Ethan J. Harris, Diren Arda Karaoglu, Madina Sukhanova, Yasmin Abaza, Theodoros Karantanos, Ann-Kathrin Eisfeld, Clare Anderson, Chenyu Lin, Yenny A. Moreno Vanegas, Talha Badar, Alexander Coltoff, Todd C. Knepper, Neval Ozkaya, Hamed Rahmani Youshanlouei, Sinan Cetin, Anand A. Patel, Adam S. DuVall, Michael W. Drazer, Peng Wang, Melissa Tjota, Jeremy P. Segal, Girish Venkataraman, Sandeep Gurbuxani, Jason X. Cheng, Daniel A. Arber, Richard A. Larson, Olatoyosi Odenike, Jonathan Webster, Bijal Shah, Wendy Stock, Caner Saygin
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引用次数: 0
摘要
成人tp53突变急性淋巴细胞白血病(ALL)是一种预后较差的高风险亚型,但其分子结构和临床意义仍未完全确定。在这项多机构研究中,在2010年至2024年期间,在8个学术中心接受治疗的830名成年ALL患者中,我们证明TP53突变是B-ALL(中位1.9年vs 5年)和T-ALL(中位1.6年vs 9.5年)总生存期较差的独立预测因子,与年龄、生物疾病亚型或治疗无关。基因组分析显示,90%的TP53突变是dna结合域错义变异,经常与B-ALL的次二倍体和T-ALL的NOTCH1/FBXW7突变共同发生。与髓系恶性肿瘤不同,双等位基因TP53突变不会恶化预后,变异类型(错义与截断)不会影响生存。tp53突变型B-ALL比tp53野生型B-ALL表现出更高的CD20阳性(65% vs 31%),但对常规化疗的反应较差。新的免疫疗法(例如,inotuzumab/ blinatumumab)或venetoclax-containing联合方案改善了缓解率,但复发是常见的,通常是CD19/CD20/CD22丢失(三阴性)或获得新的突变。首次缓解的同种异体移植倾向于生存获益(中位数,3.3年vs 2.2年)。这些发现强调tp53突变型ALL是一种独特的、耐化疗的实体,需要量身定制的治疗方法,抗原逃逸突出了免疫治疗持久性的挑战。
Clinical and molecular characterization of TP53-mutant acute lymphoblastic leukemia in adults
TP53-mutant acute lymphoblastic leukemia (ALL) in adults is a high-risk subtype with poor outcomes, yet its molecular landscape and clinical implications remain incompletely defined. In this multi-institutional study of 830 adult ALL patients treated at eight academic centers between 2010 and 2024, we demonstrated that TP53 mutations are independent predictors of inferior overall survival in both B-ALL (median, 1.9 vs 5 years) and T-ALL (1.6 vs 9.5 years), irrespective of age, biologic disease subtype, or therapy. Genomic profiling revealed that >90% of TP53 mutations were DNA-binding domain missense variants, frequently co-occurring with hypodiploidy in B-ALL and NOTCH1/FBXW7 mutations in T-ALL. Unlike myeloid malignancies, biallelic TP53 mutations did not worsen outcomes, and variant type (missense vs truncating) did not influence survival. TP53-mutant B-ALL exhibited higher CD20 positivity than TP53-wild type B-ALL (65% vs 31%) but had inferior responses to conventional chemotherapy. Novel immunotherapies (e.g., inotuzumab/blinatumomab) or venetoclax-containing combination regimens improved remission rates, yet relapses were common, often with CD19/CD20/CD22 loss (triple-negative) or acquisition of new mutations. Allogeneic transplantation in first remission trended toward survival benefit (median, 3.3 vs 2.2 years). These findings underscore TP53-mutant ALL as a distinct, chemo-resistant entity necessitating tailored approaches, with antigen escape highlighting challenges of immunotherapy durability.
期刊介绍:
Blood Cancer Journal is dedicated to publishing high-quality articles related to hematologic malignancies and related disorders. The journal welcomes submissions of original research, reviews, guidelines, and letters that are deemed to have a significant impact in the field. While the journal covers a wide range of topics, it particularly focuses on areas such as:
Preclinical studies of new compounds, especially those that provide mechanistic insights
Clinical trials and observations
Reviews related to new drugs and current management of hematologic malignancies
Novel observations related to new mutations, molecular pathways, and tumor genomics
Blood Cancer Journal offers a forum for expedited publication of novel observations regarding new mutations or altered pathways.