In Lower-Risk MDS, Genomic Dynamics Heighten Likelihood of Treatment

Clonal evolution is the process by which cancer cells change over time and is a factor in the development and progression of cancer, as well as treatment resistance.

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Clonal evolution appears to increase the likelihood that a patient with lower-risk myelodysplastic syndromes (MDS) will undergo subsequent treatment, according to a new study. However, possibly because of that treatment, clonal evolution was not associated with inferior outcomes.

The study was reported in the journal HemaSphere.¹

About 30% of people with MDS will progress to acute myeloid leukemia (AML), noted corresponding author Christina Ganster, PhD, of the University of Göttingen, in Germany, and colleagues. Whether or not a patient’s disease will progress is closely tied to genomic dynamics, they said. If a patient acquires novel genetic aberrations (clonal evolution) or if the patient experiences clonal expansion they are at a greater risk of transformation to AML and face a shorter life expectancy.² Both clonal evolution and clonal expansion contribute to clonal dynamics, the authors said, and are generally “lumped together” in studies of clonal evolutionary events.

However, most of what scientists know about the impact of clonal dynamics (CD) on patients with MDS relates to patients with high-risk MDS, Ganster and colleagues said.

“Although CD plays an important role in high‐risk patients in disease progression and transformation into acute myeloid leukemia, knowledge about CD in lower‐risk MDS (LR‐MDS) patients is limited due to lack of robust longitudinal data considering the long clinically stable courses of the disease,’ they wrote.

In an effort to fill that research gap, Ganster and colleagues recruited 68 adults with low-risk or intermediate-1 risk MDS to participate in their study. Participants underwent a genetic analysis within 12 months of their initial MDS diagnosis. They were followed for a median of 40.5 months, and underwent a median of 7.5 assessments over the course of the follow-up period to check for clonal evolution and clonal expansion.

The investigators detected clonal evolution in 30 of the 68 patients. Forty-seven total clonal evolution events were observed, which translated into a rate of 1 clonal evolution event every 5.7 years, they said. Most of the events (40/47) were noted during follow-up; the other 7 were noted at diagnosis.

The overall CD rate was 1 event every 4 years. The authors said this shows that CD is “rather frequent” in LR-MDS, even though it is even more frequent in high-risk cases.

“This reflects the long period of a clinically stable course in these low‐risk patients,” they wrote. “However, the long median observation time in our study of 40.5 months finally resulted in 53% of patients with CD and 44% with [clonal expansion].”

Whether clonal evolution was linked with inferior outcomes proved to be a tricky question to answer. Patients with at least 1 clonal evolution event were more likely to undergo subsequent treatment. Forty-three percent of patients with clonal evolution received disease-modifying therapy, compared with 13% of patients without clonal evolution. One-third of patients with clonal evolution underwent hematopoietic stem cell transplantation, compared with just 3% of patients without clonal evolution. Five of 30 patients (17%) with clonal evolution experienced transformation to AML, and 6 of 38 patients (16%) without clonal evolution experienced AML transformation.

“Although there is an association between clonal evolution and treatment, there is also an obvious and significant interdependency between [clonal evolution] and worsening of blood counts, providing the basis for in‐label therapeutic intervention,” Ganster and colleagues wrote.

Thus, while in this study clonal evolution was not associated with interior patient outcomes, the investigators said that lack of a correlation may be the result of treatment initiation sparked by the detection of clonal evolution. The investigators said the lack of a correlation was “unexpected,” but they said it made sense in context.

“The proof of CD was closely associated with the timely implementation of a [disease-modifying therapy] in our study, thus possibly turning a seemingly disadvantage (genetic progression and deterioration of blood counts) into a clinical benefit for the patients,” they concluded.

References

1. Mazzeo P, Ganster C, Wiedenhöft J, et al. Comprehensive sequential genetic analysis delineating frequency, patterns, and prognostic impact of genomic dynamics in a real-world cohort of patients with lower-risk MDS. Hemasphere. 2024;8(9):e70014. Published 2024 Sep 23. doi:10.1002/hem3.70014
2. Neukirchen J, Lauseker M, Hildebrandt B, et al. Cytogenetic clonal evolution in myelodysplastic syndromes is associated with inferior prognosis. Cancer. 2017;123(23):4608-4616. doi:10.1002/cncr.30917