Meet The Professors: Myelodysplastic Syndromes Edition, 2016Case discussion: An 88-year-old man with high-risk MDS (Dr Brenner)
26:38 minutes.
TRANSCRIPTION:
DR BRENNER: So this gentleman was actually 83 when he was diagnosed. Relatively healthy. Had a history of coronary artery disease but otherwise had good health. And on routine blood work, toward the end of 2010, he was found to be neutropenic with an active neutrophil count of 300. He was actually at another center at this time, and he underwent a bone marrow that showed MDS and refractory anemia with excess blasts. He had 18% blasts. He had a monosomy 7 and a 7q deletion. DR LOVE: Could you talk a little bit about how he presented at that point? What kind of condition he was in? And what his baseline was a couple of years before? DR BRENNER: He’s a active tennis player. And it was really just a routine. He goes to his physician roughly once a year. And it was just a routine CBC. He felt fine. DR LOVE: So initially he felt totally fine. DR BRENNER: Completely asymptomatic. DR LOVE: It was just the lab finding. DR BRENNER: Correct. And then he had this bone marrow that showed high-risk MDS and high-risk cytogenetic changes. And the other physician actually recommended that he undergo 7&3 induction therapy. DR LOVE: Wow! Wow! DR BRENNER: So he came to see me as a second opinion and I said, “We’re not going to do that,” and actually recommended that we treat him with a hypomethylating agent. And I started him on azacitidine. And after 4 cycles, his neutropenia completely resolved. And tolerated treatment well. He was getting 5 days a month therapy. And I repeated a bone marrow after about 7 cycles, and at this time he had no evidence of any blasts. His bone marrow was actually interpreted as being normal, and he had no evidence of the monosomy 7 or 7q deletion. DR LOVE: Before you go on with the case, just a basic question. Guillermo, how do you decide between decitabine and azacitidine? A pretty simple question. DR MORGANSTEIN: That’s not a simple question. DR GARCIA-MANERO: We helped develop decitabine, and we have worked quite a bit of azacitidine. The bottom line is that there’s only 1 trial with really survival data on a Phase III type of context, and that’s azacitidine. So sometimes I think that I can judge what the taste of the community is because MD Anderson is a pure referral center — we don't really have an internal — maybe 0.1 % of referrals come from the house — and I can tell that in the front-line setting — I don’t know what Harry thinks about — aza has become the standard of care. And it’s based on the survival data. Both drugs are approved. In my opinion, probably they are equivalent, but one has, like, hardcore survival data. And it’s hard not to use in the front line the other agent, even if you like it very much, without that data. DR ERBA: I agree. And I appreciate how you said that, especially coming from MD Anderson, I mean, where decitabine was developed. And it’s an incredibly effective drug. The issue is, for this patient, okay, you have a patient with — I didn’t do the calculation, but I’m going to say this is high-risk disease, and you’re trying to give him something that has a proven survival benefit. And the only study that has shown a proven survival benefit is azacitidine. Now, we all understand, though, that the decitabine studies were flawed. The largest Phase III studies in decitabine did not use the MD Anderson dosing regimen. They used the older regimen of a 3-hour infusion every 8 hours for 3 days, a little bit more myelosuppressive, 6-week cycles there. And probably the biggest flaw of all those studies is they didn’t allow maintenance. And that was a real shot in the foot. And so I agree that the drugs are probably equivalent, and based on that some people use decitabine because it’s 5 days instead of 7 days. And in this patient, I would definitely use the 7-day regimen. I would not use 5 days because there’s no data in these higher-risk patients. But you have to go where the data is. The data shows a survival benefit for azacitidine. And we do remember that in that conventional care study, that study comparing aza with conventional care, a proportion of the patients did receive 3&7, but this group was too small to make any comparison of survival between 3&7 and azacitidine. They were all lumped together. DR LOVE: Before we go on with the case, just to clarify, Neil, why did you say it’s not that straightforward a question? DR MORGANSTEIN: Because 88 I think is the extreme, but you still hear 7&3 come up in elderly and I had my own fairly strong opinion that that’s really the wrong thing to do. And you don’t say that very often. Two, I think that this is where the community differs a little bit, I agree. You gave 5 days initially? Yes, I usually give 5 days as well. Logistically, you do 5 and then 2 on Monday and Tuesday. You’re not open on Sunday. Do you give it intravenous? Do you give it IM? Do you subQ? So there are these little details