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2025 Patient Seminar Session: Expert Panel
The Hairy Cell Leukemia Foundation hosted this session with the following panelists: Dr. Michael Grever, The Ohio State University; Dr. Kerry Rogers, The Ohio State University; Dr. Jae Park, Memorial Sloan Kettering Cancer Center; and Dr. Sameer Parikh, Mayo Clinic
Topics discussed during the panel discussion included, but were not limited to current treatments, clinical trials, supportive care such as antibiotics, vaccines, and exercise.
Transcript of Panel Discussion
Opening Topic: Current Treatments in Hairy Cell Leukemia
Dr. Michael Grever
The change in HCL therapy has been remarkable. When I first got involved in HCL with Dr. Bouroncle back in the 1970s, the period of patients doing well was about four years. Now, we can tell people that they can plan on living a normal life. And if they relapse, people on this panel and our other colleagues have developed regimens to help people get back into another remission.
It’s important to get to a center where you can evaluate the molecular characteristics of the leukemia. In some patients, particularly with the variant hairy cell leukemia, they lose an important gene called p53. And that predicts that you’re not going have a good long-term response. You may get a temporary reduction in the leukemia, but it’s short-lived. And if it’s a short-lived response, then you’re going have the side effects without the benefits.
I have one patient who had been treated with several courses of a purine analog, and the spleen would shrink but then would rapidly regrow. And when we evaluated her, we found that she had only one arm of chromosome 17, and on the remaining arm of 17 she had a mutation in p53.
The BTK inhibitors may have some benefit in this group. So, we placed her on ibrutinib. She was off study because we didn’t have the study open at that time, but we also added rituximab. And she went into complete remission and has no remaining hairy cell leukemia visible. She’s now out two years from therapy. She’s a farmer and she’s very active.
There are several different abnormalities that can be identified. For example, there is a gene called MAP2K1, and if there are mutations there, that sometimes affords the possibility of using other innovative drugs. It’s going to be very interesting to try and utilize the information from these molecular studies so that we can optimize therapy.
There’s no doubt that the purine analogs with rituximab have the best long-term response. One has to be careful though. I had a relatively young man who had been hospitalized with a very serious pneumonia, and he needed to be treated. Rather than putting him on cladribine and rituximab, because we were concerned that he might have a progression of his infection, we treated him with pentostatin alone. He went into a complete remission after six months’ worth of therapy. And he has negative minimal residual disease by the most detailed tests.
So, one of the observations that Dr. Kreitman has really helped is the simultaneous administration of cladribine and rituximab can achieve negative evidence of residual leukemia. But one of the things that we don’t really know is, does the prolonged duration of therapy with pentostatin have an equal chance of achieving that, maybe with less toxicity?
So, you have to be careful about using the intensive regimens if somebody has an active or recent serious infection.
Jae has done some innovative work with using a monoclonal antibody as part of therapy with a BRAF inhibitor in the upfront setting – and that is potentially useful in people who have a serious infection, because you don’t encounter all the consequences of severe prolonged myelosuppression.
Dr. Sameer Parikh
It’s critical to get the correct diagnosis.
When there are multiple treatments necessary in a few years after initial therapy, where we would expect that the response would last for many years, that calls into question, “what are we missing”? At that time, reevaluating everything is very important.
And I’ll throw a plug for participation in clinical trials because that’s really the best way to treat any particular disease. For example, in the frontline setting, Dr. Park is leading a trial that is evaluating the role of standard therapy with cladribine and rituximab versus the combination that Dr. Grever just mentioned with vemurafenib and obinutuzumab. I think that’s a very important clinical trial because that’ll set the stage for potentially chemo-free treatment options in the frontline setting for our patients with hairy cell leukemia.
Dr. Michael Grever
There are sometimes social factors that come into these decisions. I have a 93-year-old patient who is the sole care provider for his wife who has severe dementia. I treated him with vemurafenib, and we were able to maintain him functional for four years. And he’s still taking care of his wife.
I have another patient who is younger; they live in rural Ohio. Her father was dying with cancer, and she was his sole support. So, if we had treated her with intensive chemotherapy, she might’ve ended up in the hospital with nobody to take care of her father.
She’s now in complete remission. We treated her with pentostatin. I also added a second course of therapy because she still had residual disease, but she’s perfectly functional now. And we’re going to probably proceed with some post-treatment with rituximab.
So sometimes the social situations mandate that you take a tailored approach.
Dr. Jae Park
There are some special circumstances: a fertility aspect or pregnancy, or they have upcoming surgery but they’re cytopenic and worried about the infectious complications. The good news is that hairy cell patients have great options in those special circumstances.
I’ve had some patients where I’ve treated with vemurafenib, which is non-myelosuppressive, and we do typically combine that with an anti-CD20 antibody like obinutuzumab or rituximab. Even if you just get vemurafenib for two weeks, three weeks or just a month – by the end of it, your blood counts are almost normal or closer to normal, especially platelet counts are usually the very first one to recover.
