Background: Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy characterized by uncontrolled proliferation and impaired differentiation of myeloid cells in the bone marrow. The tumor suppressor gene TP53 plays a crucial role in maintaining genomic integrity and preventing the development of cancer. TP53 mutations are frequently observed in AML (∼10% of patients) and are associated with aggressive disease behavior, resistance to therapy, and poor prognosis. Summary: Recent changes in classification of TP53-mutated myelodysplastic syndrome (MDS) have occurred related to the allelic status of TP53 and more importantly to harmonize MDS/AML patients as a homogeneous hematological malignancy. Current treatment regimens involve hypomethylating agents +/− venetoclax or intensive chemotherapy although unfortunately independent of treatment regimen the overall survival (OS) of this patient cohort is around 6 months with poor long-term outcomes after allogeneic stem-cell transplantation. Recent developments geared toward the treatment of TP53-mutated MDS/AML have focused on immunotherapies. Key Messages: Notably, there is optimism surrounding these new therapies that could provide breakthroughs with improving outcomes either as monotherapy or combined with established nonimmune therapies. This paper aims to provide an overview of TP53-mutated MDS/AML, including the underlying mechanisms, clinical implications, and emerging therapeutic strategies targeting this hematologic malignancy.

TP53 mutations are the most widely mutated genes across all malignancies. The TP53 gene is located on chromosome 17p13.1 which encodes proteins that function as a tumor suppressor, initiating apoptosis when signaled [1]. A pathogenetic role of p53 inactivation in malignancy has been demonstrated, as prior experiments that introduced a wild-type p53 (WT-TP53) in tumor cells with known p53 mutations were observed to lose their tumorigenicity [2]. The large majority of de novo acute myeloid leukemia (AML) cases have wild-type TP53 alleles, with the frequency of TP53 mutations occurring in about ∼10% of patients with AML, although this may be an underrepresentation when deeper sequencing is incorporated. Importantly, this subset of patients in large prospective trials has represented 20–30% of patients, partially related to referral bias of this very high-risk population and underscoring the critical need to improve outcomes in this patient population. Additionally, the frequency of TP53 mutations does increase with age or chemotherapy-related cases of AML [3]. The mechanism by which TP53 mutations are harbored in chemotherapy-related AML (t-AML)/myelodysplastic syndrome (MDS) has been advanced. Genome sequencing revealed that the total number of somatic single nucleotide variants is similar in t-AML and de novo AML, suggesting that prior chemotherapy does not induce genome-wide DNA damage [4]. In a small sample of t-AML, the offending TP53 mutation was present at very low frequencies (<0.7%) in either leukocytes or bone marrow several years prior to the development of t-AML, including cases where the mutation was present before the patients had actually received chemotherapy. Studies on animal models revealed the hematopoietic stem cells (HSCs) containing TP53 mutations expanded after exposure to chemotherapy. This suggests that TP53 mutations are not directly caused by cytotoxic therapy, but these preexisting, age-related mutations in HSC clones are resistant to chemotherapy and expand after treatment [4]. These data are also consistent with recently clonal hematopoiesis of indeterminate potential (CHIP) studies in patients with malignancy [5]. For example, the rate of CHIP was nearly double in patients with malignancy versus patients without and notably 38% of the patients had TP53 CHIP in this cohort [6].

Roughly 70–80% of the TP53 mutations in de novo AML are missense mutations resulting in amino acid alterations. The majority of the mutations fall between the codons 125 and 300 [7]. Missense mutations result in an extended half-life of the altered proteins when compared to its wild-type shorter-lived equivalent leading to the accumulation of unfolded protein that is evident on immunohistochemistry. It has not been delineated as to why the TP53 mutations result in a longer half-life. A proposal is that it could be linked with the incomplete degradation produced by the E3 ubiquitin ligase MDM2, as the MDM2 ubiquitin ligase activity is essential for p53 regulation because it is encoded by WT-TP53 [7].

