The Era of Targeted Therapy for Acute Myeloid Leukemia - Episode 5
Harry Erba, MD, PhD: This leads to the next discussion. In 2017, we’ve seen something that we haven’t seen since 2000—2000 is when gemtuzumab ozogamicin was given accelerated approval. That was the last time a drug was approved by the FDA for AML until this year. And now, we have 4 drug approvals. Let’s talk about those, because I want to spend the next section talking about drugs that are now commercially available for our patients with acute myeloid leukemia and how we’re going to fit them in. We need to discuss the data, and then discuss how we are utilizing these drugs.
I’d like to think about these 4 drugs in the following way: They’re all targeted, but they’re targeted in different ways. CPX-351, as the investigators called it, is the liposomal daunorubicin/cytarabine formulation. That’s targeted to a clinically defined group of patients, those with treatment-related AML and AML with myelodysplasia-related changes. And then, there are 2 drugs that are targeted to mutations. Those are midostaurin, for patients with previously untreated AML with FLT3-ITD or FLT3-TKD mutations, and enasidenib, which is the oral IDH2 inhibitor, approved for IDH2-mutated AML in relapsed or refractory disease, so not up front. And then, finally, we have a different kind of targeted therapy, an antibody drug conjugate against CD33, gemtuzumab ozogamicin. It is back.
Eunice Wang, MD: And it’s for everybody.
Harry Erba, MD, PhD: And it’s for everyone—pediatrics, adults, up front, with chemotherapy, relapsed/refractory, and the unfit. Now we have to set this into perspective. A quick update about CPX-351: This is the liposomal formulation. I don’t believe it’s just a fancier and more expensive way of giving those 2 drugs. There’s something about the biology of giving daunorubicin/cytarabine in a fixed 1-to-5 molar ratio that actually may make this combination synergistic, and the liposomal formulation allows you to deliver that. It appears to deliver it a little bit more selectively to the marrow and to the leukemic cell if you believe the preclinical models that have been generated. So, it’s based on preclinical development. There was a randomized phase II study in older patients with AML that compared CPX-351 to 7 and 3 chemotherapy, and we saw a benefit only in the subset of patients with secondary AML. And that is what was the genesis of the large phase II trial.
Eunice Wang, MD: How did they define secondary AML?
Harry Erba, MD, PhD: Clinically, and you’re exactly right. We’re going to discuss that very point as we go along. It was defined clinically, and the phase III study was for patients between 60 and 75 years old who had AML that was previously untreated. It was treatment-related AML. It was AML with an antecedent hematologic disorder, whether they received a hypomethylating agent or not. It was for a patient with CMML (chronic myelomonocytic leukemia), not just MDS. It was for patients with apparently de novo AML with cytogenetically defined myelodysplasia-related changes. To your point, Eunice, no, it was not a molecular panel. And I agree with you—we don’t have those molecular data yet.
Alexander E. Perl, MD: We also don’t have the definition that comes from morphology. You’ll get a pathology report that says, “This is AML with myelodysplasia-related changes, based on the way it looks under the microscope.” Those were not the inclusion criteria for the study. So, we don’t know if it benefits those patients. I’m not saying it doesn’t, but that can be subjective.
Eunice Wang, MD: That could be subjective, right?
Alexander E. Perl, MD: That can be subjective, and you have to be careful with that.
Eunice Wang, MD: I think that our pathologists might all differ.
Harry Erba, MD, PhD: Not only is it subjective with that third subset of myelodysplasia-related changes, but now the WHO criteria of 2016 have added a nuance, right? That is, if they have 50% or more dysplasia in more than 2 lineages but no nucleophosmin, no biallelic CEBP-alpha mutation. So, what do you do if you actually give CPX-351 based on the label, and then find out from your next-generation panel that they have favorable risk? I don’t think you’ve done them a disservice, but it’s not really in the label anymore.
Alexander E. Perl, MD: There were patients on the study who had a nucleophosmin mutation. It’s not to say that those patients were excluded, it’s just that we don’t know there’s a proven benefit.
Harry Erba, MD, PhD: Right.
Eunice Wang, MD: Jorge, did you want to say something?
Jorge E. Cortes, MD: I was going to emphasize what Harry mentioned. I think that you’re not going to do a disservice to these patients. The randomized phase II studies—both the frontline and the salvage settings—show that there was a trend for survival for the overall population, and it was significant for secondary AML. So, you can say that at the very least, it is equivalent to 3 plus 7 chemotherapy.
Eunice Wang, MD: They didn’t do worse.
Jorge E. Cortes, MD: Exactly, so they don’t do worse. You may decide to change therapy because of costs or other considerations, but it’s not a necessarily an adverse approach.
Eunice Wang, MD: Yes.
Jorge E. Cortes, MD: Now, I do have a question about that, because we consider these for secondary AML, but one group that was not included is secondary for myeloproliferative neoplasm. So, should we use it or not in that subset, not based on the label?
Harry Erba, MD, PhD: I would say, first of all, I think that’s a great clinical trial to do. Those patients have a horrible outcome, who progressed from myelofibrosis and ET or polycythemia vera. But you have to be careful, because that would be an off-label use. The myelodysplasia really changes MDS or an overlap of MDS, MPM (malignant pleural mesothelioma)—like CMML, or a typical CNL [chronic neutrophilic leukemia], but it did not include those patients. So, it would be an off-label use. I don’t think we know enough to say, “Yes, we should be using that drug.” Yes, we need something better than 7 and 3 chemotherapy, and we should do the clinical trial to evaluate that.
Transcript Edited for Clarity