Critical Updates in TP53 MDS Prognosis: 2025 Findings

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Introduction

TP53 MDS prognosis remains one of the most challenging aspects of myeloid malignancies, with survival outcomes dramatically worse than other genetic subtypes. Patients harboring TP53 mutations exhibit dismal survival rates, with a median overall survival of only 5-10 months, compared to those with wild-type TP53. The prevalence of TP53 mutations varies significantly across myeloid neoplasms, occurring in approximately 8-12% of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cases, whereas therapy-related myeloid neoplasms show much higher frequencies, ranging from 20-40%.

Despite recent advances in treating other forms of myeloid neoplasms, patients with TP53-mutated MDS continue to face dismal outcomes. Those with multi-hit (biallelic) TP53 mutations demonstrate complex karyotyping, primary resistance to chemotherapy, and substantially poorer overall survival compared to patients with monoallelic mutations. Furthermore, within the European Leukemia Net unfavorable risk category, mutant TP53 strongly correlates with decreased survival, with two-year overall survival rates of just 12.8% for TP53-mutant cases compared to 42.5% for TP53 wild-type patients. The MDS prognosis score models have consequently evolved to account for this genetic aberration as a defining high-risk feature. However, survival beyond one year remains rare after conventional treatments, including induction chemotherapy with or without consolidative allogeneic stem cell transplantation.

This article examines recent developments in understanding TP53-mutated MDS, including biological mechanisms, diagnostic classification updates, prognostic indicators, and emerging therapeutic approaches that may alter the trajectory for patients with this challenging molecular subtype.

TP53 Mutation Biology in MDS: 2025 Perspective

The TP53 gene stands as a pivotal tumor suppressor in myeloid neoplasms, often referred to as “the guardian of the genome.” Located on chromosome 17p13.1, this 20-kb gene encodes a 393-amino-acid phosphoprotein critical for maintaining cellular integrity [1]. Recent advances in molecular analysis have expanded our understanding of how TP53 mutations drive the aggressive nature of myelodysplastic syndrome (MDS).

TP53 gene structure and functional domains

The TP53 protein comprises several distinct functional domains, each contributing to its tumor-suppressive capabilities. These domains include:

N-terminal transactivation domain: This region recruits the transcriptional machinery and interacts with transcriptional coactivators, such as p300/CBP, to initiate transcription of p53 target genes. It is essential for triggering cell cycle arrest, DNA repair, and apoptosis genes.
DNA-binding domain (DBD): The central DBD helps p53 recognize and bind to DNA consensus sequences, regulating downstream target genes. This domain contains most pathogenic TP53 mutations, which affect DNA binding and tumour suppressor function.
Oligomerization domain: This region near the C-terminus facilitates the formation of p53 tetramers, which are essential for stable DNA binding and transcriptional control. Oligomerisation mutations diminish p53’s stability and transcriptional efficacy.
Carboxy-terminal regulatory domain: Phosphorylation, acetylation, and ubiquitination in this flexible area regulate p53 function. It regulates stress-induced p53 activation and degradation by fine-tuning its DNA-binding affinity and turnover.

The DBD represents the most frequently mutated region in MDS, with six major mutational hotspots identified at codons 175, 245, 248, 249, 273, and 282 [2]. Mutations in this domain prevent the proper binding of p53 to its transcriptional targets, thereby disrupting its ability to regulate the cell cycle, DNA repair, and apoptosis [2]. Alternatively, mutations in the oligomerization domain result in the loss of both tetramerization and tumor suppression functions [1].

Mechanisms of inactivation: missense, LOH, cnLOH

TP53 inactivation occurs through multiple genetic mechanisms, with missense mutations being the most prevalent. In fact, approximately 75% of TP53 mutations in MDS/AML are missense variants, primarily clustering in exons 4-8, which encode the DNA-binding domain [3]. These mutations differ fundamentally from those of other tumor suppressors, such as RB1 and VHL, which more commonly result in complete protein loss [4].

Notably, TP53 alterations can be categorized as either monoallelic or biallelic. Monoallelic mutations, in which only one TP53 allele carries a point mutation, account for 25-30% of cases [3]. In contrast, biallelic alterations occur in 70-75% of cases, typically resulting from a point mutation on one allele (usually a missense mutation) accompanied by loss of the second allele [3].

The three predominant mechanisms of biallelic TP53 inactivation include: multiple mutations (18.4–28.8%, median 22.6%), a mutation with deletion of the trans allele (22.5–42.2%, median 33%), and a mutation with concomitant copy-neutral loss of heterozygosity (cnLOH) (12.2–20.6%, median 17%) [5]. The variant allele frequency (VAF) carries substantial prognostic implications, with a 20% threshold identified as clinically relevant in distinguishing patient outcomes [6].