Despite the majority of the TP53 mutations being missense mutations, there is a wide constellation in the TP53 gene function which lends the effects of these mutations to also have variability in terms of magnitude of the loss of function of the tumor suppressor activity of TP53. TP53 mutations cluster at several hotspot amino acid residues, the vast majority arising in DNA binding domains encoded by exons 5–8. The most 6 common hotspots are located at R175H, Y220C, M237I, R248Q, R273H, and R282W. It was previously hypothesized that there was a spectrum of the functionality of the expressed TP53 gene ranging from complete loss to partial loss and even gain of function [8]. However, research investigating the above hotspots elucidated that TP53 mutations in myeloid malignancies demonstrate a universal dominant-negative effect, therefore rejecting the previous gain-of-function hypothesis at least in myeloid malignancies. Dominant-negative mutations abolish the functionality of the wild-type gene. The dominant-negative effect hypothesis was supported in a clinical observation that showed no outcome difference in event-free or overall survival (OS) between patients who harbored missense versus truncating TP53 mutations [9].

Recently, the International Working Group for Prognosis in MDS (IWG-PM) investigated a large number MDS patients for TP53 mutations and allelic imbalances of the TP53 locus showing that roughly one-third of patients having TP53 mutations displayed a single-hit of the gene whereas two-thirds of patients displayed a multi-hit in the TP53 mutation. TP53 mutations are considered to be multi-hit if any of the following criteria are met: the presence of 2 different TP53 mutations, a single TP53 mutation with VAF >50%, or having a single TP53 mutation with 17p loss on karyotype [11]. The noted correlation between TP53 and high-risk characteristics, complex karyotype, and poor survival were directly analogous with patients having multi-hit mutations of TP53. TP53 mutation is clearly the driver of poor OS as compared to patients with complex karyotype without a TP53 deletion, patients with TP53 mutations had a worse prognosis in terms of shorter OS and disease-free survival [12].

Patients with multi-hit TP53 mutations were largely associated with high-risk occurrence of MDS and dismal outcome regardless of the Revised International Prognostic Scoring System; however, patients with single-hit mutations did not result in significant differences when compared with those with wild-type TP53 gene mutations [13]. Notably, patients with single-hit TP53 mutations in this cohort were enriched with non-increased blast phenotypes and good risk cytogenetics such as deletion 5q. A complex karyotype was found to be significantly associated with the presence of a multi-hit TP53 mutation, as it was found in 84% of TP53 multi-hit subjects, compared with 17% of TP53 single-hit subjects. In a statistical analysis of 1,519 AML and MDS subjects the most frequent occurrence of a double-hit event constituted of a TP53 mutation combined with a deletion, and ≥2 TP53 mutations was the 2nd most frequent double-hit event (29% vs. 16%, respectively) when taking into account all subjects that had non-wildtype TP53 [14]. Additionally, the TP53 variant allele frequency is tightly consistent with outcomes. In both MDS and AML patients, a VAF of >40% had a strong correlation to inferior survival as those subset of patients had a median OS of 124 days compared to a median OS that was not reached in patients with VAF <20% which was confirmed in a validation dataset with a 20% VAF cutoff representing the optimal cutpoint which has been further confirmed in two follow up publications (optimal VAF cutoff of 23%) [15‒17]. In a large cohort of patients with an average VAF of 39%, an increase in VAF of 1% correlated to a hazard of death increase by 1.02 [18]. Throughout the duration of treatment, the VAF can be followed and can correlate with the clinical trajectory [19].

CHIP is defined as the presence of a clonally expanded HSC due to a leukemogenic mutation without evidence of a hematological malignancy. CHIP increases with age and results in an increased risk of developing hematological malignancies in the future [20]. TP53 mutations have been demonstrated in CHIP; however, the molecular mechanisms that cause the stem-cell expansion are fundamentally unknown. Current findings suggest that various biological stressors, including hematopoietic transplantation, genotoxic stress, and inflammation, promote the expansion of HSCs with TP53 mutations. It has been demonstrated that TP53 mutations in CHIP breed resistance to chemotherapy and radiation, which leads to the expansion of TP53-mutant HSPCs following treatment. A study described that mutant TP53 interacts with EZH2, which catalyzes the trimethylation of lysine 27 of histone H3. This interaction with EZH2 leads to enhancement of the chromatin, subsequently increasing the levels of H3K27me3 in genes regulating HSPC regeneration and differentiation. Further research in this area is vital to understand the epigenetic drivers but nevertheless offers a mechanism by which mutant TP53 drives clonal hematopoiesis [21].

