世界卫生组织第5版和国际共识分类指南对TP53突变型髓系肿瘤的验证：一项独立国际队列研究

Validation of the 5th edition of the World Health Organization and International Consensus Classification guidelines for TP53-mutated myeloid neoplasm in an independent international cohort.

作者信息

Shah Mithun Vinod, Hung Kevin, Baranwal Anmol, Wechalekar Gauri, Al-Kali Aref, Toop Carla R, Greipp Patricia, Kutyna Monika M, Matin Aasiya, Ladon Dariusz, Saliba Antoine, Chen Dong, Begna Kebede, Brown Anna, Rud Danielle, Litzow Mark R, Hogan William J, Bardy Peter, Badar Talha, Kumar Sharad, Yeung David T, Patnaik Mrinal M, Foran James M, He Rong, Gangat Naseema, Hefazi Mehrdad, Scott Hamish S, Arana Yi Cecilia Y, Alkhateeb Hassan, Mangaonkar Abhishek A, Thomas Daniel, Hahn Christopher N, Orazi Attilio, Arber Daniel A, Kok Chung Hoow, Tefferi Ayalew, Hiwase Devendra

机构信息

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Department of Haematology, Royal Adelaide Hospital, Central Adelaide Local Health Network, Adelaide, SA, Australia.

出版信息

Blood Cancer J. 2025 May 7;15(1):88. doi: 10.1038/s41408-025-01290-0.

DOI:10.1038/s41408-025-01290-0

PMID:40335478

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12059121/

Abstract

The World Health Organization (WHO-5) and International Consensus Classification (ICC) acknowledge the poor prognosis of TP53-mutated (TP53) myeloid neoplasm (MN). However, there are substantial differences between the two classifications that may lead to under- or overestimation of the prognostic risk. We retrospectively applied WHO-5 and ICC to 603 MN cases harboring TP53 (variant allele frequency, VAF ≥ 2%). WHO-5 and ICC would not classify 64% and 20% of these cases as TP53 MN, respectively. Moreover, of those classified, 67.5% would be classified discrepantly. Primary drivers of discrepancies included: (i) prognostic importance of TP53 acute myeloid leukemia (AML), (ii) interaction of the blast percentage and allelic status, (iii) 17p.13.1 deletion detected by cytogenetics, (iv) complex karyotype (CK) as multi-hit equivalent, and (v) TP53 VAF threshold, we analyzed survival outcomes of each of these groups with an aim to provide clarity. TP53 AML was associated with significantly poor survival compared to TP53-wild type TP53 AML, myelodysplasia-related (AML, MR 4.7 vs. 18.3 months; P < 0.0001), supporting its inclusion within TP53 MN as a distinct subentity. Secondly, the survival of TP53 with blast 10-19% was poor regardless of the allelic status. Thirdly, for cases with a single TP53 with VAF < 50%, 17p13.1 del or CK serve as practical surrogates of biallelic inactivation, obviating the need for an additional copy number analysis. Finally, TP53 AML, MDS multi-hit/multi-hit equivalent with VAF < 10% had significantly poorer survival compared to TP53 MDS VAF < 10% without CK and 17p del, and were comparable to those with VAF ≥ 10% (14.1 vs. 48.8 vs.7.8 months, P < 0.0001). Collectively, these findings address key areas of contention and provide valuable insights that will guide future revisions of the WHO and ICC classifications.

摘要

世界卫生组织（WHO-5）和国际共识分类（ICC）均承认TP53突变型（TP53）髓系肿瘤（MN）的预后较差。然而，这两种分类之间存在显著差异，可能导致对预后风险的低估或高估。我们对603例携带TP53（变异等位基因频率，VAF≥2%）的MN病例进行了WHO-5和ICC的回顾性应用。WHO-5和ICC分别不会将这些病例中的64%和20%归类为TP53 MN。此外，在那些被分类的病例中，67.5%的病例分类会存在差异。差异的主要驱动因素包括：（i）TP53急性髓系白血病（AML）的预后重要性，（ii）原始细胞百分比与等位基因状态的相互作用，（iii）细胞遗传学检测到的17p.13.1缺失，（iv）作为多次打击等效物的复杂核型（CK），以及（v）TP53 VAF阈值，我们分析了这些组中每组的生存结果，旨在提供明确信息。与TP53野生型TP53 AML、骨髓增生异常相关（AML，MR 4.7个月对18.3个月；P<0.0001）相比，TP53 AML的生存明显较差，支持将其作为一个独特的亚实体纳入TP53 MN。其次，无论等位基因状态如何，原始细胞比例为10%-19%的TP53患者生存较差。第三，对于单个TP53且VAF<50%的病例，17p13.1缺失或CK可作为双等位基因失活的实用替代指标，无需额外的拷贝数分析。最后，与无CK和17p缺失的TP53 MDS VAF<10%相比，TP53 AML、MDS多次打击/多次打击等效且VAF<10%的患者生存明显较差，与VAF≥10%的患者相当（14.1个月对48.8个月对7.8个月，P<0.0001）。总体而言，这些发现解决了关键的争议领域，并提供了有价值的见解，将指导WHO和ICC分类的未来修订。