Understanding Hairy Cell Leukemia
September 19, 2023
Presenter: Dr. Kerry Rogers, The Ohio State University
Hosted by the Hairy Cell Leukemia Foundation (HCLF) with Dr. Kerry Rogers from the Ohio State University and moderated by Anna Lambertson, HCLF Executive Director. This program is part of a quarterly webinar series hosted by the HCLF in collaboration with HCL Centers of Excellence.
Presentation materials
Transcript of Dr. Rogers’s presentation
Dr. Kerry Rogers
People attending this webinar have variable degrees of understanding of hairy cell leukemia, so I would like to start with the basics.
Hairy cell leukemia is a chronic type of blood cancer. Chronic means people have it for a long time. The cells that become cancer cells in hairy cell leukemia are a type of white blood cells called B lymphocytes. These are immune system cells. The original description for HCL was leukemic reticuloendotheliosis.
Hairy cell leukemia is diagnosed based on the presence of hairy cell leukemia cells. Frequently this requires a bone marrow biopsy, usually done at diagnosis. Although the leukemia cells are usually in the blood (that's why it's classified as leukemia), they can be in the bone marrow, lymph nodes, spleen, and elsewhere. I have had patients with hairy cell leukemia with bone involvement. This is a blood cancer, so it can be anywhere the blood goes. It is very normal for blood cancers to be in multiple places in the body.
The leukemia cells for hairy cell leukemia are identified commonly by two things. One is something we call morphology, which is what they look like, and this is how hairy cell leukemia got its name. Hairy cell leukemia cells look like mature lymphocytes. The features of the cell nucleus have cytoplasmic hair-like projections around them; that’s why it’s called hairy cell leukemia.
Cytoplasm is the material inside the cells, and there are markers on it. Physicians and researchers identify different cells using these different markers which we call cluster differentiation (CD).
There are several B-cell markers such as CD19 and CD20, and CD11C, CD25, CD103, and CD123. The markers can be determined by a test called flow cytometry, which is a test where they paint the cells with antibodies with different fluorescent markers linked to them that target these markers we're looking for. We fire them in front of a laser that provides a readout, or we can use special stains to look in the bone marrow .
Classic hairy cell leukemia has a mutation called BRAF V600E. That's in about 98% of cases of classic hairy cell leukemia. There are a few cases of classic hairy cell leukemia that have different BRAF mutations, but if you’re trying to figure out the diagnosis and there's a BRAF mutation, you know this supports a diagnosis of classic hairy cell leukemia.
There's a variant form of hairy cell leukemia which is rarer; it's about one out of 10 cases. HCL variant looks the same as classic hairy cell leukemia with the hairy projections, but the markers are slightly different. The variant form doesn't usually have CD25, and it has a different spectrum of mutations.
Recently, the World Health Organization (WHO), which is the organization that classifies different cancers, has started calling the variant of hairy cell leukemia ‘splenic lymphoma with prominent nucleoli,’ which is a visual or morphological description that lumps it in with some other cancers.
There's something about hairy cell leukemia in some cases that causes the bone marrow to grow extra fibrous tissue, which can interfere with blood cell production. It does reduce or go away with treatment of hairy cell leukemia, but this is an interesting feature that helps diagnose HCL. It's called reticulin fibrosis.
HCL is rare
Leukemia is a relatively rare cancer compared to breast cancer or lung cancer, which are more common. There are both acute and chronic leukemias, myeloid and lymphoid leukemias, and then within chronic lymphoid leukemias, hairy cell is very rare. CLL, which is the most prevalent adult leukemia, is also a chronic lymphoid leukemia.
Hairy cell leukemia is pretty uncommon, about 2% of adult leukemias. Estimates for how many cases there are in the United States vary, from 1100 to between 600-800.
The median age at diagnosis is 55, but HCL occurs in both younger and older adults.
It is more common in men, with about four men for every one woman diagnosed. And it is more common in white people. The expected survival for hairy cell leukemia is decades, and in most cases, it does not shorten the natural lifespan. Most people diagnosed with hairy cell leukemia who are over the age of 40 statistically would not expect a shorter lifespan than people who are the same age and sex but did not have hairy cell leukemia.
