Non-Chemotherapy Agents & Anti-CD22 in HCL Treatment

Transcript:

Robert J. Kreitman, MD: In talking about agents that are not chemotherapy and work in hairy cell leukemia, when would you use ibrutinib in the relapsed-refractory setting?

Farhad Ravandi-Kashani, MD: I have used ibrutinib only in a clinical trial setting. In that setting, it has shown activity. It’s not highly active and does not produce complete morphological remissions in most patients, but it does produce durable benefits on most patients who have used it. Particularly in a hairy cell leukemia variant, in a few patients who have used ibrutinib, I’ve seen durable clinical benefit. I think it’s an oral agent and clearly, again, it has to be used continuously. Also, there are some minor adverse effects. As you know, this drug is effectively being used almost universally now in treating chronic lymphocytic leukemia [CLL], so it’s a tolerable agent. But in general, I don’t think the responses in hairy cell leukemia are as remarkable as those we see in CLL.

Robert J. Kreitman, MD: One of the things we see is the time it takes to get the best response can be a long time. Some of these patients can take up to a year or more to develop a complete remission. The interesting thing is before they respond, and this may be in the first few months of treatment, their normal blood counts can actually get worse. You don’t want to start someone on ibrutinib who has very poor blood counts and is in danger of having neutropenic infections that are potentially lethal, because that patient may actually get worse before they get better. Ibrutinib is known to increase the risk of infection and bleeding. However, we have also seen patients who have classic hairy cell leukemia who do very well on this drug, and over a long period of time they can achieve complete remission.

I’ve not personally seen patients with classic hairy cell leukemia become MRD [minimal residual disease]—free. These patients generally have MRD that’s visible in not only in the bone marrow aspirate or bone marrow biopsy but also the blood. However, we did see a patient with hairy cell leukemia-variant who had large lymph nodes that got smaller and smaller, to the point that we could no longer feel the lymph nodes. For that patient, because he had a lot of rituximab before the ibrutinib, we could not detect hairy cell only by these lymph nodes. This patient is technically MRD-free now. Patients can have some benefit with ibrutinib, both the hairy cell classic and hairy cell variant, although I agree that this drug seems to be much more effective in patients with classic rather than variant hairy cell.

Farhad Ravandi-Kashani, MD: Last, and not least, is a drug that you and your group were instrumental in development, and essentially it is a product of research at the NIH [National Institutes of Health] for many years, and that is the anti-CD22 recombinant immunotoxin, moxetumomab pasudotox. Since I believe you’re the person who has worked most extensively with this drug, perhaps you could give us your take on its role, its activity, and importantly, adverse effects.

Robert J. Kreitman, MD: Let me start by just going way back to what an immunotoxin is. I work with Ira Pastan at the NIH, and he and D. David Fitzgerald, even before 1989—when I started in the lab—had been working on immunotoxins, which are proteins that can kill cells through a toxin action. The protein that we used in the lab is called pseudomonas exotoxin.

The way it works is it binds to the surface of the cell. It goes inside through receptor-mediated endocytosis. Then it’s cleaved, and then a fragment of the toxin gets to the cytoplasm, where 1 molecule should be sufficient to kill a cell. This has been found similarly for diphtheria toxin, which has a similar mechanism. It inhibits ADP-ribosylation elongation factor 2. This causes apoptotic cell death.

That’s a mechanism of action. Back in the ’90s, David Fitzgerald constructed an anti-CD22 recombinant immunotoxin which was called BL22. We tested that in patients with hairy cell leukemia, found responses and moxetumomab pasudotox, which originally was called HA22, is actually a high-affinity version of BL22, which binds 14-fold better. It’s more selective for CD22-positive cells. As we know, hairy cell expresses CD22 in very high amounts—not quite as high as CD20 but very high amounts. The nice thing is that in patients who’ve had CD20-directed therapy, including rituximab, whereas the rituximab may still be on their hairy cells, the CD22 is unblocked and can be acceptable to the Moxe. So we called moxetumomab pasudotox, Moxe.

Transcript Edited for Clarity