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通讯作者:

沈文怡,E-mail:bangbangswy@163.com

中图分类号:R733.3

文献标识码:A

文章编号:1007-4368(2024)02-271-06

DOI:10.7655/NYDXBNSN230864

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目录contents

    摘要

    骨髓增生异常肿瘤(myelodysplastic neoplasms,MDS)患者的预后与其细胞遗传学和分子遗传学特征密切相关, TP53基因作为MDS最常见的突变基因之一,其异常是MDS独立的不良预后因素以及向急性髓系白血病(acute myeloid leuke- mia,AML)转化的危险因素之一。新近更新的第5版世界卫生组织血液淋巴肿瘤分类标准(the 5th edition of the who classifica- tion of haematolymphoid tumours,WHO 2022)以及髓系肿瘤和急性白血病的国际共识分类(international consensus classification of myeloid neoplasms and acute leukemia,ICC)将伴有TP53双等位基因失活(biallelic TP53 inactivation,biTP53)的MDS作为独立的亚型列出,该亚型患者预后极差,生存期极短。目前针对伴TP53基因异常的MDS患者的治疗尚未能有效改善该类患者预后,新型靶向药物、免疫治疗等均在探索中,本文就国内外对伴TP53基因异常的MDS的临床研究进展进行综述。

    Abstract

    The prognosis of patients with myelodysplastic neoplasms(MDS)is closely linked to their cytogenetic and molecular genetic characteristics. Among the most prevalent genetic mutations in MDS,the TP53 gene abnormalities stand out as an independent adverse prognostic factor for MDS and a significant risk factor for the progression to acute myeloid leukemia(AML). The recently updated 5th edition of the WHO classification of haematolymphoid tumours(WHO 2022)and international consensus classification of myeloid neoplasms and acute leukemia(ICC)recognizes MDS with TP53 biallelic inactivation(biTP53)as a distinct and independent subtype. Patients within this subtype face an exceedingly grim prognosis with an extremely short survival period. Currently,available treatments for MDS patients with TP53 gene abnormalities have proven ineffective in improving their prognosis. Consequently,there is a growing focus on exploring new avenues such as targeted therapies and immunotherapy. This article provides an in-depth review of the progress in clinical research related to MDS with TP53 gene abnormalities,both within domestic and international contexts.

    关键词

    骨髓增生异常肿瘤TP53预后治疗

  • 骨髓增生异常肿瘤(myelodysplastic neoplasms, MDS)是一组起源于造血干细胞的异质性髓系克隆性疾病,其特征是髓系细胞发育异常,表现为无效造血、难治性血细胞减少和向急性髓系白血病 (acute myeloid leukemia,AML)转化的高风险。第5 版世界卫生组织血液淋巴肿瘤分类标准(the5th edition of the who classification of haematolymphoid tu⁃ mours,WHO 2022)以及急性白血病的国际共识分类 (international consensus classification of myeloid neo⁃ plasms and acute leukemia,ICC)诊断标准均将 TP53 等位基因状态纳入MDS的分型诊断标准中,并将伴有 TP53 双等位基因失活(biallelic TP53 inactivia⁃tion,biTP53)的MDS作为独立的亚型[1-2],该类型预后极差,中位总生存期(overall survival,OS)仅8.7个月[3-4]。目前尚无针对伴TP53基因异常的MDS患者的明确有效治疗方案,治疗手段仍以去甲基化药物、异基因造血干细胞移植、最佳支持治疗以及临床试验等为主,部分新药临床试验显示出对此类患者的初步疗效,但仍需进一步大样本研究的验证[5-7]。本文就伴TP53基因异常的MDS的临床、分子学特征、预后特征及目前国内外治疗的研究进展进行如下综述。