And that was enough for the patients to get through the surgery they needed without committing to three to four months of a therapy and waiting for the immune system to recover. We have some temporary but very effective tools to get them through [so they can] get to the surgery, procedures or pregnancy and carry on with their lives.
That is another good observation, which may not be appreciated in a non-specialty center. So, if you’re in one of those kinds of situations or questions, I think there’s one benefit of asking your doctor to reach out to the Hairy Cell Leukemia Foundation or the experts nearby, so that we can help. And it’s not everyday circumstances, but these happen often.
Topic: Approved vs Off-Label Therapies
What is currently approved, what is currently used off-label?
Dr. Kerry Rogers
FDA-approved means we call this on-label. So that means that there’s enough research in that particular disease and evidence that the FDA has approved that particular drug.
Off-label means the drug is approved for something else. I was talking about vemurafenib, which is approved for malignant melanoma but not approved in hairy cell leukemia. So that is off-label.
Then there are drugs that are investigational. So those are drugs that are not approved for any reason. Those are drugs that are in clinical trials that are not approved. So, there could be a drug in a clinical trial that’s approved for that condition, approved for a different condition and used in the clinical trial. Then there’s strictly investigational drugs, which you can’t get from a pharmacy really under any circumstance because they’re investigational. You can only get it through a clinical trial.
When you look at the group of off-label drugs, there are a couple key differences that might affect whether it will be approved by insurance or can be given to someone. Generally, drugs that are approved – are on-label – insurance will pay for them. In fact, they’re required to in most cases. So, if a drug is FDA-approved or on-label, there should not be issues getting it for that condition.
If it’s off-label but evidence-based or guideline-based, usually there’s still not a whole lot of trouble getting it approved by insurance. So, drugs like vemurafenib are in a bunch of guidelines, including the NCCN guidelines in the US, guidelines for how we treat cancer. So even though it’s off label, it’s still in these guidelines for what standard care is.
Then there’s off-label – there might be some papers on it, but it’s not in the guidelines – and that can be difficult to get insurance to pay for. So sometimes that requires some discussion back and forth with the insurance company; your physician submitting some of the research papers or calling and talking to a doctor at the insurance company to get it approved.
Sometimes they won’t approve it and there can be other pathways to get drugs, like getting it from the drug company. I will say in hairy cell leukemia, because it’s so rare, sometimes insurance companies say, “You filled out the forms explaining this to us, that’s fine,” because it is such a rare cancer. In hairy cell, sometimes because it’s rare, if you provide some explanation then they’re a little better about covering it.
Dr. Jae Park
I typically haven’t had that much difficulty with cladribine, pentostatin or added rituximab for the hairy cell leukemia patients, even though not all of them are FDA-approved indications for hairy cell leukemia specifically. They are approved for many different blood cancers.
The vemurafenib–obinutuzumab combination, which is the BRAF inhibitor and anti-CD20. Those are not approved for hairy cell leukemia. They’re approved, as Dr. Rogers mentioned, in another disease. It’s not always successful getting them, which is one reason that we’re doing the clinical trial to [make] it easier to get them.
We and others in Italy have published this kind of regimen in both the relapsed setting and frontline setting, and a similar regimen is in the NCCN guidelines, which is our US cancer guidelines, but with some specific caveats.
They’re there with the circumstances of patients with very low blood counts and with concurrent infection. The second condition is older, frail patients. So, if you’re not meeting those criteria – like younger patients who don’t have a concomitant or concurrent infection – some insurance companies, not all, may give some pushback, “Yes, it’s endorsed by NCCN, but only for those two specific populations. You don’t meet the criteria and therefore we may not approve it.”
So even though it makes perfect sense for those two populations, where chemotherapy may not be desired, you can also argue that it works well in other settings. So, why do we have to subject that medicine only to that subset of the population? Why not younger fit patients or all patients?
But that’s one reason we’re doing the clinical trial. If you can get both drugs approved by the insurance and off the clinical trial, that’s one thing, but it’s not always possible to get the vemurafenib regimen off trial.
And we also want to make sure that those are still very good options compared to chemotherapy head-to-head as well, both for efficacy and for toxicity. There are unique toxicities for both, and that’s one reason we’re doing the clinical trial. In Italy, similar studies are going, so hopefully those will enlighten us more and make it easier for our patients to get the therapy they need, what we think is the best for them.
Dr. Michael Grever
There are other medical considerations too. The purine analogs, for the most part, are excreted through the kidneys. And so, if you have somebody with kidney insufficiency you have to be very careful about deciding on using the purine analog. And if you do use it, you must be careful to adjust the dose. And there are not 100% safe guidelines for doing that.
We have seen one patient on hemodialysis with severe hairy cell leukemia who responded very nicely to low dose vemurafenib. So, there are several medical conditions that need to be taken into consideration.
Dr. Sameer Parikh
Sometimes we have patients who question, “Why would you prescribe something that’s not FDA-approved?” Because that we consider [FDA approval] as a bar for anything that we use in our day-to-day practice.
