Current and Future Treatments for the Management of Myelodysplastic Syndrome - Episode 12
Shared insight on the challenges inherent in using chemotherapy for patients with myelodysplastic syndrome.
Bart Scott, MD, MS: When we get patients with MDS [myelodysplastic syndrome] chemotherapy, there are specific challenges in that patient group, and it has to do with the MDS diagnosis. First, the median age of diagnosis is 72, so many patients may have coexisting comorbidities that could limit our therapeutic options. Another issue is that many patients already have profound cytopenias, low blood counts, and one of the major [adverse] effects of the chemotherapy that we give to treat MDS is low blood counts. In thinking broadly about the types of chemotherapy the patients with MDS receive, they would fit into 2 large groups: induction AML [acute myeloid leukemia]-like chemotherapy and hypomethylating therapy.
We’ll start with the induction AML-like chemotherapy. This is pretty aggressive. We generally reserve this for patients who are younger without a lot of comorbidities, who potentially have the option of a curative approach with allogeneic transplantation. There is a debate right now among the experts about whether patients should receive induction chemotherapy at all or whether they should receive hypomethylating therapy combined with another agent like venetoclax, for instance. That is a debate that we’re having, and there are clinical trials that are planning to address this issue. For now, induction chemotherapy is still used to treat some patients with MDS. They can have [adverse] effects of infection. They can have [adverse] effects with low blood counts. It does require that patients be hospitalized at least for the duration of the administration of the induction chemotherapy.
The blood counts don’t tend to come back until about 3 weeks after the administration of the induction chemotherapy, so they may have a lot of [adverse] effects with infections, and they would likely need to be heavily transfused during that period.
Now when thinking about hypomethylating therapy, they tend to have a lower [adverse] effect profile, which is the benefit of that therapy. On the downside, when you look at the complete remission rates, it tends to be less than what you observe with the induction chemotherapy. The hypomethylating therapy does lead to less hospitalization for IV [intravenous] antibiotics. They can be given outpatient, so patients don’t need to be admitted; that’s the benefit.
Both azacitidine and decitabine, which are the 2 major types of induction chemotherapy, are generally given intravenously. Both are being developed in oral formulations, and azacitidine can also be administered through the subcutaneous route, but for right now, if you were to receive azacitidine or decitabine, it would have to be given in a clinic or a hospital. For that reason, because of the way most clinics are set up, weekend administration is not a possibility. Many of these patients are getting 5-day treatment of hypomethylating therapy with either azacitidine or decitabine, and they have to travel from their home to the clinic to receive the treatment. The hypomethylating therapies may cause some mild nausea, and they may cause cytopenias requiring transfusion dependence.
Amer Zeidan, MBBS, MHS: One of the challenges with the use of hypomethylating agents in the long run is that they often require frequent administration: around 5 to 7 days each month. What we have found out with experience, and there's clinical data to support that, is that, if patients who are responding stopped treatment, the MDS is almost always going to come back, and it becomes resistant. Even if you tried to restart the hypomethylating agent back up, it's unlikely to result in another response. We run into this situation often because some patients can have responses with hypomethylating agents that last for years, but they are tired of coming back and forth 7 days every month to get the hypomethylating agents. We've tried to overcome that by sometimes spacing the treatment to every 5 or 6 weeks, but ultimately, we unfortunately have some patients who say, "You know what? I'm done. I cannot keep coming," especially when they don’t need blood transfusions, so they are just coming to get the hypomethylating agent injection.
Another situation where we commonly have a problem with IV treatments is that we have patients who get taken off quite quickly, maybe in the community setting where they get 1 or 2 cycles, and the physicians don't give the hypomethylating agent enough time to work. Those drugs can take 4 to 6 cycles before we see a response, so we generally try to persist on the treatment until the patient responds. We don’t continue beyond 6 cycles unless the patient has a response. Chronic therapy for years with hypomethylating agents that require intravenous or subcutaneous administration is a problem, and definitely having an oral alternative would make things easier for many patients.
The use of hypomethylating agents could be subcutaneous or by injection. Subcutaneous use is somewhat faster. It can take 10 to 15 minutes to get the subcutaneous injection, so it's fast. However, even in the most efficient places, the patient has to come register, probably wait in the waiting room, and then leave, so it probably takes a couple of hours for any single day for 7 days in a row for patients to get the hypomethylating agents. In some centers, you get a weekend break, so the patient would get their azacitidine from Monday to Friday, and then again on Monday and Tuesday, with a weekend break. It's a good commitment for a big chunk of the month, 2 to 3 hours each time. If they live far from the center, they have to drive maybe 1 hour each way, so that could take a lot of time. With the intravenous use with decitabine, it takes less than an hour to do it, but again, it has the same issues related to frequent visits, and on top of that, you need an intravenous access to give an intravenous drug frequently. That comes with some risk of infection, clotting of the venous access, and the need for flushes to make sure it functions. Some patients do not like to have one of those indwelling catheters. Then they have to be stuck each time for the 5 days when they come for the decitabine or the 7 days when they come for the azacitidine; every single time, they have to have a temporary intravenous cannula put in and removed, which comes with pain, bruises, and discomfort to the patient. There are some issues that come with that.