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Rationale for Combination Therapy in MDS

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: Tuesday, Aug 02, 2016


Transcript:

Mikkael A. Sekeres, MD, MS:
Let’s transition now, if it’s okay, to talk about some novel approaches and future directions. One of the areas that’s been explored is combination therapies. And I think the theory here has been that if you accept the premise that biologically higher-risk MDS, in particular, is very similar to acute myeloid leukemia in older adults, it’s certainly legitimate to treat acute myeloid leukemia more aggressively. Why shouldn’t it be more legitimate also to treat higher-risk MDS more aggressively? So, some of the combinations that have been looked at have been azacitidine and lenalidomide, taking advantage of complementary mechanisms of action or azacitidine and histone deacetylase (HDAC) inhibitors—the theory being that the HDAC inhibitors will work synergistically with hypomethylating agents in treating the disease.

And there was a study we conducted through the North American Intergroup Mechanism in which we enrolled 277 patients and divided roughly evenly among three treatment arms: azacitidine monotherapy, azacitidine and lenalidomide, and azacitidine plus vorinostat, which is an HDAC inhibitor. Now, the combination of azacitidine and lenalidomide in phase II settings yielded an overall response rate of slightly over 70%, or roughly double what you would have expected from azacitidine monotherapy. The overall response rate was about 36% in the AZA001 study. For azacitidine and vorinostat in a study that originated here in New York, the overall response rate was also slightly over 70%.

In this randomized study, that was powered based on overall response rate to try to improve that 20% higher than azacitidine monotherapy. In fact, the azacitidine monotherapy overall response rate fell out right at 36% or 37%, right exactly where you would expect it. The azacitidine and lenalidomide combination had an overall response rate of 49%, so higher, but not significantly higher. And the azacitidine and vorinostat overall response was actually lower than azacitidine monotherapy, but not significantly lower. One bright spot in that combination were patients who had chronic myelomonocytic leukemia. In this population, the azacitidine and lenalidomide overall response rate was actually double that of azacitidine monotherapy, and that was a significant difference. So, it may be that in these overlap disorders, there is a role for combination therapy. I would ask you, do you think that combination therapies in MDS are dead or is this an area that we should continue to explore?

Jamile Shammo, MD: You know we talked about that at some point, and I think that we probably have enough trials that demonstrated that the combination of a hypomethylator plus an HDAC inhibitor is not going to work. The SWOG (Southwest Oncology Group) trial, the one that you mentioned, is one such trial. But, perhaps you weren’t going after the right HDAC inhibitor; I’m not exactly sure. I think the only way to go is to actually try it. I tend to like sequential therapy, rather than combination therapy, because often you end up with cytopenia, so you end up holding on to the dose and maybe you’re not delivering adequate therapy that you’d like to give otherwise. Sequence maybe is something that needs to be explored. But, I’ll ask you, what do you think is the reason why your phase II study showed 40% CR (complete response) and the SWOG study didn’t? Was there any difference in the patient population?

Mikkael A. Sekeres, MD, MS: It’s an interesting question. One of the findings that came out of this study is that patients who were on combination arms were significantly more likely to undergo dose reductions and premature discontinuation of their therapy. So, it may be that people who were treating these patients saw the cytopenias, got scared, and dose-reduced or stopped the therapy entirely before patients could reach the 6-month point (when a marrow was to be obtained to determine whether or not that patient was in remission) or the 4-month point (when the study mandated those bone marrows were to be obtained). That was a major concern.

It may be that the best approach is to start off with monotherapy and then add in the other agents as patients start to experience a response and you don’t see the therapy-related cytopenias as much. But, I will tell you anecdotally, I would receive e-mails from all over the country or Canada with people saying, “This cytopenia happened. I dose-reduced. Now this cytopenia is happening, should I dose reduce again?” And I would e-mail back and say, “Wait, wait, wait. You shouldn’t have dose-reduced to start with.” So, it’s a challenge to give combination therapies to older adults with MDS, period. And it may be that we need to. I was born a leukemia doctor first, so I’ve always been more aggressive about therapy that I give my patients and believe in an induction course to try to get the disease under control. But, maybe that’s the wrong approach. Maybe the correct approach is to give less therapy to start with until patients start to experience a response, and then add in the second therapy.

Jamile Shammo, MD: I agree.

Rami S. Komrokji, MD: First, I’m glad you took the question because we were going to toss it back to you. I was waiting for you to ask, but then you answered it. But, when you think why you are thinking of combinations—exactly as you mentioned—even improving the response rates, more patients would respond to treatment or have a longer duration of response. And I think it may matter what the combination is like. We’re maybe not as smart in selecting the combinations. Maybe we should look for agents that are not myelosuppressive that could be delivered early on or—as you mentioned—kind of an add-back strategy later on.

I think we also, at least now in the Consortium, are looking at subsets of patients. So, we know that those patients that have p53 mutations, for example, do very poorly. We are looking at studies looking at hypomethylating agents plus a p53 modulator. I think there are some subsets we could start looking at, based on the molecular data. But, I agree with you: the HDAC concurrent therapy, there probably is no reason to do another study. We’ve had several different classes of HDAC inhibitors not working, so those could be sequential. But, there are patients who probably would still benefit from the combination, whether it’s the type of the combination or maybe the sequence of the combination how to do it. I like the idea of starting one hypomethylating and then adding the other one. There are so many studies ongoing now, I think there is excitement about, like, checkpoint inhibitors, and many of them are going into combinations with hypomethylators. We are looking in the Consortium, again, about if there were any deletion inhibitors added to a hypomethylating agent. So, that’s my take on it.

