Analysis of Molecular Mutations in AML and MDS Have Prognostic Impact on Outcomes After Allogeneic HCT

Complex karyotypes, TET2 mutations lower survival rates

Hamilton_insetFor patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), the only therapy with curative potential is allogeneic hematopoietic cell transplant (HCT). Yet survival after transplant is poor, and identifying those patients who are likely to benefit from HCT remains challenging.

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Now next-generational sequencing analysis by Cleveland Clinic researchers reveals that molecular mutations in AML and MDS have prognostic impact on outcomes after allogeneic HCT. The study found that both complex karyotypes and TET2 mutations in MDS and AML were associated with poor overall survival (OS) after transplant. Results of the study were presented at the 57th American Society of Hematology Annual Meeting & Exposition in December.

“In the past year, scientific evidence has begun to accumulate about the prognostic significance of molecular mutations in AML and MDS,” says lead researcher Betty Hamilton, MD, an associate staff physician in Cleveland Clinic’s Department of Hematologic Oncology and Blood Disorders and Blood and Marrow Transplant Program. Yet, data on the effect of molecular mutations on allogeneic HCT outcomes among AML and MDS patients was lacking, she says.

Researchers examine 60 most commonly mutated genes in myeloid neoplasias

In their study, researchers performed mutational analyses—using a panel of the 60 most commonly mutated genes in myeloid neoplasias—on 123 patients with MDS and AML, who subsequently underwent HCT. Mutations were analyzed individually and by molecular pathway, and the median follow-up on patients in the study was 35 months.

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Seventy-two percent of the AML and MDS patients in the study had at least one mutation—most frequently in STAG2 (10.2 percent), TET2 (9.8 percent), ASXL1 (8.1 percent) and RUNX1 (8.1 percent). In multivariable analysis, complex karyotype was significantly associated with poor overall survival (HR=2.7) and poor relapse-free survival (HR=3.9). TET2 mutations were associated with a complete response prior to transplant, but after HCT, patients with TET2 mutations had poor overall survival (HR=2.4) in multivariate analysis. The presence of any of the DNA methylation mutations (TET2, DNMT3A, IDH1, IDH2) was also associated with poor relapse-free survival (HR=1.7).

The results of the study indicated that the three-year OS among patients in the study with a complex karyotype was 23 percent. Yet OS was far better among those without a complex karyotype–48 percent. In patients with TET2 mutations, OS was just 14 percent, but in those without TET2, OS was 46 percent.

Mutational analysis of AML, MDS patients could become standard of care

“Many studies show that patients with complex karyotype have poorer overall survival. Yet our study’s finding about the prognostic importance of TET2 mutations is interesting—particularly since it was associated with treatment response before transplant,” Dr. Hamilton says. She noted that this finding will need to be confirmed and validated in other studies.

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Dr. Hamilton and fellow researchers at Cleveland Clinic are planning a larger study on the prognostic significance of molecular mutations in AML and MDS patients, using tissue samples from 200 to 300 patients, she says. Researchers will analyze molecular mutations in these AML and MDS patients over time—at the time of diagnosis, after initial treatment, at the time of relapse, and after use of salvage chemotherapy or transplant.

“This research work will help us understand the significance of molecular mutations in AML and MDS, and their potential effects on patient prognosis and outcomes,” Dr. Hamilton says. “It also shows us that performing mutational analysis for AML and MDS patients may eventually become a standard of care.”.

Dr. Hamilton can be reached at hamiltb2@ccf.org or 216.445.7580.