Precision Medicine in Acute Myeloid Leukemia Treatment - Episode 11
Harry Erba, MD, PhD: I’m going to ask each of the panel members to comment on issues that I’m seeing in my own clinic. Let’s start with the clinical trial that was just reported with HMAs [hypomethylating agents] that showed no laboratory or clinical evidence of tumor lysis syndrome [TLS]. In the low-dose Ara-C [cytarabine] study, there were 2 patients who had laboratory evidence but no clinical. As I have begun to use this, I have seen definitely laboratory evidence of tumor lysis syndrome, and I’ve been quite happy when I’ve had these patients hospitalized because I was worried what would have happened if they weren’t. Sasha [Alexander]?
Alexander E. Perl, MD, MS: And there are cases that had true clinical TLS that have happened, including patients who went into full-blown renal failure, did need dialysis. It wasn’t captured on the trial, which suggests that it’s rare, but it doesn’t mean it doesn’t happen. So you need to be aware and prepared for that, and we have actually followed the recommendations that came from the trial and that are on the label in terms of monitoring of these patients. Does that mean that everybody is at the same level of risk? I don’t think that means everyone is at the same level of risk. And we have also done the ramp-up in the dose, starting low and then increasing out of concern that there may be some dose dependent effect here.
Harry Erba, MD, PhD: Right. This is not the CLL [chronic lymphocytic leukemia] ramp-up though. It’s 100, 200, 400 [mg].
Alexander E. Perl, MD, MS: No, it’s over just a few days.
Eunice Wang, MD: Remind me if I’m wrong, but on the trial you were not allowed to have, for example, a white count of 70,000.
Alexander E. Perl, MD, MS: That’s important.
Eunice Wang, MD: Patients who were enrolled on the trial had to have a white count below 30.
Daniel Pollyea, MD, MS: But not a de novo white count. You were permitted to get them down with Hydrea or pheresis.
Eunice Wang, MD: But I think that’s an important distinction.
Daniel Pollyea, MD, MS: It is, yes.
Eunice Wang, MD: Because you don’t want people in the community to have a [patient with] AML [acute myeloid leukemia] walk in there with a white count of like 50 or 100 and them starting potentially the venetoclax immediately.
Daniel Pollyea, MD, MS: There were significant mitigation techniques that were employed on all patients in the clinical trial. Getting the white blood cell count down, using allopurinol in every patient, very aggressive hydration measures, inpatient hospitalization, the intra-patient dose escalation. I think that accounts for a large amount of the lack of tumor lysis syndrome. And like we’ve been saying, it really does need to be respected.
Harry Erba, MD, PhD: I agree with the mitigation attempts, but getting back to Eunice’s point, I completely agree. Only 10% of the patients who went on that trial required hydroxyurea. And when you look at the demographics, about a quarter to a third had what we used to call MDS [myelodysplastic syndrome], 20% to 30% blasts.
Eunice Wang, MD: Right. They had lower level disease than maybe you’re seeing in the community, right?
Harry Erba, MD, PhD: They had lower level. But patients with real leukemia, I do what was done in the study, I admit them to begin treatment.
Eunice Wang, MD: I agree with that. When we look at the patients on the study, it’s actually somewhat deceiving because the FDA indication is for individuals 75 and above who have significant comorbidities, maybe not eligible for intensive chemotherapy. And one interpretation of that is if you have an 85-year-old gentleman coming in who’s in a wheelchair, who has AML, maybe a high white count, that that person would be an ideal candidate for venetoclax therapy. And the temptation is, based on our CLL [chronic lymphocytic leukemia] colleagues, is maybe we’ll just do this as an outpatient. Well, I think again it’s very deceiving.
Again, you can correct me if I’m wrong, but a significant proportion, half of the patients on the trials were actually under the age of 75. They did have a performance status of 0 to 2 to meet eligibility. My impression is that because of the fear and the close monitoring, and the need for Hydrea, and hydration, and allopurinol, most of the patients in that study did receive their initial ramp-up and their initial course in hospital. Although there was about a 6% 30-day mortality, again, some of these individuals were not 80-something years old in a wheelchair. They were 60, 65, they were walking around, they were ambulatory. Some of them may even in some centers been considered candidates for intensive chemotherapy based on that criteria.
Harry Erba, MD, PhD: Well, 10% went on to transplant.
Alexander E. Perl, MD, MS: The reason they’re not a good candidate is they have a bad heart or bad kidneys or things that make it hard to give them appropriate hydration.
Eunice Wang, MD: Right.
Jorge E. Cortes, MD: The other aspect of that is the prolonged myelosuppression.
Harry Erba, MD, PhD: That’s what I was going to come to you next about. Tell us more about the myelosuppression, and how do you manage it? Do you just keep going with the venetoclax?
Eunice Wang, MD: Do you admit them at MD Anderson [Cancer Center]?
Jorge E. Cortes, MD: Well, we admit them for the ramp-up. We can discharge them. But it’s important because of what you were mentioning, that the label is for these older patients and fragile patients and whatever. I think that the drug is safe. It’s just that it needs proper management. I think what’s important is that for people to recognize at the beginning what we just discussed, but then there’s this prolonged myelosuppression. These patients have to be monitored continuously and recognize that the myelosuppression is going to stay there. Do your prophylactic antimicrobials. Make sure that you protect them, that you educate them that they need to come to the emergency center, if they’re already out, right away with the first fever and treat that aggressively. Because a 75-, 80-year-old who develops an infectious complication is not going to handle it as well as a 40-year-old.
Eunice Wang, MD: Mostly respiratory infections, pulmonary infiltrates, sepsis.
Jorge E. Cortes, MD: Exactly.
Eunice Wang, MD: Those were the main causes of death.
