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Hypomethylating Agents in MDS: Factors to Consider

Panelists:Rami S. Komrokji, MD, Moffitt Cancer Center; Ellen K. Ritchie, MD, New York Presbyterian Hospital; Mikkael A. Sekeres, MD, MD, Cleveland Clinic; Jamile M. Shammo, MD, FASCP, FACP, Rush University Medical Center
Published: Wednesday, Jul 27, 2016


Transcript:

Mikkael A. Sekeres, MD, MS:
Ellen, what are your selection criteria as you think about higher-risk MDS patients and whether you’re going to recommend a hypomethylating agent versus recommending those patients go to transplant?

Ellen K. Ritchie, MD: It depends on a lot of factors. Again, getting to know the patient and what their goals are, I think is a very important part of the initial discussion. I agree with you very much that a person who goes forward to transplant who’s an elderly person, it may be 2 to 3 years out of their life that they’re at the functional level that they were prior to going into transplant. And that’s a very hard thing to understand, actually, for a lot of people. So, a lot of discussion has to go forward talking about the risks and benefits of that period of time of convalescence.

I also look very closely at the functional status of the patient, the care-giving situation of the patient, and whether or not they have a comorbid illness. I actually look at the caregiver very, very carefully, because an older patient who has a spouse who’s ailing does not really have a good caregiver. There’s going to have to be a child nearby who’s willing to take on that role. Having a friend in the neighborhood is not going to be enough, actually, to get them through a transplant. So, family support or patient support is critically important, I think, for an older patient that goes to transplant. And it is really an area which has not been carefully looked at. If your job is to take care of your demented spouse, that’s not going to be a good transplant candidate, so really understanding what their caregiver situation is.

It can be very murky looking at comorbid illnesses in older patients. A guy smoked for 50 years, he still plays tennis three times a week, he’s got good muscle mass, he has no other real comorbid illness, and still those patients can have problems during transplant. I think it’s very difficult to tease out those patients who are going to do better or worse than transplant. I have been surprised by patients of mine who have had multiple comorbid illnesses who’ve managed to get through transplant rather unscathed and patients who were playing six sets of tennis every single week who had a really difficult time during the transplant convalescence.

Mikkael A. Sekeres, MD, MS: I’ll ask a controversial question. We don’t have the answer to this yet, and there’s a study in Europe that’s trying to address this. And then there’s a study in the United States, the Clinical Trials Network, CTN1102. We have a patient with higher-risk MDS. Do you send that patient immediately to transplant or do you treat them with hypomethylating agents first, or do you give them AML-type induction therapy first to try to get them in remission before that transplant?

Rami S. Komrokji, MD: It is a very controversial question, and I think you will get different answers on this. I think one question you are posing, again, is almost the timing of a transplant in a higher-risk disease. In our practice, we still send them to transplant immediately. But, every now and then, you see those patients that had a complete response on hypomethylating agents, and you start doubting in your mind, should I wait on the transplant until their response is lost? And I think that’s a reasonable discussion with the patient. Because, if we know that if a patient is in complete response with hypomethylating agents, they are deriving more benefit than the average patients.

You can say, let’s wait with the time of the failure of the therapy, with a caveat that, at that time, if the disease is in AML—which one-third of the patients could go there at time of failure—then you do induction. So, I think it’s reasonable in a subset of patients if you started hypomethylators and they’re having very good response, they are in their 70s—not in a young patient—to discuss that. The question to start a treatment before transplant or not, I think, is also challenging. What’s the goal?

As I mentioned, we actually are starting in many patients—if they are symptomatic, most of them are cytopenic—with the rationale that even when we send patients to transplant, many of them are not going to get transplanted. When you start hypomethylating agents, you are starting a definitive therapy for their disease. And whether a response prior to transplant or not makes a difference in the outcome of transplant, that’s also a very controversial issue. We know that hypomethylators are probably as good as intensive chemotherapy in a majority of patients. The French had published a study looking at azacitidine versus intensive chemotherapy prior to transplant. We don’t know whether a response, like a complete response or a cytogenetic response, matters.

In the past, many of the studies were based on chemotherapy and showed that with chemotherapy or no chemotherapy, there was no difference; they were all retrospective. In my opinion, they were biased. Patients that had higher blasts got chemotherapy; patients that had lower blasts did not. In patients that get chemotherapy, if they achieve a CR, they did better with transplant. I try not to do intensive chemotherapy as much as I can. So, if I go with hypomethylating agents for the reasons I mentioned, I do think if there is a response post transplant, that matters and that we may need to rethink that strategy. But, hopefully this answers the question.

Jamile Shammo, MD: There’s probably no answer to that unless you do randomized trials. But I think I tend to do the same. I’d rather start with a hypomethylator because I still feel like I have one other option to go to. Should this disease prove proliferative, then at least I may fall on induction chemotherapy if this is a transplant candidate. But, clearly, there’s no trials to support this kind of an approach. But, maybe the ones that you’ve mentioned will give us a signal one way or the other.

Mikkael A. Sekeres, MD, MS: I think our approach is similar, and for the reasons you both elucidated. For younger patients with higher blast percentages—so 17%, 18%—maybe if you had moved the bone marrow biopsy needle 1 mm over, it would have been 21%. Those folks we will take through induction chemotherapy as if they have leukemia, because even though they have MDS, the remission rates for those patients are still 40%–—which is the highest remission you’re getting, much higher than you’re going to get with a hypomethylating agent for older adults or those who have a lower blast percentage. And we can define lower blast percentage however we want, probably up to 10% or 12%. Those folks we will take through hypomethylating agents, particularly because you don’t know if the transplant is going to happen. And I think that was a critical point. For all these folks, we know how many actually make it through transplant: 50% as you mentioned. So, for the 50% who don’t make it to that transplant, we don’t want them sitting on their ducks waiting for something that’s never going to happen.

