Larger multi-center trials are necessary for determining the optimal treatment strategy among patients with TP53-mutated myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), according to a letter published in Blood Advances.1
Previous research has suggested that patients with TP53-mutant MDS or AML have inferior survival outcomes compared to those without such mutations. Authors of a recently published paper have suggested that higher patient TP53 variant allele frequency (VAF) increases the risk of relapse, particularly where VAF is greater than 40%.2
Although previously conducted clinical trials aimed to establish the use of therapies targeted to TP53-mutant disease, results have been disappointing, with 1 major phase 3 study into a novel compound missing its primary endpoint in 2020.This population of patients, therefore, represents a group with major unmet clinical need, according to the present letter’s authors.
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The authors note that their own data, as well as other work previously published, suggest that some patients with TP53-mutated MDS or AML may benefit from transplant, which may yield a median overall survival of up to 17.6 months. Bridge therapy with hypomethylating agents (HMAs) may improve responses to transplant, though further data are needed in both cases.
Biologically speaking, there also appears to be a link between eliminating evidence of minimal residual disease and improved clinical outcomes. This may be because TP53-mutant clones allow for increased resistant disease proliferation after treatment, which may explain the higher rate of relapse in this patient population.
Although a major open question for this patient population is whether they — and moreover, which individuals — should undergo transplant, large, controlled trials into this area are lacking. The authors suggest that future work should rectify this gap in knowledge.
“Better treatment options may not be far away for this patient group with clearly unmet need deserving therapeutic improvement,” they wrote. “A call to action is warranted for a more robust multi-center meta-analysis and collaboration for this genetically defined high-risk patient population in order to better design future prospective studies.”
Disclosure: The study author(s) declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
References
- Patel SA, Cerny J. TP53-mutant myelodysplastic syndrome and acute myeloid leukemia: the black box of hematology. Blood Adv. Published online January 28, 2022. doi:10.1182/bloodadvances.2021006580
- Short NJ, Montalban-Bravo G, Hwang H, et al. Prognostic and therapeutic impacts of mutant TP53 variant allelic frequency in newly diagnosed acute myeloid leukemia. Blood Adv. 2020;4:5681-5689. doi:10.1182/bloodadvances.2020003120
