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Persistent mutations in bone marrow associated with poor myelodysplastic syndrome outcomes
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Patients with myelodysplastic syndrome who had persistent mutations detected in bone marrow samples after allogeneic hematopoietic stem cell transplantation appeared at increased risk for disease progression, according to an exploratory study published in The New England Journal of Medicine.
Myelodysplastic syndrome is the most common myeloid cancer diagnosed among U.S. adults. Although HSCT leads to cure for some patients, disease progression after transplant is common and molecular predictors for progression remain unclear.
Eric J. Duncavage, MD, associate professor in the department of pathology and immunology and section head in the department of hematopathology at Washington University School of Medicine in St. Louis, and colleagues evaluated whether the presence of myelodysplastic syndrome-related mutations after transplant were associated with PFS among 90 adults. Patients underwent HSCT after a myeloablative or reduced-intensity conditioning regimen for myelodysplastic syndrome at Washington University in St. Louis between 2002 and 2015.
The researchers used enhanced exome sequencing to detect mutations before transplantation and evaluated mutation clearance with error-corrected sequencing to genotype mutations in bone marrow samples obtained 30 days after transplantation.
Researchers found validated somatic mutations in bone marrow samples from 86 patients (96%) before transplantation. Thirty-seven percent of these patients had at least one persistent mutation — with a maximum variant allele frequency of at least 0.5% — 30 days after transplantation.
Disease progression occurred among 35 patients after HSCT, with a median time to progression of 141 days (range, 27-1,308). Fifty-one patients did not have progression after a median follow-up of 356 days (range, 45-2,786).
Univariate analyses showed variables associated with the cumulative incidence of progression included the Revised International Prognostic Scoring System score (P = .03), TP53 mutation status (P = .003) and conditioning regimen (P = .007). Age at transplantation (P = .03), type of myelodysplastic syndrome (P = .03) and TP53 mutation status (P = .03) were associated with PFS.
Patients with disease progression demonstrated mutations with a higher maximum variant allele frequency at 30 days (median maximum variant allele frequency, 0.9% vs. 0%; P < .001).
PFS appeared lower among those who underwent a reduced-intensity conditioning regimen and had at least one persistent mutation with a variant allele frequency of at least 0.5% at day 30 (P .001).
Even after adjusting for conditioning regimen, a greater proportion of patients with at least one persistent mutation at day 30 experienced progression (53.1% vs. 13%; HR = 3.86; 95% CI, 1.96-7.62) and fewer achieved 1-year PFS (31.3% vs. 59.3%; HR = 2.22; 95% CI, 1.32-3.73).
Results of multivariate analysis confirmed patients with a mutation with a variant allele frequency of at least 0.5% detected at day 30 were at higher risk for disease progression (HR = 4.48; 95% CI, 2.21-9.08), and had poorer PFS at 1 year (HR for progression or death = 2.39; 95% CI, 1.4-4.09).
“Using our sequencing method, we're identifying residual tumor cells before a pathologist could see them under the microscope and before a patient develops symptoms,” study author Matthew J. Walter, MD, professor of medicine at Washington University School of Medicine in St. Louis, said in a press release. “At that moment, there may be time to intervene in ways that could delay the cancer from coming back or potentially prevent it completely.
“Now that we have detected mutations early and shown that it predicts a higher risk of recurrence, we want to determine the best course of action for those high-risk patients,” Walter added. – by Jennifer Southall
Disclosures: Duncavage reports grants from Leukemia Lymphoma Society, NCI, Specialized Program of Research Excellence in AML of the NCI, and Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences of the NIH during the conduct of the study, as well as personal fees from AbbVie and Cofactor Genomics outside the submitted work. Walter reports grants from Leukemia and Lymphoma Society Quest for Cures, Leukemia and Lymphoma Society Scholar Award, NCI, Gabrielle's Angel Foundation, Lottie Caroline Hardy Trust and Edward P. Evans Foundation during the conduct of the study. Please see the study for all other authors’ relevant financial disclosures.
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