Outcomes Associated With Mutation Persistence After HSCT for Myelodysplastic Syndrome
In a single-institution study reported in The New England Journal of Medicine, Duncavage et al found that mutation clearance after allogeneic hematopoietic stem cell transplantation (HSCT) was associated with better outcomes in patients with myelodysplastic syndrome.
Study Details
The study involved 90 consecutive patients with a history of myelodysplastic syndrome who had undergone allogeneic HSCT after a myeloablative or reduced-intensity conditioning regimen at Washington University between 2002 and 2015. All patients had sufficient DNA available for sequencing studies. Samples of bone marrow and skin were obtained before transplantation, and bone marrow samples were obtained 30 days after transplantation. Mutations before transplantation were identified using enhanced exome sequencing. Mutation clearance was assessed using error-corrected sequencing to genotype mutations in the posttransplantation bone marrow samples.
Mutation Persistence and Outcomes
At least one validated somatic mutation was present before transplantation in 86 of 90 patients (96%). Of them, 32 patients (37%) had at least 1 mutation with a maximum variant allele frequency ≥ 0.5% (equivalent to 1 heterozygous mutant cell/100 cells) at 30 days after transplantation. Among the 86 patients, 35 had disease progression after transplantation, with a median of 141 days to disease progression, and 51 did not have disease progression, with a median follow-up of 356 days. Patients with disease progression had a higher maximum variant allele frequency of mutations at 30 days vs those without disease progression (median maximum variant allele frequency = 0.9% vs 0%, P < .001).
The presence of at least 1 mutation with a variant allele frequency ≥ 0.5% at day 30 vs an absence of such mutation was associated with a higher risk of disease progression (53.1% vs 13.0%, conditioning regimen-adjusted hazard ratio [HR] = 3.86, P < .001) and a lower 1-year progression-free survival (31.3% vs 59.3%, conditioning regimen-adjusted HR = 2.22, P = .005). Progression-free survival was poorer among patients who received reduced-intensity conditioning and had at least one persistent mutation with a variant allele frequency ≥ 0.5% vs patients with other combinations of conditioning regimens and mutation status (P ≤ .001).
On multivariate analysis, the presence of mutation with a variant allele frequency ≥ 0.5% at day 30 vs no such mutation remained significantly associated with a higher risk of disease progression (HR = 4.48, P < .001) and a lower 1-year progression-free survival (HR = 2.39, P = .002).
The investigators concluded, “The risk of disease progression was higher among patients with [myelodysplastic syndrome] in whom persistent disease–associated mutations were detected in the bone marrow 30 days after transplantation than among those in whom these mutations were not detected.”
The study was funded by the Leukemia and Lymphoma Society and others.
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