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Webinar Series: Understanding Hairy Cell Leukemia

November 8, 2023

Speaker: Dr. Robert Kreitman, National Cancer Institute, NIH

Hosted by the Hairy Cell Leukemia Foundation (HCLF) with Dr. Robert Kreitman from the NIH. Moderated by Anna Lambertson, HCLF Executive Director.

Presentation Materials

View Dr. Kreitman’s presentation slides.

View a recording of Dr. Kreitman’s presentation.

Please note that the Q&A recording will not be shared, but a transcript has been included below.

Transcript of Dr. Kreitman’s Slide Presentation

Overview of Hairy Cell Leukemia

Hairy cell leukemia is a B-cell malignancy that comprises 2% of all leukemias. It's about 1,200 new cases per year in the United States in 2023. The patients present with low blood counts, large spleens, and the cells have these cytoplasmic projections that look like they're hairy.

The cells are bright positive for CD22, CD20, and CD103. In classic hairy cell leukemia, they're positive for CD25. Classic hairy cell is driven by the BRAF V600E mutation.

Now, purine analogs, cladribine and pentostatin, can induce long-term complete remissions but are not known to be curative and have decreased efficacy with each repeated course. There are variants of hairy cell that lack CD25 and we call that hairy cell variant or HCLv. There are variants that can have CD25, but they express unmutated IGHV4-34. Either way, these respond poorly to purine analogs.

The diagnosis of HCL is usually made by flow cytometry of the blood and bone marrow, and this is important to be able to exclude other disorders. So, most patients do get a bone marrow before they get started on treatment. It's important to determine if it's classic hairy cell or a HCL variant. Ninety percent of patients will have classic hairy cell, about 10% will have variant.

HCL Variants

In HCL variant, the spleens are much bigger, they're severely enlarged in hairy cell variant. Patients can have lymph nodes. And the blood counts, instead of being low like in classic hairy cell, can be normal in hairy cell variant. Leukemic cells in the blood are high in hairy cell variant, and often low in classic. The CD25 and the BRAF mutation is present in classic hairy cell, but it's absent in hairy cell variant and response to cladribine or pentostatin is good with classic, but poor with variant.

Now, this other variant, the IGHV 434 hairy cell, is in a smaller percentage of patients. The spleens can be severely enlarged, they can have lymph nodes. They often have low levels of normal blood cells, and they can have high leukemic cells in the blood. They can be positive for CD25 just like classic, but they're anything but classic. They often do not have the BRAF mutation and the response to cladribine and pentostatin is poor. We'll talk about what is good to treat those patients with. HCL variant tends to be common among patients who are relapsed and refractory.

Now, how do you treat hairy cell variant? We found that only 7% of 42 patients reported in literature had complete remissions, versus if you added rituximab. Cladribine given for five daily doses and rituximab beginning on day one of cladribine for eight weekly doses gives you 95% complete remission. This was in a trial we did of 20 patients. Single agent cladribine or pentostatin should no longer be used for a hairy cell variant. That goes for the IGHV 434 variant as well.

What do we mean by complete remission? We mean that there's no hairy cells visible by the standard stains like H&E stain or Wright's stain of the bone marrow and blood, there's resolution of the enlarged spleen and lymph nodes, and high hairy cell counts have normalized.

You can have complete remission with minimal residual disease. MRD is determined by special stains of the blood in bone marrow, or flow cytometry of the blood or bone marrow aspirate. The latter is the most sensitive test. Usually, if that's negative, everything else is going to be negative. The molecular studies like PCR can be positive.

The importance of MRD is that complete remission can last longer if the MRD is negative. We always want to try to get MRD negative complete remission or MRD-free complete remission.

The long-term results of cladribine and rituximab (CDAR) for hairy cell variant, are that 95% of 20 patients got complete remission. Eighty percent of the 20 patients were MRD-free and achieving MRD-free complete remission by one month or six months, either in the bone marrow or just by blood if the patient didn't get bone marrow, was important. Patients live longer if they were MRD-free by these time points.

