Importance of Hydration With Moxetumomab Pasudotox
Given potential side effects, Dr. Robert J. Kreitman reviews the importance of hydration for patients with hairy cell leukemia receiving moxetumomab pasudotox.
PUBLISHED June 18, 2019
Robert J. Kreitman, M.D.: The reason this drug [moxetumomab pasudotox] causes kidney problems, we don’t know exactly, but we feel that there’s something like CD22 in the kidneys that the drug binds to nonspecifically. But if we can keep the urine from being very concentrated, we can keep the drug in the blood not so concentrated, then we feel that patients can tolerate it perfectly well. The drug causes a syndrome in addition called capillary leak syndrome. This is an important syndrome that’s caused by poking holes in the blood vessels. The way the drug works, as I said, is that it binds to the surface of the malignant cell, goes inside, and then once inside a place called the cytoplasm, the drug can kill the cell.
Now, when you have lots of molecules of the drug in the blood vessels and the drug needs to get out of the blood vessels, then it can poke holes, it can go through the cells lining the blood vessels. Those are called endothelial cells, and those are living cells. So it can kill some of those cells, and as it’s going through those cells and killing those cells, it can cause leaking. It can poke holes in the blood vessels, which isn’t necessarily a bad thing. We actually hope that the drug gets out of the blood vessel because then it can kill some of the hairy cells that are outside the blood vessels.
But what it does is it causes a little bit of leaking, and so patients will have leaking of blood, fluid and protein from the inside of the blood vessels out. They won’t lose blood, but they’ll lose fluid and proteins. And so it’s important for patients to drink to keep from being dehydrated. And so what we found by trial and error is that if patients are drinking about a cup of water an hour, which we find is very manageable, they can keep from being dehydrated. But the trick is that that even goes at night. And so we try to average out a cup an hour, so that patients, if they’re sleeping for three hours at a time at night, they’ll get up and drink about two or three cups of water. And what that will do is keep them from being dehydrated.
We liken it to a leaking bucket. If you have a bucket that has a few tiny holes in it, it’s constantly leaking. And if you don’t do anything to fill up the bucket over a certain period, that bucket is going to become empty or going to become almost empty to the point where that’s going to be similar to someone being dehydrated. So if you drink a little bit of water at a time, you can keep that bucket full even though it’s leaking. That’s what we explain to patients nowadays to try to get them to understand that it’s a gradual process. And you can’t just drink a gallon of water or you can’t really rely on getting a liter of IV intravenous fluid right away because that’s going to overflow the bucket. And what we see then is patients may have some difficulty breathing or they may have some edema, some swelling. Did you remember having any swelling or having shortness of breath or having those side effects along the way?
Vince Fazio: I do not remember any swelling and shortness of breath. Like I said, the drug was almost side effects-free for me.
Robert J. Kreitman, M.D.: Fortunately, some people have that experience too. But we find that many people do have swelling, they have edema. And oftentimes they notice it if they’ve gone through the seven or eight days of the treatment. The treatment is given every other day for three doses. And we know that patients on day eight, if their laboratory test results look OK, they’re going to be fine. There is a syndrome that patients could get into that combines a decrease in kidney function, which goes along with an increased creatinine in the blood, with decreased platelets. And that combination we call hemolytic uremic syndrome [HUS]. We see this in a low percentage of patients with MOXE [moxetumomab pasudotox], less than 10 percent. And it seems like it’s a syndrome called HUS that we see in a patient who might have a bad hamburger, and they end up on dialysis getting plasmapheresis. This is not the kind of side effect that we see with moxetumomab pasudotox. With moxetumomab pasudotox, patients don’t need anything special when they have that side effect. And fortunately, you didn’t have that side effect. But when patients get it, they only have to stop the drug. They can continue drinking water, and we just have to wait for it to resolve.
Really the worst thing about that side effect is it means that you can’t continue with the moxetumomab pasudotox. And when we look over the patients’ history who have had those side effects, oftentimes, we can see that they weren’t really keeping up with the drinking, and they weren’t able to drink for one reason or another. And what we found on the phase 3 trial of moxetumomab pasudotox — the trial that started after your trial finished — is that sometimes patients really didn’t feel like drinking because they had some nausea or they had some fever, so that was making them dehydrated also or they were getting a headache. And what we found is that those three symptoms could be rapidly eliminated by taking a steroid called dexamethasone. A very low dose, 4 mg orally, would take away that symptom within an hour or two or a few hours, and then patients could get along with drinking fine after that. So that’s what we recommended doing.
In your trial, the phase 1 trial of moxetumomab pasudotox, we found that only two out of 49 patients had this syndrome called HUS, and it was very mild. In the phase 3 trial, we had a different amount of drug. We found that of the first nine patients that we treated, three had the HUS toxicity. And at that time, we instituted the precautions of drinking a cup an hour and also taking the dexamethasone if headache, nausea, or fever prevented patients from keeping up their fluids. And so of the next 17 patients, only one patient had a very mild case of HUS. So I don’t think we can prevent HUS with this drug 100 percent, but I think we can get very close to a very low percentage by these precautions, which are simply to drink plenty of fluid gradually, a cup an hour approximately, and not to go more than two to three hours a night without getting up to drink more water and obviously to urinate. And if one has nausea or even a queasiness feeling, headache or fever, we recommend taking a 4 mg dose of dexamethasone.
It’s not every patient who will need that. We found that only about half the patients need it, and maybe only one or two of the three doses that are given per cycle of the moxetumomab pasudotox. But we think that this is really important and that could prevent patients from having side effects.