Are remissions for AML patients 'better' after daunorubicin and cytarabine liposome injection

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Published: 24 Dec 2019
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Prof Daniel Ryan - University of Rochester, Rochester, USA

Prof Daniel Ryan speaks to ecancer at the ASH 2019 meeting in Orlando about the quality of remission after daunorubicin and cytarabine liposome injection.

He outlines the parent study and results, before explaining this subgroup analysis and results.

Are remissions for AML patients 'better' after daunorubicin and cytarabine liposome injection

Prof Daniel Ryan - University of Rochester, Rochester, USA

This is a subgroup analysis of a larger study that was performed to evaluate the effectiveness of a new drug called Vyxeos, it’s made by JS Pharmaceuticals, and it’s really an interesting idea. It’s a combination of the conventional drugs that are used to induce remission in adult AML. So you have daunorubicin and Ara-C mixed together in a liposome because it has been found the optimal ratio of those two drugs to each other when they are exposed to leukaemia cells is 5:1. If you give the drugs to the patients separately or you mix them together, which you don’t, you give them separately, they metabolise at different rates and so it’s never 5:1 all the time. But this liposome keeps them at the optimal ratio until they are exposed to the cancer cells. The idea was is that any better?

The parent study, the large study, showed that there was indeed a significant effect, a higher rate of complete remission and complete remission with incomplete platelet or neutrophil recovery, and a higher rate at which patients could go to haematopoietic cell transplantation. The question that we wanted to ask in this study, which was taking the same group of patients and looking at a subset of the patients, was really to say of those patients with the diagnosis of AML with myelodysplasia related changes who achieved complete remission or complete remission with incomplete neutrophil or platelet recovery how did they do. There are really two questions – one is the subgroup of AML MRC, which is a morphologic and cytogenetic classification of AML – you  have to have morphologic dysplasia or prior myelodysplastic syndrome or cytogenetics that are associated with myelodysplasia. We previously reported of a subgroup of that AML MRC patients as to how they did in terms of the induction of remission and the response in that subgroup of patients, which was the majority of the patients in the trial but it’s still a subgroup, was very similar to the overall.

For this abstract we’re now looking at the question of are the remissions that are induced the same? That is, you could say that with this new drug, yes, you get more people going into remission, that’s wonderful, but once they’re in remission then everybody’s equal and then it goes on. Or are the remissions achieved with Vyxeos deeper, if you will? That appears to be the result. So if you look at the conclusions that we found with this subgroup analysis, number one is that if you now look at just the patients who achieved remission, and it’s about 48% of the people who got the Vyxeos and 31% of those who got the conventional 7 3, and now just start the clock at 100%. You’ve got remission – now what happens? You still see that the people who got the Vyxeos did significantly better in terms of overall survival.

Then you could ask the question how about of those who then underwent haematopoietic cell transplantation and you landmark it from the beginning of the HCT treatment they still did better. So it just seems that even in this subgroup the people who achieve remission with Vyxeos seem to have a better remission, if you will, a deeper remission, because they did better afterwards.

So those are the major conclusions of the study. I’ll stand back from just the data and talk about what this means to the practising haematologist and haematopathologist, and that’s my background as a haematopathologist. It’s interesting because as you see your career evolves you look back to when certain diagnostic categories were of interest, maybe in terms of prognosis but not in terms of what you actually did with the patient. The AML seen with myelodysplasia-related changes is an example of that. We can make that diagnosis in the past and it connoted a poor prognosis but there wasn’t anything you could do with the patient. You would give them 7 3, you would treat them whether or not they had the myelodysplasia related changes diagnosis. But now all of a sudden it matters because now this puts patients in this high risk AML subgroup along with the therapy related AML so that these patients, once they get this diagnosis, you can do something different. You can give them this drug, this Vyxeos. So the practicality of it is now when you see a patient with AML you really need to make sure, obviously some of these things are easier than others to get at, one is the prior therapy – is there a history of prior therapy? Is there history of previous myelodysplastic syndrome? Can this be documented? Sometimes it’s a little bit difficult to get the records – the patient may have come from somewhere else – but you have to think about it and say, yes, this is an important characteristic, this patient could be treated differently.

Then the other major thing is the cytogenetics and about a third of these patients or so fall into this category because they have these myelodysplasia related cytogenetics like the -5 or the -7, this sort of thing, and there’s a whole list of them. So now the question is it actually matters whether you have these cytogenetic changes; in the past it was just a prognostic feature. So the haematopathology lab and haematology service need to get together in advance with intention and say, ‘Okay, we’re going to get some patients like this. We need to plan to see how we can get the cytogenetic results back fast enough so that we can use them to treat the patient with this therapy,’ because you want to treat them this way from the get go. How fast you have to treat somebody with AML is going to depend on a lot of clinical characteristics and so forth having to do with the patient. But you need to plan this ahead of time because cytogenetics traditionally takes a little bit of time to perform and there are significant costs associated with gearing up your lab to do this stuff stat or to set up the appropriate fluorescence in situ hybridisation strategies to get it done right away. You wouldn’t do that unless there was a good reason to do it and now there’s a good reason.

So from a practical standpoint it said, ‘Hey, this is an important diagnosis.’ For the pathologist you’ve got to put it a diagnostic line, it can’t be buried in the descriptive minutiae, you’ve got to say, ‘This is AML MRC,’ so that you can now give this patient the opportunity to be treated with this improved therapy.