  • 1 MDS中TP53基因异常概况

  • TP53 基因位于染色体 17p13.1,是人类肿瘤发生过程中最常见的突变基因之一,大部分TP53基因异常会导致TP53功能部分或完全丧失,使细胞脱氧核糖核酸(deoxyribonucleic acid,DNA)损伤修复以及凋亡功能下调,最终破坏基因组的完整性和稳定性从而致病[8]。各类型TP53基因异常在MDS中的发生率远低于其在实体肿瘤中的比例,为5~10%[9],包括点突变、大片段缺失、拷贝数中性的杂合性缺失 (copy nutral loss of heterozygosity,cnLOH)等[4]。研究表明,TP53 突变大多发生于第 4~8 号外显子区,最常见的突变位点为 p.R248W/Q、p.R175H、p. P72R、p.R273H、p.Y220C 等[10-11]。约 2/3 的伴 TP53 异常的MDS患者被检出存在TP53“多重打击”,导致 biTP53,进一步导致MDS恶性克隆缺乏有功能的野生型 p53 蛋白。其中 24%的患者携带多个位点的 TP53突变,22%的患者同时出现基因突变和17号染色体短臂缺失,21%的患者为基因突变伴cnLOH[4]

  • 2 伴TP53基因异常MDS患者的临床及分子学特征

  • 在MDS中,TP53基因异常通常与疾病高危、进展及 AML 转化相关[3-4912]。一项研究表明,相比 TP53 野生型 MDS(TP53 ⁃ wildtype myelodysplastic neoplasms,TP53w ⁃ MDS)患者,TP53 突变型 MDS (TP53 ⁃ mutated myelodysplastic neoplasms,TP53m ⁃ MDS)患者平均血小板计数更低(47×109 个/L vs.70× 109 个/L,P=0.002),骨髓原始细胞比例更高(9% vs.5%,P <0.001)[12]。骨髓增生异常肿瘤伴TP53双等位基因失活(myelodysplastic neoplasms with biallelic TP53 inactivation,biTP53⁃MDS)患者比TP53单位点突变患者具有更高的骨髓原始细胞比例(9% vs.4%,P <0.001)、更低的全血细胞计数[4]。TP53突变和复杂核型(complex karyotype,CK)通常伴随发生。一项研究表明,TP53m ⁃MDS的中位染色体异常数为 8,而 TP53w ⁃MDS 患者的中位染色体异常数仅为4(P <0.001)[13]。MDS伴CK患者TP53突变比例可达 78.3%,且 TP53 多位点突变的比例明显高于 TP53 单位点突变[314],占 TP53 突变的 89%[12],提示残存的有功能的野生型p53蛋白在维持基因组稳定性中发挥至关重要的作用。

  • TP53m ⁃MDS患者相比TP53w ⁃MDS患者平均突变基因数目更多(2.52 vs.1.96,P=0.016)[15],且两者的高频突变基因也有差异[12]。国际工作组(interna⁃ tional working group,IWG)一项研究提示 TET2 (10%)、DNMT3A(9%)是TP53m ⁃MDS中最常见的共突变基因,而 TP53w ⁃MDS 中最常见的突变基因为 ASXL1(14%)、U2AF1(9%)、RUNX1(8%)、DNMT3A (8%)[12];另一项纳入 261 例 MDS 患者的研究提示 TP53m ⁃MDS患者常见的共突变基因为TET2(15%)、 DNMT3A(11%)、ASXL1(7%)和 SF3B1(7%)[3]。亚组分析表明,TP53单位点突变MDS患者的平均基因突变数目显著高于biTP53患者,约90%的单位点突变患者存在1个及以上共突变基因,其中50%患者有3个及以上共突变基因;而高达40%的biTP53患者无共突变基因[4]。TP53单位点突变患者的TET2、 SF3B1、ASXL1、RUNX1、SRSF2、JAK2、BCOR和CBL 的突变频率显著高于 biTP53 患者[4]。在伴 CK 的 TP53m ⁃MDS患者中,平均共突变基因数目相比非CK 患者更少[12]

  • 3 伴TP53基因异常MDS患者的预后特征

  • 3.1 TP53等位基因状态及等位基因突变频率(vari⁃ ant allele frequency,VAF)对预后的影响

  • 多项研究表明,TP53等位基因状态在MDS预后中有着重要作用[3-413]。biTP53 是独立于修订版国际预后评分系统(revised international prognostic scoring system,IPSS⁃R)的不良预后因素,而TP53单位点突变患者与野生型TP53患者相比则无明显的生存劣势[4]。在 Bernard 等[4] 的研究中,biTP53 与 TP53单位点突变MDS患者的中位OS分别为8.7个月 vs.2.5 年(P <0.001),5 年 AML 转化率分别为 44% vs.21%(P <0.001),TP53w ⁃MDS患者的中位OS 为3.5年,TP53单位点突变与TP53w ⁃MDS患者的OS 差异无统计学意义。相比biTP53,TP53单位点突变 MDS患者对去甲基化治疗、异基因造血干细胞移植有更佳的治疗反应[4]