The TP53 mutation was also associated with shorter overall survival. Although 80% achieved MRD-free complete remission (CR), only five or 25% stayed MRD-free. One stayed MRD-free but died of Parkinson's. In other words, they died from a different cause. In patients with MRD-free CR who become MRD positive, you can use delayed rituximab and that is often successful in re-achieving MRD-free CR for many years. Hairy cell variant patients relapsing after CDAR may be less resistant to chemo, less sensitive to chemo. In other words, it's harder to get a response the second time around. More intense first line treatment like pentostatin and rituximab or bendamustine and rituximab has been tried with a lot of success.

Cladribine and rituximab (CDAR) in Classic HCL

In patients with classic hairy cell, we tried using cladribine and rituximab (CDAR) by the same schedule (as described above). This was a randomized trial. One hundred percent complete remission (CR) with CDAR versus 88% with cladribine alone. But the MRD-free CR rate was hugely different, 97% versus 24%, and the difference got even bigger when we followed patients longer. 94% stayed MRD-free after CDAR versus only 12% after cladribine alone. We then allowed patients to get delayed rituximab if they became MRD positive in the blood at least six months after the cladribine or in the case of delayed rituximab if they got positive in the blood six months after that. They could get a total of two courses of rituximab.

We found that the MRD-free rates long-term are 47% when you have patients get delayed rituximab. In fact, when you look at either of these approaches, if you follow patients and you give them delayed rituximab when they need it, a very small percentage, only zero to 3% of our patients needed more treatment by six and a half years. If you compare it to a group of 90 patients treated and reported in 2009 after cladribine alone or cladribine or pentostatin alone, 28% of those patients needed more treatment by six and a half years. By either approach, this can prevent relapse or delay relapse.

Bendamustine, Pentostatin

In patients who are relapsed, we have tested bendamustine and rituximab versus pentostatin and rituximab, and you can see that in the bendamustine and rituximab, the bendamustine is given by days one and two and the rituximab on days 15 of six cycles. These are 28-day cycles. The pentostatin and rituximab are each given together every other week. We get, by either of these approaches, 65% to 73% complete remission rate. Most of the complete remissions are MRD negative. This also works very well for hairy cell variant even in first line.

While highly effective, however, this approach may be toxic due to chemotherapy, and so that brings up the issue of can we achieve complete remission without chemo?

Chemotherapy-free Options

Moxetumomab pasudotox

This is a treatment that unfortunately is currently not available. We hope it will continue to be available in the future. Moxetumomab pasudotox was a recombinant immunotoxin, which is approved by the FDA for relapsed hairy cell and hairy cell variant that's bound to CD20. It binds to CD22 and it contains a toxin which goes inside the cell and kills the cell. It's very, very powerful. But the protein toxin could cause antibodies that would reject it and that would prevent MRD-free CR. We found that adding rituximab that binds to CD20, that increases the MRD-free rate from less than 50% to greater than 70% by lowering anti-drug antibodies and more rapidly achieving MRD-free CR. Moxe was taken off the market for business reasons.

What about targeting the BRAF pathway with oral drugs? In classic hairy cell, mutated BRAF carrying the V600E mutation overstimulates MEK which overstimulates ERK and that causes a cancer. If it happens in a colon cell, it causes colon cancer. If it happens in a skin melanocyte cell, it causes melanoma. If it happens in a B cell, it can cause hairy cell.

Vemurafenib and other BRAF inhibitors

Vemurafenib inhibits BRAF V600E and resulted in 35% to 45% complete remissions in hairy cell, all MRD positive. Dabrafenib also inhibits BRAF V600E, but trametinib is a drug that inhibits MEK. Dabrafenib alone achieved 30% complete remissions in hairy cell. Both drugs were more effective and less toxic than vemurafenib in melanoma and effective in hairy cell.

