Impact of TP53 Mutation on Survival Outcomes in Acute Lymphoblastic Leukemia at a Tertiary Center
Authors: Patel Meera , Mohamed Ahmed N , Zureigat Hadil , Zabor Emily C. , Nurse Daniel P. , Bedelu Yohana B. , Chen Mark Jinan , Nakitandwe Joy , Jain Akriti G. , Molina John C. , Balderman Sophia , Singh Abhay , Gerds Aaron T. , Mukherjee Sudipto , Carraway Hetty E. , Advani Anjali S. , Mustafa Ali Moaath K. 
Published: December 2024

Background: Acute lymphoblastic leukemia (ALL) is an aggressive form of acute leukemia in adult patients. Molecular profiling of ALL using next-generation sequencing and karyotyping, along with the advent of measurable residual disease (MRD), has improved the prognostication of ALL. TP53 plays a critical role in the cell cycle and apoptosis regulation after DNA damage, and its role in tumorigenesis is well-established in several solid organ and hematologic malignancies. TP53 mutations are found in roughly 15% of newly diagnosed ALL patients (Chiaretti Haematologica, 2013). In adult ALL, there are a few studies that have associated mutated TP53 with poor survival or lack of response to therapy, mostly in a small cohort of patients.

Methods: We conducted a single-center retrospective cohort study to investigate how TP53 mutational status impacts overall survival (OS), event-free survival (EFS), and the clinical response rate for ALL in adult patients (≥18 years). Baseline variables were collected and included: age, gender, ethnicity, comorbidities, subtypes of ALL, cytogenetics, BCR-ABL1 status, mutational profile based on next-generation sequencing, ECOG performance status, all treatment lines and responses, and follow-up data. Response to first-line treatment included composite complete response (CCR) (complete response (CR) + complete response with incomplete count recovery (CRi)) and responses assessed by MRD by flow cytometry (MRD-FC). EFS was defined from the date of diagnosis to the date of refractoriness, progression, or death. OS was defined from the date of diagnosis to the date of death. The Kaplan-Meier method was used to estimate survival probabilities, and a log-rank test was used to test for differences according to TP53 status. Multivariable regression was used to adjust outcomes.

Results: From 1/2017-8/2023, 161 ALL patients were diagnosed and treated at the Cleveland Clinic. Of these, 72 patients had NGS at baseline, defined from day -30 to +30 from diagnosis. Eleven patients (15.3%) had TP53 mutation (muTP53-ALL) at baseline. The median age at diagnosis for muTP53-ALL was 65 years, and 56 years for the TP53 wildtype ALL patients (wtTP53-ALL). All muTP53-ALL were B-cell subtypes compared to 44 patients (72%) in the wtTP53-ALL group (P=0.05). None of the muTP53 ALL group had a BCR-ABL1 rearrangement compared to 20 (33%) in the wtTP53 ALL group (P=0.03). Philadelphia-like mutations were present in around 9% of both groups (P&gt;0.05). Two patients in the muTP53-ALL group received an allogeneic transplant compared to 21 in the wtTP53 ALL group. High-risk cytogenetics was seen in 36% vs. 6.6% in the muTP53 and wtTP53 ALL groups, respectively (P&lt;0.05). On multivariable logistic regression, muTP53 compared to wtTP53 had a similar CCR odds ratio (OR: 0.77, 95%CI 0.14-4.8, P=0.8). The muTP53 ALL were much more likely to achieve an MRD-FC negativity compared to wtTP53 ALL (OR: 9.93, 95%CI 2.1-73.8, P=0.003). With a median follow-up of 16.2 months, the 12-month OS was 62% vs 90% in the mtTP53 vs. wtTP53 ALL (mortality hazard ratio (HR): 3.26, 95%CI: 1.12-9.51, P=0.047). For EFS, the median follow-up was 17.7 months. The muTP53 had lower 12-month EFS (45%) compared to wtTP53 ALL (85%) (HR: 2.83, 95%CI: 1.01-7.9, P=0.07), but this was not statistically significant.

Conclusion: The muTP53-ALL patients had similar CCR to first-line therapy to wtTP53-ALL. However, they had worse OS, likely because of relapses. The findings highlight the significant impact of TP53 mutation on outcomes in ALL. Because of the above, further research is needed to explore whether using upfront immunotherapy like inotuzumab ozogamicin or blinatumomab in the upfront setting, as well as administering allogeneic transplant early in the treatment course of muTP53-ALL would decrease the risk of relapse and improve long-term survival. Although muTP53 ALL achieved a higher MRD-FC negative response compared to wtTP53 ALL, this did not translate into long-term survival in the muTP53 ALL. Whether using NGS for B-cell and T-cell receptors as a method for MRD testing, like clonoSEQ®, would provide a better prognostic tool is currently unknown.