  • Yabe等[9] 认为根据TP53 VAF值可以将MDS分为不同的预后亚组,TP53 VAF>60%的患者比TP53 VAF<60%患者预后更差,中位OS为5.5个月vs.27个月(P=0.044)。而 Grob 等[16] 则认为 TP53 VAF 值对 OS无显著影响。Swoboda等[17] 分析了在环铁细胞增多的 MDS 患者中 TP53 VAF 值对预后的影响,发现 TP53 VAF>40% 与 <20% 的患者之间 OS 无差异 (18.0 个月 vs.11.7 个月,P=0.77)。Montalban⁃Bravo 等[3]的研究表明,伴 CK 的 MDS 患者的中位 TP53 VAF 值较不伴 CK 患者明显升高(33.9% vs.5.1%, P <0.001),提示高TP53 VAF值更易合并CK可能是 TP53 VAF值导致不良结局的原因之一。在疗效方面,TP53 VAF值下降程度与去甲基化治疗的客观缓解率(objective response rate,ORR)、OS呈正相关,而初治时 TP53 VAF 值越高,疾病持续缓解时间越短。TP53 VAF值在治疗有效的患者中呈现下降趋势,61%的 MDS 患者疾病进展或转 AML 时 TP53 VAF值升高[3]。TP53 VAF值对MDS患者预后和疗效的影响还需要更多的临床研究去验证。

  • 鉴于不同TP53等位基因状态拥有独特的生物学特征,且其对疾病转归有重要影响,近来 WHO 2022 以及 ICC 诊断标准均将其纳入 MDS 的诊断分型中,并将 MDS ⁃ biTP53 划分为独立的亚型[1-2]。 WHO 2022标准诊断biTP53需满足以下条件之一: ①存在≥2 个不同位点的突变;②单位点突变,且 TP53 VAF>50%;③单位点突变伴17号染色体短臂缺失(17p⁃);④单位点突变伴cnLOH[1]。ICC标准诊断 biTP53 需满足以下之一:①存在≥2 个的基因突变位点,VAF 值均>10%;②单位点突变,且 VAF>50%;③单位点突变伴 17p ⁃;④单位点突变伴 cn⁃ LOH;⑤单位点突变伴CK[2]

  • WHO 2022标准与ICC标准关于biTP53的诊断大体相同,且均未对不符合 biTP53 诊断标准的 TP53m ⁃MDS进行特别分类,但两者之间尚存在以下差异:①ICC 标准认为多位点突变需 VAF 值均> 10%,而WHO 2022标准对此未作要求;②ICC标准认为TP53单位点突变合并CK时,即可诊断biTP53,而WHO 2022标准则未对此进行说明。哪种诊断标准更适合临床应用还需要更多的临床研究加以验证。

  • 3.2 共突变情况对预后的影响

  • 其他基因共突变状态对TP53m ⁃MDS患者OS的影响尚无定论。Weinberg等[13] 的研究提示在TP53m ⁃ MDS中,有无其他基因突变以及共突变基因数目均对 OS 没有显著影响。Bernard 等[4] 则报道,在 TP53 单位点突变MDS患者中,无共突变基因、1~2个共突变基因、3~4个共突变基因、5个及以上共突变基因患者的5年生存率分别为81%、36%、26%、8%,存在显著差异;而biTP53患者的预后与共突变基因数目无关,5年OS均<6%。此外,在TP53突变的基础之上获得新的基因突变可能是MDS疾病进展的驱动因素,Montalban⁃Bravo 等[3] 报道 65%的 TP53m⁃MDS 患者在疾病进展时检测出新的基因突变,如IDH1、 TET2、KDM6A等。

