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<p><i>TP53</i>-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 <i>TP53</i> 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 &gt;90% of <i>TP53</i> 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 <i>TP53</i> mutations did not worsen outcomes, and variant type (missense vs truncating) did not influence survival. <i>TP53</i>-mutant B-ALL exhibited higher CD20 positivity than <i>TP53-</i>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 <i>TP53</i>-mutant ALL as a distinct, chemo-resistant entity necessitating tailored approaches, with antigen escape highlighting challenges of immunotherapy durability.</p>

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Clinical and molecular characterization of TP53-mutant acute lymphoblastic leukemia in adults

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月14日

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  • 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

摘要

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.