I want to emphasize that it’s not because of lack of efficacy, because as Dr. Park mentioned, there are multiple trials that have been done in Italy and the US that show that this drug works, even in combination with rituximab and obinutuzumab. I think the real reason it’s not FDA-approved is because a company needs to submit the application packet to the FDA, to gather all the information. And that’s a very time-consuming process.
I just want everyone to understand, as patients - it’s not that the drug is not safe or not effective or has excessive toxicity that it’s not approved.
Dr. Jae Park
It’s a lot more work for the drug company to get the registration-ready or capable data quality. There are specific forms and procedures they need to go through.
Dr. Kerry Rogers
I think there’s a difference too between FDA-approved and standard of care. So, there are drugs where there’s so much information about them, it is a standard – meaning many, and most, physicians would consider this a usual, customary, appropriate and standard treatment – but it’s still not FDA-approved.
Topic: Research and Clinical Trials Addressing Limitations of Standard Therapy
This is about research and clinical trials that are either underway or may soon begin to address the limitations of standard therapy. The therapies that are available and often used to treat patients don’t work for everyone, and there are plenty of patients that have circumstances that require something else, an alternative.
Dr. Jae Park
We and others have previously conducted a single-arm study, not a randomization study, in the population of newly diagnosed patients, both young and old, using the vemurafenib–obinutuzumab regimen. And we have shown that it is highly effective in getting normal or near-normal blood counts in almost all patients – as effective as chemotherapy in a single-arm study. That’s how that regimen was able to get on the NCCN guidelines. Patients can get those drugs now based on that clinical trial.
But that’s not enough, and it’s restricted.
We are doing a frontline study that is a randomization: 50% of the patients get randomized to what’s considered to be the “standard of care” or the conventional chemotherapy arm, and that’s the cladribine plus rituximab together. The other half of the patients will be getting vemurafenib, which is an oral BRAF inhibitor, plus obinutuzumab, which is like rituximab – another anti-CD20 antibody.
This is a larger, more controlled study to compare the drugs head-to-head. In drug development, this is one of the gold standards, the best way we can show and compare what is better and what are the pros and cons of each treatment approach.
This randomized clinical trial is enrolling patients. In both arms there’s no placebo, meaning everybody will be getting one of these regimens. Everyone will be getting a very effective therapy.
Both treatments work really well; they just have different side effects. Chemo has the usual side effects of low blood counts and depending on where you start with your blood counts, you may be more likely to need a blood or platelet transfusion and fevers. Vemurafenib, on the other hand, does not have those side effects, but it has its own unique side effects of rash and joint pains.
This clinical trial is underway in the United States. It started at Memorial Sloan Kettering Cancer Center (MSK) in New York. The second site, Ohio State University, is about to open. And our third site is Dana-Farber; that is probably going to open in quarter one of next year.
You need to be close to the center or treated at the center to participate in this clinical trial. So, if any of you are nearby, it will be a great opportunity to contribute. The sooner we can complete the study, the more we learn and can get a deeper understanding of the pros and cons.
In this study, we’re not only looking at the efficacy, but the side effects, duration or frequency of hospitalizations, or their immune reconstitution – meaning how quickly they recover their T cells, which are part of our immune cells, and B cells too, and infectious rates. This is funded by the Hairy Cell Leukemia Foundation and Blood Cancer United.
Dr. Kerry Rogers
For clinical trials, you have to get the care associated with the trial at that site, because we’re responsible for you. But we do see people that travel to participate in clinical trials. Depending on what the treatment is, sometimes that’s worth it.
So don’t think just because you don’t live near a center that has that trial, if you are able to travel to participate, sometimes that’s worth it, and sometimes it doesn’t require quite as many visits or travel as you might think.
Dr. Jae Park
And because these are advanced studies – meaning these are not the first time we’re doing this – the number of visits is very manageable. A lot of the blood work can be done locally too, although you do need to come in to receive IV infusions of the treatment. But the labs and other things could be done locally.
So, it’s worth exploring if you’re interested.
Dr. Kerry Rogers
And then the ibrutinib study: We have people from out of state that came to participate and really benefited.
When you think about people with hairy cell that aren’t benefiting from what we consider standard treatments, it might be extremely worth it to travel somewhere to participate in a trial with a drug that you absolutely can’t get as a standard of care, either on- or off-label.
It’s unfortunate that we don’t have it set up so everyone can do that closer to home. But putting in the effort to travel somewhere can make a huge difference in treatment outcomes.
Currently there’s a study of venetoclax that Bob Kreitman is leading; we are participating in it. It’s an NCI-CTEP-sponsored study, a National Cancer Institute program. This is a drug that works in other B-cell cancers and has a unique mechanism that’s not like current drugs in hairy cell. So, that’s an important trial for the group of people that aren’t benefiting the way they need to out of our other standard therapies.
It will be exciting to see how effective that is once we get all the data. I’m also excited, if it works, to combine that with some other agents – might be a good strategy there.
Dr. Michael Grever
Back in the 1970s, when alpha-interferon hit the news, everybody wanted to use alpha interferon. We organized a study and enlisted local participation from many institutions to compare, in a randomized way, pentostatin versus alpha interferon.
