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Webinar: Understanding Hairy Cell Leukemia
February 29, 2024
Speaker: Dr. Tim Call, Mayo Clinic
Hosted by the Hairy Cell Leukemia Foundation (HCLF) with guest speaker Dr. Tim Call from the Mayo Clinic.
Presentation Materials
Transcript of Dr. Call’s presentation
Dr. Tim Call:
Thank you, Anna. Thank you to the Foundation and thank you to each of you who have come here virtually today to learn together. I'm going to give an update of where we are in hairy cell leukemia.
History of Hairy Cell Leukemia and Early Treatment
Hairy cell leukemia has probably been present for thousands of years. But in the modern era, it was first described in 1958 by Dr. Bertha Bouroncle. She was a mentor to Dr. Michael Grever from the Ohio State University and some of the early members who started the Hairy Cell Leukemia Foundation.
I was a resident in internal medicine and graduated in 1983. Prior to that time, there was no effective chemotherapy for hairy cell leukemia. The only thing that could be done was a splenectomy, to remove the spleen. This allowed the counts to improve for a period of months or years, sometimes longer.
Starting in the mid-80s, three drugs came on the market, first interferon and pentostatin. Then came 2-CdA or what's called cladribine. Interferon was available for a while, but pentostatin and cladribine really changed the treatment of hairy cell leukemia. In the late 90s, rituximab became available; it’s what's called a monoclonal antibody. More recently, we have BRAF inhibitors, MEK inhibitors, and understand more about the molecular basis of hairy cell leukemia.
Hairy cell leukemia is rare, it's about 2% of adult leukemias. There's a male to female predominance. The median age is in the mid-50s, but it can present in the 20s or in the 80s.
Disease Presentation
Regarding presentation, things we look at medically: when a person comes with what's called pancytopenia, meaning low blood counts in all the various lines, the red blood count, the white blood count, and the platelets, we call it pancytopenia. That's one of the tip-offs. There's a cell called a monocyte. If it’s low, that's a tip-off. The spleen may be enlarged.
HCL may also present at the time of an associated infection, because HCL itself does lower our immunity. Sometimes with automated hematology, HCL is now found simply because a blood count was done.
We think about the bone marrow. The bone marrow is the factory of the blood. It's contained within the marrow cavities of the bones, so it's located diffusely across our system. Every day, it is making new red blood cells, which live about 120 days, white blood cells which last a week or two, and platelets. We have early stem cells in the bone marrow that are derived from previous generations of stem cells.
Then within the white blood cells there are subtypes: lymphocytes, monocytes, and neutrophils, etc. Hairy cell is a leukemia where there's an increase in lymphocytes. They tend to accumulate in the bone marrow or the spleen. They crowd out the healthy marrow and that's why the blood counts become low.
This is a case I had a number of years ago, a previously healthy man who presented to the emergency room with cough and fever. A chest x-ray showed a left lower lobe pneumonia. He was admitted and started on antibiotics. When I say empiric, it means our best guess. Sometimes we don't have cultures back yet, so we start antibiotics, based on what the pneumonia looks like, until we get the cultures. The numbers he had showed anemia, the hemoglobin was 7.8. Normal should be 13 to 16. The platelets were lower than normal, and the white blood count was quite low at 0.7.
We look at the subtypes of the white count. Neutrophils, which are bacterial infection fighting cells, were low, so he classified as having neutropenia, which increases his risk of infection. He was started on antibiotics and, in fact, was found to have Legionnaires' or Legionella. He improved his pneumonia, and initially the team thought perhaps the blood counts were low because of the infection. But it persisted and we were consulted. In the blood, there were larger cells called hairy cells.
Cell Markers
You see a barcode here. On the surface of almost all blood cells, and almost all cells, there are codes that identify it as a specific type. Using technology today, we can identify the code, define what the surface of the cells look like, and define the cells.
We do it through what's called flow cytometry, where cells are stained with fluorescein and then put through an analyzer. There's also a molecular marker called BRAF, which is present in nearly 100% of HCL that is obtained by a different technique.
The patient was noted to have a mildly big spleen. He had pneumonia. His blood smear showed what we call a leukoerythroblastic smear, which is a sign of crowded bone marrow. A bone marrow biopsy was done and in the bone marrow, we removed liquid marrow and tried to take a piece of the marrow through a needle. Marrow involves both cells and fat.