  • 3.3 CK对预后的影响

  • CK 被认为是 MDS 的独立预后不良因素,TP53 突变合并CK预后更差[121418]。有研究表明,TP53m ⁃ MDS伴CK的患者比不伴CK的患者的中位OS更短 (10.7个月vs.22.1个月,P <0.001)[3]。在一项关于异基因造血干细胞移植治疗 TP53m ⁃MDS/AML 患者的研究中,9例伴有CK及12例无CK的TP53m ⁃MDS/ AML患者3年OS分别为38.1%和91.7%(P=0.004)[19]。 Stengel 等[20] 的研究显示,在 TP53 单位点突变 MDS 患者中,伴有CK比无CK的中位OS更短(14个月vs.46 个月,P=0.035);而在 biTP53⁃MDS 患者中,伴有 CK 与无 CK 的中位 OS 差异无统计学意义(4 个月 vs.2 个月)。治疗相关 MDS 相比原发性 MDS, biTP53 发生率分别为 84%和 65%[4],且更易合并 CK[3-41321],预后更差[13]

  • 4 伴TP53基因异常的MDS的治疗

  • 4.1 去甲基化药物(hypomethylation agents,HMA) 为基础的治疗

  • HMA主要包括地西他滨(decitabine,DAC)和阿扎胞苷(azacitidine,AZA),目前仍是高危 MDS 的一线治疗选择[22-23],主要通过降低基因启动子区域 CpG岛的甲基化而达到治疗目的[24]。有研究表明, TP53m⁃MDS 患者与 TP53w ⁃MDS 患者相比,对 HMA 治疗的反应率没有显著差异(ORR:45% vs.32%, P=0.13),但持续反应时间更短(5.7 个月 vs.28.5 个月,P=0.003)[22]。另一项研究则显示,TP53m⁃MDS 患者较TP53w ⁃MDS患者接受HMA治疗后更易达到完全缓解(complete remission,CR)/部分缓解(partial remission,PR)(83.3% vs.71.4%,P=0.012)[25]。 Chang等[23] 研究发现,接受HMA治疗的TP53m ⁃MDS 患者比 TP53w ⁃ MDS 患者更易达到 CR(66.7% vs.21.3%,P=0.001),但OS更短(14个月vs.39个月,P= 0.012),可能与TP53m ⁃MDS患者在达到CR后更易复发以及转AML有关。

  • 维奈克拉是一种 B 细胞淋巴瘤⁃2 基因(B⁃cell lymphoma⁃2,BCL⁃2)抑制剂,可诱导依赖BCL⁃2及其下游信号通路生存的恶性细胞的凋亡[26]。Bazinet 等[27] 和Ball等[28] 分别报道,维奈克拉联合HMA治疗 TP53m ⁃MDS 患者的 ORR 为 67%和 36%。Ball 等[28] 报道维奈克拉联合HMA治疗MDS(11例伴有TP53 突变)患者的中位OS为19.5个月,其中在HMA单药治疗失败后接受维奈克拉联合HMA治疗的患者的中位OS仍可达11.4个月。但Zeidan等[29] 报道维奈克拉联合 HMA 治疗 TP53m ⁃MDS 患者的 ORR 仅为 20%。维奈克拉能否有效改善TP53m ⁃MDS患者的预后,仍需更多研究数据验证。

  • 4.2 异基因造血干细胞移植(allogeneic hematopoi⁃ etic stem cell transplantation,allo⁃HSCT)

  • allo⁃HSCT 是唯一可能治愈 MDS 的治疗选择,但 TP53m ⁃MDS 患者接受 allo ⁃HSCT 后 3 年 OS 仅为 20%[30]。一项关于allo⁃HSCT 治疗TP53m ⁃MDS/AML (21例MDS,21例AML)患者的研究显示,3年OS为 66.3%,其中,23例TP53单位点突变患者3年OS为 60.6%,8 例 biTP53 患者 3 年 OS 为 57.1%[19]。TP53 突变是 MDS 患者接受 allo⁃HSCT 后复发、进展以及死亡的主要原因之一,这可能和TP53突变高度抑制免疫微环境以及造成免疫逃逸有关[30]。一项纳入 21例MDS和26例AML患者的研究指出,TP53微小残留病变可作为 allo⁃HSCT 后预后预测因子,TP53 突变完全清除组与TP53突变持续存在组的中位OS 分别为 21.7 个月和 8.1 个月(P=0.106)[31]。关于 TP53突变患者移植后维持治疗的研究数据有限,需要更多临床试验进行探索。

