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.
Authors
- Caner Saygin (ORCID: https://orcid.org/0000-0001-7617-8356)
- Wendy Stock (ORCID: https://orcid.org/0000-0002-8349-9200)
- Sandeep Gurbuxani (ORCID: https://orcid.org/0000-0003-0716-8730)
- Diren Arda Karaoğlu (ORCID: https://orcid.org/0000-0002-7639-729X)
- Yasmin Abaza (ORCID: https://orcid.org/0000-0002-9156-7912)
- Todd C. Knepper (ORCID: https://orcid.org/0000-0001-7651-2406)
- Michael W. Drazer (ORCID: https://orcid.org/0000-0002-8171-4106)
- Bijal Shah (ORCID: https://orcid.org/0000-0003-4328-6021)
- Hamed Rahmani Youshanlouei (ORCID: https://orcid.org/0000-0003-0263-8895)
- Madina Jh. SUKHANOVA (ORCID: https://orcid.org/0000-0002-1843-7038)
- Anand Patel (ORCID: https://orcid.org/0000-0002-0296-8686)
- Theodoros Karantanos (ORCID: https://orcid.org/0000-0002-6792-8298)
- Girish Venkataraman (ORCID: https://orcid.org/0000-0002-8674-2608)
- Neval Özkaya (ORCID: https://orcid.org/0000-0003-0541-1979)
- Yenny Alejandra Moreno Vanegas
- Clare Anderson (ORCID: https://orcid.org/0000-0002-5970-5799)
- Adam DuVall (ORCID: https://orcid.org/0000-0002-9163-8792)
- Olatoyosi M. Odenike (ORCID: https://orcid.org/0000-0002-4027-4124)
- Ethan Harris (ORCID: https://orcid.org/0000-0002-8735-1959)
- Jonathan Allen Webster (ORCID: https://orcid.org/0000-0003-3647-6345)
- Melissa Yuwono Tjota (ORCID: https://orcid.org/0000-0002-5869-3175)
- Daniel A. Arber (ORCID: https://orcid.org/0000-0002-2160-9689)
- Chenyu Lin (ORCID: https://orcid.org/0000-0002-4542-4232)
- Richard A. Larson (ORCID: https://orcid.org/0000-0001-9168-3203)
- Alexander Coltoff
- Talha Badar (ORCID: https://orcid.org/0000-0003-1548-918X)
- Ann‐Kathrin Eisfeld (ORCID: https://orcid.org/0000-0001-6442-1419)
- Peng Wang (ORCID: https://orcid.org/0000-0003-4303-6081)
- Jason X. Cheng (ORCID: https://orcid.org/0000-0002-1672-9803)
- Jeremy P. Segal (ORCID: https://orcid.org/0000-0002-0958-3295)
- Servet Çetin
Institutions
- Northwestern University (US)
- Johns Hopkins University (US)
- Medical University of South Carolina (US)
- Duke University (US)
- Johns Hopkins Medicine (US)
- Moffitt Cancer Center (US)
- University of Chicago (US)
- Mayo Clinic in Florida (US)
- The Ohio State University (US)
Publication Details
- Journal
- Blood Cancer Journal
- Published
- 2025-08-14
- DOI
- https://doi.org/10.1038/s41408-025-01350-5
- Citations
- 5
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 9.39
Funders
- U.S. Department of Defense
- DOD Peer Reviewed Cancer Research Program