Genetic profiling may aid treatment decisions in MDS
medwireNews: Mutations in the TP53 gene are the strongest independent predictor of reduced survival after allogeneic hematopoietic stem cell transplantation in patients with myelodysplastic syndrome (MDS), results of a genetic profiling study show.
Furthermore, the “effect of TP53 mutations on the risks of relapse and death was not attenuated by myeloablative conditioning regimens” suggesting that “the escalation of the intensity of the conditioning regimen in order to improve outcomes in patients with TP53 mutated MDS will not be successful,” Benjamin Ebert (Brigham and Women’s Hospital, Boston, Massachusetts, USA) and colleagues remark.
Pretransplantation samples taken from 1514 patients with MDS were sequenced for 129 genes with known or suspected involvement in the pathogenesis of myeloid cancers or inherited or acquired bone marrow failure syndromes. The researchers found that 79% of patients had at least one mutation and there were 32 genes that were mutated in at least 20 patients.
Among these, only mutations in TP53 – present in 19% of the patients – were associated with significantly shorter survival, at a hazard ratio (HR) of 1.71 for death compared with no mutation, after adjustment for clinical factors such as age, Karnofsky performance status score, and hematologic variables.
TP53 mutations were also linked to a significantly shorter time to relapse (HR=2.03) compared with no mutation.
For the 1011 patients who did not have TP53 mutations and were 40 years of age or older, those with RAS pathway mutations had significantly worse survival than those without such mutations (median, 0.9 vs 2.2 years), due to a significantly higher risk for relapse.
By contrast, patients with JAK2 mutations had significantly shorter survival than those without JAK2 mutations (0.5 vs 2.3 years) because of a significantly increased risk for death without relapse.
Looking at the effect of conditioning intensity on outcomes, the researchers found that survival rates were worst among patients with TP53 or JAK2 mutations irrespective of whether they had received myeloablative or reduced-intensity conditioning.
But the adverse effect of RAS pathway mutations on the risk of relapse was only evident in patients who underwent reduced-intensity conditioning, with the 1-year cumulative incidence of relapse significantly higher among patients with than without RAS pathway mutations, at 42% versus 20%.
“Overall, these findings indicate that high-intensity conditioning regimens may benefit patients with RAS pathway mutations but not those with TP53 or JAK2 mutations”, Ebert and co-authors remark in The New England Journal of Medicine.
They conclude: “[O]ur findings show that analysis of mutations in patients with MDS at the time of transplantation can predict outcomes and identify subgroups of patients who will derive the most benefit from particular conditioning regimens.”
By Laura Cowen
medwireNews is an independent medical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2017