Clinical Insights on Treating Myelodysplastic Syndrome

In the myelodysplastic syndrome [MDS] treatment space, recent approvals and ongoing research are shaping the future. In this Precision Medicine Perspectives series titled “Recent Updates in the Management of Lower-Risk Myelodysplastic Syndrome,” Elias Jabbour, MD, an expert hematologic oncologist at The University of Texas MD Anderson Cancer Center, gives a comprehensive overview of myelodysplastic syndrome and discusses the treatment landscape for patients with lower-risk MDS.

Targeted Oncology™: What is myelodysplastic syndrome and how does it manifest?

Elias Jabbour, MD: It involves myeloid cells, and dysplastic means change. It’s a disease of the stem cell that can lead to a blockage of the maturation of the blood lineage. Every human being has a stem cell that can give birth to red blood cells that go to the organs, platelets that make clots to prevent bleeding when somebody is injured, and white blood cells, which fight infections as part of the immune system. For whatever reason, whether it’s induced by chemical or chemotherapy or de novo, there’s damage to the stem cell. As a result, there’s a blockage of the maturation. Therefore, at the beginning, we have accumulation of abnormal young cells, and the end result is a decrease of the production of normal elements. This is why patients will present with anemia, most often thrombocytopenia, neutropenia, and then eventually this disease can go from low risk to high risk and ultimately transform into AML [acute myeloid leukemia]. But before MDS is manifested, with the understanding of the physiopathology of MDS, we’re trying to decipher it at an early stage. But with MDS, we essentially have a lack of production of normal cells, and it can be low risk or high risk. And of course, the management is different based on staging of the disease.

Targeted Oncology: How are patients with MDS diagnosed? What testing do you typically use for those patients?

Elias Jabbour, MD: Usually, a patient will complain of anemia, or a blood test shows anemia, most often, or they could be thrombocytopenic or neutropenic. That usually triggers a bone marrow evaluation to look at the stem cell and the factory where these blood cells are being produced to see whether there’s an abnormality. A patient will have a blood test and eventually have a bone marrow evaluation with a biopsy to look at the smear. And then on top of that, we look for chromosomal abnormalities. We do cytogenetic testing and molecular testing. This allows us to put together all these elements to come up with the staging of the disease and see whether the patient has low-risk or high-risk disease, because treatment will depend on whether the patient has low risk or high risk. Every patient should have a blood test, bone marrow, and molecular analysis and karyotype. People may try to step away from the bone marrow evaluation, but we’re not at that stage yet.

Targeted Oncology: Can you talk about some risk factors associated with MDS? You briefly touched on the risk stratification, but could you talk about the criteria? How do you define lower vs higher risk?

Elias Jabbour, MD: Traditionally, we put age to the side, and we look at cytopenias, anemia, or anemia plus something else. We look at whether the blast percentage is high or low. Usually the cutoff is 10%, meaning above or below 10%. We look at chromosomal abnormalities. For example, if you have multiple abnormalities or deletion of chromosome 5, it’s favorable. Then we add the molecular features as well. We put all this together to classify patients as having low risk or high risk. Simply speaking, the low risk is when the blasts are below 10%, the patients have one cytopenia at most, and chromosomal elements are favorable. Usually, survival is acceptable and patients who rely on blood transfusions will improve their quality of life first. Whereas with high risk, the blasts are above 10% or patients have very poor chromosomal abnormalities or, increasingly more today, multiple adverse mutations. These are where the survival is short and we have to intervene in order to correct the survival via treatment and allogeneic stem cell transplantation.

Targeted Oncology: How do you approach genetic or cytogenic testing in patients with MDS?

Elias Jabbour, MD: There are 2 elements to that. There’s karyotyping, which usually is done via G-banding [Giemsa banding] technique. Some people will do FISH [fluorescence in situ hybridization] testing to test for certain abnormalities, but the standard of care is karyotyping. The second element to that is next-generation sequencing for target mutations that are common in MDS, such as ASXL1, SF3B1, and others. These are very important because you put them together to see, No. 1, whether you can have the therapy choice in ring sideroblastic anemia, or to give an idea of the prognosis of disease, such as TP53 mutation, which is really bad in secondary MDS. It tells you about the prognosis, how it’s going to be, and therefore directs your therapy accordingly.

Targeted Oncology: Could you comment on the current treatment landscape for patients with lower-risk MDS? What are the currently available treatment options? What factors do you consider when choosing therapy?