Research has debated whether TP53 missense mutations confer a gain-of-function (GOF) or dominant-negative effect (DNE). Recent evidence suggests that in myeloid malignancies, DNE predominates, where mutant p53 forms tetramers with wild-type p53, neutralizing its function [2]. This explains why patients with biallelic inactivation demonstrate more aggressive disease characteristics, including complex karyotypes and higher bone marrow blast counts [7].

Role in hematopoietic stem cell regulation

TP53 serves as a master regulator in hematopoietic stem cells (HSCs), maintaining their quiescence and genomic stability. Normal p53 function prevents excessive self-renewal and preserves the integrity of the hematopoietic system [4]. When TP53 mutations occur, they confer a competitive fitness advantage to HSCs, particularly under selective pressure from cytotoxic therapy [2].

This selective advantage explains the enrichment of TP53 mutations in therapy-related myeloid neoplasms (t-MN), where they are found in 20-40% of cases—a substantially higher frequency than the approximately 10% observed in primary MDS [8]. In t-MNs, TP53 mutations typically present with larger clone sizes (median VAF 46.2% versus 32.2% in primary MDS) and primarily exist within ancestral clones [8].

By transforming HSCs into pre-leukemic stem cells, TP53 mutations substantially contribute to leukemogenesis and treatment resistance [3]. Although a TP53-mutated clone alone may be insufficient for complete transformation, it creates a proleukemic state that requires fewer cooperating mutations than other subtypes—indeed, 85% of TP53-mutated MDS/AML cases lack additional driver mutations [3].

Recent studies utilizing single-cell sequencing technologies have enhanced our ability to detect subclonal mosaicism with distinct TP53 clones, although technical limitations persist [9]. Additionally, advances in understanding the downstream transcriptomic signatures of biallelic TP53 have revealed that mechanisms beyond mutation and deletion contribute to p53 dysfunction, including aberrant splicing, promoter methylation, and altered protein isoform usage [3].

Clonal Hematopoiesis and TP53-Driven Disease Evolution

Understanding the evolutionary trajectory of TP53-mutated MDS begins with recognizing its precursor states. Clonal hematopoiesis represents a critical stepping stone in the pathway toward malignant transformation, with TP53 mutations playing a central role in this process.

CHIP and CCUS as precursors to TP53-mutated MDS

Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence of somatic mutations in myeloid driver genes at a variant allele frequency (VAF) ≥2% without overt hematologic abnormalities. Meanwhile, clonal cytopenia of undetermined significance (CCUS) represents CHIP accompanied by unexplained persistent cytopenias. TP53 mutations are found in approximately 4-5% of individuals with CHIP [2], creating a reservoir of pre-leukemic stem cells that may eventually progress to overt malignancy.

The mutational landscape of TP53 in CHIP resembles that of MDS and AML, characterized primarily by missense mutations concentrated in the DNA-binding domain [2]. This pattern suggests that the same TP53 mutations identified at the CHIP stage already exist within the founding clone that can ultimately evolve into MDS/AML. Interestingly, studies of individuals with Li-Fraumeni syndrome, who carry germline TP53 mutations, reveal an increased propensity to develop MDS and AML with age [4], further establishing the link between these mutations and myeloid malignancy development.

Moreover, the risk of transformation from CHIP to myeloid neoplasm is heterogeneous, influenced by clone size, complexity, allelic state, and external selection pressures [2]. Patients with CCUS demonstrate a 14-fold higher probability of developing a myeloid neoplasm compared to those without evidence of clonal disease [10], highlighting the increased risk associated with the combination of cytopenias and clonality.

Selective pressure from cytotoxic therapy

Perhaps the most compelling evidence for TP53’s role in disease evolution comes from therapy-related myeloid neoplasms. Rather than directly inducing TP53 mutations, cytotoxic therapy creates selective pressure that allows pre-existing TP53-mutated hematopoietic stem cells to preferentially expand [2][2]. This selective advantage occurs because TP53-mutant cells resist apoptosis induced by DNA-damaging agents.

Radiation therapy and chemotherapy, including platinum compounds or topoisomerase-II inhibitors, have been shown to drive the expansion of clones carrying mutations in DNA damage response genes, predominantly TP53 [2]. Studies comparing mutation burden in the genomic region containing TP53 found similar rates between therapy-related and de novo AML, providing further evidence that chemotherapy selects for—rather than creates—these mutations [11].