In Italy, a study of vemurafenib combined with rituximab achieved 87% complete remissions and 57% MRD-free complete remissions in relapsed hairy cell.

Now, these agents have side effects, including skin rashes and cancer for vemurafenib, and fever chills for dabrafenib and trametinib.

There are other inhibitors. There is a BRAF inhibitor called encorafenib, and a MEK inhibitor called binimetinib. They're currently being tested here at the NIH. Encorafenib causes fever less often than dabrafenib. On the encorafenib and binimetinib protocol, rituximab can be given to convert MRD positive complete remission to MRD negative complete remission.

What about a chemo-free initial treatment for hairy cell leukemia? Dr. Jae Park and Dr. Martin Tallman from Memorial Sloan Kettering Cancer Center led a study using vemurafenib with the anti-CD20 antibody, obinutuzumab, starting on cycle two, day one. 28-day cycles. The obinutuzumab was also given on day 8 and 15 of cycle 2 and day 1 of cycle 3 and 4.

The reason that vemurafenib was given a head start of 28 days before the first dose of obinutuzumab, was that so it could minimize the hairy cell burden, so that obinutuzumab toxicity could also be minimized, although five patients still had reactions. The vemurafenib toxicity was usually mild to moderate and included rashes in 93% of the patients, joint pains, itching and fatigue. Of 30 patients enrolled, three stopped treatments early because of toxicity. Of the 27 patients completing treatment, all achieved complete remission, and 87% or 26 patients achieved MRD-free complete remission. At a median follow-up of 35 months, none of the 27 patients completing treatment have relapsed. However, and although none of these 26 MRD-free CRs became MRD positive, bone marrows were not done after one year. But an advantage to this approach is that T-cells, particularly CD4, were spared and they would be killed by chemo, so it's nice to have a chemo-free option. Although, as I said, that follow-up is somewhat more limited than a chemo option like CDAR.

Ibrutinib

There are other chemo-free drugs like ibrutinib. It's approved for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma. It inhibits Bruton's tyrosine kinase, and it achieves 19% complete remissions in hairy cell, mostly MRD positive. It's also effective in the hairy cell variant, unlike the BRAF inhibitors, which can't be used in hairy cell variant. The ibrutinib can cause atrial fibrillation and it can increase the risk of bleeding and infections, but in general, it's still better tolerated than the BRAF MEK inhibitors. It can take many months and even years to work in a hairy cell. You don't want to use it in patients with severely low blood counts who need a quick response.

Venetoclax

There's also venetoclax that targets BCL2. Dr. Enrico Tiacci reported six patients who progressed at 6, 18, 25, and 37 months after vemurafenib and rituximab. Two of these six patients achieved MRD positive complete remissions with venetoclax at 400 milligrams a day. Dr. Forconi reported that one of his patients that was treated with venetoclax also got a CR. Three of the patients also received rituximab. One patient with MRD positive CR to venetoclax had a decrease in MRD when rituximab was added. One who had a marginal response, in other words not even a partial response to venetoclax, had an MRD positive complete remission to venetoclax plus rituximab. A multi-center trial of venetoclax in hairy cell leukemia is going to begin soon in the United States and it's going to be centered here at NCI CTEP and run in multiple other centers in the US.

CAR T Cells

The final option I wanted to talk about is CAR T cells. This is an exciting option that's found to be very effective in many different leukemias, can even cure some types of hematologic malignancies. You take the normal T-cells out of patients and engineer them to go after the hairy cells. This can be by adding CD19 to the surface of these CAR T cells. You can grow millions of these CAR T cells, and you can infuse them back into the patient. Then these CAR T cells can bind to cancer cells and kill them. That is currently being tested at the NIH.

Summary of Treatment Options

In conclusion, first line treatment of hairy cell is still purine analog plus or minus rituximab, although vemurafenib and obinutuzumab is a chemo-free option now that could be considered. CDAR eliminates MRD and decreases relapse long-term compared to cladribine alone. Hairy cell variant, which lacks CD25 and BRAF V600E should not be treated with purine analog alone. These purine analogs, cladribine, pentostatin, and bendamustine, can be combined with rituximab to eliminate MRD and relapsed hairy cell, albeit with chemotherapy toxicity.