The marrow was pretty much packed with cells. When you look at the labs and the cells under microscope, you can see, in the right lower, a hairy cell where you have the purplish nucleus, the cytoplasm. The membrane of the cytoplasm shows that lacy appearance, and that's why it became known as hairy cell leukemia.
Why are these hairy cells? It's because of an overexpression of a specific protein called beta-actin and leukocyte-specific transcript. Those cause the shape of the membrane to change.
Hairy cell tends to be a slower-growing leukemia. How do leukemias grow? The cells are expanding.
There's intracellular speak, so the cells tell each other to keep replicating. BRAF, MEK, and ERK are signals that tell the marrow to keep making these cells. When we look at treatment, like cladribine and pentostatin, they interfere with DNA synthesis and repair, at the nucleus level. BRAF and MEK inhibitors break the message and that's what stops the growth.
Diagnosis and Response to Treatment
We have a protocol for looking at how we make the diagnosis, what tests do we need?
Expert pathology review: When you have a rare disease, some people think because it's rare, it's simple. Because hairy cell can be treated quite effectively now, oncologists may think it's simple.
But there are variants to classic hairy cell leukemia. There's hairy cell variant, and diseases like splenic marginal zone lymphoma can mimic hairy cell. So, it is important that your slides be reviewed at an HCL Center of Excellence or large university center, or by someone who really understands, to make sure it is hairy cell.
When we look at therapy, what we need to be thinking, as physicians and patients is, what are we trying to achieve with therapy?
‘OR’ stands for overall response, what percent of the people treated responded. For a response, you want to see at least a 50% improvement. Above that, you see CR, complete response, how many people had a complete response. The more complete response, the more likely of a long-term cure, or the longer the time of remission. PFS refers to progression-free survival. That means, if you treat, how long until it might come back or not?
So, if a treatment may not cure it, but it has a longer progression-free survival, then that's something that may be very important.
Adverse Events (Side Effects)
What are the adverse events? Certain drugs need to be metabolized by the kidney or the liver, so problems with the kidney or liver may affect that. You’ll read about what's called MRD, minimal residual disease. We use molecular techniques, post-cytometry or DNA-based techniques, to determine if there are any cells left because a microscope is going to miss 1 in 10,000 cells.
Now as the sensitivity increases, the higher chance of a false positive. How do we interpret a one in a million cell in a person who looks totally well and in remission? You want to be careful not to overtreat them because you could have poor side effects. So when we're talking about MRD, it's not something I can answer for you individually, but something you would want to talk to your provider about, if that has any implication in your case.
Cladribine was developed at Scripps Institute in La Jolla, and began being used in the early 90s. Pentostatin was being used slightly before that. They both have very high response rates. There's been no head-to-head comparison that shows one is better than the other; we find that both of them achieve a complete response rate of 72 to 95%, with the majority of the overall response rate approach of 100%. The median time of remission is 8 to 12 years, with survival over 10 years greater than 95%.
A recent publication from the Italians looked at 330 patients treated with frontline cladribine. Following treatment, 80% of the patients were estimated to be alive 15 years after diagnosis. I have patients who have had hairy cell and alive 30 plus years post-treatment. Pentostatin is equally effective. It has some difference in how it's administered, and there are some differences in side effects and metabolism.
Rituxan came in about 1998. It attacks what's called CD20, which is on the surface of lymphocytes, and it works in synergy with cladribine and other chemo drugs and increases the response rate. If you look at MRD negativity, if you look at the diagram, you can see that you get much higher clearance of the marrow using the combination. Again, just to be aware of that. Either cladribine alone or cladribine with Rituxan can be an option. I think more and more we're moving towards Cladribine plus Rituxan.
Another program for frontline has been vemurafenib and obinutuzumab. We'll talk more about vemurafenib in a short period of time. But this is using an agent that attacks what's called BRAF, and obinutuzumab is related to rituximab. It's a second generation rituximab. It’s not a chemotherapy-based regimen. Studies have shown very high response rates. Dr. Jae Park at Memorial Sloan Kettering has been doing studies in this, and there are clinical trials. We know we can have very high response rates with this or rituximab. We don't have the 20, 30 year data, so that has to be discussed.