that is not necessarily straightforward. And I think the community’s developed a kind of — when I see people at academic centers — a slightly different I don’t say “standard of care” but paradigm in these elderly people. And they’re elderly, I mean 70, 75, 80. Driving becomes an issue. And how you give it. So I don’t think it’s exactly that straightforward. DR LOVE: Why don’t we continue on with the case. DR BRENNER: So he stayed on therapy for 47 cycles. But with each month he tried to talk me into giving him less therapy because it was a 40-minute drive for him. And he ultimately went onto a 3-day-a-week schedule every 6 weeks. That was the most he would agree to do. And then around the summer of 2015, he started developing neutropenia again, although again, he was asymptomatic. DR LOVE: Can I just ask, Harry, would you have acquiesced to this 3-day-a-week thing or just say, “Why don’t we just stop treatment?” DR ERBA: I wouldn’t have stopped treatment. I would have — and I’m sure you probably did this: I would have tried as hard as I could to keep him from making that decision. DR LOVE: He would have taken it orally, I’m sure, right? DR BRENNER: Right. I mean, we did speak that oral azacitidine is under development. But that probably would have been something he would have been willing to do. It was a traveling issue for him. DR LOVE: Is that where you think we’re heading in the future, Guillermo? DR GARCIA-MANERO: I hope so. There are 2 oral hypomethylating agents. One is very advanced. CC-486 is the oral azacitidine. And there are 2 or 3 Phase III trials. Actually, there’s one trial, actually a maintenance AML trial. So your patient would not really qualify. And there is a front-line, low-risk MDS study, and there’s some study post-transplant. So there’s another compound, talking about decitabine, that is a combination of oral decitabine with an oral cytidine deaminase inhibitor. This enzyme is the catabolizer of decitabine. And data presented at ASH this year shows that this oral decitabine combo is achieving PK and PD levels similar to decitabine. So I think that these two, aza and decitabine, at some point in the next few years they are going to be oral approaches for sure. DR ERBA: Sure. It’s a real issue, but let’s remember, when the CALBG study was done of azacitidine versus supportive care. Patients were allowed to take the azacitidine, mix up a slurry and inject it. I think that’s why they only saw one third of patients having injection site reactions because they saw them like a month later and it wasn’t there. Because everyone I see gets an injection site reaction or just about. So that would be another option. DR LOVE: Would that have been an option? Could you get visiting nurses to do that? DR ERBA: No. No. Another option in a different universe. DR LOVE: Right. DR BRENNER: In France. DR ERBA: So in different practice. Yes. So the other option would have been to try to give the patient subcutaneous azacitidine, preferably at home, but it doesn’t get reimbursed. So there are issues with that. The important point here, though, for people listening, you gave 4 cycles to see a response. You didn’t stop after one. And it sounds like he did pretty well for those 4 cycles. But I would go to the point of saying, even if the patient has an infectious complication, seems to be needing more transfusions, if you decide to do this, you need to push ahead. And I always tell my patients on day 1 that this is an investment of 4 to 6 months before we abandon it, unless there’s clear progression. And then the other thing you did is, you kept this man on for 4 years getting therapy. So you did a great job. There is data, however, that as you cut back on the number of doses and you start to lengthen out the time between cycles, that the effects on hypomethylation changed. So some of the tricks I’ve used, I’ve repeated the marrow. And you don’t necessarily have to repeat a marrow. Because, as we said, this patient had a hematologic response, so it’s kind of cool he had a cytogenetic remission. And if he’s in a clinical trial, I definitely want to know that, but this 88-year-old man didn’t necessarily need to know that. So I have that kind of discussion with my patient. But if a patient was thinking about coming off treatment, that’s when I definitely do a marrow. And I do FISH or some molecular study to find molecular evidence of the disease and I can say, “This is showing you what I know. The disease is still there. And by the way, when this doesn’t work anymore, which we're going to get to, I have no idea what to do. And your prognosis is grim.” And so when people start to say, “I want to stop,” I say this is the only thing I know how to do. DR LOVE: We, as a CME group, are always trying to go out and figure out what people are doing in practice. And I have heard this comment, the question of whether people give up on hypomethylating agents too soon. You say your practice is all referral. Do you think that there are people out