In summary, MDS patients with multi-hit TP53 mutations and/or high VAF/CK represent a homogeneous entity with poor outcomes. We recently assessed the impact of TP53 status along with complex cytogenetics in different clinical subsets of TP53-mutated MDS [22]. In the study of 2,355 MDS patients, 21% had a TP53 mutation. Further breakdown showed 78% of patient’s had biallelic status and 22% of them had monoallelic mutations. Compared to the TP53 wildtype, patients with monoallelic mutations had a 2-fold increase risk of death with a HR of 2.1, and the patient’s with biallelic mutations had even worse prognosis with the risk of death quadrupling with a HR of 4.0. In further analysis, there was a greater difference in OS between single-hit and double-hit TP53 mutations in MDS (HR = 3.1; 2.43–4.09) when compared to AML (HR = 1.5; 1.2–2) [17]. Complex karyotypes were also a poor prognostic indicator with the median OS at 1.0 years versus 2.1 years (p < 0.001) in patients with noncomplex karyotypes. Critically, the allelic status was highly prognostic in patients without complex karyotype but was not prognostically relevant in patients with complex karyotype, highlighting the potential subgroup where allelic status determination is most relevant [22].

The most recent classification of myeloid neoplasms and acute leukemias was most recently updated in 2022, with the last update prior to that in 2016. In 2016, TP53-mutated AML was included under multiple subsets: AML with myelodysplasia-related changes, therapy-related AML (t-AML), and AML not otherwise specified despite the TP53-mutated AML patients having a uniformly poor prognosis independent of what subset of AML they were grouped under. Subsequently, the ELN guidelines have been updated to alter AML classifications forgoing the previous AML w/MDS-related changes and have now added new categories including AML-specific cytogenetics/gene mutations and AML with mutated TP53. Mounting evidence indicates that from a clinical and molecular perspective, TP53-mutated AML and MDS represent a clear-cut disease entity. Specifically relating to AML with mutated TP53: if there are ≥20% blasts in the bone marrow or peripheral blood then it is designated as AML, but if there are 10–19% blasts then it is classified as MDS/AML [23].

The World Health Organization (WHO) has updated a 5th version of classifications of MDS and AML in 2022. MDS with biallelic TP53 inactivation is now recognized as a new entity [25]. Notably, the WHO did not recognize an MDS/AML overlap category based on bone marrow myeloblasts, independent of TP53 mutation status. The International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias published their consensus in 2022. Under the new guidelines, MDS, MDS/AML, and AML (all with mutated TP53) are defined by blast percentages of <10%, 10–19%, and ≥20%, respectively. The presence of a single TP53 mutation in the context of complex karyotype is considered equivalent to a multi-hit TP53. However, complex karyotype without a TP53 mutation does not qualify as an equivalent due to these cases having improved prognosis when compared to TP53-mutated MDS [27‒29]. Notably in ICC, the allelic status of TP53 was only included in patients with 0–9% bone marrow myeloblasts supporting relatively uniform poor outcomes in MDS-with excess blast (MDS-EB) and AML patients with a TP53 VAF of >10% with the goal of not including potential TP53 CHIP in prognostic modeling although further work on this topic is warranted (e.g., potential artificially low VAF based on BM cellularity, etc., in patients with clearly negative prognostic features such as TP53 VAF of 7% but with very complex monosomal karyotype).

Diagnostic separation between MDS and AML as described above has been a popular subject of discussion with evolving guidelines. Conventionally, the definition of AML has been described as >20% myeloblasts in the peripheral blood or bone marrow. However, in comparison of outcomes in TP53 mutant MDS versus AML patient populations, there has been found to be no significant difference in outcomes in patients with >5% blasts. An in-depth large cohort study characterized patients with AML or MDS-EBs using the IPSS. After analysis, there was no statistical significant difference in outcomes in patients between the AML and MDS-EB mutant TP53 subgroups (p = 0.549). Further analysis looked at OS stratified by CK status and if allogeneic hematopoietic stem-cell transplantation (HSCT) was performed. The results were consistent over both populations of AML and MDS-EB. Both TP53-mutated AML/MDS-EB constitute similar clinical and pathologic outcomes, suggesting that the aforementioned groups should be considered a single entity [11].

