A Rare but Treatable Disease: Therapeutic Considerations for Hairy Cell Leukemia

Martin S. Tallman, MD

While uncommon, the prognosis for hairy cell leukemia (HCL) is quite favorable, explains Martin S. Tallman, MD, adding that most patients respond to the standard of care,

cladribine, with relapse rates between 25% and 35%.

However, as the biology of HCL continues to be further understood, markers such as BRAF mutations has opened the door to new therapeutic strategies for patients.

In an interview with OncLive, Tallman, c

hief of Leukemia Service, Cassidy Family Endowed Faculty Chair, hematologic oncologist, Memorial Sloan Kettering Cancer Center, discusses the biology, prognosis, and current treatment options available in HCL.

OncLive^®: Given that hairy cell leukemia (HCL) is a relatively rare form of leukemia, what are some of the characteristics of the disease?

Tallman: HCL is quite uncommon. There only 600 to 800 cases per year in the United States. Interestingly, for unclear reasons, it is much more common in men than women—approximately 4 to 5 times more common in men than women—and the etiology is completely elusive. [It is believed] there is a genetic component, because there are 6 or 7 reports in the world’s literature of first-degree relatives or brothers who have the disease. When you have such a rare disease and you see reports of it occurring in a mother and a son or a father and a son, it makes one wonder [if] there is a genetic component. But the details of that genetic predisposition are completely unknown.

The diagnosis of HCL is made almost solely based on the findings of a bone marrow aspiration biopsy. The aspirate is often not able to be obtained, which may be a clue to the diagnosis, because the disease may be associated withfibrosis or scarring in the bone marrow. Although one would think that a grown adult could pull up the liquid aspirate, those strands of fibrosis are apparently so taut and tight that we often have difficulty aspirating. In fact, if you can aspirate, we used to say that that may be a clue that the diagnosis is not HCL, because it’s so characteristically inaspirable. So, the answer is really in the bone marrow biopsy, and if we get aspirate, it helps, and then we use the flow cytometry to determine the immunophenotype to look at the markers on the surface of the cell.

The physical examination is interesting in that the positive findings are confined to splenomegaly, to enlargement of the spleen. There [are] almost never enlarged lymph nodes at the time [of] diagnosis, and the liver is usually not enlarged, and we do not often find a skin rash and heart and lungs are usually normal. The only finding of any consistency is enlargement of the spleen, and some of the largest spleens we see, in fact, are in HCL.

In addition to the immunophenotype by flow cytometry, we [also assess for] BRAF mutation. The BRAF mutation is quite pathognomonic; not 100%, but almost every patient with HCL is positive. The one exception is about 15% of patients who have a variant called the HCL variant, and they are BRAF negative. Vemurafenib is a new treatment that is a BRAF inhibitor; it is a very effective agent in classical HCL, but not very active in patients with a variant because they’re BRAF negative.

The median age is about 48 to 50. Additionally, we find pancytopenia, or low blood counts, in about 85% of people. The variant, in addition to being BRAF negative, can present with leukocytosis, but a classic HCL [case] is almost always a very low blood count. We also see monocytopenia, which is quite characteristic.

If a physician or other healthcare professional sees a young to middle-aged man with pancytopenia and a big spleen, one really has to think seriously, as uncommon as it is, about HCL.

Could you offer some perspective regarding the variability on HCL prognosis?

HCL has an excellent prognosis. The treatment of choice today is a purine analogue agent called cladribine, and it’s either given in a 5- or 7-day schedule. The response rate is extremely high. In fact, roughly 85% of patients achieve a remission by routine evaluation. Some percentage of patients will have evidence of minimal residual disease by special studies, either immunohistochemical stains or immunophenotype by flow cytometry, but this can be, and often is, such an indolent disease that even if someone has some evidence of minimal residual disease by special studies, we don’t usually introduce additional therapy as long as their preferable blood count is recovered to normal. So, [the] overall outlook is extremely favorable. The relapse rate is about 25% to 35%, and most of those patients at 2 years or after, and the treatment of choice actually, interestingly enough, is another class of cladribine, often followed by rituximab. The outlook is extremely favorable.

Can you discuss the BRAF mutation and how you see its continued emphasis in research and treatment over the next several years?

The discovery of the BRAF mutation opened the door to BRAF inhibitors like vemurafenib [Zelboraf], which has been used in melanoma. BRAF mutations have been found in melanoma interestingly enough, and vemurafenib has been used extremely successfully. This led to the development of vemurafenib, an oral BRAF inhibitor. It was first used in previously treated patients, and now we have an open trial testing the combination of vemurafenib in newly diagnosed patients with the anti-CD20 antibody obinutuzumab [Gazyva]. Another BRAF inhibitor is dabrafenib [Tafinlar], which has not been studied in an organized way, but has been given to patients with HCL. In short, the discovery of the BRAF mutation really opened the door to a whole new strategy to treat patients with HCL.

What is the role of rituximab in treatment regimens for patients with HCL?

Several [articles] have suggested that the administration of rituximab to patients with minimal residual disease after cladribine can eradicate minimal residual disease. However, we do not know that those patients live longer. In other words, it sounds intuitive that it is better to have no disease than a little disease left, but that’s not necessarily true. HCL is such a slow-growing disease. Patients can have evidence of minimal residual disease, and in fact, some patients can have evidence of overt morphologic disease for up to 15 to 20 years. Some clinicians have suggested that it is better to have no disease than a little disease, and therefore they are enthusiastic about administering rituximab after cladribine. My feeling is [that] there’s no evidence that it will prolong survival. Patients often do extremely well with a minimal residual disease, and they can have residual disease for decades.

In relapsed/refractory HCL, can you share your perspective on recent changes to the guidelines regarding second line and the use of therapies there?

The treatment of choice for patients with HCL who have relapsed at least 1 to 2 years after treatment with cladribine is, in fact, another cycle of cladribine. We may follow it with rituximab in that setting. We do not like giving more than 2 cycles of cladribine, because we risk immunosuppression and stem cell damage.

There is a drug that has been approved by the FDA called moxetumomab pasudotox. It is an immunoconjugate, and it is indicated in patients with HCL who have already been exposed to at least 2 different treatments, one of which must be a purine analogue. If someone had 2 courses over 3 or 4 years cladribine, they would not be eligible, but if they had cladribine once and then rituximab a few years later, then they would be eligible. If someone fails 2 cycles of cladribine a few years a part, they could get moxetumomab pasudotox, they could get rituximab alone, or they could get vemurafenib outside the context of a clinical trial, because it is commercially available. It would be off label, but they could get that. One could give pentostatin [Nipent], but I’m less enthusiastic about that because it has its toxicities and it requires prolonged therapy.

As you look at the current treatment spectrum now and as it evolved over the last several years, how do you expect the treatment paradigm to continue to evolve?

There will be more studies with vemurafenib and other, perhaps more potent, less toxic BRAF inhibitors. Combinations will also continue to be used. Exploiting the BRAF inhibitors probably with antibodies will be the direction that future research will take in the next 5 years.

Although HCL is rare, it’s highly treatable. We do not know if it is curable yet, but it is a disease that has fascinated healthcare professionals in the field because the cells themselves are interesting and because they have hair-like projections. HCL has a clear clinical presentation, and it’s such a gratifying disease to treat because of the new effective therapies, so I’d say it’s actually a very interesting and fascinating disease to work in. n