Transcript Edited for Clarity
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Transcript:

Mikkael A. Sekeres, MD, MS:
Ellen, what are your selection criteria as you think about higher-risk MDS patients and whether you’re going to recommend a hypomethylating agent versus recommending those patients go to transplant?

Ellen K. Ritchie, MD: It depends on a lot of factors. Again, getting to know the patient and what their goals are, I think is a very important part of the initial discussion. I agree with you very much that a person who goes forward to transplant who’s an elderly person, it may be 2 to 3 years out of their life that they’re at the functional level that they were prior to going into transplant. And that’s a very hard thing to understand, actually, for a lot of people. So, a lot of discussion has to go forward talking about the risks and benefits of that period of time of convalescence.

I also look very closely at the functional status of the patient, the care-giving situation of the patient, and whether or not they have a comorbid illness. I actually look at the caregiver very, very carefully, because an older patient who has a spouse who’s ailing does not really have a good caregiver. There’s going to have to be a child nearby who’s willing to take on that role. Having a friend in the neighborhood is not going to be enough, actually, to get them through a transplant. So, family support or patient support is critically important, I think, for an older patient that goes to transplant. And it is really an area which has not been carefully looked at. If your job is to take care of your demented spouse, that’s not going to be a good transplant candidate, so really understanding what their caregiver situation is.

It can be very murky looking at comorbid illnesses in older patients. A guy smoked for 50 years, he still plays tennis three times a week, he’s got good muscle mass, he has no other real comorbid illness, and still those patients can have problems during transplant. I think it’s very difficult to tease out those patients who are going to do better or worse than transplant. I have been surprised by patients of mine who have had multiple comorbid illnesses who’ve managed to get through transplant rather unscathed and patients who were playing six sets of tennis every single week who had a really difficult time during the transplant convalescence.

Mikkael A. Sekeres, MD, MS: I’ll ask a controversial question. We don’t have the answer to this yet, and there’s a study in Europe that’s trying to address this. And then there’s a study in the United States, the Clinical Trials Network, CTN1102. We have a patient with higher-risk MDS. Do you send that patient immediately to transplant or do you treat them with hypomethylating agents first, or do you give them AML-type induction therapy first to try to get them in remission before that transplant?

Rami S. Komrokji, MD: It is a very controversial question, and I think you will get different answers on this. I think one question you are posing, again, is almost the timing of a transplant in a higher-risk disease. In our practice, we still send them to transplant immediately. But, every now and then, you see those patients that had a complete response on hypomethylating agents, and you start doubting in your mind, should I wait on the transplant until their response is lost? And I think that’s a reasonable discussion with the patient. Because, if we know that if a patient is in complete response with hypomethylating agents, they are deriving more benefit than the average patients.

You can say, let’s wait with the time of the failure of the therapy, with a caveat that, at that time, if the disease is in AML—which one-third of the patients could go there at time of failure—then you do induction. So, I think it’s reasonable in a subset of patients if you started hypomethylators and they’re having very good response, they are in their 70s—not in a young patient—to discuss that. The question to start a treatment before transplant or not, I think, is also challenging. What’s the goal?

As I mentioned, we actually are starting in many patients—if they are symptomatic, most of them are cytopenic—with the rationale that even when we send patients to transplant, many of them are not going to get transplanted. When you start hypomethylating agents, you are starting a definitive therapy for their disease. And whether a response prior to transplant or not makes a difference in the outcome of transplant, that’s also a very controversial issue. We know that hypomethylators are probably as good as intensive chemotherapy in a majority of patients. The French had published a study looking at azacitidine versus intensive chemotherapy prior to transplant. We don’t know whether a response, like a complete response or a cytogenetic response, matters.

In the past, many of the studies were based on chemotherapy and showed that with chemotherapy or no chemotherapy, there was no difference; they were all retrospective. In my opinion, they were biased. Patients that had higher blasts got chemotherapy; patients that had lower blasts did not. In patients that get chemotherapy, if they achieve a CR, they did better with transplant. I try not to do intensive chemotherapy as much as I can. So, if I go with hypomethylating agents for the reasons I mentioned, I do think if there is a response post transplant, that matters and that we may need to rethink that strategy. But, hopefully this answers the question.

Jamile Shammo, MD: There’s probably no answer to that unless you do randomized trials. But I think I tend to do the same. I’d rather start with a hypomethylator because I still feel like I have one other option to go to. Should this disease prove proliferative, then at least I may fall on induction chemotherapy if this is a transplant candidate. But, clearly, there’s no trials to support this kind of an approach. But, maybe the ones that you’ve mentioned will give us a signal one way or the other.

Mikkael A. Sekeres, MD, MS: I think our approach is similar, and for the reasons you both elucidated. For younger patients with higher blast percentages—so 17%, 18%—maybe if you had moved the bone marrow biopsy needle 1 mm over, it would have been 21%. Those folks we will take through induction chemotherapy as if they have leukemia, because even though they have MDS, the remission rates for those patients are still 40%–—which is the highest remission you’re getting, much higher than you’re going to get with a hypomethylating agent for older adults or those who have a lower blast percentage. And we can define lower blast percentage however we want, probably up to 10% or 12%. Those folks we will take through hypomethylating agents, particularly because you don’t know if the transplant is going to happen. And I think that was a critical point. For all these folks, we know how many actually make it through transplant: 50% as you mentioned. So, for the 50% who don’t make it to that transplant, we don’t want them sitting on their ducks waiting for something that’s never going to happen.

Transcript Edited for Clarity
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