPC数据也很少。我们使用高灵敏度多色流式细胞术(HS-MFC)对141例NDMM患者的CTPC和PBMRD进行了前瞻性研究。在化疗三个周期(PBMRD1)和六个周期(PBMRD2)结束时,对可检测到基线 CTPC 的患者的 PBMRD 进行了监测。患者接受以硼替佐米为基础的三联疗法,不计划进行前期移植。在基线风险因素中,CTPC ≥ 0.01% 与无进展生存期 (PFS) 差(危险比 [HR] = 2.77; p = 0.0047)和总生存期 (OS) 差(HR = 2.9; p = 0.023)独立相关。在可检测到基线 CTPC 的患者中,在随后两个时间点均检测不到 PBMRD 与较长的 PFS 相关(HR = 0.46;p = 0.0037),而在任何时间点均检测到 PBMRD 与较短的 OS 相关(HR = 3.25;p = 0.004)。检测不到的联合PBMRD(PBMRD1和PBMRD2)优于基于血清免疫固定的反应。在多变量分析中,任何时间点检测到的PBMRD都与不良的PFS(HR = 2.0; p = 0.025)和OS(HR = 3.97; p = 0.013)独立相关。因此,我们的研究结果表明,使用 HS-MFC 评估 CTPC 和 PBMRD 可为未计划进行前期移植的 NDMM 患者提供可靠的无创生物标志物。序贯 PBMRD 监测在改善现有风险分层和反应评估模型的效果方面具有巨大潜力。
{"title":"Circulating tumor plasma cells and peripheral blood measurable residual disease assessment in multiple myeloma patients not planned for upfront transplant","authors":"Prashant R. Tembhare,&nbsp;Harshini Sriram,&nbsp;Twinkle Khanka,&nbsp;Sanghamitra Gawai,&nbsp;Bhausaheb Bagal,&nbsp;Sitaram G. Ghogale,&nbsp;Nilesh Deshpande,&nbsp;Karishma Girase,&nbsp;Jagruti Patil,&nbsp;Syed Khaizer Hasan,&nbsp;Dhanalaxmi Shetty,&nbsp;Kinjalka Ghosh,&nbsp;Gaurav Chatterjee,&nbsp;Sweta Rajpal,&nbsp;Nikhil V. Patkar,&nbsp;Hasmukh Jain,&nbsp;Sachin Punatar,&nbsp;Anant Gokarn,&nbsp;Lingaraj Nayak,&nbsp;Sumeet Mirgh,&nbsp;Nishant Jindal,&nbsp;Manju Sengar,&nbsp;Navin Khattry,&nbsp;Papagudi G. Subramanian,&nbsp;Sumeet Gujral","doi":"10.1002/hem3.63","DOIUrl":"https://doi.org/10.1002/hem3.63","url":null,"abstract":"<p>Circulating tumor plasma cells (CTPCs) provide a noninvasive alternative for measuring tumor burden in newly diagnosed multiple myeloma (NDMM). Moreover, measurable residual disease (MRD) assessment in peripheral blood (PBMRD) can provide an ideal alternative to bone marrow MRD, which is limited by its painful nature and technical challenges. However, the clinical significance of PBMRD in NDMM still remains uncertain. Additionally, data on CTPC in NDMM patients not treated with transplant are scarce. We prospectively studied CTPC and PBMRD in 141 NDMM patients using highly sensitive multicolor flow cytometry (HS-MFC). PBMRD was monitored at the end of three cycles (PBMRD1) and six cycles (PBMRD2) of chemotherapy in patients with detectable baseline CTPC. Patients received bortezomib-based triplet therapy and were not planned for an upfront transplant. Among baseline risk factors, CTPC ≥ 0.01% was independently associated with poor progression-free survival (PFS) (hazard ratio [HR] = 2.77; <i>p</i> = 0.0047) and overall survival (OS) (HR = 2.9; <i>p</i> = 0.023) on multivariate analysis. In patients with detectable baseline CTPC, undetectable PBMRD at both subsequent time points was associated with longer PFS (HR = 0.46; <i>p</i> = 0.0037), whereas detectable PBMRD at any time point was associated with short OS (HR = 3.25; <i>p</i> = 0.004). Undetectable combined PBMRD (PBMRD1 and PBMRD2) outperformed the serum-immunofixation-based response. On multivariate analysis, detectable PBMRD at any time point was independently associated with poor PFS (HR = 2.0; <i>p</i> = 0.025) and OS (HR = 3.97; <i>p</i> = 0.013). Thus, our findings showed that CTPC and PBMRD assessment using HS-MFC provides a robust, noninvasive biomarker for NDMM patients not planned for an upfront transplant. Sequential PBMRD monitoring has great potential to improve the impact of the existing risk stratification and response assessment models.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.63","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140333284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
From hypoxia single-cell gene signatures to HIF targeting of AML leukemic stem cells 从缺氧单细胞基因特征到针对急性髓细胞性白血病干细胞的 HIF
IF 6.6 2区 医学 Q2 Medicine Pub Date : 2024-03-29 DOI: 10.1002/hem3.59
Thomas Mercher, Juerg Schwaller