there who are maybe stopping or kind of giving up on it? DR GARCIA-MANERO: Yes and no. And you may not like this comment, actually. And I will be interested to see what you think — how long it takes in the community for information actually sometimes to become like a standard practice. Because when we started using these drugs, I bet you that the median exposure will be 1 cycle. DR LOVE: Really? DR GARCIA-MANERO: Oh yes. Sometimes even 1 dose. I can tell you the first 2 cases I referred out to community, they got 1 dose. Came back. Actually, because of the issue of a skin toxicity. So now we're in a situation where I think people understand that you have to push it 4, 6, 8 cycles. But it has taken a decade. That’s what is amazing. So this message that sounds very simple, it took probably hundreds of lectures by hundreds of doctors, and it has taken probably over a decade. And if sometimes I’m asked to go to some place outside the US to talk about this, the question comes. Now, in other countries the issue is about the cost and things like this. But there’s this thing that this still is very important and it has taken a long time. Sometimes these educational tools are not as effective as we think because it took a long time. DR LOVE: Just before Erik comments, I’m just kind of curious. Are there specific clinical situations, Harry, because I’m sure not everybody is kind of on board, that are particularly prone to people “stopping early”? DR ERBA: I mean, and the patient has complications. I mean, that’s usually the biggest issue. They usually can buy on to the fact that they’re going to have to come in for these treatments, and we discuss how that’s going to happen. Will they come and live close to the center with their daughter or something like that? But it’s the complications and feeling worse before they get better. That’s the biggest issue up front. DR RUPARD: Yes. Part of the problem there is sometimes they feel worse and they never get better. And I find that these negotiations that, like Warren had with his patient, getting him down to 3 days, for me those are often with the family member who’s bringing the patient in on a daily basis rather than with the patient him or herself. And that’s where it gets really tricky. And I think that’s why in the community — I mean, I see so many of the cases. It seems like I see at least 2 new ones a week, these elderly Caucasian males or females usually with cytopenias and a bone marrow that looks like MDS. And it’s very hard in many cases to push them to that 4 to 6 months of therapy where they’re feeing worse and worse and worse, hoping that you’ll get that pot of gold at the end of the rainbow. DR LOVE: So why don’t we continue on with the case? DR BRENNER: So when he developed recurrent neutropenia in the summer of 2015, I repeated his bone marrow that showed 10% to 12% blasts. He had monosomy 7, a monosomy 17, translocation between 11p and 14q. He had 11p minus. And I also did next-generation sequencing that showed a DMNT3A splice site mutation and an IDH2 mutation. He did go for an academic opinion that I sent him for at that time because his performance status was still good. He was still interested in potentially doing something. And I sent him to an academic center. And there was not a clinical trial available for him, but they recommended that we put him back on full dose azacitidine, a 7-day schedule a month. So I did that for about 2 months and he tolerated it terribly. He just felt much worse. He became anemic, which he had never been anemic before. Became thrombocytopenic. He had quite a severe attack of bronchitis and just felt terrible. DR LOVE: Before you continue on, Harry, what would you be thinking at that point? DR ERBA: There is no standard of care outside a clinical trial for this situation. And going back to full dose or switching to decitabine I’ve never seen work. It usually makes things worse. And so when they lose the response to a hypomethylating agent, going back to it is just going to cause problems. So really a clinical trial would be the best option. DR LOVE: Clinical trial. So just to clarify, before we go on, though, Guillermo, what about the role of NGS in MDS? What do you look for? What targetable mutations exist? And what do you think about what’s seen with this patient? DR GARCIA-MANERO: Okay. So first of all, I agree with Harry, that Warren, this is like a fantastic case. Actually, this is like beautiful practice that you did here. And I think the comments of Erik are also very pertinent. We could spend the whole morning on this case. It’s just really important. There are so many aspects here that we could break this disease. You pointed out some issues that are critical. This issue of the family. Someone that is almost 90. There are geriatric issues. This is not a criticism. I think this is real practice, whether this type of care is palliative or not. There are so many aspects of what we’re trying to do here that they have to be actually on a case