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Editorial theme | TP53-mutant AML

Oct 12, 2020

Tumor protein 53 (TP53) is a tumor suppressor protein that binds to DNA, acts as a transcription factor, and induces cell cycle arrest, apoptosis, and cellular senescence. Therefore, mutations in the TP53 gene lead to aberrant cell proliferation and division. Approximately 8% of patients with de novo acute myeloid leukemia (AML) have a TP53 mutation. However, the incidence is higher for patients with therapy-related AML/myelodysplastic syndrome (MDS) at ~30%, and more frequent in older (> 65 years) patients with complex karyotype at ~70%.1 TP53 mutations are associated with complex cytogenetics including chromosome 5, 7, and 17 abnormalities, poor prognosis, and higher relapse rates, and thus represent an area of high unmet need.2

TP53 mutations in AML are mostly missense and frequently result in loss of function phenotypes that promote clonal expansion of hematopoietic stem cells. Gain of function mutations can also occur and result in genomic destabilization, loss of cell-cycle control, enhanced proliferation, dysregulation of epigenetic pathways, and chemoresistance.1

The impact of TP53 mutations on outcome

Recently, hypomethylating agents (HMAs) have become the standard of care for patients with AML who are ineligible for intensive chemotherapy. Numerous studies have investigated the impact of TP53 mutations on the outcomes of AML and MDS treated with HMAs with varying results, suggesting there is some heterogeneity of response in this group of patients.

Welch et al. demonstrated that among patients treated with 10-day decitabine, response rates were higher in those with TP53 mutations than those with wild-type TP53 (100% vs 41%, respectively; p < 0.001) but was not associated with a lower overall survival.3

In a recent study published in the journal Annals of Hematology, Heiko Becker and colleagues investigated chromosome 17p loss and TP53 mutations in patients with AML treated with decitabine (15 mg/m2 every 8 h for 3 consecutive days, total dose of 135 mg/m2, every 6 weeks). This study analyzed the results of the phase II trial 00331 (German Clinical Trials Registry DRKS00000069) in older adults who were ineligible for intensive chemotherapy. Of the 45 patients with samples available for sequencing, eight had TP53 mutations. There were no differences in response rates (compete response, partial response, or anti-leukemic effect) between patients with wildtype and TP53-mutated AML, however those with a TP53 mutation had a shorter overall survival (p = 0.036).4

In a subgroup analysis of the randomized phase III AZA-AML-001 study (NCT01074047) in older patients with newly diagnosed AML who were treated with azacitidine (5 mg/m2/day for 7 days) or conventional care regimens (CCR: intensive chemotherapy, low-dose cytarabine, or best supportive care), the median OS was significantly reduced for patients with TP53 mutations compared with wild-type (2.4 vs 12.5 months, respectively; p = 0.026) in the CCR arm, but was not significantly different in the azacitidine arm, (7.2 vs 12.0 months, respectively; p = 0.40).5

It is important to note that the analysis of TP53 mutations are often based on relatively small patient numbers, which could account for some of the disparity seen across the studies in TP53-mutated AML.

Emerging therapies for TP53-mutated AML


Eprenetapopt is a small molecule that, once converted into the active form, restores wildtype p53 conformation and function, thus reactivating the protein. Results of the ongoing phase II GFM-APR trial (NCT03931291), which assessed the safety and efficacy of eprenetapopt plus azacitidine as maintenance therapy for patients with TP53-mutant AML or MDS following allo-SCT, were recently presented at the 25th European Hematology Association (EHA) Annual Congress. The results showed encouraging safety and efficacy profiles, with an ORR of 78% in patients with AML with < 30% blasts and 100% in patients with AML with > 30% blasts, as well as a median OS of 13.9 and 3.0 months, respectively. Full details of the presented results can be found here.

Eprenetapopt is also being evaluated as a frontline therapy in a phase I trial (NCT04214860) in combination with venetoclax and azacitidine in patients with TP53 mutations. This trial was recently expanded to include a cohort with the triplet regimen, details of which can be found here.


