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1425 Clinical and Molecular Characterization of TP53-Mutant Acute Lymphoblastic Leukemia

Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemias: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, ALL, Diseases, Lymphoid Malignancies
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Ethan Harris, BS1*, Madina Sukhanova2*, Yasmin Abaza, MD2, Yenny Alejandra Moreno Vanegas, MD, BSc3, Talha Badar, MD4, Chenyu Lin, MD5, Alexander Coltoff, MD6, Anand Ashwin Patel, MD7, Peng Wang, MD, PhD8*, Melissa Tjota, MD, PhD9*, Jason Xiaojun Cheng, MD, PhD10, Sandeep Gurbuxani, MBBS PhD11, Girish Venkataraman, MD, MBBS11, Daniel A. Arber, MD12, Adam S Duvall, MD13, Michael W Drazer, MD, PhD14, Richard A. Larson, MD7, Olatoyosi Odenike, MD7, Bijal D Shah, MD15, Wendy Stock, MD7, Ibrahim Aldoss, MD16 and Caner Saygin, MD7

1University of Chicago Medical Center, Chicago, IL
2Northwestern University, Chicago, IL
3Mayo Clinic, Jacksonville, FL
4Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL
5Duke University Cancer Institute, Durham, NC
6Medical University of South Carolina, Charleston, SC
7Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL
8The University of Chicago, Chicago, IL
9University Of Chicago, Chicago, IL
10Department of Pathology, The University of Chicago, Chicago, IL, Chicago
11Department of Pathology, University of Chicago, Chicago, IL
12University of Chicago, Chicago, IL
13Department of Medicine, University of Chicago, Chicago, IL
14Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL
15University of South Florida Morsani College of Medicine, Tampa, FL
16Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA

Introduction: TP53 mutations are found in 18% of adult patients (pts) with acute lymphoblastic leukemias (ALL), and portends poor prognosis (Saygin, Blood Cancer Discov 2024). TP53 mutations are often associated with low hypodiploidy and Li Fraumeni syndrome (germline) in children. However, we and others have shown that TP53-mutant (TP53-m) ALL arises from pre-existing TP53-m clonal hematopoiesis in adults as opposed to germline origin. The impact of co-occurring mutations, TP53 allelic frequency (AF) and different types of treatment on outcomes of TP53-m ALL are not fully characterized. We set out to investigate the clinical and molecular predictors of outcomes in adults with TP53-mutant ALL.

Methods: We retrospectively studied 107 patients with TP53-m ALL treated at seven different academic centers in North America. Genetic profiling of pre-treatment bone marrow samples was performed with a comprehensive panel covering 147 myeloid and lymphoid genes. We also performed RNA-sequencing to identify fusions that define ALL subtypes. Single nucleotide polymorphism (SNP) array was used to define low hypodiploidy.

Results: The median age at diagnosis was 59 years (range, 10-80), 42% were female, 70% White. 89% of pts had B-ALL while 11% had T-lineage ALL. 24% of pts were classified to have therapy-related ALL based on their history of exposure to genotoxic therapy for another cancer. 45% of pts had hypodiploid karyotype, 79% of whom were low-hypodiploid. 7% had hyperdiploid karyotype and 5% had BCR::ABL1. 11 pts had two different TP53 variants. 90% of TP53 variants involved the DNA binding domain. Most frequently observed co-occurring mutations involved CDKN2A (20%), NOTCH1 (12%) and RB1 (10%) genes.

71% of pts were treated with standard cytotoxic chemotherapy, while the remaining pts received newer antibody-based therapies (i.e., inotuzumab, blinatumomab) or venetoclax in first-line setting. 11% of pts received allogeneic hematopoietic cell transplant (HCT) in first complete remission (CR1) while 3% received HCT after relapse (CR2 or CR3). When patients with vs without low hypodiploidy were compared, we did not observe a significant difference in overall survival (OS) as outcomes were poor in both groups (median, 17 vs 19 months, p= 0.89). However, pts who had TP53 AF >0.5 had significantly worse OS when compared to pts with TP53 VAF <0.5 (13 vs 25 months, p= 0.03).

Conclusions: TP53-m ALL is a very high-risk disease subtype and its dismal outcome is independent from presence of co-existing low hypodiploidy. Loss of heterozygosity, characterized by TP53 AF >0.5 is associated with even worse survival. New therapies are urgently needed to improve outcomes in this subset.

Disclosures: Badar: Takeda: Other: advisory board ; Morphosys: Other: Advisory Board; pfizer: Other: Advisory board. Lin: Autolus: Consultancy; Rigel: Consultancy; ADC Therapeutics: Consultancy. Patel: Pfizer: Research Funding; Bristol Myers Squibb: Honoraria; Sobi: Honoraria; AbbVie: Honoraria; Sumitomo: Research Funding; Kronos Bio: Research Funding. Drazer: Argenx: Consultancy. Larson: AbbVie, Amgen, Ariad/Takeda, Astellas, Celgene/BMS, Curis, CVS/Caremark, Epizyme, Immunogen, Jazz Pharmaceuticals, Kling Biotherapeutics, MedPace, MorphoSys, Novartis, and Servier: Honoraria; Astellas, Celgene, Cellectis, Daiichi Sankyo, Forty Seven/Gilead, Novartis, and Rafael Pharmaceuticals: Research Funding; UpToDate: Patents & Royalties: royalties. Odenike: AbbVie; Blueprint Medicines; BMS; Bristol-Myers Squibb/Celgene (Inst); Celgene; CTI; Impact Biomedicines; Kymera; Novartis; SERVIER; Taiho Pharmaceutical; Treadwell Therapeutics: Honoraria; AbbVie (Inst); Agios (Inst); Aprea AB (Inst); Astex Pharmaceuticals (Inst); AstraZeneca (Inst); Bristol-Myers Squibb (Inst); Celgene (Inst); CTI BioPharma Corp (Inst); Daiichi Sankyo (Inst); Incyte (Inst); Janssen Oncology (Inst); Kartos Therapeutics (Ins: Research Funding. Shah: Adaptive Biotechnologies: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Bristol Myers Squibb: Consultancy; Eli Lilly: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; Autolus, Beigene, Century Therapeutics, Deciphera, Jazz, Kite/Gilead, Pfizer, Precision Biosciences, Novartis, Takeda: Consultancy; Jazz Pharmaceuticals, Kite-Gilead, Servier: Research Funding; Pepromene Bio: Other: DSMB. Stock: Adaptive: Consultancy, Honoraria; Kura: Research Funding; Kura, Servier, Newave, Adaptive, Jazz, Asofarma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Aldoss: Kite Pharma: Other: consulting fees; Sobi: Other: consulting fees; AbbVie: Other: research support; Takeda Pharmaceuticals: Other: consulting fees; Pfizer: Honoraria, Other: consulting fees; Jazz Pharmaceuticals: Other: consulting fees; Amgen: Honoraria, Other: consulting fees; Syndax Pharmaceuticals, Inc.: Other: consulting fees.

*signifies non-member of ASH