by case. I can’t say, “Oh, this big gorilla. No, they should get this.” No. You’re right. The patient may not be interested in driving the 50 miles to your center. But that said, I think, first of all, this is a very illustrative case. So you first gave 4 years of therapy to this patient. And again, I don’t think this is palliative therapy any more. And then the question is, what is the natural history of these patients when they fail these drugs? So the median survival of these patients, once you stop compound, is around 4 to 6 months. But we just wrote a small paper because I was curious about this particular question, that is, what happens when you stop therapy in a patient who has a complete response? And we went back to 2 clinical trials that I did around 5, 6, 7 years ago where we did this. We didn’t know better and stopped decitabine or azacitidine after 24 months. And, actually, we saw that in general. The responses are short — again, 4 to 6 months — and this is our study where we have 50 patients or something like this — there were a couple of outliers, like this gentleman, who had been on therapy for a few years. Actually, those patients, like your case, could be maintained off therapy for close to a year. So it’s not that they’re going to die right away. These are outliers, very specific cases that had very deep responses like your case, that maybe, in this situation, you could foresee a little bit of stabilization of the disease without therapy. Going back to your question. First of all, I agree with Harry. They very, very, very rarely respond to what I call the contralateral agent, or even putting them back. This is something that we’re putting quite a bit of research effort. Why is that they become resistant to re-introduction of the drug? This is not like in lymphoma. You can switch to 1 line too. So this is mystery. Why is this? Somehow the bone marrow adapts to these drugs and they react. I think this is actually a situation where next-gen sequencing may be the future. And it’s already there in this paragraph, if you allow me. So if you ask me, okay, can I give you $5, each test costs $1, what are the tests that you will do today? You would probably do 3, maybe 4 tests. You for sure will ask for IDH1 and IDH2. He actually happens to have an IDH2 mutation. There is no drug approved for this, but there are a lot of clinical trials with very, very powerful oral, very well-tolerated compounds, that I think are going to have a really important role in MDS and in AML. And for him, actually you may want to look for a center that has a study with this compound because this could be transformative. I mean, this compound may expand his survival significantly if you can get him on a trial. So IDH1, IDH2, very important. There is a little bit of a trick, also. That is, FLT3 mutations are rare in MDS. On paper, you should never check FLT3 mutations on a baseline diagnosis. But at the time of failure, around 20% of the patients will acquire an FLT3 mutation. This IDH2 mutation was probably present at baseline. You didn’t check. It was fine because they’re usually like an initial mutation. But in a fraction of patients, at the time of HMA failure, there’s an acquisition of FLT3. Now, someone may be seeing me, he says, “How do you know that there was not a various small clone that you couldn’t detect by these techniques and now is emerging?” Whatever it is, a fraction of these people may now have FLT3-mutated disease. They tend to have a little bit of a high white count. They tend to be the more proliferative. They do extremely well with FLT3 inhibitors, actually in combination with azacitidine. So for instance, off protocol, things that we’ve published, sorafenib plus aza may rescue some patients like this. And, of course, if you have access to a clinical trial with one of the new FLT3 inhibitors, that would be very pertinent. DR LOVE: I think maybe midostaurin is going to become available. DR GARCIA-MANERO: It has not really been tested in MDS. I was thinking about dropping this. But the reality is that IDH1, IDH2, FLT3 — and some of these patients may also acquire mutation in the Ras genes. The inhibitors we have are not so supereffective, but it may be that there is a clinical trial option targeting Ras. But he has an IDH2 mutation, so you need to think about this. So I think next-gen sequencing is going to be important for this group of patients. DR LOVE: Warren, can you kind of bring us up to date? DR BRENNER: So I stopped his therapy in October. He’s been off treatment since then with normalization of his prior neutropenia, normalization of his anemia. And he basically feels fine. DR LOVE: So Harry, would you like to explain what’s going on? DR ERBA: So let me go back to explaining why he responded or why we think he might have responded, and the next-gen panel showed 2 mutations, a DNA methyltransferase 3A mutation, IDH2. That, with TET2, are the 3 — and IDH1 — are the 3 or 4 genes that are often mutated as part of epigenetic