The current first-line therapy for high-risk MDS are hypomethylating agents (HMAs) such as decitabine and azacitidine. In AML, TP53 mutations have a lower rate of successful response to standard chemotherapy regimens and poor OS (<6 months). Specifically, patients with TP53-mutated AML who undergo treatment with standard anthracycline-based and cytarabine-based induction regimens have inferior outcomes, where the post-induction response rates are only 20–30% and short median OS were associated with higher toxicities and increased hospital stays [18, 31–34]. Even in patients who achieved complete remission, genome deep sequencing showed that TP53 mutations persisted in 73% of those patients [30]. Given these data, many consider HMA +/− venetoclax (VEN) as a first-line treatment option irrespective of patient age and fitness given comparable outcomes and less morbidity of treatment.

VEN is a bcl-2 inhibitor that is used in newly diagnosed AML and works by blocking an anti-apoptotic pathway. Although there was limited efficacy as single-agent therapy, combination with HMAs has led to a paradigm shift in the management of elderly AML [31]. However, there has not been an improvement in OS in the TP53 mutant subset. In the initial study of HMA + VEN, although responses rates were reasonable TP53 (CR/CRi of 47%), the median OS was 7.2 months [33]. Notably, follow-up analysis from this study showed that TP53 mutant patients were both enriched with primary refractory disease to HMA + VEN as well as higher allele burden correlating with a low burden of disease. Similarly in the pivotal VIALE phase 3 study, although CR/CRi rate was improved over single-agent azacitidine at 55%, there was no improvement in median OS. Recently, there has been a combined analysis from the above studies that clearly shows no improvement in OS in the TP53 mutant patient population. Notably, the true CR rate was also not notably different (∼20% in patients with TP53 mutation and adverse cytogenetics) which supports the decreased efficacy in this patient population [35]. Together, these data support that median OS with azacitidine + VEN is ∼6 months and nearly identical to that of single-agent HMA. These data raise questions on the utility of adding VEN to TP53 mutant AML patients, which may be dependent upon transplant eligibility but clearly support novel clinical investigation (Table 1). The above studies partnered VEN with the HMA azacitidine. There was significant interest in decitabine, particularly an extended course of 10-day decitabine over the initial 1–2 cycles, based on a small cohort of patients with a 100% blast clearance [36]. In this cohort, the true CR rate was 56%. However, in a randomized 10-day versus 5-day decitabine study, there was no improvement in response rates or OS and over 1/3 of the cohort was TP53 mutant with no difference in CR or OS based on decitabine schedule [37]. Due to the aforementioned positive response with decitabine as monotherapy, studies were then done to investigate VEN + decitabine. Patients who underwent dual therapy with a 10-day course of decitabine + VEN had a composite CR rate of 57%, however the median OS was only 5.2 months. In addition, these patients had a high 60-day mortality rate of 26%, which may be secondary to the TP53 patient population [38]. Given all of above, there is a case to be made to treat TP53-mutated AML with single therapy HMA instead of dual therapy of VEN + HMA as there is no improvement of the median OS with dual therapy versus monotherapy despite the increase in CR, particularly in patients without the possibility of transplant. Cytogenetics plays an important role involving the outcomes, as patients whose TP53 mutations were cleared to <5% variable allele frequency after HMA therapy had a predilection for improved outcomes [15].

Table 1.

