TP53 mutations not only profoundly affect the progression trajectory of chronic lymphocytic leukemia (CLL), but are also directly associated with poor prognosis, becoming an important factor that cannot be ignored when assessing disease severity and formulating personalized treatment strategies. At the highly anticipated 29th Annual Congress of the European Hematology Association (EHA 2024), Dr. Consuelo Bertossi from the Department of Internal Medicine III at the University of Ulm in Germany, through an exciting oral presentation, deeply analyzed the "The Landscape of TP53 Mutations and Their Prognostic Impact in Chronic Lymphocytic Leukemia (S101)", providing valuable data and insights for the attendees, which has important guiding value for clinical practice and scientific research exploration. To further discuss this cutting-edge topic, "Oncology Frontier-Hematology Frontier" specially invited Dr. Consuelo Bertossi for an interview on the spot, sharing the impact of TP53 mutations on survival rates, the efficacy of targeted drugs, and future research directions.Oncology Frontier-Hematology Frontier：We’d like to start with the specific characteristics of TP53 that have an impact on survival in CLL. Could you elaborate on this?
Dr. Consuelo Bertossi：We looked in detail at the characteristics of TP53 mutations in CLL to determine their impact on survival. We found that both mutations inside and outside the binding domain, as well as those with gain-of-function and loss-of-function, impact survival. We translated this genetic information into the clinic by performing pathogenicity predictions using tools like the UMD-database Seshat and the IARC, and our clinical results reflected these predictions. Variants of unclear significance, such as in-frame alterations or benign missense mutations, had the same survival outcomes as wild-type TP53. Interestingly, splice site mutations were the worst alterations, performing worse than missense hotspot mutations. Another novel finding was that partially active TP53 variants do not impact survival, aligning with observations from mouse models in solid oncology.
Oncology Frontier-Hematology Frontier：Moving on to targeted drugs and their efficacy in CLL with TP53 mutations, what were your findings?
Dr. Consuelo Bertossi：We confirmed that TP53-mutated patients have worse survival outcomes under venetoclax and obinutuzumab therapies, as shown in the CLL14 trial and our larger cohort of nine G-CLSG studies. Venetoclax-based regimens do not nullify the adverse prognostic role of TP53. We also analyzed time-limited ibrutinib in combination with other novel compounds and found a numerically inferior PFS and OS for TP53-mutated patients, though not statistically significant due to limited observations. Continuous ibrutinib therapy may also be impacted by TP53 mutations, as suggested by other trials.
Oncology Frontier-Hematology Frontier：Can you discuss the significance of minor TP53 mutations with variants of unclear significance?
Dr. Consuelo Bertossi：Minor TP53 mutations with variants of unclear significance (under 10%) were associated with shorter OS but not PFS. This might be influenced by the dynamics of the TP53 clone and salvage therapies like allogeneic stem transplants. This finding has also been observed by Professor Davide Rossi. Our next step is to perform longitudinal analysis to see if TP53 clone evolution occurs under targeted therapies, not just chemotherapy.
Oncology Frontier-Hematology Frontier：Are there specific treatment strategies or drugs that target TP53 in CLL?
Dr. Consuelo Bertossi：Currently, there are no TP53-targeted therapies in CLL to my knowledge. In ovarian cancer, PARP inhibitors are used for TP53-mutated cases, but nothing similar has been investigated in CLL yet.
Dr. Bertossi’s research profoundly reveals the role of TP53 in CLL, especially key insights into various mutations, coexisting risk factors, and the prognostic significance of different therapies. Dr. Bertossi’s insights not only deepen our understanding of the complexity of TP53 mutations but also strongly call for continued research investment and international cooperation to accelerate the development of innovative treatment strategies. The aim is to break through the existing treatment bottlenecks and bring a brighter prognosis for patients.
With the continuous advancement of medical technology and the vigorous development of this research field, a deep understanding of the dynamic changes of TP53 mutations and their intrinsic connection with the pathogenesis of CLL will become the key to optimizing treatment plans, achieving precision medicine, and ultimately improving the quality of life for CLL patients. This understanding not only points the way for researchers but also inspires the medical community to keep moving forward, working together to strive for a better future for CLL patients.
