Myelodysplastic Syndrome & Acute Myeloid Leukemia
Updates on TP53-Mutant AML and MDS With Excess Blasts
TP53-mutated acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) represent a difficult-to-treat phenotype. Although there are signs indicating that clinical research is inching forward, new therapeutic targets are a priority for this group of patients.
Assistant Professor of Medicine
“ . . . the field continues to reassess the best approach to TP53-mutated disease. For anyone with this type of disease, the consideration of enrolling in a clinical trial, at any phase, is appropriate.”
TP53 mutations confer an aggressive phenotype to MDS, AML, and many other cancers, and there are increasing nuances in our understanding of the outcomes in TP53-mutated disease. For instance, those who have 1 intact TP53 gene may have better outcomes than those with aberrancy at both alleles, either through chromosome 17p deletion or through biallelic mutations. We have also learned that there is likely some variable impact depending on where the mutation is in the TP53 gene. Analytic tools can be used to estimate the effect of a point mutation in TP53, and patients whose disease has a mutation with a worse-predicted phenotype may, in fact, have worse outcomes than those with a less severe–predicted phenotypic impact.
There is an argument being made for categorizing TP53-mutated myeloid neoplasms essentially as their own disease entity, in recognition of this particularly high-risk subset of MDS and AML. Patients with this mutation require novel strategies, regardless of which side of the 20% threshold the blast count falls. Patients who have TP53-mutated MDS/AML historically have not had as favorable responses to initial standard chemotherapies. In our practice, we often consider the role of azacitidine- or decitabine-based initial therapy for these patients. In AML, after the US Food and Drug Administration approval of venetoclax in the frontline setting, several studies have evaluated the activity of venetoclax combination therapy in TP53-mutated disease. A challenge in these subset analyses has been that the responses with the combination have been shorter than hoped, suggesting that adding venetoclax may not change the outcomes of TP53-mutated AML as much as desired.
In many ways, therefore, the field continues to reassess the best approach to TP53-mutated disease. For anyone with this type of disease, the consideration of enrolling in a clinical trial, at any phase, is appropriate. In randomized trials that are currently ongoing, it will be interesting to see whether patients with TP53 mutations respond differently, for instance, when an immune checkpoint inhibitor is added to standard azacitidine. We have seen some data presented from trials with APR-246 and APR-548; these are small molecules designed to increase the affinity of mutant p53 for DNA and to reactivate p53 function. In the phase 3 study, there was a numerically higher rate of complete remission in the APR-246–plus-azacitidine group, but it did not meet statistical significance and it was lower than the predicted response rate. We are waiting to see if a difference in survival will be reported; however, even if survival were improved with APR-246, we would still need new therapies for this group.
Allogeneic stem cell transplantation has been explored in the molecular subgroup as well. Although some patients with TP53-mutated disease will be cured by transplant, it is a small percentage. There is a growing body of evidence suggesting that if the TP53 variant allele fraction is reduced to low or nondetectable levels right before transplant, those patients may do better, perhaps providing a direction for new trials. There is also interest in initiating some sort of maintenance therapy after transplant, to help a new donor immune system that is learning what the disease looks like.
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Bories P, Prade N, Lagarde S, et al. Impact of TP53 mutations in acute myeloid leukemia patients treated with azacitidine. PLoS One. 2020;15(10):e0238795. doi:10.1371/journal.pone.0238795
ClinicalTrials.gov. APR-246 & azacitidine for the treatment of TP53 mutant myelodysplastic syndromes (MDS). Updated July 29, 2021. Accessed May 11, 2022. https://clinicaltrials.gov/ct2/show/NCT03745716
ClinicalTrials.gov. APR-548 in combination with azacitidine for the treatment of TP53 myelodysplastic syndromes (MDS). Updated January 19, 2022. Accessed May 11, 2022. https://clinicaltrials.gov/ct2/show/NCT04638309
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Niparuck P, Police P, Noikongdee P, et al. TP53 mutation in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome. Diagn Pathol. 2021;16:100. doi:10.1186/s13000-021-01162-8
Sallman DA, DeZern AE, Garcia-Manero G, et al. Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes. J Clin Oncol. 2021;39(14):1584-1594. doi:10.1200/JCO.20.02341
Ta R, Hasserjian RP. TP53-mutated acute myeloid leukemia and myelodysplastic syndrome with excess blasts: two sides of the same coin? The Hematologist. 2022;19(3). doi:10.1182/hem.V19.3.202231