Response and survival rates on standard of care and novel therapies for TP53-mutated AML

Agent/regimenStudy phaseResponse, %CR rate, %Median OS, monthsReference
Azacitidine or decitabine II CR/CRi 22–38 13–22 2.6–7.6 [40‒42
VEN + azacitidine or 5-day decitabine Ib/II, III CR/CRi 55 20 4.7–7.2 [35
VEN + 10-day decitabine II ORR 66 57 5.42 [38
Magrolimab + azacitidine (AML) Ib ORR 48 33 10.8 [43
Magrolimab + azacitidine (HR-MDS) Ib ORR 68 40 16.3 [43
Magrolimab + VEN + azacitidine Ib/II ORR 74–86 64 7.4–10.8 [44
Eprenetapopt + azacitidine (MDS) Ib/II ORR 73 50 10.4 [45
Eprenetapopt + azacitidine (AML) Ib/II ORR 64 36 10.8 [45
Eprenetapopt + VEN + azacitidine ORR 64 38  [47
Sabatolimab + HMA Ib ORR 40–56.9 40 6.4–21.5 [48
Flotetuzumab I/II ORR 60 47 10.3 [49
Agent/regimenStudy phaseResponse, %CR rate, %Median OS, monthsReference
Azacitidine or decitabine II CR/CRi 22–38 13–22 2.6–7.6 [40‒42
VEN + azacitidine or 5-day decitabine Ib/II, III CR/CRi 55 20 4.7–7.2 [35
VEN + 10-day decitabine II ORR 66 57 5.42 [38
Magrolimab + azacitidine (AML) Ib ORR 48 33 10.8 [43
Magrolimab + azacitidine (HR-MDS) Ib ORR 68 40 16.3 [43
Magrolimab + VEN + azacitidine Ib/II ORR 74–86 64 7.4–10.8 [44
Eprenetapopt + azacitidine (MDS) Ib/II ORR 73 50 10.4 [45
Eprenetapopt + azacitidine (AML) Ib/II ORR 64 36 10.8 [45
Eprenetapopt + VEN + azacitidine ORR 64 38  [47
Sabatolimab + HMA Ib ORR 40–56.9 40 6.4–21.5 [48
Flotetuzumab I/II ORR 60 47 10.3 [49

There is a role for allogenic hematopoietic stem-cell transplantation (Allo-HSCT) in the treatment of TP53-mutated AML. However, it has been shown that a somatic mutation of TP53 is independently associated with poor outcomes and decreased survival after receiving Allo-HSCT in patient with MDS/AML [50]. Patients harboring a TP53 mutation with a complex karyotype had a median OS of only 4.8 months with >80% passing away within 2 years of transplantation. Early relapse was the leading cause of death in these patients [51]. In patients who received Allo-HSCT after achieving CR1, the median OS was 17.6 months and 2-year OS was 50% compared to 9.1 months and 12%, respectively, to their counterparts who did not receive Allo-HSCT after CR1. Another important prognostic factor in the effectiveness of Allo-HSCT is the variant allele frequency of the TP53 mutation. In a cohort of patients with TP53-mutated VAF <40%, there was a significant improvement in median OS of 32.2 months versus 9.5 months in patients who underwent Allo-HSCT compared to patients who did not, respectively. However, this increase in median OS was not seen in patients with TP53-mutated VAF >40% who underwent Allo-HSCT versus those who did not (median OS was 9.8 months and 8.0 months respectively) [53]. In a cohort of MDS patients, 3-year OS was similar between patients with single-hit versus multi-hit TP53 who received HSCT (22% ± 8% vs. 20% ± 6%). However, the incidence of MDS relapse or progression to AML was higher in multi-hit versus single-hit TP53 at 3 years (74% ± 6% vs. 62% ± 8% at 3 years; p = 0.03). Presence of complex karyotype or chromosome 17p deletion did not affect OS or incidence of MDS relapse/AML progression. It has been suggested that the long-term survival after HSCT of TP53-mutated MDS is limited to the subset of patients who achieved a VAF reduction to <5% prior to transplant. An analysis of post-HSCT revealed that 3-year OS was not significantly different between patients with a pre-HSCT TP53 VAF of ≥5% versus <5% (22% ± 12% vs. 18% ± 10%; p = 0.95) although the size of this cohort is small and baseline VAF was lower than in historical cohorts. In this study, the benefit of HSCT over non-HSCT treatment was independent of TP53 allelic state, VAF, complex karyotype, or mutation clearance after pre-HSCT treatment. These data imply that no patient with TP53-mutated MDS should be excluded from consideration for HSCT on the foundation of TP53 status. Despite the benefit of HSCT, the survival advantage remains modest [54]. Importantly, there are no absolute predictors of favorable and adverse outcomes and thus at this time, patients with TP53 mutation should still be recommended for allograft although with careful consideration from patient perspective given worse outcomes (Fig. 1). We still highly favor achievement of complete cytogenetic remission and TP53 VAF <5% (i.e., not to bridge to transplant too early if deeper remission is possible) with strong consideration of HMA maintenance as a potential to improve transplant outcomes in this molecular cohort.

