Myelodysplastic syndromes are a family of clonal disorders of the hematopoietic stem cell, characterized by ineffective blood formation, cytopenias, and a variable risk of transformation to acute myeloid leukemia. Patients classified as higher-risk, typically by a Revised International Prognostic Scoring System score of 4 or above, face a median overall survival of roughly 16 to 21 months. Although leukemic progression remains the dominant lethal force, infectious complications account for a substantial share of deaths in this population, a fact that has traditionally been attributed to neutropenia, transfusion-related iron overload, and treatment-related immunosuppression. What has remained largely unexplored is whether specific molecular lesions shape infectious vulnerability independently of these conventional hematologic factors.

TP53, the guardian of the genome, is among the most adverse molecular lesions in myeloid malignancy. Biallelic inactivation, meaning loss of normal TP53 function through combined mutational, cytogenetic, or copy-number mechanisms, is strongly associated with genomic instability, complex karyotype, treatment resistance, and rapid disease progression. Previous work had already hinted at a connection between TP53-altered myeloid disease and infectious complications, including pulmonary infection, invasive fungal disease, and infection-related mortality. But the infectious burden specifically tied to biallelic TP53 in strictly defined higher-risk myelodysplastic syndromes had never been systematically characterized.

The Ningbo team, led by Binbin Lai and Guifang Ouyang, retrospectively analyzed 97 hospitalized patients with higher-risk myelodysplastic syndromes identified through hospitalizations between June 2023 and April 2026. Thirty-one of these patients carried biallelic TP53 alterations. Clinically significant infections were defined as suspected or documented events requiring inpatient management or intravenous anti-infective therapy, a deliberately conservative threshold that excluded mild outpatient episodes. Infection events were adjudicated using inpatient clinical notes, imaging, microbiologic evidence, anti-infective treatment records, and discharge diagnoses, and severity was graded retrospectively according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 6.0.

The numbers are striking. During a median follow-up of just 0.8 years, 59 patients, or 60.8 percent of the cohort, developed clinically significant infections, and 27 patients, or 27.8 percent, died from infection. Among patients with biallelic TP53 alterations, the infection rate reached 87.1 percent, compared with 48.5 percent in those without. Recurrent infection, defined as two or more episodes, occurred in 54.8 percent of the biallelic group versus 30.3 percent of the non-biallelic group. Infection within 100 days of diagnosis struck 77.4 percent of biallelic patients versus 28.8 percent of others, and within one year, 83.9 percent versus 39.4 percent. Infection incidence density, measured in episodes per person-year, was dramatically higher in the biallelic group, with a median of 7.93 episodes per person-year compared with 0.00 in the non-biallelic group.

Once infected, patients with biallelic TP53 alterations fared far worse. Among infected patients, 85.2 percent of the biallelic group experienced infection-related death, compared with 12.5 percent of the non-biallelic group. Most infections in the biallelic group were graded as CTCAE grade 5, meaning fatal, while most in the non-biallelic group were grade 3, severe but survivable. Anti-infective treatment escalation, meaning upgrade to advanced or combination intravenous antibiotics, was required in 85.2 percent of infected biallelic patients versus 31.3 percent of infected non-biallelic patients. Antifungal therapy was added in 74.1 percent of infected biallelic patients versus 15.6 percent of infected non-biallelic patients, a pattern consistent with the elevated risk of invasive fungal disease previously reported in TP53-mutated myeloid malignancy.

Perhaps the most intriguing technical finding concerns the cellular immune profile. Baseline neutrophil counts, hemoglobin levels, and platelet counts were comparable between the two groups, yet patients with biallelic TP53 alterations had significantly lower circulating counts of CD3-positive T cells, CD4-positive helper T cells, CD8-positive cytotoxic T cells, and natural killer cells. The median CD4-positive T-cell count in the biallelic group was 193 cells per microliter, less than half the 398.5 cells per microliter observed in the non-biallelic group. Natural killer cell counts showed a similar pattern, with a median of 54 cells per microliter versus 101. These measurements, obtained at diagnosis before any documented infection, suggest that the immune deficit in biallelic TP53 disease extends beyond neutropenia into the adaptive and innate cellular arms of immunity.

The association persisted in multivariable analysis. Using Cox proportional hazards regression, the team found that biallelic TP53 alterations remained associated with shorter composite event-free survival, a prespecified endpoint combining infection-related death and transformation to acute myeloid leukemia, with a hazard ratio of 7.56 and a 95 percent confidence interval of 2.79 to 20.46. Very-high-risk status on the Molecular International Prognostic Scoring System, which integrates clinical, cytogenetic, and molecular abnormalities, also remained significant with a hazard ratio of 3.51. Among infected patients, Firth penalized logistic regression, a technique designed for situations with limited events, showed that biallelic TP53 alterations remained associated with infection-related death with an odds ratio of 7.52 and a 95 percent confidence interval of 1.15 to 49.37.

The authors are careful to frame these findings as hypothesis-generating rather than causal. This was a single-center retrospective study of hospitalized patients, and hospital-based inclusion may introduce selection bias. Retrospective ascertainment of infections, antimicrobial exposure, and causes of death may introduce information bias, and limited microbiological confirmation restricted pathogen-specific analyses. Moreover, IPSS-R, IPSS-M, cytogenetic risk, and biallelic TP53 status share substantial prognostic information, making it difficult to disentangle the independent contribution of any single variable. All 31 patients with biallelic TP53 alterations were classified as IPSS-M very high risk, meaning the two categories overlap almost completely. The authors also note that baseline measurements describe cell abundance but do not directly measure immune function, and that the absence of longitudinal immune profiling limits mechanistic interpretation.

Nevertheless, the practical implications are considerable. If infection risk in higher-risk myelodysplastic syndromes is shaped by molecular disease architecture, then risk stratification may need to incorporate TP53 allelic status and cellular immune profiling alongside conventional neutrophil counts. Such an approach could help identify patients who require closer infection surveillance, earlier diagnostic evaluation for occult infection, and more individualized supportive-care strategies. The early and often fatal infectious burden observed in biallelic TP53 patients also raises the question of whether timely transplant referral, before severe infectious complications occur, might improve outcomes in carefully selected transplant-eligible patients. Universal antibacterial or antifungal prophylaxis cannot be recommended based on these retrospective data, but prospective multicenter studies should evaluate whether TP53 allelic status and immune-cell measurements improve infection risk assessment beyond established clinical factors. For a disease whose molecular signature has long been synonymous with treatment resistance and rapid progression, the possibility that the same signature also renders patients defenseless against ordinary pathogens adds a new and urgent dimension to the clinical management of higher-risk myelodysplastic syndromes.

Subject of Research: Infectious burden and cellular immune impairment in higher-risk myelodysplastic syndromes with biallelic TP53 alterations

Article Title: Infectious burden and cellular immune impairment in higher-risk myelodysplastic syndromes with biallelic TP53 alterations

Article References: Lai, B., Yan, X., Chen, L., Wang, Y., Sheng, L., & Ouyang, G. (2026). Infectious burden and cellular immune impairment in higher-risk myelodysplastic syndromes with biallelic TP53 alterations. Frontiers in Cellular and Infection Microbiology, 16, Article 1908881. https://doi.org/10.3389/fcimb.2026.1908881

Image Credits: AI Generated

DOI: 10.3389/fcimb.2026.1908881

Keywords: Infectious, burden, cellular, immune, impairment, higher-risk, myelodysplastic, syndromes, biallelic, TP53, alterations, scientific research