Clinical features of HCL
There are a couple of clinical features I want to cover. One is, many people are diagnosed with no symptoms, so they'll see that their blood counts are low when they go for a physical or get tested before surgery or some other reason, and then end up seeing a hematologist, getting a bone marrow biopsy, and they have hairy cell leukemia. One of the most common findings is low blood counts, and these can be mild and asymptomatic, or very severe and requiring transfusions. The low blood counts are usually due to either the bone marrow is so full of hairy cells that the healthy blood-producing cells can't make enough cells, or the fibrosis fills up the marrow and crowds out the healthy blood-producing cells.
The monocyte is a type of white blood cell. In hairy cell leukemia, the normal monocytes decrease, so you'll see people with relatively normal blood counts and their monocyte count will be zero. When the hairy cell is in remission, you'll see the monocyte count in the blood normalizes.
People with HCL can get big spleens, at times very large spleens. Your spleen is in the upper left side of your abdomen, and there's a lot of space in your abdomen to expand. People can have enlarged lymph nodes, bone lesions, or other features. Sometimes people have fatigue that will limit their usual activities. Sometimes the fatigue is from the hairy cells, but usually it's from anemia or low red blood cell amounts. Then, many people actually have an infection at time of diagnosis, and hairy cell, being a cancer of immune system cells, impacts the healthy and normal functioning of the immune system and increases risk for infections that don't occur in individuals that don't have some form of immune compromise. That's a special situation, if people have both an infection and need treatment for hairy cell.
When to treat hairy cell leukemia
People might be surprised to learn that treatment is only needed when there's something to improve. We don't have to treat HCL just because it exists. People with cancers usually think, get it early, get treatment right away, as quickly as you can, but we don't think this makes a difference in hairy cell leukemia. And in other chronic B-cell cancers, early treatment does not improve survival at all. There's really no reason to treat people that aren't having any problems with it, and it would just expose them to side effects before that would be needed.
Before treatment, a bone marrow biopsy can be helpful. One, to make sure low blood counts are from hairy cell leukemia. If that wasn't determined previously, you wouldn’t want to treat hairy cell leukemia and find out that there's something else going on in the bone marrow. Assessment of general health and organ function is important to help select treatment. And we want to make sure it's known if the patient has infections or any disease symptoms.
HCL Treatment
Here are the major treatment options for hairy cell leukemia, the first is the one that's had the most impact to date on outcomes for hairy cell leukemia, and that's a class of chemotherapy called purine nucleoside analogs. These are cladribine and pentostatin. Development of these drugs has taken the expected survival for people living with hairy cell leukemia from an average of four years to their natural lifespan where today people die of something else. That is really due to the impact of these drugs, so this is huge. They're the most commonly used treatment. They're usually used as a first treatment but can be given multiple times, and sometimes they're combined with anti-CD20 antibodies.
The good news is that there are treatments beyond purine analogs today, something that people in the field, including myself, have been working on, because there are patients who couldn't tolerate purine analogs, have already received several courses with very short remissions, it's not working well anymore, or they had side effects where the purine analogs are unsuitable. So there is a need for other treatments.
BRAF inhibitors inhibit that mutation that's in classic hairy cell leukemia, vemurafenib being the most studied. BTK inhibitors inhibit a protein called BTK in B-cells. We've been leading a study here that multiple centers have participated in looking at ibrutinib. Moxetumomab pasudotox is not currently available, but I would like to mention it briefly, and then there are some older treatments that could be useful in special circumstances.
Pentostatin and cladribine
Here are the purine analogs, pentostatin and cladribine. I know of no one who thinks that one is more effective than the other. There are big differences in the administration schedule. Cladribine is given continuously for seven days, or more commonly, daily for five days, so that means coming for treatment Monday through Friday, over one week. Pentostatin is given every two weeks until the blood counts improve, and then you get two consolidation doses, so it can be drawn out. People don't generally get more than a year of pentostatin, but it does entail months of getting treatment as opposed to five days. You might think, "Why wouldn't I want this done in one week?" If you get your entire chemotherapy course in one week, the recovery is much more than one week, so it is harder in terms of the decrease in blood counts. Cladribine is not recommended for anyone with an infection and is somewhat less tolerable because you get all the chemotherapy at once, even though it's given over one week, and it can take months to recover. I've seen some people where at two or four months, their blood counts still had not recovered from cladribine, so just because the administration is short doesn't mean that the total consequence is short.