Fig. 1.

Suggested treatment algorithm for TP53-mutated MDS/AML.

Fig. 1.

Suggested treatment algorithm for TP53-mutated MDS/AML.

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Newly developed therapies have been undergoing investigation to try to improve outcomes in patients with TP53-mutated AML (Table 2). One targeted immunotherapy is magrolimab, a CD47 inhibitor that has been studied with TP53-mutated MDS/AML. Magrolimab is a human-derived monoclonal antibody that specifically binds to CD47 and is overly expressed on tumor cells. It inhibits CD47 interacting with the signal regulatory protein α (SIRPα), which is a protein expressed on phagocytic cells. Blocking this signal then allows macrophages to induced phagocytosis on these tumor cells. In a phase 1b trial, magrolimab was studied in AML patients non-eligible for intensive chemotherapy with focus on TP53 mutant patients in this large phase 1b study (n = 72 for TP53 mutation). In this study, the combination of magrolimab with azacitidine had a overall response rate of 48.6%, a CR rate of 33%, and the median OS of 10.8 months [55]. In a similar study with TP53-mutated MDS, the same combination of azacitidine + magrolimab led to a CR of 40% and median OS of 16.3 months [43]. Triple therapy with magrolimab + VEN + azacitidine in TP53-mutated AML had an impressive CR rate of 64% and cleared the TP53-mutated clones in 88% (8/9) of patients in complete remission with both complete and incomplete hematologic count recovery. Notably at the most recent ASH congress in a cohort comparison versus historical HMA + VEN treated patients, the triplet had a near doubling of OS although was similar to the azacitidine + magrolimab cohort described above [44]. Notably, there were 2 recent pivotal studies of magrolimab in AML. In the ENHANCE-2, the azacitidine + magrolimab combination was compared to azacitidine + VEN or 7 + 3 with a primary endpoint of OS in TP53 mutant AML patients independent of age or fitness. In the ENHANCE-3 studies, this will be for all-comer elderly AML where azacitidine + VEN + magrolimab will be compared to azacitidine + VEN and likely around 20–30% of the cohort may be TP53 mutant [56]. Recently, the phase 3 ENHANCE-2 study was discontinued for futility with no survival benefit compared to standard of care therapies in TP53-mutated AML after the primary endpoint of OS was not met. However, these data have not been presented and subset analysis of this study is warranted. This negative result is compounded by the recent closure of ENHANCE for higher risk MDS where the study was also futile for an improvement in OS versus HMA alone. Major questions from this study are the % of patients who are TP53 mutant and outcomes in wildtype for mutant populations. As of August 2023, the FDA placed a partial clinical hold on the enrollment of new patients in clinical trial thereby affecting the ENHANCE-3 trial [57].

Table 2.

Ongoing clinical trials for novel therapies for the treatment of TP53-mutated MDS/AML