This selection mechanism explains why TP53 mutations occur in 25-40% of therapy-related myeloid neoplasms compared to only 5-10% in de novo cases [3]. Multiple studies have confirmed this model through paired sequencing analysis, demonstrating that TP53 mutations detected in therapy-related MDS/AML were often present at low VAFs (0.9-22.3%) in samples collected years before malignancy development [3].

Latency and transformation risk

The progression from clonal hematopoiesis to overt myeloid malignancy follows a variable timeline. Therapy-related myeloid neoplasms typically develop 1-5 years after exposure to cytotoxic therapy, with 54% diagnosed ≥5 years and 29% diagnosed ≥10 years from the primary malignancy [3]. This latency period reflects the time required for clonal expansion and acquisition of cooperating mutations.

Several factors influence transformation risk:

Variant allele frequency (VAF): A TP53 VAF greater than 10% serves as a clinically useful threshold for identifying patients with poor survival outcomes [3].
Mutation complexity: The presence of ≥2 somatic mutations correlates with an 88% positive predictive value for subsequent diagnosis of myeloid neoplasm [6].
Co-mutations: Monoallelic TP53 mutations frequently co-occur with mutations in TET2 (29%), SF3B1 (27%), ASXL1 (16%), and DNMT3A (16%), potentially affecting disease evolution [2].

Notably, while TP53 mutations promote self-renewal in mouse models, they fail to induce overt leukemia without additional oncogenic events [2]. Therefore, the transformation from CHIP to MDS requires either additional mutations driving cell proliferation or persistent selection pressure that enables TP53-mutated clone expansion [2][4].

Recent evidence suggests that the combination of hematopoietic stem cell-intrinsic factors (such as genetic predisposition) with extrinsic factors (including genotoxic therapies and alterations to the bone marrow microenvironment) influences clonal evolution and ultimately determines the progression risk [3].

Diagnostic Classification Updates: WHO-5 vs ICC 2025

Recent classification systems have introduced substantial changes in how TP53-mutated MDS is diagnosed and categorized. The 5th edition of the World Health Organization (WHO-5) and the International Consensus Classification (ICC) 2025 represent divergent approaches to defining this high-risk entity, with discrepancies that affect both diagnostic precision and patient management.

Discrepancies in blast thresholds and allelic status

A fundamental distinction between these classification systems lies in their treatment of allelic status and blast thresholds. The WHO-5 classification introduced a unique category for MDS distinguished by biallelic TP53 inactivation, considering it a homogeneous category regardless of blast percentage (0-19%) [12]. In contrast, the ICC prioritizes allelic status in conjunction with blast percentage for risk stratification [13].

For cases with <10% blasts, discrepant diagnoses primarily stem from complex karyotype (CK) being considered evidence of biallelic TP53 inactivation exclusively in the ICC [1]. Among MDS and AML cases with TP53 mutations, 64% would be classified differently between WHO-5 and ICC [14]. In one study examining 603 patients with TP53 mutations, applying WHO-5 criteria would classify only 36% as TP53-mutated myeloid neoplasms, while 64% would be excluded [13].

The ICC introduced an MDS/AML category (10-19% blasts) requiring only monoallelic TP53 abnormality, whereas WHO-5 maintains the requirement for biallelic TP53 inactivation in this blast range [1]. Remarkably, clinical outcomes appear similar between cases meeting the WHO-5 criteria for biallelic TP53 abnormalities and those with a single TP53 mutation plus a complex karyotype, suggesting that CK reliably identifies cases with biallelic TP53 inactivation [1].

VAF cutoffs and their clinical implications

Both classification systems diverge on variant allele frequency (VAF) thresholds. The ICC mandates a VAF ≥ 10% for TP53 mutations, whereas the WHO-5 does not specify a VAF cutoff [13]. This discrepancy has substantial clinical implications, as studies demonstrate that patients with TP53 VAF <10% constitute 10% of myeloid neoplasm cases [1].

Importantly, optimal TP53 VAF thresholds for prognostication appear to be ~20%. One study found that patients with monoallelic TP53 mutations and VAF ≥20% shared similar prognoses with those having multihit TP53 mutations, whereas patients with monoallelic TP53 and VAF <20% demonstrated survival similar to TP53 wild-type cases [11].

In therapy-related MDS, the median overall survival (OS) for monoallelic cases reached 22 months, compared to 12 months for biallelic TP53-mutated cases [15]. Likewise, patients who underwent hematopoietic stem cell transplantation achieved a median survival of 21 months, compared to 10 months for those who did not [15].

