DR FEINSTEIN: This is a 71-year-old gentleman who presented to his primary care physician for routine follow-up, was asymptomatic at the time. He had routine bloodwork, which included a CBC, which demonstrated a white blood cell count of 1.78 x 10³/mcL with a hemoglobin of 10.9 g/dL and a platelet count of 14,000/mcL. He was referred to the emergency room. He underwent bone marrow biopsy, which confirmed acute myeloid leukemia with 50% blasts. He was quite fit, had no significant past medical history.

He began induction chemotherapy with cytarabine and idarubicin. His karyotype returned back as being normal. His AML FISH panel was negative. He was NPM1-positive, CEBPA, FLT3 and c-KIT-negative. His induction chemotherapy was complicated by E coli bacteremia, which he tolerated extraordinarily well. His day-14 bone marrow demonstrated therapeutic aplasia, and now we’re awaiting recovery of his counts.

DR LOVE: So Rich, any thoughts?

DR STONE: I think that he has about as favorable a risk disease as you can get when you’re 71. So I think 3 + 7 was reasonable. And the issue is whether he should be consolidated with an allogeneic stem cell transplant with reduced-intensity conditioning.

There, if you look at a paper” published a few years ago looking at this type of patient, people who were between 60 and 70 and even people between 70 and 80 did well with nontransplant-based chemotherapy. I would at least discuss that with the patient and give him the option, if he has a good unrelated matched donor, because probably he has no young siblings. I would offer him that as a consolidation, but I think chemotherapy based with modified high-dose ara-C offers a pretty good chance for cure in a 70-year-old guy with a genetic abnormality.

DR LOVE: Anything else about this case you want to get some feedback on?

DR FEINSTEIN: I guess 1 question I would have is — and I know that this is a moving target right now, the issue of minimal residual disease. And if he opts not to proceed forward with a nonmyeloablative allogeneic transplant, how frequently would you marrow him? Would you observe him for minimal residual disease, at which point that would push your hand more toward an allogeneic transplant?

DR STONE: I think it’s an interesting point. We don’t know. MRD in AML is not standardized, nor is it standard yet. So to answer that question is difficult. I would get a multiparameter flow panel at end of induction when he’s in remission. And in Europe, they would also do PCR or NPM1. The value of that right now is not clear, although Europeans would use that, at least in younger patients, to decide what to do further.

Curiously, if you have MRD going into a transplant, you do worse. So if you’re duty bound to transplant somebody, it’s the ones that are MRD-negative who do better. So you might argue, “If he’s got MRD positivity after induction, he should get more therapy before he gets a transplant.” That’s kind of the way we look at ALL right now, right? If they’re MRD-positive, they do really poorly with a transplant. We might give them blinatumomab or some other agent to clean up the MRD and maybe make them a better transplant candidate. So it’s totally a moving target. I tend not to do too many bone marrows in people after they’re in remission. I go by the counts.

DR CORTES: Yes, it’s a fascinating story, a moving target these things on the MRD, as Rich mentioned, because the patients that do not have minimal residual disease detectable, their probability of relapse, and particularly in a patient with this low risk, is very low with chemotherapy alone. For the patients that have minimal residual disease detectable after induction, at the time of remission and certainly at 3 months, they have a much higher risk of relapse.

The emerging data with transplant also shows that the patients with less or with no minimal residual disease have the best outcome. But the problem now is that we really need something for the patients that have minimal residual disease. That’s the one that you instinctively think, “That’s the one I want to transplant.” And we now sometimes are having a bit of a struggle with “our” transplant. Doctors say, “We need less disease.” The only way I can get them to less disease right now is more chemotherapy, and that comes with complications and risks, et cetera, and not always benefit. I mean, it doesn’t get rid of it. We don’t have a blinatumomab in AML today.

So what do you do? And then what happens if the patient relapses, because sure, it can improve, but in the meantime, it could also relapse. What do you do in that setting? And like I joke with my transplant colleagues, “So if this patient relapses while I’m trying to get to the minimal residual disease-negative status that you want, does that count on your denominator or my denominator or both?” And there’s no answer to that.

So I think that these patients with minimal residual disease are a real problem, because even transplant — I still think that that’s the best you can do for such a patient. But even transplant is not able to do as well on those patients as it does when they have — so the patients that have more sensitive disease have better treatment options. We know that. What about the patients that don’t have that sensitive disease? What do we do with those patients?

And I think that perhaps the monoclonal antibodies, because we have experience with blinatumomab, we are hoping that we can extrapolate that to some of the monoclonal antibodies that are coming in AML and that that’s going to be the way to approach these patients, or, if you have targeted strategies like an FLT3 patient, an FLT3 inhibitor, et cetera, that when you get to those kind of approaches, that can overcome what chemotherapy and transplant, the way we do it today, cannot do.

DR JOHL: Is there any data to show that patients with minimal residual disease, they will relapse for sure? I mean, do we have any data that MRD positivity leads to relapse in most of these patients?

DR CORTES: It’s not 100%. So that’s a very fascinating question, because it’s neither the ones with minimal residual disease undetectable are 100% cured, nor are the ones with detectable minimal residual disease are 100% relapse. So that is a very strong predictive factor, but there’s something else that determines who we think in that group is going to relapse and who is not. What is it? And we don’t understand that.

Because of the experience of the blinatumomab, which essentially what it does is bring the T-cells toward the leukemia cells and eliminate, you could think that perhaps immune recognition has something to do with that, and if you enhance it, it gets better. Right now we’re analyzing that in our patients with minimal residual disease and doing an extensive panel of immune markers, et cetera. But today, we don’t understand what else. It’s the presence of the minimal residual disease, but we don’t know what else determines within that group, both the good and the bad, which one will relapse and which one will not. But it’s not 100%.

Module 1: Current and future approaches to targeted therapy for acute myeloid leukemia (AML)

Module 2: Other clinical issues in AML management

Module 3: Case discussions