Frontline Treatment Options for Patients with AML

EP: 1.Overview of Acute Myeloid Leukemia (AML)

EP: 2.Diagnosis and Cytogenetic Testing in AML

EP: 3.The Goals of Treatment in AML

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EP: 4.Frontline Treatment Options for Patients with AML

EP: 5.Intensive Induction Therapy In AML

EP: 6.Treatment Options for Secondary AML

EP: 7.Treatment Options for AML Patients with IDH2, RUNX1, or DNMT3A Mutations

EP: 8.Treatment of Patients Unfit for Intensive Induction with Venetoclax + Azacitidine

EP: 9.Case Presentation: An 81-Year-Old Male with AML

EP: 10.Management of Cytopenia in Patients on Venetoclax + Azacitidine Therapy

EP: 11.The Importance of Bone Marrow Biopsies in AML Patients on Venetoclax Treatment

EP: 12.Unmet Needs and the Future of AML Treatment

Hetty Carraway, MD: I’m going to pivot to you, Dr Stein, and have you talk about the frontline treatment options for patients with AML [acute myeloid leukemia], and launch into a more robust discussion about how treatment differs between those that are younger than 60 years vs older than 60 years.

Eytan Stein, MD: It’s a good question. The younger than 60 years or older than 60 years comes from the NCCN [National Comprehensive Cancer Network] guidelines, which still stratify patients into those who are younger than or older than 60 years …about whether a patient should receive intensive induction chemotherapy or go with a lower intensity therapy. The NCCN needs to get away from this 60-year-old cutoff because it creates a lot of confusion and is a bit of a historical artifact. A recent iteration of the NCCN guidelines changed it from a strict age cutoff of 60 years old to something along the lines of biologically younger than or older than 60 years old. If you’re a 70-year-old who runs marathons, you fall into the biologically younger than 60 category. But this age dichotomy creates a lot of confusion.

The way I think about whether a patient is a candidate for intensive induction chemotherapy—which is where I’m going to restrict my comments to right now—has to do with the health status of the patient and the biological fitness of the leukemia. What do I mean by that? The health status of the patient is relatively easy to define in the sense that someone who has many comorbid medical conditions probably isn’t a great candidate for intensive induction chemotherapy. If they come into your office in a wheelchair and can’t get on the examination table, even if they’re 55 years old, they might not be the best candidate for intensive induction chemotherapy.

Similarly, if you have a patient who’s 71 years old but is spry and running marathons, maybe that patient is a good candidate for intensive induction chemotherapy. When you layer biological fitness on top of that, what the patient should receive becomes much clearer. [I define] biological fitness as given a particular patient’s cytogenetic and molecular genetic abnormalities, whether they’ve got favorable, intermediate, or unfavorable-risk disease, what are the chances that patient is going to respond to intensive induction chemotherapy? A couple of examples would be illustrative. For example, if you have a 63-year-old patient who has a very complex karyotype therapy-related acute myeloid leukemia with multiple TP53 mutations, that patient might not do well with an intensive induction chemotherapy approach. The remission rates are probably in the 10% to 20% range. You might want to think about doing something different from intensive induction in that patient.

Similarly, I just saw a patient in the clinic 3 weeks ago: a 74-year-old with therapy-related acute myeloid leukemia with an inversion 16. This patient had therapy-related AML where the therapy causes an inversion 16. She falls into the favorable-risk category. Because of that, I chose to give her intensive induction chemotherapy despite her being significantly older than 60 because I think that she’s curable with intensive induction chemotherapy.

When you think about the intensive induction chemotherapy approaches, I think about it as follows. The backbone that we’ve been using in most of the world for 40 years is 7+3: 7 days of cytarabine and 3 days of an anthracycline, such as daunorubicin or idarubicin. We now have therapies that we can add on to that backbone. For example, if you have a FLT3 mutation and you’re a candidate to get intensive induction, the standard of care is to get 7+3 with midostaurin.

There was a recent clinical trial called QuANTUM-First [NCT02668653] that was presented at EHA [European Hematology Association Congress] a few weeks ago showing that the combination of a second-generation FLT3 inhibitor called quizartinib with intensive induction chemotherapy is better than intensive induction chemotherapy alone. For your FLT3-mutated patients, the standard of care is intensive induction with a FLT3 inhibitor, whether it’s midostaurin or quizartinib if it ends up getting approved.

For many patients with favorable-risk acute myeloid leukemia, many centers will incorporate the use of the antibody-drug conjugate gemtuzumab ozogamicin, which is an anti-CD33 antibody-drug conjugate given in combination with intensive induction chemotherapy. Again, it’s this 7+3 backbone adding on the antibody-drug conjugate gemtuzumab ozogamicin for favorable-risk acute myeloid leukemia.

Finally, we have something that Dr Carraway is going to talk about in a couple of minutes: the use of a liposomal formulation of 7+3 called CPX-351 in patients with secondary or therapy-related acute myeloid leukemia. The important message is that when Dr Carraway and I got into this field, how you treated AML was much simpler. We didn’t have many options; there were one or two options. Now it has become somewhat more complicated because we have targeted molecular therapy and antibody-drug therapy that’s used in combination with intensive induction, so you need to know the specific kind of AML the patient is dealing with before you embark on a treatment regimen.

Transcript edited for clarity.