Dynamics of Two Mutational Paths in the Progression of MDS

Myelodysplastic syndrome (MDS) is a chronic, preleukemic disease of the marrow associated with a variety of genetic changes in bone marrow cells. A new whole-exome sequencing study uncovers the dynamics of genetic alterations during progression of MDS to more aggressive acute leukemia and clarifies the impact of specific genetic defects on expected clinical behavior.

The study represents the largest genomic assessment of MDS to date and identifies a handful of critical mutations that drive the disease’s evolution toward cancer. Complete results of the study are published in Nature Genetics.

“We have mapped a series of mutational paths that myelodysplastic syndromes can take toward either aggressive cancers or manageable chronic conditions,” says Jaroslaw Maciejewski, MD, PhD, senior author on the paper and chairman of the Department of Translational Hematology and Oncology Research at the Taussig Cancer Institute. “These successions have meaning for treating oncologists in terms of both how to approach treatment and what to communicate with patients.”

Researchers leveraged whole-exome and/or targeted sequencing of 699 patients. Of those, the study performed longitudinal analysis of 122 patients to follow the disease progression from a mutational perspective.

Furthermore, the study included data from previously sequenced patients, for a total of 2,250 cases evaluated for mutational enrichment patterns.

“The novelty of this paper is that we have sequenced enough patients to help understand the drivers that push patients from MDS to leukemia,” Dr. Maciejewski says. “It’s important to have a critical mass of patients, which helps characterize impact and influence of the less common mutations.”

Two mutational paths, two very different outcomes

A series of mutations enriched in secondary acute myeloid leukemia (sAML) (rather than high-risk MDS), tended to be newly acquired, and associated with faster sAML progression and a shorter overall survival than wild type.

Study authors classified these seven enrichments as Type-1 mutations, which identify a higher risk disease, frequently drive MDS toward sAML, and are associated with poor clinical outcomes. Type-1 mutations are FLT3, PTPN11, WT1, IDH1, NPM1, IDH2 and NRAS.

Conversely, the following mutations had a weaker impact on disease progression toward sAML, even in patients currently classified as having high-risk MDS. The study classified these as type-2 mutations, which include TP53, GATA2, KRAS, RUNX1, STAG2, ASXL1, ZRSR2 and TET2.

In both type-1 and type-2, MDS remained a progressive disease. The study helps elucidate whether the disease is likely to develop into cancer or display increasing degrees of MDS-related morbidities.

Additionally, both types demonstrated patterns of propeller or driver mutations, which tended to set the course for disease progression, regardless of other genomic alterations happening within the malignancy.

These driver mutations appear to be sequential, Dr. Maciejewski says, leading the disease through a stepwise progression.

“Some of the mutations are dominant—they commandeer disease progression and set the stage for the next step in disease,” he says.

Clinical impact and drug development

In both subtypes of MDS, disease progression tended to follow a stepwise progression, triggered at each juncture by the key mutations identified above.

Armed with this knowledge, physicians and drug developers may be able to move forward with new solutions for patients with MDS.

“This is the largest genomic data set for MDS, and it is our hope that our team—and others—can take this information to design new clinical trials and develop new targeted therapies,” says Dr. Maciejewski.

Using a molecular profiling approach to treatment could have multiple benefits. Profiling could help not only identify targets for existing therapy but also inform whether disease should be monitored or treated aggressively.

For example: “If a patient develops a type-2 mutation versus a type-1, your treatment might be less aggressive,” says Maciejewski. “However, without more clinical data, we don’t yet know.”