Focus
Overcoming the TP53 Mutated AML Treatment Dilemma
BY: Dr. Mohsin RoshanApr 18, 2024
Dr. Marco Marchionni

Doctor at National Health Service (NHS) United Kingdom (UK)

Tumour protein 53 (TP53) gene is located on the chromosome 17 that encodes for the p53 protein, which is a tumour suppressor protein with 393 amino acid responsible for regulating cellular stress1. Notably, TP53 can be inactivated directly due to mutations in the TP53 gene or indirectly as a result of alterations in genes whose products interact with p53 in about half of the cancers1, including the acute myeloid leukaemia (AML). Interestingly, AML is the most common type of acute leukaemia in adults with an annual age-adjusted incidence rate of 4.3/100,000 rising to 15-20/100,000 in those above the age of 602. TP53-mutated (TP53mut) AML occurs in approximately 5-15% of AML cases and 75% of these cases are diagnosed using the next-generation sequencing (NGS)2. Nevertheless, this type of mutation often carries a dismal prognosis, and some studies have demonstrated a three-year overall survival (OS) of 0%. Thus, to understand the complexity of TP53mut-AML, we have invited Dr. Marco Marchionni, one of the doctors at the National Health Service (NHS) in the United Kingdom (UK), to discuss further on the diagnostic challenges faced in clinical practice as well as the recent treatment advances in TP53mut-AML.

 

The Secret Identity of TP53-mutated AML

AML harbouring TP53 mutations is now classified as a distinct AML subtype according to the International Consensus Classification (ICC) of myeloid neoplasms and acute leukaemias3. Interestingly, TP53mut-AML is associated with an adverse prognosis and the TP53 mutation is mostly observed in older adults with AML and characterised by the genomic instability. Dr. Marchionni explained that there is a significant increase in TP53 mutation among older adults with de novo AML and this type of mutation allows the tumour cells to evade apoptosis, and confer tumour resistance, giving a poor prognosis3. But why is TP53mut-AML on rise? Well, there are many reasons behind this and the most important one being the difficulties in diagnosing the mutation using conventional diagnostic tools. For instance, the TP53 mutations is often identified using the gene sequencing, however, the sequencing alone may miss 16.4% of patients with structural TP53 abnormalities that is not detected by the convention NGS4.

 

Are there any gender or ethnic differences in TP53mut-AML? Dr. Marchionni explained that male predominance in AML has been documented previously5, but the gender differences in incidence of TP53mut-AML is still not well reported; therefore, more studies would be needed in this area to determine if there are treatment discrepancies in different gender groups; similarly, the prevalence of TP53mut-AML in Asian population remains scarce. More importantly, a study by Niparuck et al., (2021) evaluated the prevalence and treatment outcomes of TP53mut-AML and myelodysplastic syndrome (MDS) patients. A total of 132 AML/MDS patients were included in the study and P53 mutation was found in 10.6% patients. The study demonstrated a 3-year OS of 22% in the whole populations, and a 1-year OS in TP53mut-AML/MDS was much shorter than that in TP53 wild-type AML patients (14% versus 50%, respectively; p=0.001) (Figure 1)6. The conclusion reached was that the prevalence of TP53 mutation in de novo AML and MDS with excess blasts (EB) patients was low and this may effect the survival rate of these patients6.

 

Figure 1. Overall survival in AML/MDS and AML patients with and without TP53 mutation6. AML= acute myeloid leukaemia; MDS= myelodysplastic syndrome; TP53= tumour protein 53.

 

A Treatment Approach for TP53-Mutated AML

AML remains a challenging haematologic malignancy and presence of TP53mut-AML poses a therapeutic challenge, considering that standard treatment faces significant setbacks in achieving a meaningful response in such cases3. Hence, there is a pressing need for development of innovative treatment modalities to overcome the resistance to convention treatment attributable to the unique biology of TP53mut-AML3. It is important to note that the TP53 mutation is considered as an adverse-risk genetic abnormality according to the 2022 European LeukemiaNet (ELN) risk classification due to the associated complex karyotype, advanced age, and resistance to standard therapies. Furthermore, patients with TP53mut-AML have a lower probability of achieving a remission when treated even with intensive chemotherapy and consequently, have a poor outcome, even in those patients who have undergone allosteric haematopoietic stem cell transplant (allo-HSCT)7. But why? What makes TP53mut-AML so omnious? Dr. Marchionni explained that TP53 mutations seen in AML patients carry a variant alleles frequency (VAF), which is the proportion of variant alleles within a genomic locus, that provides insight into tumour clonality in somatic genomic testing8. So, what does that mean? In simple terms, the higher the TP53 mutation VAF, the poorer the prognosis due to a loss of heterozygosity within the tumour cells9.

 

Recent treatment advances in TP53mut-AML have identified polo-like kinase-4 (PLK4) as a potential novel therapeutic target since the expression of PLK4 is often suppressed by the activated p53 signalling TP53 wild-type AML and increased in TP53mut-AML cell lines10. Thus, prolonged inhibitor of PLK4 may suppress the growth of TP53mut-AML and cause DNA damage, apoptosis, and defective cytokinesis. This was evident in an animal study where PLK4 inhibitor induced cytokine and chemokine expression in mice. Furthermore, mice treated with PLK4 inhibitor and anti-cluster of differentiation 47 (CD47) antibodies synergistically reduced the leukaemic burden and prolonged animal survival10. But is this translatable to humans as well? Dr. Marchionni suggested that currently it is too early to determine whether the novel PLK4 inhibitors are useful in treating patients with TP53mut-AML patients and more long-term clinical trial to assess their suitability and safety are needed. Other treatment options for TP53mut-AML include the use of azacitidine monotherapy which has shown some treatment efficacy in patients with TP53mut-AML, however, the results are not so promising3. What about allo-HSCT, since this has been advocated for high-risk genetic group? A multi-centre study by Badar et al., (2023) analysed the factors that predict the survival among patients with TP53mut-AML receiving allo-HSCT.