  • 4.3 p53小分子稳定剂

  • Eprenetapopt(APR⁃246)是一种小分子p53蛋白稳定剂,通过恢复p53蛋白的构象和功能,从而诱导癌细胞的程序性凋亡[32]。APR⁃246 联合 AZA 的协同作用是通过下调细胞中的 FMS 样酪氨酸激酶 3 (FMS⁃like tyrosine kinase3,FLT3)通路介导的[33]。一项探索APR⁃246联合AZA治疗TP53m ⁃MDS(40例)及 TP53m ⁃AML(11例)患者的Ⅱ期临床试验结果表明,接受 AZA 联合 APR⁃246 治疗的 TP53m ⁃MDS 患者的 ORR 为 73%,完全缓解率(complete remission rate, CRR)为50%,且TP53 VAF值在治疗有效的患者中呈下降趋势[5]。在另一项针对APR⁃246联合AZA用于 TP53m ⁃MDS(34 例)及 TP53m ⁃AML(18 例)患者的 Ⅱ期临床试验中,TP53m ⁃MDS 患者的 ORR 为 62%,中位缓解持续时间为10.4个月,且TP53 VAF与治疗反应持续时间、OS 呈负相关[34]。在一项纳入 19 例HSCT后TP53m ⁃MDS患者及14例TP53m ⁃AML患者的 Ⅱ期临床试验中,1年OS为79%,中位OS为20.6个月[35],接受AZA联合APR⁃246治疗的TP53m ⁃MDS患者的中位OS为586 d [32]。仍需进一步行大样本量研究明确APR⁃246的治疗潜力。

  • 4.4 CD47单克隆抗体

  • CD47在正常细胞以及肿瘤细胞中普遍表达,可使癌细胞逃避免疫系统的监测,从而避免被巨噬细胞破坏[36-38]。Magrolimab 是以 CD47 为靶点的免疫球蛋白 G4(immunoglobulin G4,IgG4)单克隆抗体,抑制 CD47 的表达,使恶性细胞被免疫系统吞噬清除[36-38]。在一项研究Magrolimab联合AZA治疗初治高危 MDS 患者的 Ib 期临床试验中,共纳入 95 例患者(TP53w ⁃MDS 70 例,TP53m ⁃MDS 25 例),结果显示 TP53w ⁃MDS 患者的 CRR 为 31%,未达到中位 OS; TP53m ⁃MDS 患者的 CRR 为 40%,中位 OS 为 16.3 个月[6]。另一项Magrolimab联合AZA用于初治中高危 MDS(18例)以及AML(25例)患者的Ib期临床试验中,Magrolimab联合AZA治疗初治MDS患者的ORR 为100%,CRR为54%,其中2例TP53m ⁃MDS患者中, 1例CR,1例骨髓层面CR[39]。Magrolimab 或许可以改善TP53突变患者的不良预后,但是仍需要更大样本量的研究去进一步验证。

  • 4.5 TIM⁃3单克隆抗体

  • T淋巴细胞免疫球蛋白及黏蛋白3(T cell immu⁃ noglobulin domain and mucin domain⁃3,TIM⁃3)是人体内的一种免疫调节因子,能诱导肿瘤细胞免疫耐受,并与白血病转化相关[40-42]。Sabatolimab 是一种以TIM⁃3为靶点的IgG4抗体,通过抑制TIM⁃3从而阻断肿瘤细胞的免疫耐受,促进免疫系统清除恶性克隆[7]。一项关于 Sabatolimab 联合 HMA 治疗 MDS 的Ib期临床试验中(共纳入53例患者,其中14例伴有TP53突变),ORR为56.9%,中位缓解持续时间为 16.4个月,其中TP53m ⁃MDS患者的ORR为71.4%,中位缓解持续时间则为21.5个月[7]。初步说明Sabato⁃ limab在TP53m ⁃MDS患者中的治疗优势,有待后续临床研究加以证实。

  • 5 结语

  • 伴TP53基因异常的MDS患者具有独特的临床特征、细胞遗传学特征及基因突变谱系。biTP53 MDS患者相比TP53单位点突变的MDS患者预后更差,更易向AML转化,最近更新的WHO 2022及ICC 分型诊断标准均将其归为独立的诊断亚型。目前尚无公认的治疗手段能够显著改善该类患者的不良结局,CD47 单抗、TIM⁃3 单抗等新靶点药物和细胞及免疫治疗的探索性临床试验初步显现出治疗潜力,仍需进一步大规模临床试验论证。

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