Transcript:Mikkael A. Sekeres, MD, MS: I wonder if I can ask you about the classic patient with lower risk MDS and who has anemia. Rami has just described to us how he approaches those patients. But what if you have a patient who has an isolated thrombocytopenia or multiple cytopenias, how do you treat those patients with lower risk MDS?
Jamile Shammo, MD: If you happen to have someone who has multiple cytopenias, potentially RCMD (refractory cytopenia with multilineage dysplasia) with less than 5% blasts, then I think using something that might result in a trilineal response would be the way to go. The only drugs I know of are hypomethylators, even though we all like to wait on this. But, again, the prognosis for people who have RCMD is not necessarily so great, so maybe you could make a case for that, particularly if they’re transfusion dependent. When it comes to isolators—thrombocytopenia is one. I think that’s a very, very small proportion of people who have low-risk MDS and have severe thrombocytopenia defined differently in different studies. Some look at less than 20,000, and some say less than 30,000. But there’s very interesting development in this area, even though it’s a small piece of the pie in this patient population. That is when we would consider a TPO agonist, or thrombopoietin agonist. Now, many of you may be aware of the initial study that looked at romiplostim, and randomized patients with low-risk disease, and platelet count less than 30,000 to either romiplostim or supportive care. And that study actually was based upon some encouraging data on improvement in platelet count with these agents, which is sort of logical. But then again the study was held because of an increase in the percentage of blasts in the peripheral blood as well as increase in the degree of fibrosis in the bone marrow.
Now, interestingly, when the drug was held, the blasts went back to the bone marrow. So, I’m not exactly sure if it was necessarily disease progression, but, needless to say, this was not an option. However, recently, at this past ASH, another very similar trial was reported, this time using an alternate TPO agonist. And that is eltrombopag in a very similar patient population, very similar design, demonstrating that there is a reasonable response rate in those patients who have severe thrombocytopenia. It’s encouraging, but I still would like to see longer follow-up and I would certainly not try to do this off study. That would be my recommendation.
Mikkael A. Sekeres, MD, MS: We participated in the romiplostim study, as I believe you did.
Jamile Shammo, MD: As I did, yes.
Mikkael A. Sekeres, MD, MS: The initial phase I/II study was really encouraging. It showed the response rates in the 40% to 50% range, and those response rates were actually recapitulated in the randomized phase II study. The problem with it, of course, is that the study enrolled patients with excess blasts, and blasts have TPO receptors. Among those patients who transformed to AML—and there was a group of patients who transformed to leukemia on that study—three-quarters of them started out with excess blasts. Now, you’d expect that some patients with lower risk MDS are just bound to transform to leukemia. It’s going to happen. So, the others were probably expected based on the population. It is very tricky to use these drugs now, given those data. So, I will occasionally use them, but I will tell you it’s about a 30-minute discussion with my patients about the risks of using them. And I really try to search for some sort of immune-mediated component to MDS and thus, platelet destruction, to justify that sort of off-label use.
Jamile Shammo, MD: I agree with you. I wonder how many of those people actually do have an autoimmune mechanism for that degree of thrombocytopenia to take place. I often will try a pulse Decadron before I actually go on and try Promacta.
Rami S. Komrokji, MD: We had an ongoing study with eltrombopag for almost 2 years. We just closed, and we treated more than 40 patients. So, I agree with what you are saying. First, we were including everybody after hypomethylating agent failures. And it’s clear if you have high-risk disease that those patients progress quickly, and that you cannot even see if there is benefit. You cannot tease out whether the drug is contributing or not. I think at this point, if they’re going to be used in the higher risk, they probably should be in combinations. In the lower risk, there is definitely a subset for whom you see benefit. And we’ve had patients ongoing on the study for 2 years, platelet transfusion independent, and doing very well. Interestingly, even in the Italian study there were some complete responses or trilineage responses similar to the aplastic anemia experience. One thing we observed in our studies is that patients that had CMML (chronic myelomonocytic leukemia)—particularly if they were proliferative—were more likely to develop leukocytosis, fibrosis, and circulating blasts. So, that’s a group—if they have proliferative CMML—for which I would shy away from using eltrombopag, even if they are at lower risk. And I think the French group had a similar experience. But in lower risk, what do you think, is it thrombocytopenia? I think that’s a very appealing option. I hope that they follow up on the Italian study, which shows safety any 1 or 2 years where that becomes an available option for patients.
Mikkael A. Sekeres, MD, MS: Ellen, we’ve mentioned a bunch of drugs that we try on patients with lower risk MDS. When do you determine that a drug has failed a patient? And, of course, we all agree that drugs fail patients, patients don’t fail drugs.
Ellen K. Ritchie, MD: I think that the drugs fail patients when the patients become transfusion dependent to the degree that their lifestyle is absolutely completely overrun by the disease—their performance status, their time in clinic, their rate of infection shows that they are not benefitting any longer from my treating them with a particular drug. So, it may be that patients are persistently neutropenic and they develop infections where obviously long-term use of this drug has not prevented that problem. Or they were not particularly transfusion dependent, have become transfusion dependent, and are maybe receiving weekly blood transfusion, or when patients are thrombocytopenic to the point that they may be needing transfusion once or twice a week, or have episodes of bleeding. I think that drugs fail patients when they’re no longer efficacious in treating their symptoms.
Mikkael A. Sekeres, MD, MS: And the rule in MDS, whether we like it or not, is that we continue drugs until those drugs fail patients, right? So, there is no 6-month course and then you stop, or 4-month course and then you stop—be it lenalidomide, or one of the hypomethylating agents, or the cyclosporine portion of ATG (anti-thymocyte globulin) therapy. We just keep going until patients reach one of those parameters you just discussed.
Jamile Shammo, MD: I wonder if you guys see the same thing in your practices, too. Often, that’s not necessarily recapitulated in practices. I often see people who had been treated and the treatment was stopped because the patient responded. Well, if they responded, it’s actually more logical to continue, but somehow that doesn’t necessarily happen, and I don’t understand exactly why this is the case.
Rami S. Komrokji, MD: I see it the other way, that ESAs (erythropoiesis-stimulating agents) are continued long time after they stop working. I think when I look at failure, I look at primary or secondary treatment failure, like patients not responding from the get-go versus somebody having a response before and then losing it—which sometimes it’s easier to tell hemoglobin went up, they were transfusion independent. If they would go back to transfusion-dependence, that’s an answer. What I struggle with is—and sometimes many patients refer to us—they start with hemoglobin of 8.5, they got 8 to 12 weeks of ESA, and it’s still 8.5 or 9. And the argument is at least they are not getting blood transfusions. I was really not always sure if this is a success of the treatment. I always try to get also the quality of life of the patient. Is he feeling better now than before? But that’s a little bit of a murky area in how to assess ESA failure, if hemoglobin didn’t go up but they are not getting transfusions.
Mikkael A. Sekeres, MD, MS: It can be tricky. We don’t want to rest on our laurels by saying stable disease is a win, right?
Ellen K. Ritchie, MD: Right.
Mikkael A. Sekeres, MD, MS: I think if we’re starting a patient on a drug, we need to see some improvement and not just assume that stable disease is somehow a benefit of that drug. Because we all have patients who’ve had stable disease for years without any therapy.
Ellen K. Ritchie, MD: Any treatment.
Transcript Edited for Clarity