Jorge E. Cortes, MD: It is very important to recognize that to manage that preemptively with prophylaxis, with transfusions, with all these things, education of the patients, keeping a close eye on these patients. Now, do you keep them in the hospital or not? I don’t know. I think that depends on how you keep them, that may be safe or not. If they’re going to be in the hospital and catch a nosocomial infection as opposed to a community-acquired infection, it may not be a good trade-off as long as the patient can be close and come right away.
Eunice Wang, MD: But you initially start out in the hospital during the ramp-up.
Jorge E. Cortes, MD: Oh, definitely, they have to start. The question is if the myelosuppression is prolonged, do you keep them there 6 weeks or 8 weeks in the hospital, and that’s where it becomes, what’s the benefit?
Daniel Pollyea, MD, MS: One really critical piece of the management of the myelosuppression [for which] the message needs to get out is, most of these patients, they achieve a remission after the first cycle, very early on. We need to institute breaks between cycles. This not a situation where you stay on schedule every 28 days like you might like in early days of azacitidine alone to get through your 4 to 6 cycles and manage the cytopenias and the expectation that hopefully you’ll be able…. This is, if you can achieve a remission or some degree of response very early on, then you can take a break off of therapy and allow count recovery before the next cycle.
Alexander E. Perl, MD, MS: In our group we’ve made it a group-wide approach to do a bone marrow biopsy 3 to 4 weeks into therapy to see, are they usually aplastic actually at that point? And if they are, we stop the therapy and we may even give growth factor therapy.
Eunice Wang, MD: That’s what we’ve done too.
Jorge E. Cortes, MD: Yes, growth factors are great.
Harry Erba, MD, PhD: I agree, that’s a very important management issue. You don’t just continue. You do a marrow, most respond; 60%, 65% require dose interruptions on the trial. But let me get back to the maintenance issue, because then you start them back on it, right, and if you were just giving them azacitidine during a complete remission, I don’t see count suppression on azacitidine once they’re in a complete remission. But I continue to see count repression here. So my question to you, Dan, is do you keep people on 28 days or are you lowering the dose or lowering the duration? What are people doing?
Daniel Pollyea, MD, MS: I think all of the above, I don’t think there’s a great solid algorithm, but we certainly have decreased the duration of the venetoclax from 28 to 21 days. We have decreased the dose or the duration of the hypomethylator. What I have found is that it is not necessarily true that count suppression correlates with bad infectious outcomes or any sort of bleeding outcomes or anything like that. For many patients they reach some equilibrium where while their counts may be suppressed, they’re not requiring transfusion support, they feel well, they’re free from infectious complications. I think managing that expectation for full count recovery versus an allowance for some count suppression in a patient who you acknowledge you’re indefinitely treating with a myelosuppressive regimen.
Harry Erba, MD, PhD: So like an ALL [acute lymphoblastic leukemia]-type of maintenance where you’re going to give effective therapy but adjust the dose, either the dose per day or the duration, so that you can have some count suppression but not too much. But clearly we have to take notice of this.
Jorge E. Cortes, MD: Yes, and we do adjust the dose. Once they go into remission we adjust the hypomethylator, sometimes the venetoclax....
Eunice Wang, MD: Harry, I want to bring up a couple of other practical points just from our own experiences. First of all, as Dan alluded to, you don’t have to wait 4 or 6 cycles as you do with HMA alone to get a response. We’ve had some colleagues do that, and really the data suggest that you do get a response within the first 1 or 2 cycles. So if you’re not going to respond after 2 cycles, it may be good to start looking for the next thing to use. The second thing we’ve run into issues with is a lot of these patients get neutropenic and they get placed on azoles.
One error that early on we were making is we were continuing to give full dose of venetoclax, and there is an interaction. So just something to mention that long term, particularly when you get into that maintenance phase where you may or may not be on and off the venetoclax to know that the doses of venetoclax really have to be dramatically decreased in the presence of azole, depending on the azole that you have.
Harry Erba, MD, PhD: Yes, the PI [principal investigator] actually says you go down to 70 mg of venetoclax if you’re on a strong CYP3A4 inhibitor. Of course that means your patient has to pay for a 15 or 20 mg pill. I just give 100 mg in that situation. But you know what’s interesting about this discussion is that, remember I started by saying I’m going to ask each of you a question about what are the challenges of managing patients, and I didn’t even have to get to the questions. These are things that we’re all facing every day. And I think it’s really important because this is a regimen that is very useful for patients, but it has to be given safely.
Daniel Pollyea, MD, MS: There are a lot of nuances to it.
Alexander E. Perl, MD, MS: I think it’s important to recognize there are patients for whom this may not be the best therapy, as much as we can look at the data and say this really looks better than what we’re used to seeing. Not everybody is a good candidate for this in frontline.
Jorge E. Cortes, MD: But I do want to emphasize, because we talked about all the problems, it’s a safe regimen.
Alexander E. Perl, MD, MS: Oh, absolutely.
Jorge E. Cortes, MD: It just needs skilled, attentive care of the patient, a good selection of the patient. It is a safe regimen but you need to know....
Eunice Wang, MD: But I don’t think they’re characterizing it…. People say well there’s high-intensity therapy and then there’s low-intensity therapy. In some of my discussions…and I know you’re going to talk about glasdegib in a minute, I don’t think venetoclax/HMA, I’m not sure I would qualify it as a very low-intensity therapy.
Jorge E. Cortes, MD: From the myelosuppressive point of view, sure....toxicity, very little.
Eunice Wang, MD: Right, I would think it’s not like HMA alone or LDAC [low-dose Ara-C] alone, certainly much more intensive than that, but not quite as much as our standard 7+3 [cytarabine/daunorubicin].
Transcript Edited for Clarity