Reactivating hope for TP53-mutated acute myeloid leukaemia?

The poor prognosis associated with TP53 mutations and their involvement in multiple pathways contributing to leukaemogenesis and drug resistance have made mutated TP53 a therapeutic target of special interest. Although infrequent in acute myeloid leukaemia, TP53 mutations have an important role in the disease course and confer a particularly poor prognosis. 1 Grob T Al Hinai ASA Sanders MA et al. Molecular characterisation of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2022; 139: 2347-2354 Crossref PubMed Scopus (66) Google Scholar Although such mutations have long been considered non-actionable, a class of small molecules that can reactivate p53 function across multiple TP53 mutations has raised expectations of a clinical breakthrough. However, neither of two previous phase 1b/2 studies combining the clinical front-runner eprenetapopt with the hypomethylating agent azacitidine for patients with newly diagnosed TP53-mutated myelodysplastic syndromes 2 Sallman DA DeZern AE Garcia-Manero G et al. Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes. J Clin Oncol. 2021; 39: 1584-1594 Crossref PubMed Scopus (197) Google Scholar or acute myeloid leukaemia 3 Cluzeau T Sebert M Rahme R et al. Eprenetapopt plus azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia: a phase II study by the Groupe Francophone des Myelodysplasies (GFM). J Clin Oncol. 2021; 39: 1575-1583 Crossref PubMed Scopus (117) Google Scholar provided convincing evidence for a clinically meaningful effect on response or outcome, tempering expectations that these drugs will readily change treatment for these patients. Nevertheless, the synergy observed between eprenetapopt and azacitidine and between azacitidine and venetoclax support treatment combinations that include eprenetapopt. 4 Maslah N Salomao N Drevon L et al. Synergistic effects of PRIMA-1Met (APR-246) and 5-azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia. Haematologica. 2020; 105: 1539-1551 Crossref PubMed Scopus (78) Google Scholar , 5 Garcia-Manero G Goldberg AD Winer ES et al. Eprenetapopt combined with venetoclax and azacitidine in TP53-mutant AML: a phase 1 dose-finding and expansion study. Lancet Haematol. 2023; 10: e272-e283 Summary Full Text Full Text PDF Google Scholar The most clinically relevant question arising from current data is whether the combination of eprenetapopt and azacitidine with venetoclax is better than either eprenetapopt and azacitidine or eprenetapopt and venetoclax for the treatment of TP53-mutated acute myeloid leukaemia. The single-arm phase 1 study described by David Sallman and colleagues 5 Garcia-Manero G Goldberg AD Winer ES et al. Eprenetapopt combined with venetoclax and azacitidine in TP53-mutant AML: a phase 1 dose-finding and expansion study. Lancet Haematol. 2023; 10: e272-e283 Summary Full Text Full Text PDF Google Scholar in The Lancet Haematology does not address these possibilities, but provides preliminary evidence of activity for the combination of eprenetapopt and azacitidine with venetoclax in treatment-naive patients with TP53-mutated acute myeloid leukaemia. What are the implications of this non-comparative study that reports an encouraging 38% complete response rate but a short response duration with limited effect on survival? The combination of eprenetapopt and azacitidine with venetoclax clearly does not eradicate leukaemic stem cells in most patients. Although patients included in this study had features known to confer worse outcomes, such as biallelic TP53-mutation status, the lack of stem-cell eradication raises the question of whether current therapeutic concepts involving restoration of p53 functionality are too simplistic, hampered by an incomplete understanding of TP53 biology and its variability among patients with TP53-mutated acute myeloid leukaemia. For example, the therapeutic efficacy of eprenetapopt could be influenced by how much of the mutant p53 protein is functionally restored and for how long, and by the ratio of wild-type to mutated TP53. Mutations might differ in their effect on p53, exemplified by the observation that nonsense and frameshift mutations typically yield truncated proteins that are short-lived and unlikely to be amenable to functional restoration. 6 Hassin O Oren M Drugging p53 in cancer: one protein, many targets. Nat Rev Drug Discov. 2023; 22: 127-144 Crossref PubMed Scopus (18) Google Scholar These truncated proteins are readily identified by immunohistochemistry, which also detects p53 overexpression resulting from multihit TP53 mutations, providing additional prognostic information and potentially preventing the treatment of patients who are unlikely to benefit. 7 Tashakori M Kadia T Loghavi S et al. TP53 copy number and protein expression inform mutation status across risk categories in acute myeloid leukemia. Blood. 2022; 140: 58-72 Crossref PubMed Scopus (21) Google Scholar Differences in responses to eprenetapopt could also be attributed to TP53-independent effects unique to individual patients. Conversely, the multitude of TP53-mediated and eprenetapopt-induced intracellular processes in cancer cells suggest additional rational treatment combinations—including, for example, the anti-CD47 antibody magrolimab, or the CD123 × CD3 bispecific dual-affinity retargeting antibody flotetuzumab, which has shown synergy with eprenetapopt in TP53-mutated acute myeloid leukaemia. 6 Hassin O Oren M Drugging p53 in cancer: one protein, many targets. Nat Rev Drug Discov. 2023; 22: 127-144 Crossref PubMed Scopus (18) Google Scholar , 8 Vadakekolathu J Lai C Reeder S et al. TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML. Blood Adv. 2020; 4: 5011-5024 Crossref PubMed Google Scholar Eprenetapopt combined with venetoclax and azacitidine in TP53-mutated acute myeloid leukaemia: a phase 1, dose-finding and expansion studyEprenetapopt and venetoclax with azacitidine had an acceptable safety profile and encouraging activity, supporting further frontline evaluation of this combination in the treatment of TP53-mutated acute myeloid leukaemia. Full-Text PDF