Harry Erba, MD, PhD: Let’s look at the last drug that was approved in 2017, gemtuzumab ozogamicin. It was approved in 2000 with accelerated approval based on 3 phase II studies in relapsed/refractory AML, showing about a 25% response rate with myelosuppression being the major toxicity and some patients developing veno-occlusive disease and sinusoidal obstructive syndrome.

But it’s a proof of principle that you can use an antibody drug conjugate to show activity and get activity in AML. This is a drug that attacks and binds to CD33, present on most myeloid blasts, covalently linked to calicheamicin. It’s internalized. Calicheamicin is released and leads to cytotoxicity.

However, one of the problems that we had with the development of the drug was that when it was added to intensive chemotherapy in the SWOG-0106 study, it did not show improvement in CR rates. It did show an improvement in overall survival. It did show an improvement in relapsed-free survival for core-binding factor leukemias, and we can talk about that. But there was also higher induction mortality, not just from liver toxicity but also from infections, hemorrhage, and a whole list of things that made the mortality 5% with the GO (gemtuzumab ozogamicin) arm versus 1%. And then, it’s taken off the market in 2010, 7 years later. Why is it back? Sasha, do you want to start?

Alexander E. Perl, MD: There are 2 reasons it’s back. It has been looked at in Europe with different doses and different dosing schedules. Importantly, at lower doses. It was approved initially at 9 mg/m² for 2 doses as a single agent. And then there are the studies looking at it in combination with chemotherapy at 6 mg/m². That’s probably too high of a dose.

The studies that were done in Europe and were effective used even lower doses or infractions of 3 mg/m². So, one of the first studies that came out was a French study that looked at 3 doses of 3 mg/m² given on days 1, 4, and 7 of 7, and 3 chemotherapy induction. That study did not show an increased induction mortality, but showed better protection against relapse ultimately leading to an improvement in event-free survival, which is the primary endpoint of the study. And actually, overall survival was a secondary endpoint, but it was still met.

A meta-analysis of 6 different studies looking at adding gemtuzumab ozogamicin at various doses to newly diagnosed patients’ treatment in combination with intensive chemotherapy ultimately showed an improvement in all but the high-risk karyotype. The adverse karyotype patients did not show a benefit, and most of the benefit actually was seen in the patients with core-binding factor disease. But a small benefit was also seen in the intermediate-risk group. Overall, it was better than not getting it. So, that’s what led to the approval of that.

Eunice Wang, MD: I would have to say, I think the meta-analysis showed a benefit for adverse cytogenetics. But a trend? It still was a beneficial, right?

Jorge E. Cortes, MD: Yes.

Harry Erba, MD, PhD: Very minimal.

Eunice Wang, MD: The only study that showed no benefit was that ALFA-701 study, where adverse cytogenetics was the only group that didn’t have a benefit. But the meta-analysis showed benefit across all of the others. That’s true, right?

Jorge E. Cortes, MD: That is correct, and the other thing that’s important is that it depends on what classification you used for it. If they used an older classification—when we’re using the ELN (European Leukemia Net), for example—there was a trend. Not a definitive trend, but I think the important thing in that regard is that, as we discussed, the cytogenetic analysis may take a little while. There was no disadvantage for the adverse cytogenetics. It could be that there was no benefit for that. If you started that and you didn’t have the cytogenetics, once you get back your cytogenetics and they’re adverse, you can decide if you want to continue it in the subsequent cycles or not based on that information.

Eunice Wang, MD: It’s sort of like what we talked about with liposomal. If you ended up getting those back, you certainly didn’t harm the patient.

Jorge E. Cortes, MD: Correct.

Harry Erba, MD, PhD: I have a very practical question now.

Eunice Wang, MD: Are you going to ask about VOD?

Harry Erba, MD, PhD: No, we won’t talk about that, OK?

Eunice Wang, MD: OK.

Harry Erba, MD, PhD: I want to ask the practical question, are you using it? It became available, approved, in the first week of September of this year. If you’re using it, what is the patient population you’re using it in? What dosing schedule? Sound bite there, go.

Alexander E. Perl, MD: I’ve used it 3 times. I’ve used it for a patient with APL who had an elevated white blood cell count, based on data from the United Kingdom saying that was effective at that time and we don’t need to use idarubicin. I’ve used it for salvage similar to the way it was used originally in a patient who didn’t want to get induction chemotherapy. I’ve used it twice in that setting.

