Leslie Andritsos, MD: As therapies for hairy cell leukemia have improved, the survival has become much longer. For example, when the only effective therapy was splenectomy, the median survival for hairy cell leukemia was about four years. In contrast, nowadays patients who have a good response to therapy will have a survival comparable to age-matched control. So it is imperative to keep in mind survivorship issues in these patients with chronic diseases and carefully select therapies that are not going to have toxicities that overlap with their other comorbidities. As the population ages, it’s imperative that we develop therapies that are tolerable for patients who are older and have other medical problems.

Gary J. Schiller, MD: There are conceptual unmet needs, and then there are some practical unmet needs. The conceptual unmet needs revolve around diagnosis. As I said at the beginning, this is a disease entity in which you have to think about the disease in order to get the diagnosis. I’ve seen patients anecdotally who have been seen by other hematologists, even at incredible institutions, where the thought never came up. And the hematopathologist did not dispense a diagnosis of hairy cell leukemia because it wasn’t entertained and because the ordering physician didn’t entertain the diagnosis. So there’s a big diagnostic problem.

There is a little bit of a conceptual problem as to how to put this in a spectrum of indolent lymphoproliferative diseases. Where did it come from, what’s the etiology, how does it occur, how do people get it? I think there are open questions in a relatively rare disease in trying to determine where the disease comes from. We also have a few conceptual issues regarding the disease and its course because the course of hairy cell leukemia has been so profoundly affected by the purine nucleoside drugs.

Before this, I still remember when what we had was splenectomy and after that, alpha interferon. And the disease course generally was not so prolonged. Now, in the era of purine nucleoside drugs, the disease course can be measured in decades. But there are patients, and I don’t just mean patients who have a variable form of hairy cell leukemia, with classic hairy cell leukemia whose disease course is short. Time to relapse between treatment episodes of purine nucleoside drugs is measured in one to two to three years. It would be nice to know who those patients are, and if we knew that and if we had some biological marker, it would lend itself to doing clinical trials with combination treatments to either delay relapse or to effect some change in the natural history.

Leslie Andritsos, MD: Vemurafenib, which is a BRAF inhibitor, has been studied in hairy cell leukemia and has shown very high response rates. It’s being studied with obinutuzumab to try to deepen and lengthen those responses. Also, ibrutinib, which is a BTK [Bruton tyrosine kinase] inhibitor, is being studied in both variant and classical hairy cell leukemia. That study is still accruing and should be finishing up soon, and we’ll be able to see the results of that study, hopefully published very soon.

In addition, purine nucleoside analogs have been studied in combination with rituximab, and it’s clear that Rituxan does help to deepen and lengthen the responses when given in combination with purine analogs. One of the open questions now is where Rituxan should be added to upfront therapy. I think that’s still a clinical trial type of question, but as we refine our risk stratification profiling, we may be able to identify those patients at higher risk of early disease progression. And it may make sense to add Rituxan to the purine analogs in those cases.

Gary J. Schiller, MD: The natural combination approach that has been studied in the past is combination purine nucleoside drug with rituximab, the monoclonal anti-CD20 antibody. Now, this therapy is highly effective. The question is whether it’s necessary. The induction of remission is almost 100%. However, the cost is severe immune suppression and no clear evidence that the duration of remission is prolonged by the intervention. Again, until we can identify who those patients are whose remission duration of purine nucleosides will be relatively short, it’s going to be hard to incorporate a second- or third-line agent into initial management because the risk of side effects might be greater than the likelihood of a favorable outcome for a minority population. But if you could identify genes that drive the disease in a different way, then it would be natural to combine purine nucleosides with a more effective monoclonal like moxetumomab, or a BRAF inhibitor with moxetumomab or rituximab, maybe even do away with purine nucleoside drugs because of their immunosuppressive effects and need for prophylactic antibiotics. But again, I think we need to know a little bit more about biology to isolate a different risk group.

Transcript Edited for Clarity