In an analysis of mutation data from patients with complex karyotype myelodysplastic syndromes (CK-MDS), the presence of TP53 mutations conferred a poor prognosis, but the risk was modified by the type and abundance of the mutation, as well as other clinical and mutational features.
According to the authors, led by Rafael Bejar, MD, PhD, of Moores Cancer Center at UC San Diego Health, these findings suggest that all patients with CK-MDS should undergo genetic sequencing of TP53 for risk assessment – even those who traditionally are considered to have the highest-risk disease. The results were published in Leukemia.
“The presence of three or more chromosomal abnormalities defines a CK and is among the most adverse prognostic markers used to risk-stratify patients with MDS,” Dr. Bejar told ASH Clinical News. However, he added, “patients with CKMDS are a heterogeneous group,” and some studies have implicated a monosomal karyotype (represented by ≥1 missing autosomes in addition to ≥1 other structural abnormalities) as being particularly adverse in this population.
“To better understand the factors that drive the poor prognosis in CK-MDS, the International Working Group for MDS molecular prognosis committee collected retrospective data on [patients with] MDS treated at 19 centers around the world,” Dr. Bejar explained. The authors reviewed deidentified clinical and mutation data from 359 patients with CK-MDS to determine which risk-associated markers “had independent prognostic value that could be used to better risk-stratify patients with CK-MDS.”
Participating centers reviewed and parsed CK and performed sequencing of the TP53 mutation, with some centers also reporting on the DNA change, the predicted impact on coding amino acid sequence, and the variant allele fraction. Overall, a total of 339 patients had TP53 sequencing performed.
Mutations were underrepresented, the researchers reported, with the exception of TP53, which was identified in 186 patients (55%). Of this group, 164 patients (89%) were evaluable for multiple mutations and 159 (85%) could be analyzed for mutation type.
After TP53, the most frequently mutated genes included:
- DNMT3A (10%)
- ASXL1 (9%)
- TET2 (8%)
TP53 mutations were associated with several other prognostically adverse features, including a lower median platelet count (47 vs. 70×109/L; p=0.002) and a higher median bone marrow blast percentage (9% vs. 5%; p<0.001) – both of which are considered unfavorable risk factors in standard prognostic scoring systems.
Compared with patients without the TP53 mutation, those with TP53-mutated CK-MDS had significantly fewer mutations of ASXL1 (5% vs. 15%; p=0.003), U2AF1 (3% vs. 11%; p=0.008), and RUNX1 (0.5% vs. 9%; p<0.001).
In 250 patients who had sequencing of 12 core genes (i.e., TP53, ASXL1, RUNX1, U2AF1, DNMT3A, TET2, JAK2, SF3B1, SRSF2, NRAS, CBL, and EZH2), 111 of those with a TP53 mutation (71%) had no additional genetic mutations, compared with 47 of those without a TP53 mutation (50%; p=0.001). Significantly fewer mutated genes were identified in the TP53-mutant group than in the TP53 wild-type group (0.39 vs. 0.81, respectively; p<0.001).
Researchers calculated overall survival (OS) from the time of sample collection to time of death from any cause. At 100 days following sample collection for mutational assessment, a landmark analysis also was performed to compare patients who received a transplant with those who did not receive a transplant.
As the authors expected, participants had a poor outcome, with a median OS of 0.9 years (range not provided). “Even shorter OS might be expected in the TP53– mutant subset given the associations between TP53 mutation status and the adverse clinical and cytogenetic measures,” the authors added. For example, within this population of patients with a CK-MDS, those who had a TP53 mutation had a higher mortality risk (hazard ratio = 2.57; 95% CI 1.97-3.34; p<0.001) and a shorter median OS (0.6 years vs. 1.5 years; p<0.001) than those without it – meaning not all CK- MDS carries the same risk.
The variant allele frequency (VAF) of TP53 mutations also modified the adverse impact of the mutations in patients with CK-MDS: Among 151 patients with TP53-mutated disease and available VAF data, individuals with a VAF above 0.4 had a shorter median OS than those with smaller clones (VAF ≤0.4; 0.6 vs. 1.1 years; p=0.004). Despite this difference, patients with a TP53 VAF ≤0.4 still had a shorter survival than patients with wild-type TP53 (1.1 vs. 1.5 years, respectively; p=0.001).
“TP53 mutation status is the most significant risk marker in this population missing from prognostic tools used in clinical practice,” the authors concluded. “Cytogenetics alone appears insufficient for the evaluation of [patients with] CK-MDS, and routine testing for TP53 mutations should be considered in this population.”
Findings from this study may be limited by “the retrospective nature of the cohort and the variable ways in which patients were assessed and had mutation testing performed at their respective institutions,” Dr. Bejar noted. “A larger, prospective study by the International Working Group on MDS is under way, which will help define how molecular information should be used to define prognostic risk in all patients with MDS, whether they have CK or not.”
The authors report relationships with Celgene, which provided funding for the study.
Haase D, Stevenson KE, Neuberg D, et al. TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups. Leukemia. 2019 January 11. [Epub ahead of print]