AMLEligibility criteriaPhasePrimary outcome measuresIdentifier
Magrolimab + VEN + azacitidine New dx of AML; R/R AML; WBC <15 × 109/L Ib/II Maximum tolerated dose of the combination drugs (phase Ib) NCT04435691 
CR/Cri 
Incidence of adverse events (phase II) 
Event-free survival (phase II) 
Multiarm study ND, R/R, and post-induction maintenance AML; WBC ≤20 × 103; ECOG 2–3 I/II Rate of CR NCT04778410 
• Magrolimab + VEN + azacitidine 
Minimal residual disease negative CR rate 
• Magrolimab + MEC 
• Magrolimab + CC486 % of patients experiencing dose-limiting toxicities 
Sabatolimab +/− azacitidine MRD + post allo-HSCT Ib/II Incidence of dose-limiting toxicities NCT04623216 
% of adult subjects with absence of relapse 
Sabatolimab + VEN + azacitidine (STIMULUS-AML1) ND AML, ECOG 0–3, not planned for HSCT II Incidence of dose-limiting toxicities NCT04150029 
% of adult subjects with absence of relapse 
Entrectinib + cedazuridine + decitabine R/R AML w/TP53 mutation Incidence of dose-limiting toxicities NCT05396859 
Nivolumab + decitabine + VEN ND AML, TP53 mutation, ECOG 0–2 Incidence of adverse events NCT04277442 
Number of patients that are able to complete 3 cycles of therapy 
Response 
Sodium stibogluconate MDS or AML w/TP53 mutation, ECOG 0–2 II Overall response rate NCT04906031 
Partial response + complete response rate 
AMLEligibility criteriaPhasePrimary outcome measuresIdentifier
Magrolimab + VEN + azacitidine New dx of AML; R/R AML; WBC <15 × 109/L Ib/II Maximum tolerated dose of the combination drugs (phase Ib) NCT04435691 
CR/Cri 
Incidence of adverse events (phase II) 
Event-free survival (phase II) 
Multiarm study ND, R/R, and post-induction maintenance AML; WBC ≤20 × 103; ECOG 2–3 I/II Rate of CR NCT04778410 
• Magrolimab + VEN + azacitidine 
Minimal residual disease negative CR rate 
• Magrolimab + MEC 
• Magrolimab + CC486 % of patients experiencing dose-limiting toxicities 
Sabatolimab +/− azacitidine MRD + post allo-HSCT Ib/II Incidence of dose-limiting toxicities NCT04623216 
% of adult subjects with absence of relapse 
Sabatolimab + VEN + azacitidine (STIMULUS-AML1) ND AML, ECOG 0–3, not planned for HSCT II Incidence of dose-limiting toxicities NCT04150029 
% of adult subjects with absence of relapse 
Entrectinib + cedazuridine + decitabine R/R AML w/TP53 mutation Incidence of dose-limiting toxicities NCT05396859 
Nivolumab + decitabine + VEN ND AML, TP53 mutation, ECOG 0–2 Incidence of adverse events NCT04277442 
Number of patients that are able to complete 3 cycles of therapy 
Response 
Sodium stibogluconate MDS or AML w/TP53 mutation, ECOG 0–2 II Overall response rate NCT04906031 
Partial response + complete response rate 

In the relapsed/refractory setting, clinical trial focus in this patient group has been with novel immunotherapy, particularly as this group has significant immune dysregulation versus wildtype as well as overexpressed PDL1 on LSC subsets [58]. One example is with flotetuzumab, a bispecific antibody-based molecule to CD3ε and CD123 engineered in a DART format. CD123 is the designated receptor for IL3. In hematopoietic cells, this signaling activates the PI3K/MAPK pathway which causes proliferation of progenitor cells and increases production of anti-apoptotic proteins [59]. Flotetuzumab blocks the CD123 signaling pathway with prevents production of CD123 hematopoetic progenitor cells. In patients with relapsed or refractory AML, a phase I/II trial was done with flotetuzumab within 6 months of primary induction failure or early relapse. Seven out of the 15 patients showed a complete response to flotetuzumab with <5% blasts. Of those 7 patients, the median OS was 10.3 months [49].

Eprenetapopt (APR-246) is an active molecule that reactivates p53 function in TP53 mutated cells. The active metabolite of APR-246 is methylene quinuclidinone which functions to bind covalently to the mutated TP53 and restores its wild-type activity [60]. A phase 1b/2 study in patients with TP53-mutated MDS/AML showed that when eprenetapopt was combined with azacitidine, there was an ORR of 71% and the median OS was 10.8 months. In the same clinical trial, 44% of the patients achieved a CR with a median duration of 7.3 months [45]. A phase 3 randomized study was done that compared TP53-mutated MDS patients to receive eprenetapopt/azacitidine or azacitidine alone. The results of the study showed that there was no statistically significant benefit in CR in the experimental arm when compared to the control arm with CR rates of 33% versus 22% respectively (p = 0.13) [46]. Additionally, a triplet combination of azacitidine + VEN + eprenetapopt showed a true CR rate of 38% supporting further investigation [47]. In the post-ASCT transplant setting, a phase 2 trial for eprenetapopt/AZA in TP53-mutated MDS resulted in a median OS of 20.6 months and a 1-year relapse-free survival of 58%, strongly supporting future investigation in a randomized phase 3 study [61].

