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Genetic Profiling and Personalized Medicine in Myelodysplastic Syndromes

TOP - January 2020, Vol 13, No 1 - Hematologic Cancers

San Francisco, CA—Personalization of therapy in the treatment of patients with myelodysplastic syndrome (MDS) is focused primarily on risk classification of patients. Once clinical risk has been ­established, treatment considerations should be informed by features such as disease subtype, prognostic somatic mutations, chromosomal abnormalities, targetable somatic mutations, immunologic features, and patient factors, according to Rafael Bejar, MD, PhD, Assistant Professor of Medicine, UC San Diego Moores Cancer Center, La Jolla, CA.

At the NCCN 2019 Hematologic Malignancies meeting, Dr Bejar provided an in-depth review of personalized therapeutic approaches in MDS, and highlighted exciting research on the horizon.

An Overview of Myelodysplastic Syndrome

MDS is a stem-cell disease. It is driven by hematopoietic stem cells—cells that give rise to other blood cells, and are characterized by their capacity for self-renewal.

“Most cells in the body, when they divide, are heading toward a final mature state,” he explained. “But stem cells can self-renew, and therefore propagate throughout our entire lives.”

There is a tight balance between self-renewal and differentiation that needs to be maintained, but as we age, mutations accumulate in these stem cells and can alter that balance. In MDS, those mutations lead to a defect in maturation.

“MDS is really characterized by ineffective hematopoiesis,” Dr Bejar said. “Unfortunately, this is not a static process, and it can evolve over time. Additional mutations will accumulate, often leading to a more profound phenotype, worsening cytopenias, and at some point, patients might transition to secondary acute myeloid leukemia” (AML).

Dozens of different somatic genetic mutations can lead to MDS. Many of the mutations occur in epigenetic regulators or splicing factors. More typical targets, such as tyrosine kinase pathway signaling, are less common in MDS than in AML or similar diseases. Most patients will have >1 mutation, but no 2 patients with MDS are truly alike.

Personalized Risk Assessment

A personalized risk assessment will help to determine the course of treatment, according to Dr Bejar.

The International Prognostic Scoring System-Revised (IPSS-R) is the “gold standard” for assessing risk in patients with MDS, and information about the patient’s karyotype, bone marrow blast proportion, and depth of cytopenias is needed to conduct this risk assessment accurately. This information is then entered into a system that determines a patient’s risk group, ranging from 0 to 10.

For example, a 65-year-old man who presents with hypercellular bone marrow with clear dysplasia in all 3 cell types, 1% blasts, and a del(5q) abnormality, would receive 1 point for del(5q), 0 points for blasts, 1 point for low hemoglobin, and 0 points for other cytopenias. This would give him a score of 2, placing him in the low-risk category, with an expected median overall survival of approximately 5 years.

“The risk groups in the IPSS-R are stratified quite nicely, with big differences in overall survival between the highest-risk patients and the lowest-risk patients,” Dr Bejar said. “But in practice, we draw a line somewhere in the middle; patients who have a score of 3.5 or lower are considered lower-risk disease, and patients who have a score greater than 3.5 are considered to have higher-risk disease.”

The NCCN guidelines for MDS are divided into 2 almost completely separate algorithms, according to lower-risk and higher-risk disease. “The therapeutic options that are listed in those different algorithms [in the NCCN guidelines] have very little overlap, suggesting that we really are treating MDS as 2 different disorders.”

How to Treat?

The World Health Organization classifies MDS into many different subtypes, but only 1 is defined by a genetic abnormality—isolated del(5q)—one of the most predictive biomarkers in MDS, for prognosis and for deciding therapy.

The treatment of choice for patients with isolated del(5q) in low-risk MDS is lenalidomide (Revlimid).

Clinically, this patient population has demonstrated frequent, deep, and durable responses to lenalidomide, exceeding 50% overall response rates and an average response duration of >1.5 years, with many exceeding 2 years. “And we believe that it likely improves overall survival,” Dr Bejar added.

For patients without a del(5q) abnormality, treatment with lenalidomide can still be considered, but the response rates are lower. In these patients, providers should consider treatment with erythropoiesis-stimulating agents (ESAs).