Everybody thought interferon was going be the answer. We accrued 340 patients on this study within three years, because the institutions were cooperating, so people didn’t have to travel long distances.
The complete remission rate with alpha interferon was 11% compared to 77% with pentostatin. And so having these comparative studies will often provide very important information.
And we had a crossover arm. If patients weren’t doing well on alpha interferon, they could go over to the pentostatin. So, there are a lot of safety features in studies. The amount of work that goes into organizing these comparison studies is enormous. Having more than one institution do the study includes patients of different varieties so that you eliminate biases.
Because you mentioned relapsed or refractory disease: Dr. Seema Bhat (from Ohio State University) is launching a new study with a new agent– tovorafenib with rituximab. She’ll be introducing this as a phase I study initially, which means you want to see what the side effects of this combination are going be and whether there are promising responses.
And after the phase I portion, if there are promising results, it’ll move into a randomized study very similar to what Dr. Park has described, where they will compare this new agent with rituximab to cladribine and rituximab. So, the systematic approach, by participating in studies, leads to great results in terms of patient care.
Topic: Venetoclax
Do you mind talking more about Venetoclax?
Dr. Kerry Rogers
So, venetoclax is an oral targeted agent; it is a pill given as a once-daily oral medication. It targets a protein called BCL2, a protein that cells need to survive, and certain cancer cells are very dependent on. So, if you block BCL2, the cells can die quickly.
It has been useful in a variety of cancers, especially other B-cell cancers. I’ve used it quite extensively in chronic lymphocytic leukemia, which is most prevalent adult leukemia.
Francesco Forconi in the UK published his results with venetoclax, where they followed a patient taking this drug over time. And Enrico Tiacci in Italy treated a handful of people with it. They had good responses, although slow.
Venetoclax is in the category of drugs that can work for people with hairy cell where the other standard treatments aren’t working. But it’s not as rapid as you’ll see in other types of cancer; it’s a slower response.
It has some side effects. It can lower the blood counts, usually around the time of starting it. And diarrhea is a common side effect.
We’ve seen with some of these drugs where time to achieve a response is slower. After we know about the drug, we can combine it with other drugs. Venetoclax has been combined with BTK inhibitors, like ibrutinib. In other cancers, it’s combined with antibodies like rituximab and obinutuzumab.
I’m hopeful that this study will have good results for people participating in it, and that we’ll learn enough about it that maybe the next step for it will be a combination that helps it work a little faster for people.
Topic: Tovorafenib Trial
Dr. Michael Grever
Tovorafenib is a RAF inhibitor. The phase I study will be evaluating the side effects of tovorafenib in combination with rituximab, but it’ll also be important to look at people with resistant disease.
When I got interested in pentostatin back in the seventies, it was based on an article that was remote from hairy cell leukemia. There was an article in the Journal of Clinical Investigation that reported that children who had a deficiency of an enzyme, adenosine deaminase, had very low lymphocyte counts.
And I found that fascinating. That would not be a good thing to have, because if your lymphocytes were low, you have problems with infection. But I wondered whether inhibiting that enzyme might be effective in treating lymphoid malignancies. That was what prompted us to look at pentostatin. But what we had to do was to define the dose that would get the enzyme reduced in the hairy cells and not tremendously lower it in the normal cells.
Understanding the pathways that are involved and understanding the targets is essential. For patients with refractory or relapsed disease, coming in at a different part of the pathway can be very effective. For example, we talked about patients who have mutations in another gene called the MAP2K1 gene.
I’ve used a MEK inhibitor in patients where the disease was resistant to all the standard therapy, and we were able to get responses. We didn’t have, at that time, enough information about what else to add to the MEK inhibitor to improve the efficacy. Understanding the basic biology and the basic molecular abnormalities can lead to very impressive therapeutic results.
We’re hopeful that this new agent, tovorafenib, will be very interesting in patients with relapsed disease or refractory disease.
Dr. Kerry Rogers
Tovorafenib is approved in one type of pediatric brain cancer, a low-grade glioma.
I think this tovorafenib trial is exciting, because we know that targeting BRAF is helpful and works well, but not for everybody. So maybe hitting HCL with a different type of drug is going to work for people where their hairy cell did not respond as well to vemurafenib.
I think it was also proposed that tovorafenib would not have some of the same skin side effects as vemurafenib, but we need to see the data from the trial to know for sure.
That’s why you do these studies – to make sure you get the side effect profile and really understand how well it works. There’s some supporting evidence, so this study will help determine if that is the case.
Dr. Michael Grever
That’s one thing about the targeted agents that’s very exciting – you can minimize the side effects; however, there’s always some overlap with some of the normal tissues. Trying to define the optimal dose and schedule for administration of new agents is important.
Dr. Kerry Rogers
That’s true. The melanoma dose of vemurafenib – a lot of people taking that dose for hairy cell needed a reduction in dose because it was probably higher than we needed.
So, just because a dose is approved in one condition doesn’t mean that’s always the correct dose for a different condition.