Another emerging therapy undergoing investigation is sabatolimab. Sabatolimab is a human-derived monoclonal antibody that is selective toward human mucin domain-3 (TIM-3). TIM-3 functions as a cell surface marker specific to CD4+ T-helper 1 and CD8+ T-cytotoxic 1 cells that produce interferon-γ [62]. TIM-3 is an inhibitory receptor than regulates immune responses that have shown to be expressed on leukemic stem cells and blasts. It has been shown to promote immune tolerance via checkpoint regulation. Due to the overexpression of TIM-3 on MDS/AML stem cells, blocking the TIM-3 leads to the destruction of selective malignant myeloid stem cells [63]. A phase 1b trial of sabatolimab + HMA in a cohort of very high/high-risk MDS or newly diagnosed AML showed promising results. Among the patients with very high-risk/high-risk MDS, the ORR was 56.9% and median duration of response was 16.1 months. In patients with high-risk MDS and an adverse-risk mutation (TP53 mutations included), the CR rate was 43% and the median duration of response was 21.5 months. With newly diagnosed TP53 mutated AML, the CR was 40% with a median duration of response of 6.4 months. However, in the recently presented double blind placebo controlled trial of azacitidine + sabatolimab versus sabatolimab alone, there was no improvement in response or OS in patients with TP53 mutant MDS [64]. The adverse events of sabatolimab + HMA were similar to HMA alone, with the two most common being neutropenia and thrombocytopenia [48]. Primary results from the double blind placebo controlled phase 2 trial showed that sabatolimab + HMA did not reveal a statistically significant improvement in CR when compared to placebo + HMA with a CR of 23.1% versus 21.0% respectively. Progression-free survival between the two groups was 11.3 months versus 8.3 months, respectively. In the TP53 mutant cohorts (n = 39 and 38), the OS was no different at 15 months [65].

Chimeric antigen receptors (CARs) T-cell therapy uses engineered T cells that can recognize tumor antigens through tumor-specific receptors with the idea to specifically target surface proteins to selectively destroy cancer cells. Several in vitro studies have shown that CAR T cells can selectively kill AML cells by way of targeting certain target proteins such as CD33, CD123, CLL-1, CD13, CD70, CD38, NKG2D ligands, and TIM3 among others [66]. The field of CAR-T in AML is in its infancy although with responses seen across early studies although major challenge in predictors of response, durability of response, safety challenges, and need for bridge to Allo-HSCT [67‒69]. Potentially combinatorial CAR may be need to significant improve efficacy. Given profound T-cell dysfunction in patients with TP53 mutations [58], allogeneic CAR may be best in this patient population as there has not been a TP53 mutant MDS/AML patients reported to date with response.

TP53-mutated MDS/AML represents a challenging subtype of hematologic malignancies with distinct clinical and molecular features. The identification of TP53 mutations in MDS and AML patients holds significant prognostic value and provides opportunities for targeted therapeutic interventions, with uniform poor outcomes in patients with biallelic disease, EBs, and/or complex cytogenetics. The presence of TP53 mutations disposes patients to a high risk of treatment failure with current treatment regimens. Due to poor outcomes in both TP53-mutated MDS and AML, it is imperative to categorize them as a homogeneous entity and prospective study needs to be uniformly done in adverse TP53 mutant MDS/AML rather than all-comer studies. Although current treatment options for TP53-mutated AML are limited, further investigations are warranted to better understand the underlying mechanisms of TP53 mutation in MDS and AML and develop effective treatments that specifically target this genetic alteration in hopes of improving survival in these ill-fated patients.

D.A.S. has received consulting from Gilead. J.D. has no conflicts of interest to declare.

There was no funding provided for this manuscript.

J.D. and D.A.S. both wrote the manuscript and approved the final manuscript for submission.

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