Harry Erba, MD, PhD: Now, you said similar to how it was used originally. You mean 9 mg/m² on days 1 and 15?

Alexander E. Perl, MD: No, I didn’t.

Harry Erba, MD, PhD: Mylofrance?

Alexander E. Perl, MD: Basically, yes. It’s single-agent 6 mg/m², and then 3 mg/m² in the follow-up.

Eunice Wang, MD: Newly diagnosed?

Alexander E. Perl, MD: No, relapsed.

Harry Erba, MD, PhD: The Italian study for previously untreated older patients who were randomized against best supportive care used 6 mg/m² on day 1, and 3 mg/m² on day 8. And there was a survival benefit, but of course, comparing it versus best supportive care. I think that would be a very difficult study to do now.

Alexander E. Perl, MD: That’s a hard study.

Harry Erba, MD, PhD: OK, how do you use it?

Eunice Wang, MD: We are definitely recommending that favorable karyotype patients, the young and fit patients, get Mylotarg (gemtuzumab ozogamicin) added on to standard 7-and-3 chemotherapy. We’ve also talked about using it in intermediate cytogenetic young and fit people, if they are not FLT3-positive, to try to give them an advantage. We have not been using it in adverse groups. Many of those patients have complex karyotypes and potentially T53 mutations, so we’ve been looking at whether we would want to use either a hypomethylating agent. Many of those cytogenetic abnormalities or complex karyotypes fall into the AML-MRC category. We have used it. I’ve offered it as a single agent to elderly people who don’t want to come in 7 or 10 days in a row for hypomethylating.

Harry Erba, MD, PhD: That’s the point for cycle after cycle.

Eunice Wang, MD: They like the idea of having a single agent. These are people who really want to minimize their treatment, and they like the idea of coming in for a couple of doses of antibody and some transfusions, but not coming in daily. We certainly have used a lot in the salvage study.

Harry Erba, MD, PhD: I have a couple of practical challenges to your approach. I agree with you. I prioritize it for patients with CBF translocations, but if you’re going to use it the way it’s supposed to be used on day 1 or days 1, 4, and 7, you need that information. So, I’ve been getting the FISH data back quickly for our CBF translocations. That’s 1 practical issue. There may be something else, but we have to move on. Jorge?

Jorge E. Cortes, MD: Yes, I’m definitely using it, more so for salvage. Our frontline CBF study has always included that because on a clinical trial, it was available even when it was taken out of the market. So, we’ve been using it and we continue to use it. Outside of a clinical trial setting, I do use it for salvage in the same patient population and for older patients, in particular. This is not an approved combination, but we’ve used it in combination with high-methylating agents, and we had a regimen that we thought was beneficial. I’ve used it occasionally like that.

Harry Erba, MD, PhD: Yes, SWOG-0703 looked at azacitidine with a dose of 3 mg/m² on day 8, and we reported in our phase II study a response rate in these older patients. It wasn’t clear to us that there was a benefit compared to historical controls, and that’s why we didn’t move it on to a phase III study.

Eunice Wang, MD: I think the only concern in our group is that there is a rate of a veno-occlusive disorder of the liver that occurs, and there are people who feel that for some of those intermediate-risk patients, especially younger patients, we don’t want to run the risk of having VOD. Looking at the studies and the meta-analysis, the rate is very, very low—in the single percentages—and there are data from the CIBMTR (Center for International Blood and Marrow Transplant Research) saying that in the case-control match study, the incidence of VOD in Mylotarg-exposed patients could be as low as 4%. But there’s still that perception, so I just wanted to mention that.

Alexander E. Perl, MD: Very few of the patients studied on that meta-analysis actually went to transplant.

Harry Erba, MD, PhD: Right.

Eunice Wang, MD: So, I think we’re a little bit more comfortable using it again in the salvage setting.

Harry Erba, MD, PhD: Or in the core-binding factor disease.

Eunice Wang, MD: Or in the core-binding factor disease.

Harry Erba, MD, PhD: Yes, I agree with that, and that’s why I don’t use in intermediate-risk, younger patients. There may be a survival benefit, but the interaction with transplant is an issue. And the other thing you mentioned, now that I’ve remembered it, is if they have intermediate risk but do not have a FLT3 mutation. Again, you have to get that information back quickly if you’re going to do this.

Eunice Wang, MD: Right, and that’s a challenge.

Transcript Edited for Clarity