Dr. Jae Park
That’s a good point about the dosing. I think the one thing that we did learn from our prior clinical trial, and others have suggested prior to our study, is that the dose we studied when we initiated that was exactly what Dr. Rogers mentioned – the same dose that was FDA-approved for melanoma.
At that time the rationale was we didn’t want to go any lower because we didn’t want to compromise potential efficacy. But what we have learned is that hairy cells are exquisitely sensitive to this type of an agent. So, you don’t need as much of a dose as we need in melanoma patients.
Luckily, even in the relapsed patient setting, plus patients who are getting side effects – either rashes or joint pains at a higher dose – vast majority of those patients required dose reduction. So, these are what we have learned only through controlled clinical trials; otherwise, all you have is anecdotal experience.
So that was the power of studies. In our frontline study, which is randomized, based on that result and collective experience from other centers – we have the dose at half of what we were doing before, which is 480 mg twice daily.
That might still not be the most optimal dosing, meaning we may still be able to go lower, especially when we combine with obinutuzumab. But we’re not studying two different doses. But this dosing is much more tolerable than before. People can still get side effects at this dosing too.
And that’s, again, another reason these types of clinical trials are important, so that we can learn, modify, and inform future studies and future patient treatment.
Topic: How to Get Involved in Clinical Trials
How can individuals get involved in these clinical trials?
Dr. Kerry Rogers
It’s important to realize is that what we’re talking about so far on this call has mostly been prospective – meaning you enroll and then we follow you after you enroll – interventional, meaning we’re giving you a treatment or intervention.
Clinical trials – for prospective interventional clinical trials, what country you’re in and what area you’re in matters a great deal. In the United States, there’s a website called clinicaltrials.gov that you can search for clinical trials for a condition.
But if you’re looking for treatment, the way to decide what clinical trials might be right for you is, one, to talk to your doctor. Even if they don’t work at a center that has clinical trials, they might be better able to look for available clinical trials. The other thing you can do is get an opinion at a center of excellence or somewhere where they’re really involved in the academics of hairy cell leukemia.
In Canada, for example, I don’t know if there are any clinical trials currently open for hairy cell leukemia. We can treat people from Canada in the United States, but it would require you to come to the United States. And there are sometimes other costs with that.
There are some clinical trials we’ve had open between the US and Canada due to some regulatory agreements, but there are a lot of things that go into this kind of research, like IRB approval. And then some of it has to be done in person because we’re responsible for you, we’re giving you a treatment.
We have a program called Destination Medicine that can help people.
If there isn’t something in your area, that can be difficult, especially if you don’t have the time or the means to travel somewhere for treatment.
I do want to mention, though, that there are non-interventional trials. The Hairy Cell Leukemia Foundation Patient Data Registry is a type of clinical trial. That’s where people sign up and agree that we can take their medical records and put them in a database with other patients. And when we have so many people, we can start asking more complicated questions.
So, for people that maybe don’t need treatment – so it’s not the right time to participate in a clinical trial – or who live in an area where there isn’t one, there’s still the opportunity to participate in the patient data registry. There’s a way to enroll without going to a center of excellence or a center that has it open and is occurring at that location. So that’s an option or a way to be involved.
I know the NIH has a study where they’re collecting biologic samples from people. So, there’s non-interventional research that can be more feasible if you can’t travel somewhere too.
Dr. Michael Grever
I’m glad that Kerry mentioned the registry because, when you’re dealing with a rare disease, the more patient information you get, the better you can predict. Any institution has a limited number of patients, it’s hard to make these clinical correlations that could impact patient care.
Regarding the registry – the other thing that is important for the patients to understand is, we’ve put tremendous effort into maintaining confidentiality. So, when you hand over your medical record, you worry, “Would this get transmitted any further?” But we have a lot of safeguards and checks to make sure that this information remains confidential.
The registry is an important study, and we would welcome anyone to try and seek more information about this.
Topic: AI in genetic sequencing
Dr. Jae Park
I don’t know if it can work for sequencing work, but AI is being used a lot in medicine right now. I think the biggest area that we are seeing an explosion is the interpretation of the collected data. We need human resources to collect the data, but it used to be a human person going through sequence by sequence or putting it together: what does it mean in the population or the big data or larger patient population?
But that’s where AI is being incorporated. I think in the future – hopefully soon – the reporting of results might be done by AI, with a human check.
Topic: Pathways
What do you mean by these different pathways? What is that all about?
Dr. Kerry Rogers
Within cells – cells are alive. And so, they have a lot of things that change in them on a continual basis. Pathways are basically how signals move between cells or within cells. So, it’s like the telephone line or communication pathway for something within a cell – or a domino effect within a cell where this protein hits this protein hits this protein, and there’s a downstream effect. If you’ve ever seen a large domino board, there are branch points – it hits this one, and then three things move. Pathways are way more complicated than this.
As researchers or scientists, we try to understand what’s going on in cells – which are complex; you can think of it like a beehive – we try to pick out individual bees interacting and moving in a direction. And that’s like a pathway. Or you can think of it like steppingstones between these different proteins.