Research utilizing recursive partitioning algorithms identified 20% as the optimal VAF cutpoint for survival prediction, with median OS for patients with TP53 VAF <20% at 685 days versus 183 days with VAF ≥20% [9]. Another study employing classification and regression tree analysis determined that patients with TP53 Mutations and a VAF ≥50% had a 2-year progression-free survival rate of only 3% [16].

Impact on treatment eligibility and trial design

These classification discrepancies directly affect treatment eligibility and clinical trial design. The WHO-5 classification suggests that TP53-mutated MDS with ≥10% marrow blasts “may be regarded as AML-equivalent for therapeutic considerations and from a clinical trial design perspective” [17]. This perspective acknowledges the continuum between MDS and AML in TP53-mutated disease.

The ICC’s MDS/AML category (10-19% blasts) was created partly to acknowledge this continuum and account for the ambiguity in blast count [9]. This reclassification potentially enables patients to qualify for both MDS and AML clinical trials, expanding treatment options [9].

From a treatment perspective, conventional therapies show limited efficacy. CPX-351, approved for therapy-related AML or AML with myelodysplasia-related changes, demonstrates reduced response rates in TP53-mutated AML [18]. Given these poor outcomes, clarified classifications facilitate clinical trial recruitment for novel agents targeting this distinct biological entity.

Ultimately, these diagnostic updates reflect growing recognition that TP53 mutations fundamentally alter disease biology and prognosis in myeloid neoplasms, necessitating distinct classification to encourage research, facilitate appropriate clinical trial design, and stimulate drug discovery for this challenging patient population [14].

Prognostic Indicators in TP53-Mutated MDS

Recent molecular investigations have yielded crucial stratifications for patient outcomes in TP53-mutated myelodysplastic syndromes. Allelic state, variant allele frequencies, and chromosomal configurations all serve as potent predictors that reshape clinical management.

Monoallelic vs multi-hit TP53 mutations

The distinction between single and multiple TP53 alterations has a profound impact on prognosis. Multi-hit TP53 mutations, present in approximately 63-80% of cases, display substantially worse outcomes than their monoallelic counterparts [5]. Patients with multi-hit mutations demonstrate a median overall survival (OS) of merely 8.7-9.4 months, whereas those with monoallelic mutations achieve 12.5-30 months [5].

Biallelic inactivation occurs through several mechanisms: multiple TP53 mutations (22-28%), a mutation with deletion of the trans allele (33%), or a mutation with concomitant copy-neutral loss of heterozygosity (cnLOH) (17%) [19]. Notably, complex karyotype occurs in 85-93% of multi-hit TP53 cases but only 58% of monoallelic cases, illustrating fundamental biological differences [20].

Variant allele frequency (VAF) thresholds

Beyond the allelic state, the percentage of cells carrying TP53 mutations offers essential prognostic information. Multiple studies have established clinically relevant VAF thresholds:

VAF ≥20%: Monoallelic mutations with VAF ≥20% demonstrate outcomes equivalent to multi-hit cases, while those <20% behave similarly to wild-type TP53 [21]
VAF ≥22-24%: Optimized thresholds identified through statistical modeling show superior prognostic power compared to the conventional 50% cutoff [22]
VAF >40%: Independently predicts poor survival with a median OS of only 124 days versus not reached for VAF <20% [8]

Correspondingly, patients with VAF >40% exhibit strong correlations with complex karyotypes—100% in one training set versus just 54% in patients with VAF <20% [8]. This explains why VAF serves as a surrogate marker for multi-hit status in many clinical settings.

Complex karyotype and chromothripsis

Cytogenetic abnormalities frequently accompany TP53 mutations, creating distinct prognostic subgroups. A complex karyotype (defined as≥3 chromosome abnormalities) is observed in 71% of TP53-mutated patients, compared to only 42% in wild-type cases [7].

Chromothripsis—extensive chromosomal shattering from a single catastrophic event—represents an especially ominous finding. This phenomenon occurs in up to 35% of patients with complex karyotype AML and correlates strongly with TP53 alterations [23]. Among chromothripsis-positive cases, 85% harbor TP53 mutations, typically with poor treatment outcomes (a 25% complete remission rate versus 47% in chromothripsis-negative cases) [23]. The 2-year survival rates for patients with chromothripsis-positive versus chromothripsis-negative tumors are striking: 0% versus 13% for event-free survival and 0% versus 28% for overall survival [23].

Furthermore, monosomal karyotypes frequently coincide with chromothripsis, particularly in cases with multi-hit TP53 [24]. These patients have a median overall survival of only 5.5-8 months, regardless of blast percentage, obliterating the traditional prognostic value of blast counts [25].

