Advances in Personalized Therapeutic Approaches in Myelodysplastic Syndromes

Personalization of therapy in the treatment of myelodysplastic syndrome (MDS) is focused primarily on the patient’s risk classification, according to Rafael Bejar, MD, PhD, Assistant Professor of Medicine, UC San Diego Moores Cancer Center, La Jolla, CA. After 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, he said.

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

An Overview of MDS

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, like tyrosine kinase pathway signaling, are less frequent in MDS than they are in diseases like AML. Most patients will have more than 1 mutation, but no 2 patients with MDS are truly alike.

Conducting a Personalized Risk Assessment

According to Dr Bejar, a personalized risk assessment will help to determine a course of treatment.

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 point system that determines a patient’s risk group, with a possible range 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.

According to Dr Bejar, “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,” he 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 National Comprehensive Cancer Network 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 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, both for prognosis and for deciding therapy.

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

Clinically, this patient population has demonstrated frequent, deep, and durable response rates to lenalidomide, exceeding 50% overall response rates and an average response duration of more than a year and a half, with many exceeding 2 years or more. “And we believe that it likely improves overall survival,” he added.

For patients without a del(5q) abnormality, treatment with lenalidomide can still be considered, but 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, 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 it may even increase hemoglobin to the point that the patient becomes transfusion-independent or asymptomatic.

A new treatment on the horizon is focused on targeting transforming growth factor-beta signaling in patients with IPSS-R very low-, low-, or intermediate-risk MDS. Using a drug called luspatercept, this process allows for a more profound red cell production and has demonstrated “fairly promising” response rates in the phase 3 MEDALIST 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.

Remember: Mutations Define MDS Risk

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

“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 noted. “And there are certain mutations that do portend worse prognosis.”

Dr Bejar and colleagues are currently working with the International Working Group for MDS to develop clinical guidelines that incorporate somatic mutations. Preliminary results from their work revealed a substantial number of prognostically adverse mutations in approximately 2000 individuals with MDS who were sequenced at various centers around the world. This is relevant because an intermediate-risk patient with one of these adverse mutations may behave much more like a traditional higher-risk individual.

“And these [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 settings, including in younger individuals and in patients headed to transplantation. 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, and a study published in the New England Journal of Medicine identified a very high response rate among patients with MDS or AML who carried TP53 mutations.

“I think what’s most striking to me was that by the fourth cycle of treatment, they could actually see cytoreduction of the TP53 clone,” he said. “This suggests that if you time the transplant appropriately—treat a patient 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 studies.

What’s on the Horizon?

A drug called APR-246 is currently being tested in a phase 3 clinical trial; this drug targets and stabilizes mutant forms of TP53 and has shown promising results in phase 1 and 2 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 be utilized 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,” he said. “While there are no newly approved drugs for higher-risk MDS, we have been borrowing from AML and their embarrassment of riches recently.”

These “riches” include drugs like enasidenib and ivosidenib that target IDH and are currently 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 is currently being explored in clinical trials and may soon be coming to the MDS arena.

“But what we need to keep in mind when we have a patient 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.”

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Last modified: December 11, 2019

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