These are like cell-signaling pathways or internal communication chains within cells. And when you think of it like a chain of connected communication, if what you need is what’s happening down here in the chain, if you take out something here in the chain, you’re not going get this thing happening here.
Take ibrutinib, which is a BTK inhibitor – it hits a protein called Bruton tyrosine kinase, which is in one of these signaling chains or pathways called B-cell receptor signaling. If you block BTK, the pathway ends here and doesn’t go through to its result. And that causes cells to die.
I will also say that cancer cells, because they’re broken – cancer cells aren’t normal, they’re broken – sometimes they have way different or more complex stuff going on than normal cells. So, you’ll see one of these pathways is more or less important to a cancer cell than it is to a healthy cell.
So, we can exploit that, because if you have something that’s way more important to a leukemia cell than it is to a healthy cell, if you can block it or target it in the leukemia cell. You’re going improve someone’s leukemia without causing as many side effects or injury to their normal cells.
Dr. Michael Grever
I think that’s an excellent explanation. If you don’t interrupt that chain, some of the signals will keep the cancer cell alive. And if you can interrupt the signal, particularly in the cancer cell, you’ll give an advantage, and that cancer cell may die without hurting normal cells.
But it’s important to be aware that these signaling pathways can have an impact on cells outside of the cancer chain as well.
Topic: Antivirals, PCP Prophylaxis, Infections
Dr. Michael Grever
Particularly when we use either cladribine or pentostatin, even when we get the leukemia to respond, there is a prolonged negative effect on the remaining normal lymphocytes. And they are important for protecting patients against viral infection.
And so sometimes it takes a year or more for the lymphocytes to recover after these purine nucleoside analogs. So, the leukemia’s in remission, but the risk of getting a serious viral infection persists. And infection is still one of the leading complications of hairy cell leukemia.
In my practice, I put the patients who are on purine nucleoside analogs on an antiviral agent to protect them against herpes zoster or shingles. Shingles is painful, it’s uncomfortable, but it’s very dangerous in somebody who’s immunocompromised.
Unfortunately, in the past, I’ve had a few patients where shingles started off as a localized, painful skin lesion but then it became disseminated and resulted in death. So, I am very adamant about making sure that the patients are either on acyclovir or valacyclovir while their lymphocytes are recovering.
There’s another area where everybody might not agree about this, but whenever patients are treated with the purine analogs and they become neutropenic –particularly if the neutrophils are less than 500 – there’s an increased risk for serious infections, and we worry about other opportunistic infections like pneumocystis pneumonia.
And so, depending on what the individual physician feels about prophylaxis against pneumocystis, and depending on how severely depressed the cells are, there are several agents.
Topic: Vaccines
Dr. Kerry Rogers
I recommend everybody get their vaccines. Vaccines are an excellent way to prevent infection. It is very important to get them before treatment because anti-CD20 antibodies really decrease the ability to get an optimal antibody response from a vaccine for six months to a year, and potentially even longer.
So, getting a vaccine right after getting rituximab or obinutuzumab is probably not going to work very well. It’s difficult with flu shots because if you wait six months, it’s probably not going help you at all, because flu will be done. But for long-term vaccines like the RSV vaccine, pneumococcal vaccine, or the Shingrix vaccine, I recommend people wait until it’s a time when they’re going to get a better response.
Dr. Jae Park
I agree. I recommend the vaccines before, especially if they’re going to get rituximab or obinutuzumab, because for a good three to six months afterwards their vaccine response will be suboptimal.
So, if the flu shot is available and it’s the right season between September and February or March, I recommend getting those vaccines beforehand. And their immunosuppression is not permanent, luckily, but it could be prolonged for months in some patients.
I think it’s important that we keep in mind the infectious risk is not just for the duration of the treatment – it can last after the treatment too.
And what Dr. Grever mentioned about PJP prophylaxis, and very specific types of infections as well as viruses, is important.
In clinical trials we systematically check their T-cell recovery. Those do get suppressed, especially with a cladribine- or pentostatin-based regimen. When the T-cell count is low, our bodies are more exposed to opportunistic infections.
So, we can check T-cell recovery in some patients we’re really worried about, to see if they’ve recovered. And that might be a good indication; if their CD4 count, for example, is 200 – which is not perfectly normal, but high enough, we might be able to remove some of these prophylactic medications.
But it is important to understand the potential risk of infections, both short and long-term.
Dr. Michael Grever
One of the major challenges we had was during the COVID pandemic.
One of my patients – we had to abbreviate the course of rituximab, because even though she did get COVID, we were able to get her started on medicines right away to get the COVID under control.
I would agree with the panelists that vaccination is really very important, particularly when you’re in the middle of a pandemic.
Dr. Sameer Parikh
I think the one thing that always comes up is, “Okay, I just started treatment last week and now I’m here. Should I get the vaccine now or should I wait?”
I think of it in two separate buckets. Is this a seasonal vaccine or is this one of those vaccines like the Shingrix vaccination where you only get two shots and you’re done.
