Meet The Professors: Myelodysplastic Syndromes Edition, 2016Five- versus 7-day therapy with azacitidine
5:55 minutes.
TRANSCRIPTION:
DR RUPARD: You implied earlier that you use 7-day azacitidine for certain higher-risk patients and you can use 5-day for a lower-risk patient. I may be extrapolating from what you said. I’m just curious. I will tell you that in the community, the 7-day is hard for me to swing, or sometimes I do Monday through Friday, Monday-Tuesday, but to be honest, most of my patients go on 5 days. DR ERBA: Okay. So this is my concern about the 5 day. Okay? So first of all, for the same reason I don’t use decitabine as my first choice, I use 7 days of azacitidine because that’s where the data is. So where’s this data for 5 days come from? It comes from the study published in JCO by Roger Lyons and his colleagues. One hundred and fifty patients, about 50 patients in each group. Five days of aza, 5-2-2, the 5 days on, 2 days off, 2 days on and then a 10-day at a lower dose. If you look at the demographics of those patients, out of the 150 there were like 4 who had RAEB-T. Okay? The majority of patients had low-grade MDS, over 50%. There was no cytogenetics. There was no follow-up bone marrows on the patients. It was a community-based practice. I asked Roger about it. He said, “We just didn’t think we could get cytogenetics,” which I didn’t think was possible with MDS. So in any case, we have limited data. And in that study, they saw in a randomized Phase II study, so not powered to show superiority of anything, they showed equivalence, maybe less myeloid toxicity with the 5 days. And, of course, there’s the convenience factor. Given that most of those patients had low-grade disease, if I’m basically treating for palliation of cytopenias, I’ll go with 5 days. If my goal is to get a patient to have a survival benefit, I’m going to at least start with 7 days. Typically, those patients are patients who are already cytopenic. So although you might say I don’t want them to come back the next week, they’re usually coming back at least once a week for counts, right? And I mean at the beginning. And so as time goes on and their counts get better, then I’m more likely to cut back to 5 days. And I’ll admit, I have no data to really say that’s okay to do, but it keeps people from falling off. So that’s why I use 7 days, because it’s in the patients with intermediate- and high-risk disease with high-grade disease that a survival benefit was shown. The last point I’ll make about that is we’ve talked a lot about being patient and waiting 4 to 6 cycles to see if you get a response. The biggest question I think we have is, what do you do with the patient who’s at 6 cycles or 8 cycles and is completely and totally stable? Is there a survival benefit there? And there was some preliminary data, I think, from the AZA-001 study subset analysis suggesting a survival benefit. More recently, Gore, who’s now at Yale, looked at this and isn’t quite so certain there’s a survival benefit. I think it’s hard to keep on that kind of therapy if they’re just cytopenic and not clearly a benefit otherwise. DR LOVE: Guillermo? DR GARCIA-MANERO: This is universal problem. I have to tell you, this is not only community. I can tell you from running some big national studies, some academic centers cannot do 7 days either. So it’s not just the community. It’s difficult. Harry is totally right. The study was designed on 7 days, and that’s the hardcore data on the high risk. DR LOVE: Like from a pharmacologic point of view, what you think if you delayed 2 days? DR GARCIA-MANERO: I asked, actually, Lou Silverman. And it’s very simple. The intention of the 7 days was because they wanted to do a 7+3. Azacitidine, whereas Ara-C, second generation, I guess 30 years ago, and these people wanted to do 7 days. And then that actually should be studied, was to add anthracycline to azacitidine. And so use that as 7 to do an eventual 7+3. That’s the explanation I was given to the 7 days. And, of course, the drug was actually approved not on a prospective trial, everybody knows this, right? In the US, this data was collected back from the CALGB trial. So this was already done. And this was the 7 days. So that’s the rationale for the 7 days. Although I agree with Harry, I use the 7 or 5 days kind of like — depending, actually, on whatever clinical trial I’m using. Because a lot of our studies are doublets where, I guess to overcome his question, we said, wait, we’re giving a second drug maybe. But on paper, if you have a prototypical patient, you should really try to do a few cycles of 7 days for sure. He’s totally right. DR LOVE: Could I just clarify? When you say “7 days,” you’re talking about 7 consecutive days? DR GARCIA-MANERO: Yes. DR LOVE: Or that’s what I’m saying. In your mind, does it matter to delay to a Monday and Tuesday? DR ERBA: In my mind it doesn’t matter to delay. I think it’s a practical matter. DR GARCIA-MANERO: Yes. DR ERBA: If I was open on Saturday, I would do it 6 days and then 1. There is no large, randomized data comparing these regimens. Just that randomized Phase II. The one thing I’ll say about the 10-day regimen of 10 days at a lower dose, we did a study in ECOG and SWOG and Gore was the lead on that study. It was a randomized Phase II study comparing a 10-day regimen with a histone deacetylase inhibitor. No benefit of the HDAC inhibitor. However, we still were able to make something out of it. The trilineage hematopoietic responses we saw with the 10-day regimen were better than what was seen in any prior study. So if you ask Steve Gore about this, he’d say, “you’re all wrong. It’s not 5 days, not 7 days. It’s 10 days.” Okay? So count yourself lucky it’s only 7 days. |