Integration into mds prognosis score models

Contemporary prognostic systems increasingly incorporate TP53 status as a pivotal variable. The International Prognostic Scoring System-Molecular (IPSS-M) explicitly distinguishes between multi-hit and monoallelic TP53 mutations, since multi-hit status independently predicts inferior outcomes [26].

Henceforth, TP53 allelic state determination has become essential for accurate risk assessment. In multivariable analyses, TP53 mutation status consistently ranks among the most powerful prognostic factors, alongside age, blast percentage, and cytogenetic abnormalities [27].

Accordingly, patients with complex karyotype MDS should undergo routine TP53 sequencing, even those traditionally considered to be at the highest risk [28]. This refinement enables more precise treatment planning and accurate determinations of clinical trial eligibility.

Immune Evasion and Tumor Microenvironment in TP53 MDS

Immune microenvironment abnormalities accompany TP53 mutations in myelodysplastic syndrome, creating a distinct landscape that contributes to disease persistence and therapeutic resistance. This immunosuppressive milieu results from complex interactions between malignant cells and immune components, ultimately facilitating disease progression through multiple mechanisms.

PD-L1 upregulation and T-cell exhaustion

TP53 mutations fundamentally alter immune checkpoint regulation within the bone marrow niche. Mutant p53 directly upregulates Programmed Death-Ligand 1 (PD-L1) expression through disruption of miR-34a, a microRNA that normally downregulates PD-L1 [10]. This mechanism differs markedly from wild-type p53, which maintains appropriate PD-L1 suppression via the miR-34 family [6]. As a consequence, hematopoietic stem cells from patients with TP53 mutations exhibit substantially increased PD-L1 expression [29].

The immunological impact of this upregulation manifests through widespread T-cell dysfunction. CD8+ T cells in TP53-mutated MDS exhibit elevated frequencies of exhausted PD1+TIM3+ populations, accompanied by a reduction in CD69+ antigen-activated T cells [30]. Functionally, these exhausted T cells demonstrate impaired proliferation, decreased cytokine production, and compromised cytotoxicity [2]. The bone marrow of patients with TP53 mutations contains notably fewer OX40+ cytotoxic T cells and helper T cells [29], alongside a marked impairment in the ability of CD3−CD28-stimulated T cells to secrete immune-effector Th1 cytokines [11].

Beyond checkpoint dysregulation, TP53 mutations also disrupt antigen presentation machinery. Wild-type p53 regulates MHC class I expression through transcriptional activation of endoplasmic reticulum aminopeptidase 1 (ERAP1), whereas p53-null tumor cells show reduced MHC class I expression, impairing CD8+ T cell recognition [6]. This creates a dual-pronged attack on T-cell function through both exhaustion and reduced target recognition.

Expansion of Tregs and MDSCs

Regulatory T cells (Tregs) represent key mediators of immune suppression in TP53-mutated MDS. Patients with TP53 mutations exhibit an expanded population of highly immunosuppressive ICOShigh/PD-1− regulatory T cells [29], accompanied by an upregulation of FoxP3 transcription [11]. These activated Tregs secrete increased amounts of immunosuppressive cytokines, including IL-10 and IL-35, which not only inhibit effector T cell function but also induce chemoresistance [31].

At the same time, myeloid-derived suppressor cells (MDSCs) proliferate in the TP53-mutated microenvironment, showing increased PD-1low phenotypes [11]. These MDSCs help tumor cells evade immune detection through multiple mechanisms. First, they secrete immunosuppressive cytokines, such as IL-10, IL-1β, and TGF-β, which are especially prevalent in high-risk MDS [2]. Second, they promote MDSC expansion through alarmins, such as S100A9 [3]. Third, they directly suppress NK cells, T cells, and B cells while modulating the production of cytokines by macrophages [3].

The expansion of both Tregs and MDSCs appears driven by chronic inflammation and dysregulated cytokine networks. Additionally, decreased numbers of ICOS+ and 4-1BB+ natural killer cells further compromise anti-tumor immunity [29]. This comprehensive suppression of both innate and adaptive immunity creates a permissive environment for leukemic progression.

Cytokine dysregulation: IL-8, TGF-β, IL-1β

TP53-mutated MDS exhibits profound perturbations in the cytokine network, which further promote immune dysfunction. Aberrant levels of growth factors, chemokines, and inflammatory cytokines characterize the bone marrow milieu, with notable increases in GM-CSF, TNF-α, TGF-β, IL-6, IL-8, IL-32, and IFN-γ [2]. These dysregulated cytokines correlate with poorer outcomes [3].