Flotetuzumab is a CD123 × CD3 bispecific, dual-affinity, host T-cell retargeting antibody. The CP-MGD006-01 study (NCT02152956) investigated whether TP53 abnormalities could be used to predict its sensitivity. The results presented at the American Association of Cancer Research (AACR) Virtual Annual Meeting demonstrated a 42% reduction in bone marrow blasts and anti-leukemic activity in 45.5% of patients with TP53-mutated AML. Full details of the results can be found here.


Magrolimab (Hu5F9-G4) is a first-in-class antibody against CD47, a macrophage immune checkpoint protein which has been shown to block phagocytic evasion and induce tumor phagocytosis. It is being investigated in combination with azacitidine in a phase Ib study (NCT03248479) for the treatment of high-risk MDS and AML. The initial results of this study were presented at the American Society of Clinical Oncology (ASCO) Virtual Meeting in 2020 and demonstrate encouraging responses in AML including ORR of 75% and a median duration of response not yet reached. Considering these results, an expansion cohort in TP53-mutated AML has been initiated. Full results of this report can be found here.

For more information on approaches and emerging therapies for TP53-mutant AML, listen to our podcast with Steering Committee member Navel Daver here.

TP53 inactivation in AML

TP53 inactivation in AML can occur by different mechanisms such as MDM2/MDMX upregulation, and the downstream effects of NPM1 and FLT3 mutations, therefore targeting of these pathways is also being investigated in the clinical setting. MDM2 regulates TP53 ubiquitination and is overexpressed in ~50% of AML. Therefore, blocking the MDM2-TP53 interaction with inhibitors such as idasanutlin, milademetan, RG7112, and HDM201 can prevent the proteasomal degradation of TP53.  As the MDM2 homologue, MDMX, is also upregulated (at the mRNA level) in hematopoietic stem cells and granulocyte-monocytic progenitors in patients with AML, a stapled alpha-helical cell-penetrating peptide, ALRN-6924, which disrupts the interaction between TP53 and both MDM2 and MDMX, has been developed and has been shown to activate TP53-dependent transcription.1

Arsenic trioxide, a standard chemotherapeutic agent, has been shown to enhance the activity of TP53 and upregulate its target genes. This induces apoptosis and inhibits the proliferation of tumor cells. It can also target mutant TP53 for degradation by the 26S proteasome pathway. Statins have also been shown to induce the degradation of mutant TP53 protein in solid tumors and are currently being tested in the AML setting.1

Current clinical trials investigating these compounds are summarized in Table 1.

Table 1. Current clinical trials investigating TP53 modulating compounds1



Combined with


Clinical Trial No













Alone or with Azacitidine












MDM2 and BCL-2

Idasanutlin and venetoclax






Alone or with cytarabine



Numerous targets

Arsenic trioxide




HMG-CoA reductase






The influence of TP53 mutations on clonal hematopoiesis and subsequent myeloid malignancy is increasingly recognized. Despite being a rare disease, TP53-mutant AML demonstrates high interpatient heterogeneity in treatment response, often with a poor outcome, and thus is an area of unmet need. However, the advancement of new therapies and treatment combinations in this field have yielded favorable response rates in this difficult to treat population. TP53 pathway dysregulation is a common feature even in non-TP53 mutant AML and therefore agents that modify TP53 function are also under clinical investigation for the wider treatment of AML.

Follow us for more updates in this field from upcoming congresses and publications during the next couple of months.

  1. Barbosa K, Li S, Adams P, Deshpande AJ. The role of TP53 in acute myeloid leukemia: Challenges and opportunities. Genes Chromosomes Cancer. 2019;58(12):875-888. DOI: 1002/gcc.22796.
  2. Takahashi K, Patel K, Bueso-Ramos C, et al. Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents. Oncotarget. 2016;7:14172-14187. DOI: 10.18632/oncotarget.7290
  3. Welch JS, Petti AA, Miller CA, et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med. 2016;375:2023-2036 DOI: 1056/NEJMoa1605949
  4. Becker H, Pfeifer D, Ihorst G, et al. Monosomal karyotype and chromosome 17p loss or TP53 mutations in decitabine-treated patients with acute myeloid leukemia. Ann Hem. 2020;99:1551-1560. DOI:
  5. Döhner H, Dolnik A, Tang L, et al. Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care. Leukemia. 2018;32:2546-2557. DOI: 1038/s41375-018-0257-z