modulation. They affect DNA methylation. There have been a number of studies now, including I think the latest one published by Bejar in Blood and colleagues, showing that there was an association between having TET2 mutations, which this patient didn’t have, and response to hypomethylating agents. And then data from Cleveland Clinic showing mutations and DNA methyltransferase 3A, IHD1 and 2 and TET2 being associated with response to hypomethylating agents. I agree that if this patient were symptomatic, I would consider a trial with an IDH2 inhibitor. The question, obviously, is, why has he responded? And he’s clearly responded again. And again, I am willing to be wrong in this individual situation – maybe the academic center got it right. You gave him 2 cycles of induction. And it would be interesting to see what his marrow looked like now if those cytogenetic changes have gone away. Because if that’s true, wouldn’t that argue that we should put him back on azacitidine as maintenance now, or would we say, he’s had his response, let’s see if he can go another year or so? I think it’s probably going to be really hard to convince this man who wanted to stop therapy anyways and then got really sick after 2 cycles to go back on treatment. But I think I would wonder very strongly, just like I’m learning for myself, what the marrow showed. So I’d probably try to repeat that. Because otherwise, I don’t know why he’s responded like this. DR LOVE: Neil, any thoughts or comments about this case? DR MORGANSTEIN: Yes. I mean, this is an incredibly common situation that we deal with, people who do relatively well, and there’s other cases with azacitidine and eventually they progress through it, some of them much sicker. And then, what do you? And even sending people where we have a quite a number of academic institutions, the re-treatment with azacitidine or decitabine, I hate to say it, is often a nontrial answer, even though it’s probably not the right thing to do. I’ve done it. And I agree, it doesn’t work. DR GARCIA-MANERO: Can I make a comment, Neil? I totally agree with Harry. Yes, he needs a bone marrow. Because there is another educational issue here that is very important. That is, that’s why this case is so amazing, is that now this patient has acquired 3 other cytogenetic changes, 11;14 and so forth. So this is called clonal evolution. And this is actually being recognized in MDS as a problem to transformation to acute myelogenous leukemia. And when this happens, actually these patients may go on to transform around 6 to 8 months after. I totally agree with Harry. You should remarrow him. And if he had responded to the therapy, you really need to discuss this with this gentleman because otherwise he is destined to transform to AML, I bet you in the next 3 to 4 months if he stopped in October. And if he’s responding, it will be a shame because maybe — and again, Erik is not going to like this, but you may bargain with him some type of low-dose type of approach maintenance. If not, if he still has 10% to 12% blasts, talk to him. He’s 88 now, but maybe someone around here has IDH2-mutated type of drawback. Harry’s right, there. And again, it’s not that nobody responds. You may occasionally see someone who has this type of behavior. But that would be very important. But again, this issue of clonal evolution in MDS, not trivial. DR LOVE: Warren, what do you think about this feedback? DR BRENNER: I think it’s very helpful. I wasn’t planning on remarrowing him, but based on the fact that the information would be useful in making management decisions, I think he may be prepared to do it, although you’ll probably need a little bit of convincing. But I think he understands his disease, and understanding that we have different options for him, depending on what the bone marrow shows, I think would be helpful rather than “let’s just see what’s going on with bone marrow” I think, from a management perspective. The other thing I just read somewhere and I was hoping I could comment was I’d read somewhere that there’s an association between p53 deletions, which he has, and response to steroids. Is that correct? Have you heard of that? DR ERBA: Yes. In fact, I think List has to do with the innate immunity issue, and I am not an expert in this field. Allen List does a beautiful job explaining this. But there are trials specifically in p53-deleted patients and looking at steroids and other immune modulators. So is it possible that with the azacitidine, got some dexamethasone as a premed or something, and maybe that’s why he’s responded? It does allow me to comment back to the monosomy 17, which suggests that he, therefore, only has one normal p53 gene. It’s either deleted from the other 17, or the next-gen sequencing missed a mutation in it. That’s what didn’t quite make sense about the next-gen sequencing. Did it miss the p53 mutation? But in any case, I’ve heard about that. I’m not sure I would put him on steroids just for that at this point. |