Hypomethylating Agents in MDS Management

Practical insight on the appropriate use of hypomethylating agents in patients with myelodysplastic syndrome.

Transcript:

Amer Zeidan, MBBS, MHS: Hypomethylating agents [HMA] are the most commonly used modality for patients with high-risk MDS [myelodysplastic syndrome]. In the United States, they're approved for patients with both higher and lower risk MDS, but we often don't use them except in high-risk MDS from the get-go, or in some patients with lower risk MDS when they stop responding to some of the less invasive procedures, such as erythropoietin-stimulating agents.

The 2 forms that we have are azacitidine and decitabine. Both of them are given by injection; azacitidine can be given subcutaneously or intravenously, while decitabine is only given intravenously. Because of that, the patients would often need to have an access like a small catheter to give them the drug, or they have repeated injections. Both of those are given for multiple days in a row each month, so you usually give them for 5 to 7 days. That requires frequent trips back and forth to the infusion center. The [adverse] effects are generally minimal; most patients will not have severe [adverse] effects. The most common [adverse] effects are fatigue, some GI [gastrointestinal] upset, some nausea, and some local reactions at the site of injection with subcutaneous azacitidine. Rarely, you can have severe toxicity related to organ damage, but that's very rare. Other [adverse] effects are low blood counts. Those could be difficult to differentiate if they are related to the hypomethylating agents or they are related to the underlying MDS, but generally, thrombocytopenia and neutropenia are [adverse] effects that are associated with the use of those agents. However, we give them routinely to patients in their 70s, 80s, and the vast majority of patients tolerate them quite well.

In terms of efficacy, those drugs have been associated with complete responses. The average response rate, if you look across trials, the overall response rate is in the range of 40% to 50%. For a complete remission, it is somewhere between 10% and 15%, so more than half of the patients will not respond. And the responses can take several months to appear, 4 to 6 months, which is quite long to treat the patient before you know for sure whether they are responding. There was some improvement in quality of life and transfusion independence, but in terms of survival improvement, azacitidine is the only HMA that has been associated with overall survival improvement in the landmark AZA-001 trial in which median survival was around 24 months. However, we and others have shown that, at the population level, the real survival with those agents is probably in the range of 12 to 16 months. That tends to be a more realistic estimate that I provide when I discuss the use of those agents with patients.

One of the bigger challenges with the use of hypomethylating agents is that they have to be given by injection either subcutaneously or by infusion. The patients have to come frequently to the clinic back and forth, 5 to 7 days in a month. You have to remember that those patients are older, so their social support is often limited because their spouse could be sick or disabled and cannot drive them back and forth. Many times, unfortunately, the patient could be widowed; the children have moved out of the home, and many times they are out of state and their friends are older, so sometimes those patients don't have anybody to drive them. That, in my experience, could lead some patients to decline being treated because they cannot find a way to come frequently to get their injections, and sometimes they elect to be treated closer to home. Luckily, those drugs are FDA approved, so they can be given by the community physician. When we need to put the patient on a clinical trial that has an HMA backbone, sometimes the patients cannot go on clinical trials even if they want to because they cannot go back and forth to the big center that frequently for those azacitidine or decitabine injections.