Elias Jabbour, MD: Usually, the aim is to improve patients’ quality of life. Often, these patients are anemic or have pancytopenia and you need to improve the count because their blasts are low. MDS can transform into AML, but not for the majority of the patients. Patients with MDS still die from MDS, and the vast majority due to pancytopenia, bleeding, infection, or heart attack. So we have to improve their counts. And certainly, a fair part of the patient population will have mainly anemia, and we need to improve the anemia.

What tools are available to us? Essentially, we have growth factor support, which can improve red blood cell production and improve the outcome. Patients respond for a while, but unfortunately, they lose the response. When they lose a response, until recently, we had HMA [hypomethylating agents] in the United States. And now we have other tools for these patients. For example, for ring sideroblastic anemia, we have a drug called luspatercept, which helps hematopoietic stem cell function differently from the growth factors we use. In a randomized trial called MEDALIST [NCT02631070], it has been shown to improve transfusion independence. We have luspatercept for a subset of patients. We have growth factors up front.

At the 2023 ASCO [American Society of Clinical Oncology] Annual Meeting and EHA 2023 [European Hematology Association] Congress, there were updates from the COMMANDS trial [NCT03682536], a randomized trial comparing EPO [erythropoietin] to luspatercept up front. It showed luspatercept is superior to EPO in improving transfusion independence with more durable responses across the board, more so in ring sideroblastic anemia. HMA therapy is an option. Patients with deletion 5 can be given lenalidomide. Patients with aplastic anemia features could benefit from immunotherapy. A patient with EGFR rearrangement could benefit from TKIs [tyrosine kinase inhibitors]. But the vast majority of these patients eventually fail if you give them EPO. It was an unmet need in the second line. We need to do something because we’ve shown that survival in low-risk MDS in the second line is around 16 months, which isn’t so good. You can do HMA, but the problem is still anemia. And patients get transfusions frequently. Therefore, there was a need for new drugs.

At the 2023 ASCO meeting and EHA 2023 Congress, we saw updates from the IMerge trial [NCT02598661] testing telomerase inhibitors in MDS. In this randomized trial, a telomerase inhibitor, imetelstat, met its primary end point of improving transfusion independence across the board. Luspatercept is approved and available, but it only covers ring sideroblastic anemia. With imetelstat, transfusion independence is seen across the board across all subsets, including ring sideroblastic anemia and non–ring sideroblastic anemia. The unmet need is for patients who do not have ring sideroblastic anemia, where we don’t have any option for them. Imetelstat is here to fill this gap by improving transfusion independence in this group of patients. Of course, we need to have a long follow-up to see how it will impact the long-term outcomes. But nonetheless, having less blood need and more durable responses is a favorable feature for this drug, and hopefully it will receive FDA approval to be used in patients with MDS who failed EPO and have such urgent need.

Targeted Oncology: What factors do you consider when choosing therapy?

Elias Jabbour, MD: No. 1, I need to see whether the blasts are increased, so I have to repeat the bone marrow evaluation. I need to see whether there are new mutations or new clones evolving that push the patient to higher risk because patients with higher risk will require HMA therapy and transplantation. Otherwise, if the blasts are still low, there are no TP53 mutations, and we don’t have a major clonal evolution, I need to go for something. Today, we’re hoping to get imetelstat approved because this will fill a major need for this group of patients.

If I see a patient with ring sideroblastic anemia, that’s a different story, and we can use luspatercept today. But the majority of these patients will not have ring sideroblastic anemia. There will be patients with low-risk MDS who are transfusion dependent and failed EPO, and therefore we need to use imetelstat for these patients. It’s the beginning of a story. I hope that it will be approved. We have to learn more about it, and then eventually, we need to learn how this drug will be used in high-risk MDS. Whether it can be used up front or in combination remains to be determined. And of course, every drug comes with safety concerns. In the IMerge trial, we saw that there’s some myelosuppression, but it’s very manageable without any impact on the outcomes of the patients.

Targeted Oncology: What are some challenges in treating MDS?

Elias Jabbour, MD: Finally, we have new drugs in MDS. For a while, we had only HMA therapy. Now we have HMA, lenalidomide, and luspatercept, and soon we’ll have imetelstat joining the MDS treatment armamentarium as well. It’s great. It’s the beginning of a journey. There still are a lot of things to be learned in how we optimize the use of these drugs. We can treat patients in the second line, but the story is not complete until we make advances in all aspects of the disease and eventually improve survival in a major way. Imetelstat is a good addition. The future will be for combinations, different dose schedules, and upfront high-risk disease. This remains to be explored, and I’m optimistic the future is going to be bright.