Acute Myeloid Leukemia: Evolving Through Targeted Therapies - Episode 15
Harry Paul Erba, MD, PhD: Chemotherapy isn’t dead. It still has a role. CPX-351, the liposomal daunorubicin cytarabine, has been approved by the FDA for patients with secondary AML [acute myeloid leukemia], those who had previous MDS [myelodysplastic syndrome], CMML [chronic myelomonocytic leukemia], patients with de novo AML [acute myeloid leukemia] with complex karyotypes or MDS-like karyotypes, and treatment-related AML. And this was based on a large phase 3 study that actually validated the results of a prior randomized phase 2 study, showing improvement in overall survival but also CR [complete response] rates and not at the cost of higher induction mortality. It was actually lower.
And I think what was most impressive about that report to many of us is that the patients who went on to allogeneic transplant for this very poor-risk AML following CPX-351 had a much better survival than those who went on to allotransplant after 7 and 3. We’re not really sure of the reason for that. It could be that we induced a deeper level of minimal residual disease with CPX-351. It could be that they weren’t as beaten up from CPX-351, but we really don’t know the answer. The question is: What populations are really benefiting?
And I think at the ASH [American Society of Hematology] meeting, R. Coleman Lindsley, MD, PhD, presented data where two-thirds of the patients, we had mutational data, and what he showed was no response benefit, no survival benefit in the TP53-mutated patients, which was a third of the population. But in patients with the secondary AML mutational profile, those are both those patients with a spliceosome mutation, chromatin modifiers, and that 1 cohesin mutation, STAG2, those patients did have an improvement in survival in that subset with CPX-351 versus 7 and 3. But, of course, we have a lot of questions about how to use CPX-351. I want to throw those open to the group. And the most obvious one to start with is: Does anyone use CPX-351, or is everyone giving AZA [azacitidine] or HMA [hypomethylating agent]/venetoclax [VEN] combinations now? Dan is smiling. You’re the first to smile, so you’re on.
Daniel Pollyea, MD, MS: I’m giving a lot more venetoclax combinations to patients that would have probably, in most places or in a recent era, felt to be pretty decent intensive induction chemotherapy candidates. And there’s a variety of reasons for that, and there’s a lot of extrapolation that goes into that. But that has eroded my use of all chemotherapy, including CPX-351. What you brought up about the presentation at ASH [American Society of Hematology] , the Coleman Lindsley presentation, is somewhat concerning because if you are now removing the TP53-positive patients from the secondary and treatment-related AML population, you’re starting to leave yourself with very little. There’s not much left if you have to subtract those patients out. And so I think it’s a commentary about disease resistance subtypes against chemotherapy approaches that maybe aren’t so dramatic or set in stone for nonintensive chemotherapy approaches.
Mark J. Levis, MD, PhD: Harry, I would take a stab and say we use about 10:1 HMA/VEN to CPX, if I had to guess.
Harry Paul Erba, MD, PhD: So, Mark, as long as you chimed in, let me ask you. So let’s say you have somebody in the labeled indication for CPX-351, a secondary AML, someone who had received an HMA before, even, or a therapy related, and they have a FLT3 mutation; would that be a patient you would consider CPX-351 with a FLT3 inhibitor?
Mark J. Levis, MD, PhD: When I’m considering CPX, I look at fitness. It’s not a drug for the unfit, even though it sort of has that reputation, uh-uh. You’ve got to be fit enough to tolerate it. And so then it’s on that paradigm, and the AZA, as you know, if they’ve had AZA before, their response to anything is less good. As far as the FLT3 inhibitor goes, no. If they’re fit enough to get CPX, I’m more likely to give 7 and 3 in a FLT3 inhibitor than CPX. We’re doing that trial investigating that.
Harry Paul Erba, MD, PhD: Gail?
Gail J. Roboz, MD: I would just bring up the point that we clearly are using a lot more HMA/VEN. But I actually believe in pharmacologic optimization of chemotherapy, and I think that I’m interested in knowing is this better, 7 and 3, and what about younger patients or patients. I mean, most patients with AML are cured with chemotherapy. We haven’t cured anybody yet, really, with the venetoclax-based or IDH-based therapies. We’re doing well, and we want to avoid, we wanted to avoid intensive chemotherapy in those patients to begin with, so we’re excited to be able to do that.
But the question is: Can 7 and 3 be replaced with CPX? And I still wonder about that. Because if it’s just plain better, if it’s better tolerated and sort of better pharmacologically, that’s still an open question that I think we have to study. I definitely feel that we have the over 70 or over 75 in bad shape doing well with HMA/VEN, begs the question that if you’re 62 and in great shape, why can’t that regimen be for you, too? And I think that has shifted the use of HMA/VEN to what is clearly the off-label setting of better patients who could theoretically target, be treated with CPX as an on-label.
Mark J. Levis, MD, PhD: To that point, we would, for the 62-year-old fit enough, we would not offer HMA/VEN; we would offer CPX if they have secondary AML.
Gail J. Roboz, MD: That’s the question that how, exactly, what is the calculus in that, and I think it’s hard sometimes. That’s a little bit in the eye of the beholder.
Harry Paul Erba, MD, PhD: And those clinical trials are being designed to look at those fit patients. Because I agree with Mark: CPX-351 still is chemotherapy with a very same profile of toxicities, maybe a little bit less mucosal toxicity but for more prolonged myelosuppression. But let’s come back to the fact Jeffery Lancet, MD, our friend from Moffitt Cancer Center, presented the 5-year update of that phase 3 study. And there’s a true plateau on the survival curve with CPX-351, much above 7 and 3, or double 7 and 3 is what I should say. We have a lot of room for improvement, and I would imagine I think most of those patients out in the tail of the curve were patients who were able to undergo allogeneic transplant. So I use CPX-351 for that fit, younger patient where I know that the goal of therapy is cure, and I’m trying to get them to transplant for a secondary AML or therapy-related AML.
Transcript Edited for Clarity