The role of hypoxia and the transcriptional regulation by hypoxia-inducible factors (HIF) is intensively studied in many tissues and pathologies and gained the most attention in cancer including acute myeloid leukemia (AML).1 Here, Velasco-Hernandez et al. addressed the important issue of the heterogeneity of hypoxia gene signature activation not only between major AML genetic subgroups but also between different populations of patient cells at diagnosis and relapse using single-cell transcriptomes. Their data support the potential of targeting hypoxia-induced gene regulation in leukemic stem cells (LSC) in AML.2

Oxygen homeostasis is transcriptionally regulated by a family of hypoxia-inducible factors (HIF) that act as transcriptional activators and repressors. Heterodimeric HIFs are formed by a constitutively expressed HIF1β subunit (encoded by ARNT) and a HIF1/2/3α (encoded by HIF1A, EPAS1, HIF3A, respectively). While constantly degraded by the proteasome under normoxia, mediated by the oxygen sensor PHD proteins, in hypoxia, HIF-1/2/3α binds to its cofactor and controls the transcription of target genes in a cell-context-specific manner.3

In their study, Velasco-Hernandez et al. first interrogated hypoxia-regulated gene expression signatures in patient-derived data sets. They found that the driver genetic lesions determined whether the disease was “HIFhigh,” including cases with core-binding factor alterations, or “HIFlow,” including cases with KMT2A rearrangements (KMT2A-r). They also addressed the HIF expression signature in various leukemic cell populations of 11 patient samples by single-cell RNA-sequencing (scRNA) and defined fractions enriched in LSCs (LSC34) or not (non-LSC34/38), based on the highest expression of a previously established LSC-6 expression score and LSC surface markers. Comparison with six different hypoxic gene expression signatures revealed that LSC34 cells had the lowest hypoxia score and lowest HIF1A levels in all patients. Importantly, in all genetic AML subgroups, the hypoxia score was higher in LSC34 compared to healthy CD34+ hematopoietic stem and progenitor cells (HSPCs). Comparing the scRNA signatures from diagnosis and relapse revealed significant inter-patient transcriptional changes with an overall inverse evolution between hypoxia and the increased LSC-6 score.

