Persistent mutations post-transplant predict MDS disease progression
medwireNews: Persistent disease-associated mutations detected in the bone marrow 30 days after stem cell transplantation are associated with an increased risk for disease progression among patients with myelodysplastic syndrome (MDS), research shows.
“These findings suggest that sequencing bone marrow samples at early clinical time points after transplantation could be used as an individualized risk-assessment biomarker for disease progression in patients with MDS,” Matthew Walter (Washington University School of Medicine, St Louis, Missouri, USA) and co-investigators remark.
They add that, in the current study, disease progression occurred a median of 67 days after the detection of a persistent mutation, which they describe in The New England Journal of Medicine as “a period that may allow for the initiation of salvage therapy or planning for a second transplantation in some patients.”
Using enhanced exome sequencing of paired samples of bone marrow and normal tissue, the researchers found that 86 (96%) of the 90 patients with MDS had at least one validated somatic mutation before allogeneic hematopoietic stem cell transplantation.
At 30 days after transplantation, over a third (37%) of these patients still had at least one mutation with a maximum variant allele frequency of at least 0.5%, which the team explains is equivalent to one heterozygous mutant cell in 100 cells.
Persistent mutations were most commonly detected in TP53 and DNMT3A, whereas mutations in NRAS and other genes were not typically detected at day 30, despite their presence prior to transplantation.
Walter and co-researchers report that the maximum variant allele frequency at 30 days was significantly higher among the 35 patients who had disease progression compared with the 51 who did not, at 0.9% versus 0.0%.
Accordingly, individuals with a variant allele frequency of at least 0.5% at day 30 had a significant 3.9-fold higher risk for progression, after adjustment for conditioning regimen, than those with a lower allele frequency, with progression rates of 53.1% and 13.0%, respectively.
The 1-year progression-free survival (PFS) rate was 31.3% among the patients with a variant allele frequency of at least 0.5%, which was significantly lower than the 59.3% observed in those with a lower mutation rate, and corresponded to a hazard ratio (HR) for disease progression or death of 2.2.
After further adjustment for known clinical and genetic risk factors, including age at transplantation, conditioning regimen, and type of MDS, having a variant allele frequency of at least 0.5% on day 30 remained associated with a significantly increased risk for disease progression and a decreased 1-year rate of PFS, at HRs of 4.5 and 2.4, respectively.
Of note, the lowest PFS rate was observed among patients with at least one persistent mutation with a variant allele frequency of at least 0.5% who received a reduced-intensity conditioning regimen. PFS in these patients was significantly lower than that among patients with other combinations of conditioning regimen and mutation status.
Walter and co-authors conclude: “Although this exploratory study has limitations, our results suggest that sequencing-based detection of tumor cells and measurable residual disease after allogeneic hematopoietic stem-cell transplantation has prognostic significance for patients with MDS.”
By Laura Cowen
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