Meet The Professors: Myelodysplastic Syndromes Edition, 2016Case discussion: A 62-year-old man with 20q minus MDS (Dr Brenner)
12:32 minutes.
TRANSCRIPTION:
DR BRENNER: So this is a 62-year-old male. He was still working when he was initially diagnosed in 2012 with some fatigue and had some blood work done by his primary care physician. Was found to have mild leukopenia. His white count was about 3, and he had a hemoglobin in the mid-9 range. He underwent a bone marrow that was consistent with myelodysplastic syndrome. No excess blasts. And he had a 20q minus. At that time, he was treated with erythropoietin and had some improvement. He didn’t require any transfusions. His hemoglobin was roughly in the 10 range. But then in the summer of 2015, he developed progressive cytopenias with all 3 lineages. And repeat bone marrow showed refractory anemia with excess blasts, 9% to 12%. He still had the 20q minus. I don’t recollect having any other additional cytogenetic abnormalities. And at that time he was started on azacitidine, which he tolerated reasonably well. He did require some increased transfusions in the beginning. But in December of 2015, repeat bone showed blast count down to 2%, minimal transfusion requirements. And the question is the role for transplant in the patient like this. DR ERBA: So first of all, going back to 2012, should he have been considered for transplant then? He had intermediate-1-risk disease and only anemia. He wasn’t having neutropenic infections or thrombocytopenic bleeding. So at least retrospective data analysis suggests that life expectancy actually is superior with any supportive care other than allogeneic transplant. And so I would have agreed with preparing the patient for the future but using erythropoietic stimulating agents in that situation. So now he’s got progression. I’m not sure about cytogenetics at this point, whether there was any clonal evolution, but started on azacitidine and has a response. So it brings up 2 questions. Number 1, in July of 2015, with progressive cytopenias and a bone marrow blast presence of 9% to 12%, let’s say you had typed him and he has a sibling donor who’s 49 years old and runs marathons, should we have sent him directly to transplant? And it’s really hard to do that logistically. But the question that always comes up is, should there be some cytoreduction? I often find that the transplanters will say, “Give him 3&7, get the blast count down and then we’ll do a transplant,” which I really don’t like doing in this situation. I don’t like doing it for a couple of reasons. Yes, you can get cytoreduction at the cost of significant complications. And if that patient doesn’t respond to 3&7 or has significant complications in terms of performance or nutritional status or organ function, the transplanter never sees the patient back and that patient is never considered in the statistical analysis that goes into outcomes of transplant. So one of the problems we have with transplant outcomes in MDS is the population that’s actually included in those studies. I’m going to finish my comments with that. And so what I typically do is exactly what you did. Even if I thought in July of 2015 that I want this patient to strongly consider allotransplant as his best long-term curative option, I would have started with azacitidine because I know that can improve survival, number 1. The second is, just because you meet a transplanter doesn’t mean you’re going to get a transplant. You might run away, screaming, “No way.” You might not have a donor. You might not have insurance coverage. You might not have a caregiver in your home to take care of you. I mean, all of these things are important issues that you might not be able to figure out on day 1. And then the third is, if the transplanter does want some cytoreduction, at least you’ve attempted that with the azacitidine. So now you have him in a response with minimal transfusion requirements. And the question is, what to do at this point? I would offer allogeneic transplant to this patient. I think we can guess what the outcome pretty well of azacitidine is going to be. Although there’s a survival benefit, let’s not forget the tail on those curves come together with the conventional care regimen at a very dismal low level after 2 or 3 years. So if he’s otherwise healthy and has a donor and has a caregiver and has insurance and all of those things line up, I would consider allotransplant. Let me finish by saying that the Bone Marrow Transplant Clinical Trials Network, BMTCTN, is a doing a very important protocol that patients like this should be considered for. They’re going to be comparing the outcomes of patients who continue on a hypomethylating agent — and this patient, actually, could start a hypomethylating agent, be referred to a transplant center and then considered for transplant. And if they get a transplant, then they’re considered on the transplant arm. So it’s a complicated design that I won’t go into the details of, but at least it’s some attempt to see what is the relative outcome of patients who continue on a hypomethylating agent or whatever conventional care regimen or go on to an allotransplant. I will say that this study has basically been mandated by CMS. CMS has threatened no longer to cover allotransplants for Medicare recipients — so he’s a little young for that, but getting there — unless there's a study at least being done. And so the BMTCTN has taken on this role, is doing the study. It’s accruing now nationally, to try to answer this question. And CMS is going to continue to fund it until the outcome. So yes, I would refer this patient for allotransplant. But if he decides not to go through with it, I know I’ve started him on the agent and I would continue him on the agent that I think has his best interest at heart. DR LOVE: So Guillermo, again, transplant? DR GARCIA-MANERO: I agree. But there’s some degree of sophistication here that goes, and these actually may sometimes not be realized by the transplanters. And I say that with all respect. So first of all, a 60-year-old gentleman now, he’s a