Acute Myeloid Leukemia - Episode 13

Case 4: High-Risk de novo AML

June 19, 2019


Naval G. Daver, MD:For our fourth case, we’re going to be discussing a high-risk de novo elderly acute myeloid leukemia [AML] patient. I’ll be discussing this case, and then we’ll open the discussion to the panel after that. This is a 75-year-old [woman] with no history of prior hematological disorder or abnormal blood counts, who comes to the emergency department with new-onset epistaxis. She also has been having bruising for the last couple of weeks, has no significant past medical history and overall, no major comorbidities or organ dysfunction, and she has a white count of 44,000 with platelets at 132. She does have a bone marrow done the same day in the emergency [department], and it shows 55% blasts and confirmation of acute myeloid leukemia with no evidence of background dysplasia or fibrosis. Molecular testing showsFLT3wild-type withNPM1mutated. She does have, overall, borderline PS [performance status]. Let’s say she uses a walker, but otherwise, no major comorbidities to speak of.

I’ll ask Dr Weinberg here, if such a patient came to your institution, what would be the tests that you would be rushing? It’s a 75-year-old. Are there particular molecular genes that people are looking for, or would they say, “No, it doesn’t really matter at this age?”

Olga K. Weinberg, MD:Well, you’d probably want to rush the cytogenetics, and make sure there’s no complex karyotype or other MRC [myelodysplasia-related changes]. Then we would always do an NGS [next-generation sequencing] panel on all our acute myeloid leukemia patients. It would probably be interesting to see if she hasTP53mutation or a more favorable mutation likeNPM1. That would be what we would do.

Naval G. Daver, MD:She hasNPM1mutation, let’s say. How often would you see aTP53orRUNX1withNPM1? Does it happen ever? Is it very rare, or do you see it routinely?

Olga K. Weinberg, MD:Actually, we do see it. I would say it’s pretty rare, maybe 5% or 10% of the timeNPM1is co-mutated with secondary types of mutations. Those patients usually tend to have cytogenetic abnormalities, too, but it can be that they have a normal karyotype. They probably will not have as good of a prognosis as a typicalNPM1-mutated AML, but it happens.

Naval G. Daver, MD:Dr Rizzieri, what would be your treatment choices and what would you choose in this 75-year-old with no MRC and, let’s say, PS borderline?

David Alan Rizzieri, MD:As you were talking, I was trying to wonder if we had time to get the cytogenetics back to see if there were complex cytogenetics, because we might think of Mylotarg at the current reduced dosing schedule in this type of patient. Though I don’t know if we have time to get that back.

Naval G. Daver, MD:If they didn’t have complex cytogenetic testing?

David Alan Rizzieri, MD:Well, in the good-risk patients, I’m not sure Mylotarg really helped them very much. But in this case, if we get them back and she’s not high risk by complex genetics, maybe this is a case where we could apply Mylotarg in a safe setting. Short of that, I think it’s a great case for, once again, the combination targeted therapies that we’ve already been talking about.

Naval G. Daver, MD:I guess you would have HMA/VEN [hypomethylating agent/venetoclax], low-dose Ara-C/[cytarabine], and then the other one that we almost never talk about at a lot of these meetings, but is approved, low-dose Ara-C/glasdegib. Has anybody here used that combination? Is there a particular group or subpopulation that you would think about it? James? Usama?

James K. McCloskey II, MD:We have used that drug. Again, we had that clinical trial, also. I think that what’s interesting about that data—and you’re right, it got overwhelmed by this wave of venetoclax—but if you look at that data, that was actually a randomized phase II study that did show improved overall survival. That’s hard to argue against, in a way, but I think one of the things that study allowed was definitely a less fit patient population. While venetoclax and HMA really did focus on these patients unfit for induction chemotherapy, the glasdegib trial let on patients who might not be fit for HMA therapy by some community standard, including patients with borderline to impaired renal function or impaired cardiac function.

I think what we got out of the glasdegib trial was not this beautiful remission, but we got these durable responses—patients with stable disease for longer periods of times, improved transfusion requirements—that I think are really valuable to that specific group of patients with other comorbidities. It is appealing because it could be given at home, as you mentioned about your patients. Low-dose Ara-C [cytarabine], while it’s not something we all embrace every day, and there might be some hurdles we jump through to get it compounded, can be injected at home, and glasdegib can be administered at home. I think that is appealing, but I will agree that it’s not something we turn to every day, and venetoclax and HMA has been our standard go-to for less fit patients.

Transcript edited for clarity.