Post-Transplant Gene Mutations Predict Risk for MDS Progression

Sequencing bone marrow samples early after patients with myelodysplastic syndromes (MDS) have undergone allogeneic hematopoietic cell transplantation (AHCT) could help identify patients who are at an increased risk of disease progression, according to findings published in The New England Journal of Medicine.

In the exploratory study, led by Eric Duncavage, MD, from the Washington University School of Medicine in St. Louis, patients who harbored at least one persistent disease-associated mutation 30 days after AHCT had higher rates of progressive disease and lower rates of progression-free survival (PFS) at one year.

“Knowing this information may provide an opportunity for earlier intervention to delay or prevent progression and also may identify patients who can be recommended for more aggressive monitoring,” coauthor Meagan Jacoby, MD, PhD, also from the Washington University School of Medicine, told ASH Clinical News.

The study included 90 patients with a history of MDS (including secondary or therapy-related MDS) who underwent AHCT at Washington University in St. Louis between 2002 and 2015. Four patients were excluded because they did not meet technical requirements for analysis, leaving 86 patients in the primary analysis.

All 86 patients had banked bone marrow samples available, and 58 had pretransplant samples available. Bone marrow samples at 30 days posttransplant were available for all 86 patients, and samples at 100 days posttransplant were available for 58 of them. Skin samples from all participants also were sequenced and analyzed. In this study, samples were considered to be positive for a mutation if the maximum variant allele frequency (VAF) was ≥0.5 percent.

The investigators used enhanced exome sequencing, which included probes for 285 genes that are frequently mutated in MDS and acute myeloid leukemia, to detect mutations in pre-AHCT samples, then evaluated mutation clearance by using error-corrected sequencing to genotype mutations in post-AHCT bone marrow samples.

During a median follow-up of 356 days (range = 45-2,786 days), 35 of the 86 patients had disease progression after transplant. The median time to progression was 141 days (range = 27-1,308 days).

Nearly all enrolled patients (n=86/90; 96%) had at least one somatic mutation detected on pretransplantation sequencing. Of these, 32 patients (37%) had at least one mutation with a VAF ≥0.5 percent at 30-day follow-up.

Patients whose disease progressed had mutations with a higher VAF at 30 days, compared with those who did not have progressive disease (median maximum VAF = 0.9% vs. 0%; p<0.001).

After adjusting for pre-AHCT conditioning regimens (either myeloablative [n=50] or reduced-intensity [n=36]), the investigators also found that the presence of at least one high VAF mutation conferred a higher risk of disease progression and a lower likelihood of PFS at one year, compared with no mutation:

  • disease progression: 53.1% vs. 13.0% (conditioning regimen-adjusted hazard ratio [HR] = 3.86; 95% CI 1.96-7.62; p<0.001)
  • PFS: 31.3% vs. 59.3% (conditioning regimen-adjusted HR=2.22; 95% CI 1.32-3.73; p=0.005)

Type of conditioning regimen also was associated with disease progression, with patients who received reduced-intensity conditioning at a greater risk for disease progression, compared with those who received myeloablative conditioning (HR=0.40; 95% 0.21-0.78; p=0.007).

“The rate of [PFS] was lower among patients who had received a reduced-intensity conditioning regimen and had at least one persistent mutation with a [VAF] of at least 0.5 percent at day 30 than among patients with other combinations of conditioning regimen and mutation status (p≤0.001),” the authors added.

When the authors further adjusted the analysis for Revised International Prognostic Scoring System score, type of MDS, TP53 mutation status, and conditioning regimen, patients with at least one persistent mutation were still at an increased risk of disease progression (HR=4.48; 95% CI 2.21-9.08; p<0.001) and had a lower rate of one-year PFS (HR=2.39; 95% CI 1.40-4.09; p=0.002), compared with those without persistent mutations.

“We hope these findings lead to post-transplant mutation testing being incorporated into routine clinical care,” Dr. Jacoby said, noting that researchers are working to develop a clinical-grade, gene panel test capable of detecting lower-level mutations. “Our goal is to move forward with a large prospective trial using the clinical-grade assay to detect mutations at 30 days and 100 days post-transplant, to determine if providing an intervention in patients who test positive for a mutation could prevent or delay relapse.”

The study’s findings are limited by its single-center design, which may reduce the generalizability of the results, and limited patient numbers.

“Incorporation of a gene panel assay to monitor minimum residual disease will need to include error-corrected sequencing that is not standard for most commercially available assays,” Dr. Jacoby added. “Many clinical assays also do not include matched normal DNA from a patient, so the assay would also need to be validated using tumor-only samples in a cohort.”

The authors reported no conflicts of interest.

Reference

Duncavage EJ, Jacoby MA, Chang GS, et al. Mutation clearance after transplantation for myelodysplastic syndrome. N Engl J Med. 2018;379:1028-41.

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