Personalized Treatment Approaches on the Horizon for Myelodysplastic Syndromes

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Despite the spate of recent drug approvals in blood cancer, it’s been more than 13 years since the U.S. Food and Drug Administration (FDA) has approved a treatment for myelodysplastic syndromes (MDS), a bone marrow disorder characterized by ineffective hematopoiesis. Nevertheless, data from a handful of clinical trials suggest the therapeutic landscape may be improving for this disease. At the 2019 National Comprehensive Cancer Network (NCCN) Annual Congress: Hematologic Malignancies, Rafael Bejar, MD, PhD, shared updates from studies underway in patients with various forms of MDS, including those with TP53 gene mutations and highlighted emerging personalized treatment strategies for the management of MDS.1

“Although patients with MDS will commonly have more than one typical mutation, the majority of patients have unique patterns of mutation,” said Dr. Bejar, Assistant Professor of Medicine at UC San Diego Moores Cancer Center. “Because no two patients with MDS are truly alike, we must continue to utilize genetic information to individualize treatment decisions.”

As Dr. Bejar explained, the revised International Prognostic Scoring System (IPSS-R) remains the gold standard for defining clinical risk in patients with MDS, but it does not account for most genetic mutations. Moreover, there are dozens of somatic gene mutations that can lead to the development of MDS, and the more that are present, the shorter the overall survival appears to be. However, certain mutations are more deleterious than others warned Dr. Bejar. “I am not advocating that we necessarily count mutations to determine a patient’s prognosis, as certain mutations portend a worse prognosis, whereas other mutations may simply be neutral.”

“Because no two patients with MDS are truly alike, we must continue to utilize genetic information to inform treatment decisions.”
— Rafael Bejar, MD, PhD

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An analysis of more than 400 patients stratified by the IPSS-R showed that mutations associated with a poor prognosis were present in approximately 20% of those with low-risk MDS.2 These patients with an adverse mutation experienced approximately 30% shorter overall survival. In a larger study that included many patients with fewer than 5% bone marrow blasts, a generally favorable finding, the presence of one or more adverse mutations was associated with an overall survival that was almost 50% less than for patients who lacked mutations.

According to Dr. Bejar, a collaborative analysis with the International Working Group for MDS found 42% of patients with MDS have a mutation associated with a poor prognosis. “We may be underestimating risk in a pretty substantial number of patients,” he added. “If patients are on the intermediate-risk border and have one of these adverse mutations, their behavior is probably going to be similar to that of traditional, higher-risk individuals.”

TP53 Mutations: Impact on Treatment Decisions

One mutation in particular—TP53, a common resistance mechanism for patients who experience disease progression on lenalidomide—has been the focus of research efforts. As Dr. Bejar reported, data suggest that TP53 mutations are particularly adverse in all settings, even in patients headed to allogeneic stem cell transplantation. A study of 1,514 patients with MDS who were enrolled in the Center for International Blood and Marrow Transplant Research Repository between 2005 and 2014 found TP53 mutations were associated with approximately 50% shorter long-term survival when compared with those who had TP53-unmutated disease.3 What’s more, noted Dr. Bejar, poor prognosis did not stratify by age. Younger patients with this mutation had equally poor outcomes as well.

“At our center, we no longer do straightforward transplantations for patients with these mutations,” said Dr. Bejar. “We try to perform transplants plus some additional or experimental therapy to increase their chances of long-term survival.”

For patients who have TP53-mutated disease, one potentially promising option involves high doses of the hypomethylating agent decitabine. A study published in The New England Journal of Medicine identified a high response rate to decitabine for patients with TP53-mutated MDS and acute myeloid leukemia (AML).4 Strikingly, said Dr. Bejar, by the fourth cycle of treatment, these patients showed substantial cytoreduction of their TP53-mutant clone.

“These data suggest that if we time the transplant appropriately and treat a patient with high-dose decitabine before transplant, patients may have less residual disease and perhaps a longer time to relapse,” said Dr. Bejar. This approach is now being tested in clinical studies.

In the aforementioned study, the use of decitabine in patients with TP53-mutant disease did not translate to an improvement in overall survival, and relapse was still common. According to Dr. Bejar, however, combining the hypomethylating agent with “some type of consolidation or maintenance therapy” could lead to longer-term remissions.

Another agent being pursued is the experimental drug APR-246, which is believed to stabilize mutant forms of the TP53 protein, allowing them to perform their normal endogenous function. As Dr. Bejar reported, phase I and II data demonstrated both a high rate of response and seemingly durable responses through the limited follow-up period.5 Like high-dose decitabine, however, APR-246 will probably not generate long-term remissions on its own, said Dr. Bejar. It will likely be combined with other agents to improve outcomes in future studies.


  • Recent research in myelodysplastic syndromes (MDS) has identified gene mutations associated with significantly worse survival.
  • Efforts to target TP53 mutations with high-dose decitabine have shown promise but should be studied in combination with consolidation therapy.
  • Studies combining IDH1/2 inhibitors with hypomethylating agents are underway in both MDS and acute myeloid leukemia, which share similar pathologic features.


‘Borrowing’ From AML, and More Personalized Therapy

As MDS and AML share similar pathologic features—approximately one-third of all MDS cases evolve to become secondary AML—researchers are starting to borrow from advances made in AML, said Dr. Bejar, particularly with respect to recently approved drugs like venetoclax and the IDH inhibitors.

According to Dr. Bejar, IDH1 and IDH2 mutations occur in approximately 15% to 20% of patients with AML. These mutations, which create novel oncometabolites, have been targeted with IDH1/2 inhibitors (ivosidenib and enasidenib, respectively), leading to improvements in response rates and subsequent FDA approval. There are currently studies in MDS and AML combining IDH1/2 inhibitors with hypomethylating agents to test their efficacy in this setting.

“Approximately 5% of patients with MDS have these lesions,” said Dr. Bejar. “We’re hoping that genetically targeted agents might be effective in treating these disorders.”

Finally, added Dr. Bejar, a truly personalized approach involving immunotherapeutic agents may be coming to MDS as well. Studies at MD Anderson Cancer Center combining programmed cell death protein 1 and ligand 1 (PD-1/PD-L1) inhibitors with hypomethylating agents are currently ongoing. “Our hope is that these agents could produce long-lasting, treatment-free immunologic responses in these patients,” he concluded. 


DISCLOSURE: Dr. Bejar has served as a consultant for AbbVie, Astex, Celgene, Daiichi-Sankyo, Forty Seven, and NeoGenomics; has received honoraria from Celgene and Xian-Janssen; and has received research funding from Celgene and Takeda.


1. Bejar R: Advances in personalized therapeutic approaches in myelodysplastic syndromes. 2019 NCCN Annual Congress: Hematologic Malignancies. Presented September 28, 2019.

2. Bejar R, Steensma DP: Recent developments in myelodysplastic syndromes. Blood 124:2793-2803, 2014.

3. Lindsley RC, Saber W, Mar BG, et al: Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med 376:536-547, 2017.

4. Welch JS, Petti AA, Miller CA, et al: TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med 375:2023-2036, 2016.

5. Bykov VJ, Zhang Q, Zhang M, et al: Targeting of mutant p53 and the cellular redox balance by APR-246 as a strategy for efficient cancer therapy. Front Oncol 6:21, 2016.