Updates in the Management of Hairy Cell Leukemia - Episode 2

Molecular Genetic Changes for Hairy Cell Leukemia

June 30, 2020
Steven Coutre, MD, Stanford University Medical Center

Farhad Ravandi-Kashani, MD, MD Anderson Cancer Center

Jae Park, MD, Memorial Sloan Kettering Cancer Center

Alan Saven, MD, Scripps Health

Andrea Sitlinger, MD, Duke University Cancer Institute

Jae Park, MD: Dr Coutre, perhaps you can enlighten us about the molecular genetic changes that have been identified in hairy cell leukemia.

Steven Coutre, MD: This is a fascinating disease because of its molecular basis. In 2011 we had the publication from Italy, from doing whole exome sequencing of patients with hairy cell leukemia. They published a report that said we sequenced these patients, and essentially every patient had a BRAF mutation, V600E. It was striking, and it is in the case of hairy cell, a disease defining mutation. In fact, those who don't have it, who have a hairy cell-like presentation, are probably the patients with hairy cell variant, which largely we consider a distinct disease these days, including how we might approach treatment. The importance of that mutation is that it leads to constitutive activation of the MAP kinase pathway, which controls cellular processes like proliferation and cell death. You get phosphorylation of ERK and MEK downstream, and that gives this cell an advantage if you will, and essentially drives the transformation from a normal cell to a leukemic cell.

We'll talk more about how we take advantage of that singular mutation from a therapeutic perspective. There have been other molecular abnormalities described, some of the cyclin-dependent kinases, for example, that typically act as tumor suppressor genes. Those are actually inactivated in some patients with hairy cell, admittedly the minority, less than 20%, but they coexist with the BRAF mutation, and they play some role in those patients. It’s acting as a suppressor gene, it’s inactivated, and the cell has an advantage. They also tend to have the same allele frequency as the BRAF mutation, suggesting that it's really an early event, a clonal event if you will, that is important to the transformative process.

Farhad Ravandi-Kashani, MD: With hairy cell sometimes you get a dry tap when you do a bone marrow. I've seen this frequently, that they send a sample for BRAF mutation, and it comes back as negative. This has to be well-publicized because, again, in most of our experience classical hairy cell almost always, perhaps even 100% of time, does have the BRAF V600E mutation. But the sampling is very important, and there are other ways of eliciting that BRAF mutation, for example, immunohistochemistry is a way of showing its existence. The reason I bring this up, I have had consultations about a patient who morphologically was classical hairy cell. Flow markers were classical hairy cell. This was a multiply relapsed patient, and they were reluctant to give the patient the BRAF inhibitors because they felt that there was no BRAF mutation. I think that point has to be emphasized, that you can actually miss this if you just use the simple dry tap from the bone marrow because you won't get adequate specimen.

Steven Coutre, MD: Dr Saven, have you ever seen a patient with classic hairy cell where you've done testing for BRAF, and you're absolutely convinced that it wasn't present?

Alan Saven, MD: Yes, it’s very uncommon. But like everything in medicine, nothing is 100%, but I think it's 99.9%. I have seen 2 or 3 patients where I repeated the bone marrows and they were aspirated. I did all the next-generation sequencing, it was negative, and they didn't have hairy cell variant. They tended not to do as well as the patients who were BRAF positive, but it's only anecdotal. I've only got a few cases, the overwhelming majority are positive, but it's not 100%.

Farhad Ravandi-Kashani, MD: I think, Alan, those are the VH4-34–positive patients, correct?

Alan Saven, MD: No, they were negative for that. They exclude each other. If you’re BRAF positive, you’re negative for the VH4-34, and vice versa.

Jae Park, MD: That’s an important point that you raised there. I had another extreme case, where everything else, immunophenotypically, morphologically, [suggested] hairy cell leukemia, but because of a negative BRAF, which was missed or there was sensitivity of the assay perhaps, the patient ended up getting treated not for hairy cell leukemia, but for another indolent, non-Hodgkin B-cell lymphoma-type of a category. The patient ended up getting complications from the therapies, and so forth. It’s important to look at all factors, not just 1 particular molecular feature, but immunophenotypically and the morphology, and then obviously clinical presentation. I do think it’s a very important point that you raised there.

Transcript Edited for Clarity