Genetic mutations in blood samples may predict outcomes and guide treatment for patients of all ages who have myelodysplastic syndrome and are undergoing hematopoietic stem-cell transplantation, according to a report published online Feb. 8 in the New England Journal of Medicine.

Allogeneic hematopoietic stem-cell transplantation is the only potentially curative therapy currently available for myelodysplastic syndrome (MDS), but mortality due to relapse and to transplant-related complications is high. “Predicting which patients are most likely to benefit from transplantation is thus a central challenge,” and identifying patients most likely to relapse could help clinicians refine conditioning regimens and relapse-prevention strategies, said R. Coleman Lindsley, MD, PhD , of the division of hematological malignancies, Dana-Farber Cancer Institute, Boston, and his associates.

Existing predictive models incorporate patient characteristics, disease-related factors, and factors related to the procedure itself, but genetic mutations aren’t yet included because they haven’t yet been comprehensively examined. The investigators performed targeted mutational analyses using banked whole-blood samples from 1,514 patients of all ages in a research registry. The samples had been collected before preparative conditioning for stem-cell transplantation at 130 medical centers in the U.S. and Germany in 2005-2014.

The analyses included targeted sequencing of 129 genes known or suspected to be involved in the pathogenesis of myeloid cancers or syndromes related to bone marrow failure. Approximately 80% of the study participants were found to have at least one such driver mutation, with a median of two mutations per patient.

Mutations in the TP53 gene turned out to be the single most powerful predictor of survival after transplantation, independent of factors such as patient age, performance status, and hematologic variables. Moreover, intensive (myeloablative) conditioning regimens did not attenuate this effect, “a finding that is consistent with clinical and experimental evidence showing TP53 mutation-mediated chemoresistance,” Dr. Lindsley and his associates said.

“Our data suggest that escalating the intensity of the conditioning regimen in order to improve outcomes in patients with TP53-mutated MDS will not be successful. … These patients, who have an exceptionally high risk of relapse-related death after transplantation, should be considered for investigative approaches to conditioning or new relapse-prevention strategies after transplantation,” they added.

Among patients over age 40, mutations in the RAS pathway were associated with a significantly elevated risk of early relapse – an outcome that might be ameliorated by more intensive conditioning. “RAS-pathway mutations may thus reflect the presence of low-volume but biologically transformed disease that, without adequate cytoreduction before transplantation, outpaces the development of effective graft-versus-leukemia activity,” the investigators said.

However, this association between RAS mutations and relapse was not seen in patients younger than age 40 years, they noted.

Conversely, JAK2 mutations were associated with a higher rate of death without relapse but not a higher rate of relapse. And this association was not affected by conditioning intensity. Although the mechanism of such an effect is not yet known, early death without relapse may be driven by factors that are susceptible to targeting by JAK2 inhibitors. In addition, minimizing treatment toxicity should be the focus of treatment in patients who carry JAK2 mutations, since their poor survival rate is driven by deaths unrelated to relapse, Dr. Lindsley and his associates said.

Mutations in the PPM1D gene, especially when accompanied by TP53 mutations, were strongly associated with previous exposure to leukemogenic therapies. “PPM1D encodes a serine-threonine protein phosphatase that regulates the cellular response to environmental stress, in part by means of inhibition of TP53 activity, which suggests that TP53 and PPM1D mutations represent convergent mechanisms of clonal survival in the context of leukemogenic exposures,” the investigators said.

“Our results… provide strong genetic evidence of the role of PPM1D mutations in the pathogenesis of therapy-related myelodysplastic syndromes.”

Mutations in the SBDS gene, which has been linked to Shwachman-Diamond syndrome, were “unexpectedly common” in young-adult patients and were associated with a poor prognosis. (Shwachman-Diamond syndrome is a rare congenital syndrome of bone-marrow failure.) This finding suggests that early stem-cell transplantation should be considered for patients who have this disorder, since transplantation after full-blown MDS develops “may not offer long-term benefit.”


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