In those instances where it’s a seasonal vaccine, the efficacy is not going be perfect. We can’t wait until six months from now because you’re not going to benefit from the vaccine in six months if it’s an influenza vaccine. In that case, even if it’s a suboptimal response, we would maybe go ahead and get the vaccine because you will get some benefit as opposed to zero benefit if you don’t take the vaccine at all.
But perhaps wait for the long-term vaccinations like the pneumonia vaccine or the Shingrix vaccination, because those you should ideally get when you’re off six to 12 months from one of these treatments, which are immunosuppressive and you won’t really mount an adequate response.
The only other thing I’ll add is the risk of skin malignancies and the need to see a dermatologist on an annual basis for a full-body skin exam. Although the data are maybe not as robust in hairy cell leukemia as we see in our CLL community of patients, even in hairy cell leukemia, it is important that you visit with a dermatologist or someone who has the expertise to do a full-body skin exam, to look at early skin cancers so they can be evaluated and treated before they become problematic.
Dr. Jae Park
In the line of supportive care, I’ll add the antibacterial prophylaxis.
When the absolute neutrophil count is than 0.5, which is what we call neutropenic or very low neutrophil count, then we do prophylactic oral antibiotics to prevent infections, and that will automatically reduce hospitalizations. So, it serves both purposes, reduces severe infections and hospitalizations. So those should continue until their count recovers, unless there is some contraindication.
Growth-factor support such as filgrastim (Neupogen) or pegfilgrastim (Neulasta), which is the white-cell G-CSF support after chemotherapy-based regimens, is not necessary for all patients. Because if your starting blood count is not that low – hairy cell patients start treatment for different reasons. Sometimes it’s white blood cell count, sometimes it’s red or the platelet, sometimes it’s all the above.
If your white blood cell count is relatively normal, you may not need those boosters or the subcutaneous injections to increase your white blood cell count. But if you’re starting low, you can also get those shortly after the chemotherapy; your duration of time being low could be shorter.
You can discuss with a treating doctor about the role of boosters, especially if your white blood cell count is low.
Topic: Exercise & Fitness
How can fitness and exercise support recovery?
Dr. Jae Park
I wish there were more data because these are common questions that people ask, especially for those who don’t need to start therapy: “What can I do now to prevent the HCL from progressing?”
It is unnerving to wait and see what happens and not be in total control. And a lot of times we’re not in control of these things. There is some research going on about the impact of diet and your microbiome – your healthy bacteria in your gut – and how that may impact your cancer recurrence or progression.
I generally, unfortunately, do not give specific recommendations because we don’t have very good scientific evidence now.
If they have other medical comorbidities, and some of them do – cardiac disease, diabetes and others – I think there are certain things that we all can do to promote our health, which is moderate cardiac exercise, watching our diet to avoid certain types of food. Too much sugar – simple sugar – is not a good thing. But how much to regulate, I don’t have a great answer.
But being mindful is one thing. At least we feel that we are doing something while we are learning to see what exact impact it may have.
And that may force us to exercise a little bit. Sometimes the diagnosis itself, even though it’s highly treatable and may be curable and most of the patients can do well, can change how we approach our health in general, to prevent other health problems.
Dr. Kerry Rogers
I’m not aware of any data in hairy cell or in similar types of diseases. We’ve seen studies in other cancers, mostly solid tumors, showing that structured exercise can improve how long people live with them. I always worry, though, applying studies from one very different type of cancer to something like hairy cell.
Also, we just told you that most people with hairy cell leukemia have a normal lifespan. So, I don’t know that the goal is to try to help people live longer when they’re going to live their natural lifespan anyway.
There are very few things that exercise isn’t good for. Moderate exercise improves fatigue, improves cardiovascular health, and is a good way to take care of yourself. I think it can help people recover from treatment.
It’s probably not good, though, if people are getting blood transfusions, are anemic and feel terrible from a treatment. You’ve got to let yourself recover before getting back to exercise. You don’t want to exhaust yourself when you’re trying to heal from something like a chemotherapy treatment.
So, it’s hard to find that balance. But in general, exercise is good unless you have unstable coronary artery disease, which is at risk for a heart attack. If anyone doesn’t know what that is, then get that fixed before you exercise.
There’s some interesting data – not in hairy cell – showing that plant-based diets with a high amount of different types of plants could be good in cancers. But again, this data isn’t in hairy cell leukemia yet.
I usually tell people to behave like they’re going to be around for a while, and that means eating and taking care of yourself like you want to live a nice, healthy lifespan.
Topic: Night Sweats and Cancer-Related Fatigue
Night sweats: what might cause them, and how can patients address them? Fatigue: is it related to the cancer and how might patients address that?
Dr. Sameer Parikh
It’s very difficult to know for sure if fatigue or night sweats are because of hairy cell leukemia or because of a variety of other medical conditions that someone can have.
The way I approach that is I say, “What is the status of your disease? Do we see any signs or symptoms of recurrence? Are your blood numbers okay? Do I feel a spleen on physical exam?”
I might even do a radiographic examination to make sure I’m not missing an enlarged spleen, to ensure that the symptoms of night sweats or fatigue are not because of relapsed hairy cell leukemia or progression of disease to the point where we would think about the need to start treatment.
