BRAF/MEK Inhibition in HCL Management

Transcript:

Robert J. Kreitman, MD: We’ve talked about the addition of rituximab to purine analog. We’ve talked about the fact that it’s really not necessary to switch from cladribine to pentostatin if you used cladribine or pentostatin the first time, to switch to a different purine analog.

Let’s talk about the use of vemurafenib in hairy cell leukemia [HCL]. We could also talk about the treatment with combination BRAF/MEK inhibition, which both of us have had some experience with.

Farhad Ravandi-Kashani, MD: I think the discovery of BRAF mutations as being almost universal in classic hairy cell leukemia has been 1 of the most exciting events in hairy cell leukemia. Especially the investigators from Italy have shown in beautiful studies that this mechanism, or development of BRAF mutation, is pathogenic in the development of hairy cell leukemia and the development of the hairs of the hairy cells. Also, studies have shown that using effective BRAF inhibition, you can actually effectively kill the hairy cells. In elaborate experiments they have shown that in using BRAF inhibitors, you can actually make the cells lose their hair, which is very exciting and intellectually a very important development.

The first study is of vemurafenib in hairy cell leukemia, which is a BRAF inhibitor that was actually developed for melanoma. There were 2 studies that were published in the New England Journal of Medicine showing that this agent is truly effective and does produce responses. This is an oral agent and the advantage is that it doesn’t produce a lot of minor suppression, but the disadvantage in my opinion is that we still don’t know how long the patient should be taking the drug.

When we use it in combinations, you mentioned the combination with the MEK inhibitor, trametinib, of another BRAF inhibitor, dabrafenib. We both participated in the study. That is a truly remarkable combination and produces, in my anecdotal experience, amazing responses in multiply relapsed hairy cell leukemia. Also, there is a combination of vemurafenib with rituximab that has been conducted in a clinical trial showing that when you add the rituximab you can actually shorten the duration of vemurafenib use.

I think these agents are exciting and effective. In terms of the duration of use as well as the cost of therapy, perhaps if you think about it in terms of comparing it to cladribine, which is now a very cheap agent, the use of such expensive oral, potentially long-term agents, could make it very expensive to treat hairy cell leukemia.

Robert J. Kreitman, MD: Right. These agents also have significant adverse effects. In the vemurafenib case, we can see squamous cell carcinomas and other skin problems. In the dabrafenib/trametinib case, we see fevers. There are other adverse effects that can be quite annoying for patients, particularly if they have to get it long term. Long term seems to be the need in patients who really want long-term control of the hairy cell because these BRAF inhibitors are not known to eliminate minimal residual disease [MRD], at least by bone marrow aspirate flow. Although we’ve seen this occasionally, we haven’t seen persistent elimination of minimal residual disease by all tests.

We’ve also seen patients who’ve been MRD-free instantaneously, but then they develop a positive MRD. We’ve seen those patients relapse if they don’t stay on treatment. That tends to be a disadvantage. Although the use of rituximab now, which is being tested in clinical trials, may change that. We’ll have to see.

Transcript Edited for Clarity