Concurrent loss of TP53 and CDKN2A with tetraploidy predicts richter transformation and poor prognosis in chronic lymphocytic leukemia

Abstract Background: Richter transformation (RT) can occur in 2-20% chronic lymphocytic leukemia (CLL) patients and has a poor prognosis with a median overall survival (OS) of less than one year. RT is associated with increased chromosome complexity. In particular, tetraploidy, a whole genome doubling event resulting in four copies of most chromosomes, is a rare genetic abnormality that is not well understood in RT. Tetraploidy increases chromosomal instability, which may potentially contribute to the development of RT-associated genomic abnormalities. Therefore, the aim of our study was to further understand the significance of tetraploidy in the development of RT and to characterize the associated genetic aberrations in patients with CLL. Methods: This institutional review board approved study includes all patients diagnosed with CLL and identified to have tetraploidy between 2004 and 2024 at The Ohio State University. Data was collected through medical chart review to include patient characteristics, cytogenetics data, treatment, time to develop RT, and OS. RT was defined as the development of large B-cell lymphoma in the setting of CLL. We excluded patients who had a diagnosis of RT prior to tetraploidy detection. Overall survival was calculated as the time from tetraploidy detection to death of all cause, censoring patients at last follow-up. OS was estimated using the Kaplan-Meier method, and cumulative incidence function was used to estimate cumulative incidence rate (CIR) of RT, treating death without RT as the competing risk. Univariable and multivariable Cox models were built to associate disease characteristics with OS. Results: Ninety CLL patients with tetraploidy were included in this study. Tetraploidy was detected at a median age of 67 (range 37-93) and a median of 5.8 years from CLL diagnosis. 35.6% of patients were women. Patients had a median of 3 prior lines of therapies (range 0-12) among which 83.3% had received a BTKi. 85.1% had IGHV unmutated disease, 81.1% had highly complex karyotype (≥ 5 abnormalities), 67.8% and 51.9% had loss of TP53 and CDKN2A, respectively. Forty (44.4%) of the patients with tetraploidy have developed RT with a CIR of 22.2%, 28.9%, and 37.4% from tetraploidy detection at 1 month, 1 year and 2 years respectively. Patients with tetraploidy were stratified based on TP53 and CDKN2A deletion status into four groups: TP53+/CDKN2A+, TP53+/CDKN2A-, TP53-/CDKN2A+, and TP53-/CDKN2A-. Upon stratification, the CIR of RT was 42.3%, 7.7%, 0%, and 8.3% at 1 month from tetraploidy detection. The median OS from tetraploidy detection was 10.2 and 33.12 months for TP53+/CDKN2A+ and TP53+/CDKN2A- respectively, while the median OS for the other two groups was not reached. Hence, patients with concurrent loss of TP53 and CDKN2A (TP53+/CDKN2A+) had significantly worse OS and a significantly higher 1-month CIR of RT when compared to other tetraploidy subgroups (p = 0.0078 and p = 0.02, respectively). In the univariable analysis for OS from tetraploidy detection, the presence of a highly complex karyotype, TP53, CDKN2A, and BCL6 aberrations by FISH, development of RT, and concurrent TP53+/CDKN2A+ deletions were all significantly associated with worse OS. In multivariable analysis, loss of TP53 (HR 2.32, 95% CI 1.10-4.90, p = 0.03) and RT (HR 2.88, 95% CI 1.58-5.27, p = 0.0006) were associated with worse OS.Conclusion: We demonstrate that concurrent TP53 and CDKN2A loss in CLL patients with tetraploidy is associated with significantly poorer OS and higher incidence of RT. These findings suggest that concurrent TP53 and CDKN2A loss may serve as a biomarker for aggressive disease in CLL patients with tetraploidy.