Moxetumomab pasudotox-tdfk in heavily retreated r/r hairy cell leukaemia

Dr Robert Kreitman - National Cancer Institute, Bethesda, USA

The phase III trial was a trial of a drug called moxetumomab pasudotox which is an immunotoxin targeting CD22 in relapsed and refractory hairy cell leukaemia that was a pivotal trial leading to FDA approval of the drug. What I’m presenting here is not the first report of that, that was last year, but is a long-term follow-up of that trial where we showed that patients who were in complete remission more or less stayed in complete remission for a longer period of time.

What were the results that you found?

What we originally found is that patients with relapsed and refractory hairy cell leukaemia could achieve what we call a durable complete remission rate of 36.3% and this is defined by having a bone marrow that shows that the hairy cells in the bone marrow go away by the standard stains and also that the radiology tests like MRI or CT that might show abnormal lymph nodes or a big spleen normalise. That has to be done to show that the patients have a complete remission. But a durable CR goes beyond that and requires that a patient have good blood counts that stay good for six months at least. So that rate was 36.3% which was a little higher than the rate that we reported originally on our phase III trial.

Now, since we have more follow-up on this trial we were able to report a one year durability of complete remission, in other words to report what percent of patients stayed having good blood counts for at least one year after being defined as a complete remission. That percentage was 32.5%. So what we find over time is that patients stayed in complete remission and that correlates with the fact that minimal residual disease, which we found to be important in this disease, can be eliminated by moxetumomab pasudotox in most of the complete remissions. Actually in 26 of 33 complete remissions we can get rid of the minimal residual disease. That’s important because we know that when we get rid of the minimal residual hairy cells, the MRD we call it, that can otherwise can lead to relapse in the future their complete remission will last longer. We’re finding evidence of that because the patients who are MRD free have longer complete remissions than patients who have MRD positive complete remissions. That’s what we find.

There’s another finding of this trial in terms of safety that the main toxicity of the drug is to the kidneys. This is why we have to make sure that patients drink plenty of water during the week of treatment and that they don’t get dehydrated. They can get dehydrated because the drug can cause leakiness of the blood vessels. So we find that the creatinine measure of the renal function over a year period of time stays in a normal range and that’s important for showing evidence of the safety of the drug.

How can these adverse events or toxicities be managed in the clinic?

Let me talk a little bit about the toxicities because they’re not the toxicities that you would see with chemotherapy. So most oncologists are not really familiar with these kinds of toxicities, they are really more used to toxicities where the patients have low blood counts – they get admitted to the hospital with bleeding or with neutropenic infections. Those are a lot more dangerous that what we see but oncologists are more used to those. This toxicity of capillary leak syndrome is due to the toxin getting out of the blood vessels and while it does that it pokes holes in the blood vessels. We actually hope that that happens in order to be able to get the toxin out of the blood vessels.

Now, that capillary leak syndrome, though, can make patients dehydrated if they are not drinking plenty of water. We used to try to avoid this and to treat it by giving extra IV fluid but this would make patients waterlogged, fluid overloaded, and that could lead to fluid in the lungs and oedema. But we find that it’s much more successful to just make sure patients are drinking plenty of water. Since moxetumomab is an out-patient type regimen that really is also very useful to have patients orally hydrate. We want patients to drink a cup of water per hour during the week that they are being treated, an average of one cup an hour, and we don’t want them to go more than three hours at night without drinking water because otherwise they’ll get up from a restful sleep where they slept most of the night but they’ll be dehydrated and they may have some kidney problems too. So that’s something that we find.

Now, moxetumomab can cause, in some cases, some mild nausea and also some headache. Either one of those symptoms can keep people from drinking water because they don’t feel well. We find that there’s a low dose of a steroid called dexamethasone that can knock that problem out very quickly. So we recommend that patients take dexamethasone, just a small 4mg dose, as soon as they have those symptoms and get back to drinking water at the rate that we believe is important.

Before we started instituting these precautions we had three out of nine patients that got a severe form of kidney problem and zero out of seventeen afterwards. Now, what is the kidney problem called? It’s called haemolytic uraemic syndrome, we abbreviate it HUS. It’s due to a decrease in platelets and an increase in creatinine, that’s what it’s composed of. It’s caused by the platelets depositing in the kidney vessels. This is a problem that will not lead to permanent injury to the kidney, it goes away on its own within a week or two, does not require plasmapheresis and really the most severe consequence of it is that they can’t get more moxetumomab. So we try to avoid this by keeping patients properly hydrated and that’s the most important message as far as toxicity.

Anything else you’d like to add at all?

I will say that this toxicity was seen fairly in a small number of patients. It was only five patients out of eighty but still we want to be careful in all patients that we treat to make sure that they’re not going to get this toxicity.

The most important message about the moxetumomab is it’s not only a good way to get relapsed and refractory hairy cell leukaemia patients back into complete remission but it’s a way to eliminate the minimal residual disease so that they don’t relapse in the future. We’re finding that there is a tail on the curve where many patients will not relapse in the future if you can get them MRD free. So this is important. But also just having a drug that’s FDA approved for multiply relapsed hairy cell, which is refractory to purine analogues, is really the first in a long time where the purine analogues alone have really been the only FDA option since the early ‘90s.