Pentostatin is generally a little more tolerable, although some people don't like the fact that it's drawn out. Pentostatin also can be used in people with certain active infections. You start with about half the dose, and generally you don't see such a low drop in blood counts when you take it because you can hold the dose if blood counts start dropping lower. So, it's a little more controllable. Also, for pentostatin, the course varies depending on how quickly it works.
Outcomes with purine analogs are extremely good. The remission rates are close to 100% with about 80% complete remission, meaning no detectable hairy cells and the blood counts normalize, or you can't see hairy cells in the marrow. This results in between two or 10 or more years in remission, and there's a fraction of people, around 10 to 20%, that don't need treatment again in their lifespan after getting these drugs. The median time to next treatment is seven to eight years, but patients with a complete remission do better than those with a partial remission. But, patients with partial remission can get re-treated with purine analogs, and occasionally, especially with cladribine because it's a fixed dose, you can get a longer remission with the second treatment.
If cladribine or pentostatin are given as a subsequent treatment, there have been several studies looking at adding rituximab, which is an antibody targeting CD20 on the leukemia cells and can prolong remission. There was a study that Dr. Bob Kreitman at the NCI that randomized patients, some receiving cladribine and rituximab together at the same time, others receiving cladribine and then rituximab later if the leukemia became detectable. Giving rituximab for eight weeks starting with the week of the cladribine did increase the rates of complete response and the rates of undetectable leukemia.
However, at 7.7 years of follow-up, there were no differences in how many people had relapsed or progression-free survival, which is how long people were alive without their leukemia returning. It's not known if the rituximab is necessary to improve long-term outcomes, although it probably does help to have less detectable leukemia. Rituximab also has more side effects, because you're getting two drugs together, and for people starting with low blood counts, some people get sick from taking the cladribine and rituximab treatment concurrently. This is an option, but it is something that needs to be discussed as a risk-benefit with the physician.
Vemurafenib
The next thing I want to cover is vemurafenib. This is an oral agent that targets mutant BRAF, and it rapidly eliminates the leukemia cells. The problem is, the remissions don't last as long because people don't take it continually. Vemurafenib is usually given for a course, and there is some work mostly led by Dr. Tiacci in Italy to add rituximab to it. It is questioned whether we should use this instead of cladribine and pentostatin as a first treatment, and that's being investigated now in studies. However, because most people with HCL do very well, it can take over a decade to see differences in treatments; the research progress in understanding these treatments is sometimes slower.
Ibrutinib
Ibrutinib is a pill that targets a protein called BTK. It's approved in four B-cell cancers but is not approved in hairy cell leukemia. It is in the guidelines from the National Comprehensive Cancer Network (NCCN), so can be used in hairy cell leukemia off-label and is very effective. There's a lot of experience with this drug in people with the variant. We reported this at a hematology meeting last year, and it leads to very good disease control. At five years, 68% of people were alive with their leukemia still in remission, and 87% of people in the study were alive. Some people did die of other things, like of infection. This is not a first treatment, so the median number of treatments people had received before enrolling in this study was four. These are people who weren't benefiting from purine analogs or other treatments.
Moxetumomab pasudotox
Moxetumomab pasudotox has largely been investigated by Dr. Bob Kreitman. It was approved for hairy cell leukemia and works but is currently not available.
Summary of treatment options
Purine analogs remain the standard treatment for hairy cell leukemia. However, good options exist for patients where purine analogs are unsuitable. Vemurafenib has been very useful in people having infection because it improves blood counts rapidly and is not immunosuppressive, so for people with serious infections at the time they need treatment for their HCL, vemurafenib has been an outstanding option and quite useful during the COVID-19 pandemic. There are some health maintenance implications for hairy cell leukemia. Remember, HCL is an immune system cancer, so it can modify the immune system. This increases the risk of other forms of cancer like prostate cancer and skin cancer, and also increases risk for infection, so it's a good reason to get all vaccines that you're supposed to, if you have hairy cell leukemia, because the risk of being hospitalized or severely ill from infection increases. Outcomes with hairy cell leukemia are good, so people can expect a normal or near normal lifespan, so make sure you get screened for diabetes, heart disease, wear your seatbelt, and do the other things, like exercise, that you need to do. Behave like you're going to be around for a while.
This transcript has been edited for clarity.