Frequently in patients who have these symptoms, you will see other indicators that the disease is progressing, the disease has come to the point where your hemoglobin might be low, or you may have other indicators that the disease needs to be treated.
In the absence of any other indicator that the disease has had progression to the point where you would benefit from treatment, I would say we need to partner with your primary care physician to evaluate for thyroid dysfunction, sleep disorders, or other things that can cause these symptoms that may not be because of hairy cell leukemia.
We have effective tools to treat hairy cell leukemia. But if your symptoms are not because of hairy cell leukemia, by treating the leukemia we wouldn’t have done you any favors, because your symptoms are unlikely to improve.
I think before we embark upon any treatment strategy for the symptom of concern, we have to ensure that it’s because of the disease and not because of other things, because these are relatively common symptoms.
Dr. Jae Park
To echo what Sameer also mentioned, it’s important that although this is very rare, if you have an unusual symptom that doesn’t match the degree of hairy cell leukemia involvement, there could be something else going on. And it’s important to look for those alternative explanations.
It’s also true when you have populations who do have recurrent hairy cell-their counts go down-but it may not always be hairy cell again the third or fourth time that’s responsible for the counts. It could be other kinds of blood cancer or other problems.
And that sometimes is the reason that we recommend a bone marrow biopsy and not just assume that, “Okay, it’s your hairy cell again, let’s treat that and see.” Sometimes that’s the right approach. Sometimes we uncover different things.
But as a patient, if you have unusual symptoms, it’s important to bring it up, just so that we don’t attribute everything to hairy cell leukemia.
Dr. Michael Grever
Also, iron deficiency certainly could present with fatigue. And iron deficiency, particularly in a man, you need to search for why. Women, if they’re menstruating, are always on the verge of having some iron deficiency, but men should not be iron-deficient.
And fatigue, if it’s related, there are simple blood tests that you can do to look for iron deficiency. And if you find it, you don’t just put somebody on iron. In a man, you need to look for why they’re iron-deficient, to make sure they’re not having occult bleeding from an undiagnosed colon cancer, for example.
As Sameer pointed out, you need to think about all the other possible things that could cause these symptoms rather than just attributing it to the hairy cell leukemia.
Final comments
Dr. Kerry Rogers
There are a lot of things that can be done for people with hairy cell leukemia, and this requires some thought to figure out what’s right for an individual person. It really matters to find a doctor that’s going to take the time to talk with you about these aspects and find treatment that’s the right one for you.
Whether or not you are healthy and needing a first treatment – where there’s a different set of considerations – or someone that’s had hairy cell that’s difficult to treat or has other health or personal considerations. Making sure you find someone who’s going to take the time to talk to you about all these things really matters.
Dr. Michael Grever
In 2007, I think, I met for the first time with the leaders of the Hairy Cell Leukemia Foundation, and they came to visit me and they said, “Are there any questions yet to be investigated?” I said, “Oh, there are plenty of questions.”
And so, they helped us organize the first meeting of the Hairy Cell Leukemia Foundation. And ever since that time, we’ve had annual meetings, and it’s been a tremendous benefit to our patients that they have this organized approach and they bring investigators together.
And one of the other things I can tell you – I’ve been in academic medicine a long time – but I’ve never worked with a group that’s more willing to share their findings and to try and help patients by sharing their findings. And so, I would really recommend that we recognize the Hairy Cell Leukemia Foundation for the support that they’ve had in this rare disease.
Dr. Jae Park
I echo 100%. We all treat different diseases, and there are wonderful organizations. But in hairy cell leukemia, the patients themselves are motivated and organized, and they ask questions. They would like to get involved, they would like to contribute, they want to learn more – which is just fantastic.
And then the investigators – we all participate in difficult questions. It is so great to know that we have colleagues that we can answer with. And I share my collective experience with my patients too.
I think that’s one example of this community collectively – because it’s a rare disease, we are learning from each other and contributing.
And then the organization itself is super involved. Some patients do ask with questions about how they can participate in a clinical trial, and it’s unfortunate that we can’t treat them all. And they ask questions like, “Would I like to be treated with vemurafenib–obinutuzumab and other arms; Can you advise my doctors about those things?”
I try to do our best. It is limited in certain ways. I want everyone to understand it’s not because we don’t want to help, but when we’re not seeing the patients directly, it’s very hard to make tangible recommendations.
But the Foundation can connect you to one of us. And we can help as best as we can so that you can get the treatment that you need and get it safely.
Dr. Sameer Parikh
I think the Hairy Cell Leukemia Foundation has been wonderful. So, I really appreciate Anna and everyone working behind the scenes constantly in making sure that events like this happen – and that you have the ability to hear from all of us and have a conduit for questions.
In addition to what Dr. Grever mentioned, although we meet once a year for these meetings, there are emails constantly that are being exchanged about challenging cases from across the world. And we all learn from this. We all provide our input. And ultimately, our end game – our goal – is the same: to help the community of patients, because that’s really what we are here for.
This transcript has been edited for clarity.