Treatments for Relapsed/Refractory HCL in Pipeline

Jae Park, MD: Another drug that’s in this similar space for a multiple relapse hairy cell leukemia, although not approved by the FDA, is a BRAF inhibitor almost near universal presence at the mutation itself and then possibly implication of pathogenesis. How do we use vemurafenib at this relapsed/refractory setting? Dr Saven, you’re a part of the US multicenter study, and a similar study happened in Italy as well, using a combination rituximab with vemurafenib in a relapse setting, which appears to increase the rate of a CR [complete response]....Perhaps Dr Saven, you can share some of the experience with vemurafenib in this relapsed/refractory population?

Alan Saven, MD: I participated in Jae’s study in the US. We used a dose of vemurafenib that was very high. It was the melanoma dose. If I remember correctly, it was 960 mg twice a day. That was a big dose, and people had a lot of adverse effects. They didn’t feel very well on the drug. They got skin rashes, dysthymia, arthralgias. If they had a hint of skin cancer before the study, they developed invasive skin cancer, keratoacanthomas, some patients even had uveitis. But the drug was active.

Most of the responses were partial rather than complete, but it took protracted therapy, probably 3 to 6 months of oral therapy, before they achieved the maximum responses. Since the completion of that study, I’ve decreased the dose to 240 mg twice a day, and the adverse effects are more manageable. Most people have minor skin changes, minor asthenia, minor arthralgias and tolerate it well. The duration of therapy isn’t really known. If the patients tolerate the therapy, I’ll often do it indefinitely.

In terms of what private practitioners will want to know is: Did you get it approved? I haven’t had any kickback yet, probably because hairy cell leukemia in this subgroup of patients with relapsed and refractory disease is a very small number of patients. If it was a common disease like melanoma or another disease, maybe I’d get more kickback, but I haven’t had kickback in hairy cell leukemia. Every time I’ve prescribed it, it has been approved. I usually use it as a single agent, but there are data showing that you can combine it with an NTP cell agent and you’ll improve the duration and depth of response.

I only have one patient who achieved a partial response under vemurafenib. He’s a young man, but his blood counts were still satisfactory, so I added trametinib. Interestingly, he achieved a CR and didn’t have an increase in adverse effects. He’s been on this combination probably for 6-months plus now. Whereas before, it was a PR [partial response], now it’s a CR.

You could argue that if he had received the vemurafenib longer, perhaps he would have gotten to the promised land, but I don’t think so. It was the MEK inhibitor that changed things for this particular patient. Mechanistically, it makes sense that you can escape through MEK pathways. My experience with a much-reduced dose from what is published—ie, 240 mg twice a day—is that it is well tolerated and achieved the responses.

Farhad Ravandi-Kashani, MD: I agree that the combinations would be more effective in terms of producing responses more rapidly because we know this from the rest of oncology practice that whenever we give a single agent, you get resistant pathways activated. I have experience with dabrafenib plus trametinib. Several patients that I’ve treated have had excellent responses. They do get fevers. Some patients when you give this combination, particularly dabrafenib, get fevers, and in 1 of my patients it was intolerable. But in general it’s extremely well tolerated, and there are no skin problems with the combination. Also, in terms of CD20 antibodies, I would use the vemurafenib in combination because it does produce deeper responses and potentially have longer duration. I’m not sure about indefinite therapy with an expensive oral agent, although we do this in every other hematological malignancy.

Jae Park, MD: There remains the question with some of the future clinical research, Hopefully, we can get some enlightenment from the several studies that are ongoing. Have any of you have used ibrutinib? And do you see a role in the relapsed/refractory hairy cell leukemia?

Farhad Ravandi-Kashani, MD: I’m a part of the NCI CTEP [National Cancer Institute Cancer Therapy Evaluation Program] study that’s led by The Ohio State University group, and we’ve used it in several patients. It is active, but it’s rarely produced CRs. It does improve counts and does provide nontoxic, generally, strategy, and the patients didn’t have many other options. In variants I’ve had a couple patients who have had very good responses. Again, not complete responses, but normalization of counts and improved quality of life. It’s an active drug, clearly. The fortunate or unfortunate thing is now we have so many good and effective strategies for hairy cell that it becomes difficult to actually even conduct these studies. The approved ibrutinib study has taken about 4 or 5 years, but it does provide us with an alternative strategy for some patients, and particularly for variants.

Transcript Edited for Clarity