When it comes to relapse, I've had patients who've relapsed at 11 years, we've retreated them with cladribine again, and they've responded for many years. Often, if they haven't had Rituxan, we'll add cladribine and Rituxan, or we can switch to a different agent.
What was found during COVID is, because cladribine and pentostatin suppress the immune system, it could conceivably hurt your chances of fighting COVID if you had just been treated.
Vemurafenib and rituximab were available, so with the Hairy Cell Foundation, we had an urgent conference meeting and we moved more to the vemurafenib and Rituxan. So, for relapse, many people are moving into this area. There's also work with a drug called ibrutinib, but it's not FDA approved in HCL yet. There was a drug called moxetumomab and, even though it was approved, the company withdrew it because of difficulty with manufacturing and a low usage rate.
If you've had treatment or are having treatment with cladribine, because of the infection risk, we can use a white blood count stimulator one time, right after the infusions. Normally, it's a five-day series of infusions, so this would be given on the sixth day to increase the neutrophils, which will cut down on infections. We often will give antibiotics preventatively for 6 to 12 months, called Bactrim or an antiviral. If a person presents like the patient I presented that presented with a pneumonia, we would now consider treating them with vemurafenib plus or minus Rituxan to enhance their total healing, then conceivably use cladribine later.
Minimal residual disease after treatment: I've had many calls on this from patients who say, "I had my treatment, I had my bone marrow, and now here I am and my doctor said there's 0.12 cells per whatever, and wants to give me more treatment," but they're totally normal. So, you want to be very careful. I've had many patients that remained without any evidence of disease for years. It was just minimal cells, which may have gone away subsequently. I've seen some situations where people got overtreated, and had complications.
Treatment with vemurafenib is effective in patients even who had had three or four different types of treatment previously. When you combine vemurafenib and rituximab, you have very good response rate, and it can last for a long period of time. Probably not forever, but it certainly has less side effects in general.
Everything has adverse events, side effects, even aspirin. With cladribine and pentostatin, adverse events were mostly what's called myelosuppression. Myeloma means marrow, so marrow suppression, low blood counts, immune suppression, increased risk of infection. But, the nausea was almost minimal, a little bit more with pentostatin. Rituximab and obinutuzumab, these two antibodies, the main side effects are either an allergic reaction, which is rare, or an infusion reaction with chills and shakes, which we pre-medicate for with Benadryl and Tylenol.
Vemurafenib
With vemurafenib, there are dose-related side effects of myalgias, muscle aches, skin changes, rash, and a slight increase in the simple skin cancers. So if you're on vemurafenib, we normally have you follow regularly with dermatologists. Sometimes there is a bit of pigmentation but, we can decrease the dose. There have been reported cases of pancreatitis. I've not personally ever seen that, but it is reported. Ibrutinib is a drug that can be used, but usually if nothing else is really working. It tends to more stabilize the disease than put it in remission.
After you're treated your blood counts will be monitored until they recover near normal, and then gradually they’ll increase the interval between monitoring. There's debate, is a bone marrow biopsy mandatory? Will it change the treatment, or could it lead to an extra treatment? The main point is, do not do the marrow too early. If it's after vemurafenib, you can do the marrow because you're going to see the response. If it's after cladribine, we can see further deepening of response even up to a year after. So usually, we wait at least six to nine months before checking the marrow.
HCL Consensus Guidelines
As a group, we have published guidelines, and these are guidelines that are adopted. Here are our previous guidelines regarding the COVID-19 situation.
Finally, we talk about our immune system. The immune system is like describing the universe, there are so many facets. We have the innate immune system, our white blood cells, our neutrophils. Those, the marrow is producing every day. If they're low, you may have immune suppression. Hairy cell leukemia itself suppresses those. Cladribine and pentostatin may suppress those. Rituximab tends not to.
Then we have the adaptive immune response. So this is, can our immune system be stimulated to produce antibodies? This is where nature's vaccination is being exposed to an infection and creating antibodies. So the immune system is very complex, but we have part of it that is defined numerically and produced by marrow cells, and part of it that can be induced either from prior infection or from vaccination. We need to switch to any questions, and I think we've covered the majority.
The transcript has been edited for clarity.