Mutations in Myelodysplastic Syndrome Could Change Therapy

Zosia Chustecka

June 29, 2011

June 29, 2011 — New mutations have been found in the bone marrow cells of patients with myelodysplastic syndrome (MDS), and some of these predict a poor overall survival, independent of established risk factors. The findings are reported in the June 30 issue of the New England Journal of Medicine.

"These findings indicate that mutations in specific genes help explain the clinical heterogeneity of myelodysplastic syndromes," say the researchers, led by Rafael Bejar, MD, PhD, from the Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts.

The research team was a collaboration of the top cancer centers in the United States — including the Dana-Farber Cancer Institute in Boston, the Memorial Sloan-Kettering Cancer Institute in New York City, and the M.D. Anderson Cancer Center in Houston, Texas — and was headed by Benjamin Ebert, MD, PhD, from Brigham and Women's Hospital.

Identifying these mutations will "improve the prediction of prognosis," the researchers note, and they explain that improving the prediction of prognosis is particularly important in this disease, because treatment is tailored to the predicted prognosis for each patient.

Currently, prognosis is determined by considering clinical features and karyotypic abnormalities, according to the International Prognostic Scoring System (IPSS). Patients are stratified into risk categories — low, intermediate 1, intermediate 2, and high — and each group is treated in a slightly different way.

This study shows that mutations independently predict poor survival, and that when this information is taken into account, it can change the risk stratification of a patient. For example, a patient who would have been considered to be at low risk using IPSS criteria, might now — taking into account mutational status — be considered to be at intermediate risk.

This could have an impact on how the patient is treated, said John Bennett, MD, from the James Wilmot Cancer Center at the University of Rochester, New York. Dr. Bennett, an international authority on MDS who is currently involved in updating the IPSS, was approached by Medscape Medical News for independent comment.

[This] helps us to pick the winners and the losers.

This finding that mutations predict prognosis "helps us to pick the winners and the losers," Dr. Bennett explained. The median overall survival in MDS is about 2 to 3 years, but some of these mutations are associated with a 3-fold lowering of median survival, he noted.

This signaling of a worse prognosis could trigger a change in treatment, he suggested. Currently, MDS patients who are considered to be at low risk are followed with a "watch and wait" strategy, and treatment is initiated by and directed at symptoms such as anemia, thrombocytopenia, and infections.

However, patients who are considered to be at intermediate risk or high risk are treated with hypomethylating agents, such as azacitidine (Vidaza, Pharmion) and decitabine (Dacogen, MGI Pharma).

This research suggests that about 20% of patients in the low-risk group have genetic mutations that predict a poor prognosis, which would shift these patients into an intermediate-risk category, Dr. Bennett explained. Similarly, the mutation findings shift some patients from the intermediate 1 to the intermediate 2 risk group.

"If you are a doctor who finds such a patient, what would you do?" he asked. "You could consider a hypomethylating agent, although there is no evidence at the moment that this would improve survival." Randomized clinical trials are now needed to explore this question, he explained.

"If I was a physician treating patients with MDS, which these days I no longer am," he noted, "I would lean toward treating the patients with mutations in the intermediate 1 risk group, but not those in the low-risk group."

Large Set of Samples

Although previous research groups have identified mutations associated with MDS, this is one of the largest studies to date. It identified several new mutations, in addition to demonstrating that they are independent predictors of poor survival.

Dr. Bejar and colleagues analyzed bone marrow aspirate from 439 MDS patients, and used a combination of next-generation sequencing and mass-spectrometry-based genotyping to identify somatic mutations in 18 genes, including 2 (ETV6 and GNAS) that have not been previously reported.

Half of the patients (51%) had at least 1 point mutation, and this included patients who had normal cytogentics, they reported.

Mutations in 5 genes (TP53, EZH2, ETV6, RUNX1, and ASXLI) predicted poor survival, independent of established risk factors.

In addition, mutations in 3 genes (RUNX1, TP53, and NRAS) were strongly associated with severe thrombocytopenia and an increased proportion of bone marrow blasts.

"As our study shows, somatic mutations in several genes are associated with distinct effects," the researchers conclude.

"It will soon be possible for clinicians to detect a broad range of point mutations in peripheral blood with the use of sensitive genotyping methods, which will not only improve the prognostication in MDS, but also facilitate the diagnosis of these disorders, the evaluation of disease progression, and the monitoring of response to treatment," they continue.

"The integration of mutation assessment in diagnostic classification and prognostic scoring systems has the potential to parse diverse MDS into a set of discrete diseases with predictable clinical phenotypes, prognosis, and responses to therapy," the researchers conclude.

Dr. Bennett added another hope to this forecast — that the identification of mutations might spur the development of targeted therapy for this disease, as it has in other areas of the cancer field. Homing in on mutations that drive the disease has shown some dramatic responses in leukemia, and recently in melanoma.

In his only criticism of the paper, Dr. Bennett pointed out that survival was reported as overall survival, whereas in MDS it is important to differentiate between overall survival and leukemia-free survival. This is particularly relevant in the low-risk group, where the main cause of death in patients younger than 60 years of age is leukemia; in those older than 60 years, the deaths are due to other complications. He speculated that the mutations are associated with poorer survival because they are pushing the transformation to leukemia, so that progression to leukemia is faster and occurs in more patients, but this is "inference from the data," he emphasized. It would be interesting to dissect the survival data further, and to separate out death from leukemia and death from other causes, he said.

N Engl J Med. 2011;364:2496-2506.

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