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Genetic profiling can identify appropriate conditioning regimens in myelodysplastic syndrome
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Analysis of genetic mutations in patients with myelodysplastic syndrome at the time of hematopoietic stem cell transplantation may help predict outcomes and identify subgroups of patients who will derive the most benefit from particular conditioning regimens, according to a study in The New England Journal of Medicine.
“Previous studies have not evaluated a large number of genetic risks or the extent to which genetic risk interacts with clinical variables,” Benjamin L. Ebert, MD, PhD, associate professor of medicine at Harvard Medical School, and colleagues wrote. “In this study, we paired genetic analysis with comprehensive clinical annotation in a large, registry-based cohort.”
Researchers analyzed samples obtained before HSCT from 1,514 patients with myelodysplastic syndrome who were enrolled in the Center for International Blood and Marrow Transplant Research Repository between 2005 and 2014. Researchers evaluated the association of mutations with transplant outcomes, including OS, relapse and death without relapse.
one mutation (range, 0-15) in 79% of patients who had undergone HSCT.
This included TP53 mutations in 19% of the patients, which were associated with shorter survival (HR = 1.71; 95% CI, 1.45-2.02) and a shorter time to relapse (HR = 2.03; 95% CI, 1.6-2.58).
RAS pathway mutations also were associated with a shorter time to relapse (HR = 1.56; 95% CI, 1.18-2.05). JAK2 V617F mutations increased risk for death (HR = 2.1; 95% CI, 1.36-3.24) but not relapse.
Among 1,011 patients aged 40 years or older who did not have TP53 mutations, the presence of RAS pathway mutations was associated with shorter survival than was the absence of RAS pathway mutations (median, 0.9 years vs. 2.2 years; P = 0.004), which researchers attributed to a high risk for relapse (P = .001). Further, JAK2 mutations were associated with shorter survival than the absence of JAK2 mutations (median, 0.5 years vs. 2.3 years; P = 0.001), owing to a high risk for death without relapse (P < .001).
However, most patients aged older than 40 years without TP53 mutations did not harbor these other mutations and had median survival of 2.3 years.
Mutations that were more common in patients aged younger than 40 years (16% of cohort; n = 241) compared with older patients included GATA2 (11% vs. 2%), PIGA (5% vs. 1%) and compound heterozygous mutations in the Shwachman-Diamond syndrome–associated SBDS gene (2% vs. 1%; P < .001 for all). Patients with compound heterozygous SBDS mutations had shorter survival (median, 1.2 years vs. not reached; P = .009), whereas patients with GATA2 and PIGA mutations had a favorable prognosis that was common in the younger cohort.
Four percent of younger patients had the compound heterozygous SBDS mutation with concurrent TP53 mutations, which was associated with a poor prognosis.
Researchers observed that mutations in the p53 regulator PPM1D were more common among patients with therapy-related myelodysplastic syndrome than those with primary myelodysplastic syndrome (15% vs. 3%; P < 0.001).
Researchers then evaluated the effect of conditioning intensity on outcomes. They found that patients with TP53 mutations had poorer outcomes whether they received reduced-intensity conditioning regimens or myeloablative conditioning regimens (median survival, 9.2 months vs. 5.7 months). Risk for relapse also was similar, “which suggests that high-intensity conditioning regimens do not influence the relapse-driven survival disadvantage of TP53–mutated myelodysplastic syndrome,” the researchers wrote.
Conversely, the adverse effect of RAS pathway mutations on the risk for relapse was evident only with reduced-intensity conditioning (1-year cumulative incidence of relapse for RAS pathway mutations compared with no mutations, 42% vs. 20%; P < 0.001). Incidence of relapse did not significantly differ among patients with and without RAS pathway mutations who underwent myeloablative conditioning (22% vs. 15%).
One-year nonrelapse-related mortality was greater among patients with JAK2 mutations than without whether they underwent reduced-intensity conditioning (53% vs. 25%; P = .007) or myeloablative conditioning (50% vs. 28%; P = .003).
Overall, these findings suggested high-intensity conditioning may benefit patients with RAS pathway mutations, but not those with TP53 or JAK2 mutations.
“Our findings show that analysis of mutations in patients with myelodysplastic syndrome at the time of transplantation can predict outcomes and identify subgroups of patients who will derive the most benefit from particular conditioning regimens,” Ebert and colleagues wrote. – by Chuck Gormley
Disclosure: Ebert reports grants from the Edward P. Evans Foundation, the NIH and the Leukemia and Lymphoma Society. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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