Treatment Options in Myelodysplastic Syndromes - Episode 7

Initiating First-Line Treatment


Rami Komrokji, MD: When do you start treatment in those patients? We could talk about both lower and higher risk.

Amy DeZern, MD, MHS: I definitely initiate treatment. Let’s start with the higher-risk patients. Sometimes these are the most obvious. Certainly, in a patient with excess blasts, densely transfusion dependent, recurrent infections in the setting of neutropenia need to begin therapy. I always describe to the patients that the blasts are a space-occupying lesion in the bone marrow not allowing room for good hematopoiesis, and we must approach that proactively. Nobody wants to start chemotherapy, but if they’re having those clear clinical consequences of their disease, it’s time to start therapy.

It’s a separate issue in patients who have very preserved counts. I actually think you and I have talked about this on a number of occasions; we practice similarly. Excess blasts alone are a point of discussion, depending on whether you’re planning moving ahead to transplant or not. It’s the depth of cytopenias that require recurrent health care interactions that usually get me to start a hypomethylating agent. We’ll talk about clinical trials later, but from a standard-of-care perspective, for higher-risk disease, we have azacitidine and we have decitabine. I won’t say I use them interchangeably. I tend toward azacitidine a bit more in my personal practice. We have a great deal of experience with that here at Sidney Kimmel Comprehensive Cancer Center for many years. I start it fairly soon. For lower-risk patients, again it’s driven similarly by what are the clinical consequences of their disease. Let’s take a lower-risk anemic patient. Are you someone who uses a lot of erythropoiesis stimulating agents [ESAs] if the patient is anemic and has lower-risk disease?

Rami Komrokji, MD: In general, in the lower-risk disease, my trigger to pull a treatment is the cytopenias as you mentioned. It’s really the degree of the cytopenia that dictates. I don’t think there is a magical number to say that I will pull the trigger on treatment. A majority of the patients, when we are treating lower risk, we are treating anemia. Most patients are anemic. Sometimes they may have concomitant thrombocytopenia and neutropenia that may, down the road, dictate your choice of therapy. But in a majority of the patients, we are treating anemia. If patients are neutropenic or at least just pure neutropenia, I rarely have treated those patients. If they have thrombocytopenia, the options are limited. In some younger patients, I’ll consider immunosuppressive therapy and hypomethylating agents. Sometimes if it’s a truly lower-risk disease, nowadays I move to a thrombocytopenia bag before hypomethylating agents. But for a majority of the patients, anemia is the major indication to treat, and I start to do that with erythroid-stimulating agents. 

For those patients, when you look at the data of the predictive models of response to erythroid-stimulating agents, it’s usually in an endogenous level. If they are more than 500—and some use a 200 cutoff with their transfusion burden if patients are getting more than 2 units per month already—the chances of response to erythroid-stimulating agents drop to probably below 10%. Once I see the patient’s hemoglobin is drifting down and they are starting to be symptomatic, I would start treatment before they get transfusion dependent, usually with erythroid-simulating agents. Sometimes you could say maybe hemoglobin of 9 g/dL is my cutoff, but really there is no magical threshold there. I use it because I don’t want them to get to 8 or 7 g/dL, when they will need blood transfusions.

I give it a trial of 8 to 12 weeks. Sometimes I go to the highest dose. Some people like to add granulocyte colony-stimulating factor because it increases the erythroid response. If it’s working, then I continue with that. If they had an adequate trial of 12 weeks or so and it’s not working, then I will move next. One thing is always this: We move to the next option, then we could talk about this later. Maybe sometimes there are situations where you keep the erythroid-stimulating agents, but in the majority of cases they should be stopped. I see patients that are getting blood every 2 weeks, and they are still on Aranesp or Procrit after a year, with the notion that maybe it’s making the blood transfusions less. I don’t think that’s the right thing we should do, so we should stop them in majority of the cases.

In the lower-risk disease, we have a few options. We have the immunosuppressive therapy, we just talked about the ESA. We talked about lenalidomide and the hypomethylating agents. Particularly in the United States, there was a longtime track record of using hypomethylating agents in the lower-risk disease. Can you discuss the role of hypomethylating agents, in both lower- and higher-risk disease—the 2 agents, and some excitement about some oral drugs coming out?

Amy DeZern, MD, MHS: I alluded to this earlier in higher-risk disease, but I actually do use both azacitidine and decitabine in lower-risk disease. Certainly, you know we both participated in a clinical trial of randomizing lower-risk patients to different schedules of azacitidine or decitabine, as few as 3 days, and I really do tailor this to the individual patient when I’m doing it in an off-trial fashion. There absolutely is a role for these hypomethylating agents in patients who are transfusion dependent. Receiving azacitidine or decitabine can diminish or at least decrease that transfusion burden, and I find it very useful for those patients. There’s always that period of time when you initiate a hypomethylating agent, that the myelosuppression from the drug can escalate the transfusion burden for the first 1 to 2 cycles during that day-10-to-22 period of a 28-day cycle. If I can push myself and the patient through, and we are patients, then really the response rate after 4 to 6 cycles can be transfusion reduction or even complete hematologic improvement even in the lower-risk patients.

The same principles apply to the higher-risk patients. Sometimes we have a little higher mountain to climb in that we must decrease the blast burden with our hypomethylating agents as well. One of the holy grails of myelodysplastic syndrome therapy, in general, was the ability to give an oral hypomethylating agent, and there was 1 approved just at the end of August for higher-risk disease. Its brand name is Inqovi, and it’s the combination of an oral cytidine deaminase inhibitor and oral decitabine. It’s a pill that has the right ratio of those 2 drugs to enable an individual patient to get the same levels as they would if they were getting their decitabine through intravenous form.

I actually think the community and even myself who participated in the clinical trials are still going to be learning how to do it. You give it for 5 days of every 28, it reaches steady state, and it has very similar kinetics and has very good response rates after a few cycles of hematologic improvement and then partial remission, even complete remissions. The ability, especially during the coronavirus era to get a treatment at home so you don’t have to come in daily to the clinic is really a very patient-friendly therapy. It’s something I’m incorporating into my practice more now that it’s commercially available.

Transcript edited for clarity.