To explore the therapeutic potential of the elevated expression of hypoxia-related genes including HIF1A in LSC34, Velasco and colleagues tested the effects of small-molecule HIF inhibitors on primary cells from six AML patients. Hypoxic long-term culture-initiating cell assays revealed that BAY87-2243, a molecule reported to inhibit mitochondrial complex I activity impairing hypoxia-induced HIF-1α and HIF-2α upregulation and HIF target genes expression, fu

与结合了单个细胞核转录组和染色质可及性的数据集进行进一步比较可提供更多见解,特别是低氧特征是否会在所报道的从急性髓细胞性白血病诊断到复发期间向B细胞样程序转变时发生改变5。在对 Hif1a、Hif2a 或两者进行条件性失活后,Vukovic 等人发现,在 KMT2-MLLT3 驱动的 AML 中,Hif2a 的消减加速了 LSC 的发育,但并不影响 LSC 的维持。Hif1a和Hif2a的消减也抑制了由HOXA9/MEIS1驱动的LSC发育。然而,CRISPR/Cas9介导的HIF2a消减并不影响人KMT2A-MLLT3+ THP1 AML细胞在常氧或低氧条件下的存活、增殖和集落形成。此外,将 KMT2A-MLLT3+ THP1 或 NOMO1 细胞暴露于 BAY87-224 也不会影响其在低氧条件下的存活。6 其他人观察到,Hif1a 的基因失活不仅不会损害化疗暴露的 KMT2A-MLLT3 驱动的 AML,反而会加速其进展,这引起了人们对骨髓恶性肿瘤 HIF 靶向治疗的担忧。然而,最近的一项研究发现,短发夹 RNA 介导的 HIF2α 基因敲除会损害体外集落形成,并诱导多个急性髓系白血病细胞系在常氧状态下进行髓系分化。敲除 HIF2α 还会影响与体内分化相关的 PDX AML 进展。此外,一种小分子 HIF2α 抑制剂(PT2385)能在常氧状态下诱导 AML 细胞系和 PDX 细胞分化。有趣的是,HIF2α 似乎受视黄醇受体调控,抑制 HIF2α 与 ATRA 对 AML 细胞分化有协同作用。然而,BAY87-224 等小分子 HIF 抑制剂与 Ara-C 协同作用的机制仍不清楚。早先的一项研究提供了一些潜在的联系,该研究显示缺氧会导致脱氧胞苷激酶的表达减少,而脱氧胞苷激酶是一种细胞抗坏血酸活化酶,BAY87-2243 的治疗可以挽救脱氧胞苷激酶的表达,这表明协同作用主要增加了 Ara-C 的抗白血病活性。据报道,多种化合物可通过各种机制抑制 HIF1a 的活性,包括减少蛋白质合成和/或表达、增加降解、干扰异源二聚化、减少 DNA 结合或干扰转录激活。Velasco 等人使用的两种抑制剂 BAY87-2243 和 PX-478 据报道都会影响 HIF1A 蛋白的表达,但具体机制仍不清楚。11 因此,进一步探索其他 HIF 抑制剂与标准化疗的潜在协同作用并探索其潜在机制非常重要。首先,正如 Velasco 等人所指出的,不同基因型的急性髓细胞性白血病患者的 HIF 基因激活存在显著差异。在一些罕见病例中,这可能是由于罕见的 AML 相关 ETV6-ARNT 融合体干扰了 HIF 二聚体所致。12 此外,正如作者所强调的,本研究排除了 IDH 突变病例产生的副代谢产物 2-羟基戊二酸,它可能通过抑制 PHD 蛋白影响 HIF1α 的稳定性。14 第三,由于 HIF 调控的靶基因网络复杂而广泛,因此需要确定可提供协同策略的关键效应物。第四,尽管有大量化合物可干扰缺氧调控 HIF 因子的表达、修饰和转录激活,但我们仍然缺乏能特异性关闭转录活性的同工酶选择性化合物。最后,更好地了解缺氧介导的 HIF 激活后果与其他细胞过程(包括线粒体/代谢或其他转录/表观遗传调控机制)之间的相互作用将非常重要15。事实上,这可能导致有趣的组合方法,不仅与标准化疗,而且与其他普遍作用的抗白血病药物,如 BH3-模拟物或 DNA 甲基转移酶抑制剂,或与 AML 癌基因特异性药物(如 menin 抑制剂)。
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