Transcript Edited for Clarity
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Transcript:

Mikkael A. Sekeres, MD, MS:
Let’s transition now, if it’s okay, to talk about some novel approaches and future directions. One of the areas that’s been explored is combination therapies. And I think the theory here has been that if you accept the premise that biologically higher-risk MDS, in particular, is very similar to acute myeloid leukemia in older adults, it’s certainly legitimate to treat acute myeloid leukemia more aggressively. Why shouldn’t it be more legitimate also to treat higher-risk MDS more aggressively? So, some of the combinations that have been looked at have been azacitidine and lenalidomide, taking advantage of complementary mechanisms of action or azacitidine and histone deacetylase (HDAC) inhibitors—the theory being that the HDAC inhibitors will work synergistically with hypomethylating agents in treating the disease.

And there was a study we conducted through the North American Intergroup Mechanism in which we enrolled 277 patients and divided roughly evenly among three treatment arms: azacitidine monotherapy, azacitidine and lenalidomide, and azacitidine plus vorinostat, which is an HDAC inhibitor. Now, the combination of azacitidine and lenalidomide in phase II settings yielded an overall response rate of slightly over 70%, or roughly double what you would have expected from azacitidine monotherapy. The overall response rate was about 36% in the AZA001 study. For azacitidine and vorinostat in a study that originated here in New York, the overall response rate was also slightly over 70%.

In this randomized study, that was powered based on overall response rate to try to improve that 20% higher than azacitidine monotherapy. In fact, the azacitidine monotherapy overall response rate fell out right at 36% or 37%, right exactly where you would expect it. The azacitidine and lenalidomide combination had an overall response rate of 49%, so higher, but not significantly higher. And the azacitidine and vorinostat overall response was actually lower than azacitidine monotherapy, but not significantly lower. One bright spot in that combination were patients who had chronic myelomonocytic leukemia. In this population, the azacitidine and lenalidomide overall response rate was actually double that of azacitidine monotherapy, and that was a significant difference. So, it may be that in these overlap disorders, there is a role for combination therapy. I would ask you, do you think that combination therapies in MDS are dead or is this an area that we should continue to explore?

Jamile Shammo, MD: You know we talked about that at some point, and I think that we probably have enough trials that demonstrated that the combination of a hypomethylator plus an HDAC inhibitor is not going to work. The SWOG (Southwest Oncology Group) trial, the one that you mentioned, is one such trial. But, perhaps you weren’t going after the right HDAC inhibitor; I’m not exactly sure. I think the only way to go is to actually try it. I tend to like sequential therapy, rather than combination therapy, because often you end up with cytopenia, so you end up holding on to the dose and maybe you’re not delivering adequate therapy that you’d like to give otherwise. Sequence maybe is something that needs to be explored. But, I’ll ask you, what do you think is the reason why your phase II study showed 40% CR (complete response) and the SWOG study didn’t? Was there any difference in the patient population?

Mikkael A. Sekeres, MD, MS: It’s an interesting question. One of the findings that came out of this study is that patients who were on combination arms were significantly more likely to undergo dose reductions and premature discontinuation of their therapy. So, it may be that people who were treating these patients saw the cytopenias, got scared, and dose-reduced or stopped the therapy entirely before patients could reach the 6-month point (when a marrow was to be obtained to determine whether or not that patient was in remission) or the 4-month point (when the study mandated those bone marrows were to be obtained). That was a major concern.

It may be that the best approach is to start off with monotherapy and then add in the other agents as patients start to experience a response and you don’t see the therapy-related cytopenias as much. But, I will tell you anecdotally, I would receive e-mails from all over the country or Canada with people saying, “This cytopenia happened. I dose-reduced. Now this cytopenia is happening, should I dose reduce again?” And I would e-mail back and say, “Wait, wait, wait. You shouldn’t have dose-reduced to start with.” So, it’s a challenge to give combination therapies to older adults with MDS, period. And it may be that we need to. I was born a leukemia doctor first, so I’ve always been more aggressive about therapy that I give my patients and believe in an induction course to try to get the disease under control. But, maybe that’s the wrong approach. Maybe the correct approach is to give less therapy to start with until patients start to experience a response, and then add in the second therapy.

Jamile Shammo, MD: I agree.

Rami S. Komrokji, MD: First, I’m glad you took the question because we were going to toss it back to you. I was waiting for you to ask, but then you answered it. But, when you think why you are thinking of combinations—exactly as you mentioned—even improving the response rates, more patients would respond to treatment or have a longer duration of response. And I think it may matter what the combination is like. We’re maybe not as smart in selecting the combinations. Maybe we should look for agents that are not myelosuppressive that could be delivered early on or—as you mentioned—kind of an add-back strategy later on.

I think we also, at least now in the Consortium, are looking at subsets of patients. So, we know that those patients that have p53 mutations, for example, do very poorly. We are looking at studies looking at hypomethylating agents plus a p53 modulator. I think there are some subsets we could start looking at, based on the molecular data. But, I agree with you: the HDAC concurrent therapy, there probably is no reason to do another study. We’ve had several different classes of HDAC inhibitors not working, so those could be sequential. But, there are patients who probably would still benefit from the combination, whether it’s the type of the combination or maybe the sequence of the combination how to do it. I like the idea of starting one hypomethylating and then adding the other one. There are so many studies ongoing now, I think there is excitement about, like, checkpoint inhibitors, and many of them are going into combinations with hypomethylators. We are looking in the Consortium, again, about if there were any deletion inhibitors added to a hypomethylating agent. So, that’s my take on it.

Transcript Edited for Clarity
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