Specifically, TP53-mutated MDS shows increased secretion of:

IL-1β, which drives pyroptotic cell death and MDSC expansion [3]
IL-8, promoting abnormal myeloid differentiation [3]
TGF-β, which inhibits T cell activation and fosters an immunosuppressive environment [10]

Interestingly, the cytokine profile changes during disease evolution—low-risk disease features elevated inflammatory cytokines (TNF-α, IL-6, IFN-γ), whereas high-risk disease demonstrates increased immunosuppressive cytokines, such as IL-10, reflecting tumor immune escape [3]. TP53-mutated AML specifically displays upregulation of proinflammatory Th17 genes, NF-κB, and PI3K–AKT signaling [11].

Due to these interacting mechanisms, TP53-mutated MDS and AML establish a profoundly immune-dampened microenvironment with immune senescence features [11]. It contributes directly to the particularly poor prognosis in TP53-MDS, as conventional therapies face an uphill battle against both the intrinsic resistance mechanisms and the extrinsic immunosuppressive shield created by the mutant TP53.

Current Treatment Outcomes and Limitations

Conventional therapies for TP53-mutated MDS face substantial limitations, ultimately resulting in modest improvements despite initial responses.

HMA monotherapy: azacitidine and decitabine

Hypomethylating agents (HMAs) remain the backbone therapy for high-risk MDS, offering overall response rates of 17-77% in TP53-mutated disease, with complete remission rates of only 10-25% [32]. The median overall survival with HMA monotherapy ranges from 8.2 to 12.4 months [32]. Notably, a small study reported 100% response rates with a 10-day decitabine regimen, albeit in only nine patients [32].

The baseline TP53 variant allele frequency (VAF) substantially impacts outcomes; patients with a VAF >40% experience markedly inferior survival, ranging from 4.1 to 7.7 months, with HMA therapy [32]. Comparative analyses between azacitidine and decitabine have shown no statistically significant differences in complete remission rates (17.5% vs. 19.2%), composite complete remission rates (22.2% vs. 25.1%), or median overall survival (8.7 months vs. 8.2 months) [33].

Venetoclax-based regimens: response vs durability

The addition of venetoclax to HMA therapy yields higher overall response rates (76% vs 49%) and marrow complete remission rates (21% vs 7%) compared to HMA monotherapy [4]. Nevertheless, complete remission rates remain similar between approaches (17% vs 12%) [4]. While more patients receiving HMA+venetoclax combinations are bridged to allogeneic stem cell transplantation (41% vs 20%) [4], this has not translated into reduced AML transformation risk or improved survival outcomes.

Both median relapse-free survival (8.47 vs. 9.90 months) and overall survival (16.33 vs. 14.20 months) remain comparable between HMA plus venetoclax and HMA monotherapy [4]. Mechanistically, TP53 mutations confer resistance to venetoclax through alterations in mitochondrial homeostasis [32]. Even among responding patients, 60-day mortality rates are similar (3% vs 3%) [4], highlighting persistent limitations in managing this aggressive disease variant.

Allogeneic transplant outcomes in TP53 MDS

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only potentially curative approach, yet outcomes for TP53-mutated patients remain poor. A systematic review and meta-analysis demonstrated an overall 21% survival rate at three years post-transplant [34], with a pooled relapse rate of 58.9% at a median of 1.75 years [34].

Patients with multi-hit TP53 mutations exhibit worse leukemia-free survival than those with single-hit mutations (18% vs 26% at 3 years) [35], though overall survival differences are less pronounced (27% vs 35%) [35]. Interestingly, patients in complete remission versus non-complete remission at transplant show similar 3-year survival rates (33% vs 34%) [35].

The minimal residual disease (MRD) status before transplantation represents a critical prognostic factor, with MRD-negative patients achieving superior median overall survival (29.5 vs. 10.0 months) [36]. Hence, achieving molecular clearance before transplantation may optimize outcomes in this challenging population.

Emerging Therapies and Clinical Trials in 2025

Innovative therapeutic approaches for patients with TP53-mutated myelodysplastic syndromes are under investigation, offering potential alternatives to conventional treatments with historically poor outcomes.