young person for MDS. So this is almost pediatric MDS for me, Harry. I don’t know what you think about this. So yes, you need to go for cure. And now you have this patient, a very good response. So Harry gave you, like, the big picture in terms of transplant overall. But let’s say I’m seeing this gentleman in this consult. You already gave him the therapy. So I agree totally with Harry. He’s 60. Apparently has no comorbidities. But I think there are a couple of things that you need to — and I say that with respect — sometimes educate the bone marrow transplant physician, because they may or may not fully understand MDS, per se, and I say that with respect. So this is actually where, for instance, it will be important to have some next-gen sequencing type of data. This patient has a 20q minus, so he had good features. Now has both. It is possible that he acquired either a cytogenetic change or a molecular change. So the group from Boston published last year what I think is a very important Paper. It needs to be better vetted, but our data is identical and I think the data from Memorial are identical. That, for instance, you have a p53 mutation. Outcomes with transplant very poor. If you have DNMT3A mutation, outcome with transplant poor. So if you have some type of genomic lesion, some of them may actually predict for poor outcomes with a transplant. And I want to explain that in a second. At ASH this year, actually there was additional data from Europe with the same. For instance, if he had one of these cases that had clonal evolution and now you’re taking him with what I call active cytogenetic response, where yes, he’s responding well but he had now 7 or a 17 or something like this, outcomes with transplant are not optimal. So I would take him to transplant. And the transplanter is going to do this. You’re going to look at him before he goes to transplant, because, for instance — and this will be in the context of some type of clinical trial, if you have a p53 mutation — and actually, I deal in my practice with this problem all the time. It’s not that you are not going to take him. If you look at the graph in this JCO paper, it’s actually prognosis is poor. But now you have someone who has done very well, he’s 62, has a donor, has day caretaker, you’re going to take the patient to transplant. The question is, can you do something to ameliorate or prevent relapse post-transplant? That is what kills these people post-transplant. So there are a number of clinical trials looking at maintenance therapy. For sure, post-transplant, you’re going to look at them in a different fashion. So there are some tricks here. And then the other thing that I think is very, very critical is the type of donor. And I see lately that there is an angle from the bone marrow transplant doctors to use very aggressive alternative sources of donors where sometimes do we want to do a haploidentical transplant when the patient has a sibling donor? And that may be very interesting research for transplanters, and I totally respect that, but in MDS most of these creative data with transplant comes from related, fully-matched donors. And to extrapolate that the haploidentical transplant is the same just because in some trial they did that is not in the context of MDS. So in summary, you should take the patient to transplant. You should be curious as the referring physician in terms of what donor are they going to use. And second, it would be prudent to kind of restage his disease at the cytogenetic and molecular level. To, in away, predict what is the risk of relapse. This may be very important to the patient and you. Because let’s say the donor is not optimal, and now they say, “We have to do an 8 out of 10 or go to some haploid.” And let’s say, God forbid, that he now has a p53 mutation, you know that he may opt not to go from transplant because you said, “I’m going to take high-risk transplant option and I have genomic mutation that puts me at high risk of relapse, why will I do that when I can maybe survive some time with a hypomethylating agent?” So this is the strategy where you require a little bit of expertise. Donor, expertise of the center and also some genomic annotations here to say, what are my odds post-transplant? You need to put all these together. DR LOVE: Could I just ask, you said there are trials looking at post-transplant maintenance. With what kind of agents? DR GARCIA-MANERO: Hypomethylating agents. This was actually also tested with lenalidomide but actually the data was, my understanding, negative. Actually, they didn’t do well in the post-transplant setting. There is data that is very intriguing. It started with a small trial that Marcos de Lima and I did many years ago. We actually were naïve. We sent this to New England Journal, thinking, “Oh…” and it ended in some small journal. It was difficult to publish. It was some resistance for this. But Marcos, who’s now in Case Western in Cleveland, designed with a really good statistician, very innovative guy we had at MD Anderson, Phase I trial — it’s called the F-Tox Model, where you can actually measure both toxicity and activity. And they put in this trial people who had 100% rate of relapse post-transplant. Okay? Apparently there’s some population where the transplanters know this. And the data suggests that first, you were safe, so you don’t lose the graft, et cetera, and second, the projection of survivals was positive. They were significantly higher than expected. So there are 2 studies that I’m aware of, probably more — there’s a randomized trial at MD Anderson and maybe a similar center randomizing between aza/no aza in this context. And I think 1 arm, oral aza trial in the post-transplant concept. I can tell you that this is becoming very popular in the transplant community, without, actually, a lot of hardcore data. But they tend to do this. So if you take patients with “active” disease, like now the blasts are 7% and you tried the best you could, or they have lesions like this, et cetera, they’d probably come back and try to do some type of manipulation post-transplant. |