TP53突变不仅深刻影响着慢性淋巴细胞白血病（CLL）的疾病进展轨迹，还直接关联到患者的不良预后，成为评估疾病严重程度与制定个性化治疗策略时不可忽视的重要因素。在备受瞩目的第29届欧洲血液协会年会（EHA 2024）上，来自德国乌尔姆大学第三内科的Consuelo Bertossi博士，通过精彩的口头报告，深入剖析了“TP53突变在CLL中的具体特征及预后影响（S101）”，为与会者提供了宝贵的数据与见解，对临床实践和科研探索均具有重要指导价值。为进一步探讨这一前沿话题，《肿瘤瞭望-血液时讯》现场特邀Consuelo Bertossi博士进行专访，分享TP53突变对生存率的影响、靶向药物的疗效以及未来的研究方向。

 

 

Consuelo Bertossi博士：我们详细研究了CLL中TP53突变的特征，以确定它们对生存率的影响。我们发现，无论是结合域内还是结合域外的突变，或者是功能增益型和功能损失型突变，都会影响生存率。我们使用UMD-database Seshat和IARC等工具进行致病性预测，并将这些遗传信息应用到临床中，结果与我们的临床结果相符。意义不明确的变异，如框内突变或良性错义突变，其生存率与野生型TP53相同。有趣的是，剪接位点突变是最差的变异，其表现比热点错义突变还差。另一个新发现是部分TP53活性突变不影响生存率，这与在实体肿瘤小鼠模型中的观察一致。

 

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.

Consuelo Bertossi博士：我们证实，正如CLL14试验所示，在9项G-CLLSG研究的更大队列中，在使用维奈克拉和奥比妥珠单抗治疗下，TP53突变患者的生存率仍然较低。以维奈克拉为基础的方案，并不能消除TP53的不良预后作用。我们还分析了时间限制性伊布替尼与其他新型化合物的联合治疗，发现伴TP53突变患者的无进展生存期（PFS）和总生存期（OS）在数值上较低，尽管由于观察次数有限，这些差异没有统计学意义。其他试验也表明，持续的伊布替尼治疗可能受到TP53突变的影响。

 

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.

 

Consuelo Bertossi博士：具有意义不明变异（低于10%）的少数TP53突变与较短的OS相关，但与PFS无关。这可能受TP53克隆动态和异基因干细胞移植等挽救疗法的影响。Davide Rossi教授也观察到了这一发现。我们下一步计划进行纵向分析，观察在靶向治疗下是否存在TP53克隆的演变。

 

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.

 

Consuelo Bertossi博士：目前，据我所知，CLL中没有针对TP53的治疗。在卵巢癌中，PARP抑制剂用于TP53突变病例，但在CLL中尚未有类似的研究。

 

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.

 

 

Bertossi博士的研究深刻揭示了TP53在CLL中的作用，特别是各种突变、共存风险因素和不同疗法的预后意义的关键见解。Bertossi博士的见解不仅加深了我们对TP53突变复杂性的认识，还强烈呼吁持续的研究投入与国际合作，以加速创新治疗策略的开发，力求突破现有治疗瓶颈，为患者带来更加光明的预后前景。

 

随着医学科技的不断进步和该研究领域的蓬勃发展，深入理解TP53突变的动态变化及其与CLL病理机制的内在联系，将成为优化治疗方案、实现精准医疗、并最终提升CLL患者生活质量的关键所在。这一认识不仅为科研人员指明了方向，也激励着医疗界不断前行，共同为CLL患者争取更加美好的未来。

 

专家简介

Consuelo Bertossi

医学博士，助理医生

德国乌尔姆大学第三内科CLL科