Treatment with ESAs should also be highly personalized. For example, if a patient has a very low hemoglobin level, is heavily transfusion-dependent, or has a very high endogenous erythropoietin level, the addition of an ESA is unlikely to be beneficial. However, if the patient has a favorable erythropoietin level and a mild or no transfusion requirement, then it is likely that an ESA will be effective, and may even increase the hemoglobin level to the point that the patient becomes transfusion-independent or asymptomatic.

A new treatment on the horizon is focused on targeting TGF-beta signaling in patients with MDS and IPSS-R very low-risk, low-risk, or intermediate-risk MDS. Using the investigational drug luspatercept, this process allows for more profound red-cell production. This drug has demonstrated “fairly promising” response rates in MEDALIST, a phase 3 clinical trial of transfusion-dependent patients who had chronic anemia and ring sideroblasts. Most patients in the trial had a rapid and substantial rise in hemoglobin after the first injection, which was sustained for the 24-week period of the analysis.

“This drug is not yet FDA approved, but we’ll see if in the coming year we’ll have another new agent for the treatment of low-risk MDS, which hasn’t seen an approval in quite some time,” he said.

Mutations Refine Risk in MDS

Certain somatic mutations change a person’s risk classification in MDS, and therapy should be adapted accordingly, Dr Bejar emphasized.

“The IPSS-R is the gold standard for defining clinical risk in patients with MDS, but it doesn’t take into account somatic mutations,” he said. “And there are certain mutations that do portend worse prognosis.”

Dr Bejar and his colleagues are working with the International Working Group for MDS to develop clinical guidelines that incorporate somatic mutations. Preliminary results from their work showed a substantial number of prognostically adverse mutations in approximately 2000 patients with MDS who had genetic sequencing at various centers around the world. This is relevant because an intermediate-risk patient with 1 of these adverse mutations may actually be more like a higher-risk patient who has no such mutation.

“And these [somatic mutations] are not rare; we can find them in about 42% of patients with MDS in general,” he noted. “So it seems like we’re underestimating risk in a pretty substantial number of patients.”

Data suggest that mutations of TP53 are particularly adverse in all MDS settings, including in younger patients and in those headed to transplant. Relapse is also very common in these patients.

“So we need something more for these individuals,” he said. “The data are so striking that at our center, we don’t do traditional transplants for patients with these mutations. We try to do a transplant plus something else that we think might be able to increase their chances of long-term survival.”

One potentially promising option for these patients is high-dose decitabine therapy; a 2016 study published in the New England Journal of Medicine identified a very high response rate to that drug among patients with MDS or AML who carried TP53 mutations.1

“What’s most striking to me was that by the fourth cycle of treatment, they could actually see cytoreduction of theTP53 clone,” he said. “This suggests that if you time the transplant appropriately (treat patients with this therapy and then get them to transplant) you might be able to get them there when they have less residual disease and maybe a longer time to relapse.” This concept is now being tested in clinical trials.

What’s on the Horizon?

The drug known as APR-246 is currently in a phase 3 clinical trial; this drug targets theTP53 mutation and has shown promising results in phase 1 and 2 clinical trials.

There has been less progress in the treatment of higher-risk MDS, but according to Dr Bejar, many of the treatments used in AML can also be used in this patient population.

“MDS is not a disease that is dramatically different from AML, especially for those patients who have higher-risk disease and many blasts. While there are no newly approved drugs for higher-risk MDS, we have been borrowing from AML and their embarrassment of riches recently,” Dr Bejar said.

These “riches” include drugs such as enasidenib and ivosidenib (Tibsovo) that target the IDH mutation, and are now being studied in combination with hypomethylating agents for the treatment of MDS. Another treatment option in this population involves targeting the tyrosine kinase–signaling cascade.

Finally, immunotherapy may soon be coming to the MDS setting and is currently being explored in clinical trials.

“But what we need to keep in mind when we have patients in front of us, is how this therapy is going to affect their quality of life,” he said. “I think in the future, all of the new drugs that are being studied will include a quality-of-life assessment to determine the potential benefit for different patient populations.”


  1. Welch JS, Petti AA, Miller CA, et al.TP53and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med. 2016;375:2023-2036.

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Last modified: July 22, 2021