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Hypomethylating Agents in Low-Risk MDS

Panelists: Vinod Pullarkat, MD, City of Hope Medical Center; Jamile Shammo, MD, Rush University Medical Center; Rami S. Komrokji, MD, Moffitt Cancer Center; Thomas Prebet, MD, PhD, Yale Cancer Center; Ellen K. Ritchie, MD, New York Presbyterian Hospital
Published: Friday, Feb 10, 2017


Transcript:

Vinod Pullarkat, MD:
Now, about hypomethylating agents (HMA): what is their impact on disease progression in the lower-risk patients?

Thomas Prebet, MD, PhD: I don’t think we have any real data showing that we have improvements of the progression. We know from several studies, and a retrospective analysis, that survival of non-deletion 5q patients with a hypomethylating agent can be pretty prolonged, even if it’s relatively shorter than what we expect for what we call a “low-risk disease.” After that, I don’t think we have any real data showing that we have a difference.

Ellen K. Ritchie, MD: The problem in treating low-risk patients, it looks like they would have a number of years to live, and you’re using a therapy for which we know, when they fail that therapy, we have no options that are successful. That really has to weigh into your decision as to whether or not you are going to do that to a patient. Only if it’s a low-risk patient that you think is really more high-risk for some other reason, where you feel a transplant might be coming down the line or you have a curative bridge for that particular patient. But, putting a low-risk patient on a hypomethylating agent also has the risk that, at the end, you have a disease that’s worsening for which you have no good alternative.

Rami S. Komrokji, MD: I think both of you covered the important points. The original use of hypomethylating agents in low-risk is mainly a United States phenomenon. It’s not approved anywhere but the United States. And because the approval originally here was based on the FAB (French-American-British) classification where it includes all the subtypes of MDS, and originally after ESA (erythropoietic stimulating agent) failure, it was the most commonly used modality for treatment. And as we are learning, as the points mentioned, should you save this for later on, should you save this for patients at a higher-risk? Because when we started looking at the outcome of those patients, those who have HMA failures, even in the lower-risk, they did not have the best outcome. The median survival was in the range of 15 to 18 months. And we see, clinically, all of those patients, starting with the response rates to the subsequent agents, are less after HMA stopped working.

Vinod Pullarkat, MD: So, it identifies a bad prognostic subset.

Rami S. Komrokji, MD: Right. Already you get into that almost-like-a-bone-marrow failure status, that, like, you are not seeing responses, like, as we mentioned, with lenalidomide. So, I totally agree with the approach that if you find higher-risk features that worry you about the disease, it’s a reasonable option, especially with thrombocytopenia. But if you are treating pure anemia patients, I think you could enroll patients on a clinical trial and save the hypomethylating agents for second and subsequent lines of therapy. It doesn’t have to be the first step after ESA failure. There are obviously things about the dosing and the schedule. All the studies that looked at survival advantage looked at 7 days of azacitidine. In the lower-risk, we’ve adopted a 5-day regimen based on a study published by Dr. Lyons a few years ago that looked at hematological improvement. That is, even now, being challenged. We heard data from the consortium looking at 3 days’ use of those agents. So, we don’t really know even what is the best schedule to get that hematological improvement, and we are talking particularly lower-risk. I think the higher-risk, there is clear evidence that the long 7 days’ duration is the treatment.

Jamile Shammo, MD: Well, I just wanted to say that in the original CALGB study, which looked at everybody, there was a quarter of patients who had low-risk disease, refractory anemia. And their responses, if you looked at the CR/PR, if I remember correctly, didn’t really matter. So, it’s reasonable to say that, for people who have low-risk disease and are transfusion dependent, but obviously times have changed. This isn’t the only drug that you have, which is what was the case at that time, and I think we have to be a little bit more selective; keeping something for later on.

Transcript Edited for Clarity
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Transcript:

Vinod Pullarkat, MD:
Now, about hypomethylating agents (HMA): what is their impact on disease progression in the lower-risk patients?

Thomas Prebet, MD, PhD: I don’t think we have any real data showing that we have improvements of the progression. We know from several studies, and a retrospective analysis, that survival of non-deletion 5q patients with a hypomethylating agent can be pretty prolonged, even if it’s relatively shorter than what we expect for what we call a “low-risk disease.” After that, I don’t think we have any real data showing that we have a difference.

Ellen K. Ritchie, MD: The problem in treating low-risk patients, it looks like they would have a number of years to live, and you’re using a therapy for which we know, when they fail that therapy, we have no options that are successful. That really has to weigh into your decision as to whether or not you are going to do that to a patient. Only if it’s a low-risk patient that you think is really more high-risk for some other reason, where you feel a transplant might be coming down the line or you have a curative bridge for that particular patient. But, putting a low-risk patient on a hypomethylating agent also has the risk that, at the end, you have a disease that’s worsening for which you have no good alternative.

Rami S. Komrokji, MD: I think both of you covered the important points. The original use of hypomethylating agents in low-risk is mainly a United States phenomenon. It’s not approved anywhere but the United States. And because the approval originally here was based on the FAB (French-American-British) classification where it includes all the subtypes of MDS, and originally after ESA (erythropoietic stimulating agent) failure, it was the most commonly used modality for treatment. And as we are learning, as the points mentioned, should you save this for later on, should you save this for patients at a higher-risk? Because when we started looking at the outcome of those patients, those who have HMA failures, even in the lower-risk, they did not have the best outcome. The median survival was in the range of 15 to 18 months. And we see, clinically, all of those patients, starting with the response rates to the subsequent agents, are less after HMA stopped working.

Vinod Pullarkat, MD: So, it identifies a bad prognostic subset.

Rami S. Komrokji, MD: Right. Already you get into that almost-like-a-bone-marrow failure status, that, like, you are not seeing responses, like, as we mentioned, with lenalidomide. So, I totally agree with the approach that if you find higher-risk features that worry you about the disease, it’s a reasonable option, especially with thrombocytopenia. But if you are treating pure anemia patients, I think you could enroll patients on a clinical trial and save the hypomethylating agents for second and subsequent lines of therapy. It doesn’t have to be the first step after ESA failure. There are obviously things about the dosing and the schedule. All the studies that looked at survival advantage looked at 7 days of azacitidine. In the lower-risk, we’ve adopted a 5-day regimen based on a study published by Dr. Lyons a few years ago that looked at hematological improvement. That is, even now, being challenged. We heard data from the consortium looking at 3 days’ use of those agents. So, we don’t really know even what is the best schedule to get that hematological improvement, and we are talking particularly lower-risk. I think the higher-risk, there is clear evidence that the long 7 days’ duration is the treatment.

Jamile Shammo, MD: Well, I just wanted to say that in the original CALGB study, which looked at everybody, there was a quarter of patients who had low-risk disease, refractory anemia. And their responses, if you looked at the CR/PR, if I remember correctly, didn’t really matter. So, it’s reasonable to say that, for people who have low-risk disease and are transfusion dependent, but obviously times have changed. This isn’t the only drug that you have, which is what was the case at that time, and I think we have to be a little bit more selective; keeping something for later on.

Transcript Edited for Clarity
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