Safety considerations for inotuzumab in patients with relapsed/refractory ALL

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Published: 23 Jan 2020
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Prof David Marks - University Hospitals Bristol NHS Foundation Trust, Bristol, UK

Prof David Marks speaks to ecancer at the 2020 ALL Assembly meeting in Frankfurt about the INO-VATE trial which assessed the use of inotuzumab in patients with relapsed/refractory acute lymphoblastic leukaemia (ALL).

He states that hepatic veno-occlusive disease is a major problem in patients treated with inotuzumab and the main risk factors associated with this were assessed using a multivariate analysis.

Dr Marks explains the results of this analysis and points out that it is important to take into account a patient's past history of liver disease.


There are two main studies, there’s a study we did from INO-VATE that is published in Lancet Haematology, Hagop Kantarjian is the first author, I’m the last author, so it’s a general look at hepatotoxicity in the trial. Then there’s perhaps a more focussed look in a paper that I’m the first author of published in Biology of Blood and Marrow Transplantation just a year back looking at the outcome of 101 patients who had an allograft after inotuzumab. So what we’re able to do in those two studies is we had enough patients to do a multivariate analysis to work out the main risk factors associated with veno-occlusive disease, because that’s the problem with inotuzumab, it’s a very effective drug but there is a clear liver signal.

We found some quite simple things. First of all the use of dual alkylator conditioning agents, so that’s commonly drugs like busulfan and thiotepa, the bilirubin at the time of transplant, if that was elevated at all there was a huge odds ratio associated with veno-occlusive disease. But also the transaminases, if they were elevated significantly then that was associated with veno-occlusive disease.

There’s one other factor that I think is worth asking a patient about and that’s a past history of liver disease. That was not quite significant, the p-value was 0.064, but it’s a numbers game – we didn’t have enough events to be certain and that is something you really would wish to know about. So there are certain categories of patient who have some of those risk factors where inotuzumab would not be your first choice drug for relapsed refractory ALL.

Are there any questions that you think will be posed to you during your workshop?

I think they’ll say, ‘How do you use these risk factors to make decisions?’ There are some patients where using a dual alkylator regimen where that may be hard to avoid and I would argue that those patients shouldn’t have inotuzumab up front. Then there are some very simple things like using ursodeoxycholic acid to prevent VOD, that’s a simple and cheap drug to use.

There are also other things – just not using drugs like azoles as antifungal agents because they can muddy the waters. At the very least they can cause abnormalities of the liver function test that possibly predispose to inotuzumab toxicity.
Many people at this conference will have used a lot more blinatumomab than inotuzumab but inotuzumab is an extremely valuable drug. It has a very high potency, it gets lots of people into complete remission. It’s about using the knowledge we have, avoiding the risk factors, and then you can make the incidence of veno-occlusive disease quite manageable.

There are lots of other things we can do. The doses of inotuzumab that we’re using are probably higher than what we need. The MD Anderson have used much lower doses, particularly in older patients, and it’s quite possible that lower doses of inotuzumab will result in lower hepatotoxicity. Then, finally, there isn’t a competition, really, between blinatumomab and inotuzumab, they’re both valuable agents. We should be using both of them, it’s just that in certain circumstances one may be a bit more appropriate than the other one.