Moxetumomab Pasudotox in HCL

Transcript:

Robert J. Kreitman, MD: There was a phase I trial that we published in 2018, last May, but later last year the pivotal trial was published in Leukemia, and it was found that about 40% of the patients could achieve complete remission with this agent Moxe, moxetumomab pasudotox.

Most of the complete remissions were MRD [minimal residual disease]—free. This was an agent that is not chemotherapy and did not have chemotherapy toxicities, yet most of the complete remissions could be without minimal residual disease. So that was good.

There are several black box warnings of this drug, and because it is both a protein and toxic, it has some unique toxicities that we don’t usually think of in chemotherapy drugs. One of these is capillary leak syndrome, and the other is hemolytic uremic syndrome.

Capillary leak syndrome is something that almost all immunotoxins have. Because they’re a protein and they work by getting into the cytoplasm and killing the cell, in order for them to get out of the bloodstream, it turns out the blood vessels are lined by living cells—which are called endothelial cells. In order for these molecules of the toxic substance to get out of blood vessels, they go through these living endothelial cells. Once they get to the cytoplasm of some of these cells, they can kill those cells, and that could poke holes in the capillary.

That’s not such a bad thing, though. We actually hope that happens in that it allows the toxic substance to escape from the blood vessels to get out and into the extravascular space, where it can interact with some of the hairy cells outside the blood vessels.

However, it does cause some leakiness. Fortunately, the Moxe has a short half-life, and so within a week after the last dose, the blood vessels are well healed. The time of treatment can be about the first 10 days of the cycle, because we give the drug on day 1, 3, and 5 of a 28-day cycle. During the first 10 days or so, patients can be quite leaky. What that means is that if they’re not drinking enough water, they can get dehydrated.

There’s another problem that seems to be unique with Moxe and does not seem to be found with other immunotoxins. For example, LMB-2—targeting CD25 for T-cell leukemias, that’s a different story that we won’t talk about today. But it’s unique that Moxe causes a syndrome of hemolytic uremic syndrome, which involves a decrease in the platelets and an increase in the creatinine. This seems to be associated with some renal insufficiency. It seems to be touched off by patients getting dehydrated.

What we do to avoid the capillary leak syndrome, as well as the hemolytic uremic syndrome [HUS], is fairly simple. We avoid excess IV [intravenous] fluid, and instead we encourage a lot of oral fluid intake. In fact, we encourage up to a cup of water every hour in patients, and not to go more than 2 or 3 hours at night without drinking water.

The way we explain it to patients and sometimes doctors, to really understand this, is that the blood vessel system, the intravascular compartment, is like a bucket. The bucket has some leaks. It’s a slow leak. If you don’t add water gradually, you’re going to get empty. But if you add a lot of water at a time, then you’re going to overflow. Overflow means that you’re going to have edema and you might have pleural effusion. You might have pulmonary edema, and that’s an excess of fluid.

We find that if we’re just using oral hydration, it’s slow, we’re actually using it through the night, and patients are not sleeping more than 3 hours at a time at night, it tends to be very tolerable and it tends to prevent this capillary leak syndrome. We found that 3 of our first 9 patients with Moxe got HUS, and of the next 17 patients for whom we followed these precautions with drinking water, only 1 patient of 17 did.

The last thing I’ll say is that we find that some patients get nausea, headaches, and sometimes fever with Moxe. This would result in dehydration partly because the patients feel as if they can’t drink. We find that as opposed to other anti-nausea medicines, low-dose dexamethasone, 4 mg orally, takes away this nausea very quickly. The patients don’t even need this more than once or twice during the cycle, and that tends to work very well.

So, these are the precautions that I would suggest in patients getting this drug to avoid the toxicities. It’s a fairly different kind of therapy that we’re used to in oncology. But it’s 1 that can be very effective.

Transcript Edited for Clarity