Eprenetapopt (APR-246) + azacitidine

Eprenetapopt represents a novel p53-stabilizing agent that binds to cysteine residues in the DNA-binding domain of mutant p53, potentially restoring wild-type function. This small molecule additionally targets cellular redox balance, promoting tumor cell apoptosis and ferroptosis [13]. In phase Ib/II trials, the combination with azacitidine demonstrated promising results in TP53-mutated MDS patients with overall response rates of 62-73% and complete remission rates of 47-50% [9]. Interestingly, 38% of patients achieved complete molecular remission with variant allele frequencies of less than 5% [9].

Yet the pivotal phase III trial failed to meet its primary endpoint—although the complete remission rate was 53% higher in the combination arm (33.3% versus 22.4% with azacitidine alone), this difference did not reach statistical significance [37]. Presently, eprenetapopt is being investigated as post-transplant maintenance therapy, where preliminary results indicate a 12.5-month relapse-free survival and 20.6-month overall survival in this high-risk population [38].

Magrolimab + azacitidine or venetoclax

Magrolimab, an anti-CD47 monoclonal antibody, disrupts the “don’t eat me” signal on cancer cells, promoting macrophage-mediated phagocytosis. Early-phase Ib data in TP53-mutated MDS showed an overall response rate of 68%, with a 40% complete remission rate and a median overall survival of 16.3 months [39]. For TP53-mutated AML, response rates reached 49% with a median survival of 10.8 months [40].

Despite these encouraging early results, the Phase III ENHANCE-2 trial was terminated for futility after an interim analysis revealed no survival benefit (4.4 versus 6.6 months) compared to standard therapy [41]. The triplet combination with venetoclax showed initial promise with response rates of 86% in TP53-mutated AML [11].

CAR-T and bispecific antibodies targeting CD123/CD33

Flotetuzumab, a CD123×CD3 bispecific antibody, has shown activity in relapsed/refractory TP53-mutated AML with a 47% response rate and median survival of 10.3 months among responders [11]. This agent mediates T-cell activation against CD123-expressing myeloid blasts.

Gene editing: CRISPR and base editing approaches

Gene editing technologies, including CRISPR/Cas9 systems, represent an emerging frontier for treating TP53-mutated myeloid neoplasms. These approaches could correct mutant TP53 or target alternative pathways to overcome p53 dysfunction [1]. Initial studies focusing on AML suggest that targeting mevalonate or Wnt pathways might overcome CAR-T cell resistance in TP53-mutant cells [14].

Future Directions in TP53 MDS Prognosis and Management

Advances in molecular profiling are reshaping approaches to TP53-mutated myeloid malignancies, creating opportunities for improved prognostication and individualized therapies.

Refining mds tp53 risk models with multi-omic data

Beyond mutation status alone, contemporary risk stratification now incorporates allelic burden into prognostic models such as IPSS-M, enabling more precise treatment planning [17]. Yet, emerging evidence suggests non-mutational p53 dysfunction occurs in some wild-type TP53 patients who should be managed similarly to those with biallelic TP53 inactivation [30]. Furthermore, single-cell defined p53LSC signatures strongly predict poor survival in AML cohorts, even outperforming traditional scoring systems [42].

Personalized therapy based on allelic burden

Therapeutic approaches are increasingly considering TP53 mutation characteristics, with VAF thresholds serving as clinical decision points. Patients with VAF exceeding 6% show substantially reduced overall survival (43.5 vs. 138 months) and progression-free survival (20.2 vs. 116.6 months) compared to those without mutations [43]. Moreover, serial TP53 sequencing reveals critical information: expanding VAF correlates with relapse, while clearance indicates improved outcomes [44]. This supports early intervention before biallelic loss of function occurs, potentially preventing development of TP53-mutated MDS/AML [44].

Biomarker-driven trial design

Future clinical trials must focus specifically on TP53-mutant populations rather than separating MDS and AML cohorts, given their biological similarities with ≥5% blasts [44]. Patient selection beyond mere mutation presence—considering mutation type and p53 protein levels—may enhance therapeutic efficacy, as demonstrated by higher complete remission rates (66% vs. 13%) in eprenetapopt trials for patients with sufficient p53 expression [9].

Conclusion

Understanding TP53-mutated MDS represents one of the most challenging frontiers in hematologic malignancies. Despite advances in molecular profiling and therapeutic approaches, patients with TP53 mutations continue to face dismal outcomes, with median overall survival ranging from 5 to 10 months. The distinction between monoallelic and multi-hit mutations has emerged as a critical prognostic determinant, fundamentally altering disease trajectory. Patients with biallelic inactivation demonstrate markedly worse outcomes, complex karyotypes, and primary resistance to conventional therapies.

