Small Study Shows Utility of ctDNA for Monitoring Treatment Response, Evolution of MDS, AML

A study of 35 patients shows that repeated plasma-derived circulating tumor DNA (ctDNA) testing is a useful, minimally invasive tool to monitor adult myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) through the evolution of disease.

In a letter that appeared in Clinical and Translational Medicine, authors from Zhejiang University School of Medicine in Hangzhou, China, report on their application of ctDNA on dynamic monitoring assessments throughout the course of disease in MDS and AML.

“Here, we assessed the feasibility and utility of ctDNA as a novel and minimally invasive biomarker based on targeted next‐generation sequencing (NGS) to monitor treatment outcome, track clonal evolution, and predict survival,” they wrote, adding that theirs the first known application of ctDNA monitoring as a prognostic biomarker in MDS and AML.

The 35 adult patients included 27 who had pre- and post-treatment plasma-derived ctDNA and paired bone marrow DNA NGS assessments, used for both concordance analysis and dynamic ctDNA analysis. Among the other patients:

• 4 patients had baseline bone marrow DNA and plasma‐derived ctDNA NGS assessments, used for concordance analysis
• 3 patients had pre‐ and post‐treatment ctDNA assessments only
• 1 patient had only post‐treatment ctDNA assessments used for dynamic ctDNA analysis.

Over the course of the study, investigators found a total of 46 mutated genes with 135 mutations in bone marrow DNA and plasma-derived ctDNA; 42 genes with 100 mutations (74.1%) were detected in both the bone marrow DNA and the plasma-derived ctDNA. Among these 100 mutations, there was a high level of symmetry in an assessment of variant allele frequencies, or VAF (R = .854, P < .001).

Investigators also compared pretreatment mean ctDNA concentrations with the bone marrow blasts at baseline by analyzing patients’ cells, and they found a similarly strong association at baseline (R = .618, P < .001), which showed that there was a strong relationship between ctDNA concentration and tumor burden. There was a “moderate correlation,” investigators wrote, between pretreatment mean ctDNA VAF and bone marrow blasts (R = .533, P = .001).

Then, investigators came up with a system for analyzing pre- and posttreatment paired samples. Patients were placed in 3 groups:

• those with a complete response (CR),
• a middle group with CR but incomplete hematologic recovery (CRi) in AML, or morphologic CR for MDS, morphologic leukemia-free state for AML, or stable disease for MDS,
• those with progressive disease (PD)

Among the patients, 16 with CR had dramatically decreased VAFs (median VAF, 16.7% pretreatment vs 0% posttreatment, P < .001). In the middle group, VAFs were largely unchanged, with median VAFs 3.6% pretreatment vs 3.3% posttreatment, P = .804. In the PD group, the VAFs increased, with median VAFs 4.7% pretreatment vs 6.7% post-treatment, P = .053. Investigators also noted that the changes in VAFs were greater pretreatment to posttreatment in patients with a CR than those without.

To no surprise, ctDNA positivity was associated with shorter progression-free survival (PFS) and overall survival (OS). “We discovered patients with increased mean ctDNA concentration have poorer PFS (median PFS, 2.8 vs. NR months, P < .001) and OS (median OS, 7.9 vs. NR months, P < .001).”

Investigators offered a caveat, however. Pretreatment ctDNA status did not have significant prognostic impact, leading investigators to conclude that pretreatment ctDNA status “was not a good biomarker to stratify the prognosis.”

The investigators conducted additional analyses of biomarkers and uncovered patterns that revealed which patients might progress from MDS to AML. One involved the FLT3 mutation, which can signal subsequent transformation to AML, another involved suppression of the PTPN11 mutation with expansion of the FLT3-ITD mutation.

“In summary,” the investigators concluded, “our study revealed that serial plasma‐derived ctDNA assessments can reflect treatment response, survival, and clonal evolution in adult MDS and AML as a minimally invasive method, which warrant the prospective use of ctDNA as a biomarker in disease monitoring.”

References

Zhou X, Lang W, Mei C, et al. Serial monitoring of circulating tumour DNA on clinical outcome in myelodysplastic syndromes and acute myeloid leukaemia. Clin Transl Med. 2023;13(7):e1349. Published online July 25, 2023. doi:10.1002/ctm2.1349