 

Among the 370 patients with TP53mut-AML, 18% were bridged to allo-HSCT with a median age of 63 years. Surprisingly, 82% of patients had complex cytogenetics and 66% of the patients had multi-hit TP53 mutation. Surprisingly, the median event-free survival (mEFS) for the time of allo-HSCT was 12.4 months (95% confidence interval [CI]: 6.24-18.55) and the median OS (mOS) was 24.5 months (95% CI: 21.80-27.25)11. The complete remission (CR) after multivariate analysis at day 100 post allo-HSTC retained significance for EFS (hazard ratio [HR]:0.24, 95% CI: 0.10-0.57; p=0.001) and OS (HR: 0.22, 95% CI: 0.10-0.50, p≤0.001) (Figure 2)11.

 

Figure 2. Study design and Kaplan-Meier survival curve showing overall survival from time of diagnosis to death/last follow-up in patients receiving allogeneic stem cell transplant after induction or salvage therapy11. Allo-HSCT= allogenic-hematopoietic stem cell transplant. CR= complete remission, CRi= CR with incomplete count recovery, OS= overall survival, PR= partial remission, MLFS= morphologic leukaemia free state.

 

The results suggested that allo-HSCT offers the best opportunity to improve long-term outcome among patients with TP53mut-AML11. However, Dr. Marchionni clarified that these types of mutations are prevalent in older adults who are often ineligible for allo-HSCT due to co-existing comorbidities, as well as some centres setting an age limit to ≤65 years. Therefore, the unmet need persists in these subset of AML patients.

 

Will the Reign of TP53-Mutated AML Ever Be Over?

Despite a better understanding on cytogenetics of AML, the therapeutic progress in TP53mut-AML remains inadequate3. Dr. Marchionni added that the cells with mutated or deleted TP53 frequently have a defective Growth 1 (G1) checkpoint and are more dependent on the G2 checkpoint to repair the damaged DNA. More interestingly, G2 checkpoint allows the p53-deficient AML cells to repair genetic lesions and continue through the cell cycle3. Therefore, inhibition of kinases that are involved in the G2 checkpoint, such as aurora kinase A (AURKA) and aurora kinase B (AURKB) may induce cell death in TP53 mutated cancer cells. Remarkably, new pharmacological strategies are taking a step further by directly regaining or rescuing the P53 function and promote the degradation of P53 mutated cells3.

 

To demonstrate the efficacy of upcoming novel agents, Dr. Marchionni shared the results from a phase 2 clinical trial in which 33 patients with TP53mut-AML received allo-HSCT and post-transplantation, they received eprenetapopt, a P53 reactivator in combination with azacitidine. Surprisingly, the 1-year relapse-free survival in these patients improved to 59.9% with an OS at 78.8%. Similarly, the median RFS (mRFS) and mOS were 12.1 and 19.3 months, respectively13 (Figure 3).

 

Figure 3. Study design and Kaplan-Meier survival and cumulative incidence analysis from the time of transplant for the entire population demonstrating (A) the relapse free survival (RFS) and (B) overall survival (OS)13. AZA= azacitidine, CI= confidence interval, HCT= hematopoietic cell transplantation, IV= intravenous, NE= not estimable, SC= subcutaneously.

 

Dr. Marchionni reiterated that these results were encouraging and confirm the necessity to implement further treatment with allo-HSCT for patients with TP53-mutated AML.

 

In conclusion, Dr. Marchionni encouraged clinicians to assess each case of TP53mut-AML separately since patients have a unique individualised cytogenetic which may or may not respond to traditional chemotherapy secondary to either VAF or other factors. Furthermore, the era of AML treatment is still evolving, and it is likely that we shall see more treatment for TP53mut-AML in the upcoming years.

 

References

1. Shin DY. Cancers (Basel) 2023; 15(19).  2. Granowicz EM, et al. Onco Targets Ther 2022; 15: 423-36.  3. Stafylidis C, et al. Journal of Clinical Medicine 2024; 13(4): 1082.  4. Fleming S, et al. Blood 2023; 142(23): 2029-33.  5. Stabellini N, et al. Cancer Med 2023; 12(6): 6711-21.  6. Niparuck P, et al. Diagn Pathol 2021; 16(1): 100.  7. Zhao D, et al. Cancers (Basel) 2023; 15(12).  8. Boscolo Bielo L, et al Trends Cancer 2023; 9(12): 1058-68.  9. Strom SP. Cancer Biol Med 2016; 13(1): 3-11.  10. Man C-H, et al. Blood 2023; 142(23): 2002-15.  11. Badar T, et al. Leukemia 2023; 37(4): 799-806.  12. Loschi M, et al. Cancers 2022; 14(18): 4519.  13. Mishra A, et al. Journal of Clinical Oncology 2022; 40(34): 3985-93.