Variant allele frequency serves as another crucial prognostic marker. VAF thresholds around 20% stratify patients effectively, with those harboring higher burdens exhibiting substantially shorter survival. These molecular findings have prompted revisions in diagnostic classifications; however, discrepancies between the WHO-5 and ICC systems highlight ongoing challenges in standardizing approaches to this entity.

The immunosuppressive microenvironment characteristic of TP53-mutated disease further complicates therapeutic efforts. Upregulation of PD-L1, expansion of regulatory T cells, and profound cytokine dysregulation collectively shield malignant clones from immune surveillance, while promoting disease progression. Current therapeutic strategies—hypomethylating agents, venetoclax combinations, and even allogeneic stem cell transplantation—yield modest responses with limited durability. Most patients relapse within a year despite initial responses.

Novel approaches targeting TP53 directly, such as eprenetapopt, have shown early promise but failed to demonstrate superior outcomes in phase III trials. Similarly, immune-directed therapies, such as magrolimab, have shown encouraging initial results but struggled to translate these into definitive survival benefits. Cellular therapies and gene editing technologies might offer new avenues for intervention, though clinical validation remains pending.

Future management will likely depend on refining prognostic models through the integration of multi-omic data, enabling more precise risk stratification beyond simple mutation status. Therapeutic decisions based on allelic burden and serial molecular monitoring could potentiate intervention timing and intensity. Biomarker-driven trial designs focusing specifically on TP53-mutant populations rather than traditional disease categories may accelerate therapeutic development for this recalcitrant entity.

Ultimately, TP53-mutated MDS requires a paradigm shift in both conceptualization and management. Recognition of its unique biology, accurate classification, and tailored therapeutic approaches will prove essential for improving outcomes. While challenges persist, ongoing molecular insights and emerging therapies offer cautious hope for meaningful advances in this otherwise devastating disease.

Key Takeaways

Recent advances in TP53-mutated MDS research have revealed critical prognostic factors and therapeutic challenges that are reshaping clinical management approaches for this aggressive disease subtype.

Multi-hit TP53 mutations predict worse outcomes than monoallelic variants, with median survival of 8-9 months versus 12-30 months, respectively, requiring distinct treatment strategies.
Variant allele frequency ≥20% serves as a critical prognostic threshold, identifying patients with poor survival outcomes equivalent to biallelic mutations regardless of mutation number.
Current therapies show limited efficacy despite initial responses, with HMA monotherapy achieving only 10-25% complete remission rates and median survival under 12 months.
Immune microenvironment dysfunction creates therapeutic resistance through PD-L1 upregulation, T-cell exhaustion, and regulatory cell expansion that shields malignant clones.
Allogeneic transplantation remains the only curative option, yet achieves merely 21% three-year survival with 59% relapse rates, emphasizing the need for novel approaches.

The convergence of molecular profiling advances and emerging targeted therapies holds promise for improving outcomes in this historically challenging patient population, although significant therapeutic gaps remain.

Frequently Asked Questions:

FAQs

Q1. What is the typical prognosis for patients with TP53-mutated MDS? Patients with TP53-mutated MDS generally face a poor prognosis, with median overall survival ranging from 5 to 10 months. These cases tend to have lower response rates to standard therapies, such as induction chemotherapy, hypomethylating agents, or venetoclax-based regimens, compared to non-TP53-mutated cases.

Q2. How does the allelic status of TP53 mutations impact prognosis in MDS? The allelic status of TP53 mutations has a significant impact on prognosis. Patients with multi-hit (biallelic) TP53 mutations have worse outcomes, with a median survival of 8-9 months, compared to those with monoallelic mutations who may survive 12-30 months. This distinction is crucial for treatment planning and risk assessment.

Q3. What role does variant allele frequency (VAF) play in TP53-mutated MDS prognosis? Variant allele frequency is a critical prognostic indicator in TP53-mutated MDS. A VAF threshold of ≥20% has been identified as clinically significant, with patients above this threshold showing outcomes similar to those with biallelic mutations, regardless of the actual number of mutations present.

Q4. What are the current treatment options for high-grade MDS transforming to AML with TP53 mutations? For high-grade MDS that transforms into AML with TP53 mutations, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative option for eligible patients. However, even with transplantation, outcomes are poor, with only about 21% overall survival at three years post-transplant.

Q5. How effective are current therapies for TP53-mutated MDS? Current therapies show limited efficacy in TP53-mutated MDS. Hypomethylating agent monotherapy achieves complete remission rates of only 10-25% with median survival under 12 months. While newer combinations, such as venetoclax with hypomethylating agents, show higher response rates, the durability of these responses remains limited, highlighting the need for novel therapeutic approaches.