A lot of people are trying to avoid these chemo drugs and go with the chemo-free options like the BRAF or MEK inhibitors that can rapidly achieve complete remission. But usually, they need rituximab to eliminate MRD. The BTK inhibitor, ibrutinib, works very slowly in hairy cell but can also achieve complete remission generally without eliminating MRD. Venetoclax, with or without rituximab, is active in hairy cell. Finally, participation in clinical trials is highly encouraged for all patients.

COVID-19

What about COVID-19? COVID-19, we've heard probably the worst of but not the last of. The virus and the vaccines produce antibodies and T cells which protect patients. Antibodies though can be low or absent after purine analogs, ibrutinib or rituximab. After rituximab, these antibodies could be low for 12 months or longer. Low or absent normal B cells can lead to poor antibodies responses. This can be dealt with by getting a vaccine prior to treatment. If you have a low normal B cell count because of disease, because of the hairy cells, and you aren't going to get a good response to therapy, you can get a BRAF inhibitor and that could normalize the B cells and allow you to get more heavy treatment.

The hairy cell patient with persistently low B cells that can't get immunized, they may require drugs like Paxlovid, Remdisivir, or Molnupiravir, but don't compromise hairy cell treatment due to COVID. Consider delaying to achieve the highest antibody level possible before starting treatment, particularly rituximab. Patients without normal B cells due to hairy cell or hairy cell variant may be treated with BRAF inhibition to restore the normal B cells even before getting the definitive treatment. These are some clinical trials that are open in the US including for untreated patients.

Transcript of Question & Answer Session

Anna Lambertson:

If you would be so kind to clarify with MRD, which is minimal residual disease, how do you determine whether a patient has or doesn't have MRD after treatment?

Dr. Robert Kreitman:

These tests, the special stains of the bone marrow biopsy, flow cytometry of the blood and flow cytometry of the bone marrow aspirate. Then there's PCR. A lot of people use BRAF PCR and that's sensitive down to about 0.05%, but flow cytometry is sensitive down to 0.002%. Very low traces of hairy cells can be detected by flow cytometry. That's our best approach.

Flow cytometry is not always that sensitive out in the community, so sometimes they can only detect down to 1%. You must see what your lab is able to detect. These are the tests that are used for MRD. The important thing is if you find that you have hairy cells by these tests, but otherwise the H&E stains are negative for hairy cells, then you might still be in complete remission, which is good, you just may have some MRD. It doesn't necessarily mean that if these tests are positive that you’ve relapsed or need more treatment. Usually, need for more treatment is related to the normal blood counts being low.

Anna Lambertson:

We received a lot of questions about CDAR which refers to cladribine plus rituximab. One of the questions is, what does the research say about the length of remissions with just cladribine? If you receive cladribine alone, what is the median remission that a patient can expect?

Dr. Robert Kreitman:

With cladribine alone, it was reported in 2009 that the median duration of remission was about 16 years if you were checking blood counts. In other words, it took a median of 16 years for patients to have low blood counts to the point where they needed more treatment. If you check bone marrows, then studies show that particularly in younger patients, it takes less than five years to relapse with hairy cells in the bone marrow using H&E and Wright's stain of the bone marrow and blood. Usually, these tests are positive before the blood counts become low enough for needing more treatment. Those are the time ranges that we see, but many patients do relapse within just a few years. It's a statistical issue where it doesn't necessarily mean that that's going to happen with you.

Anna Lambertson:

I think it is important to remind those listening that every patient is different. This research is presenting statistical data, but every patient is different and the results that a patient sees in a study may or may not be what they experience after treatment.

A lot of patients want to know how do you go about determining whether a patient's profile makes them better suited for cladribine by itself or cladribine and rituximab? And when you're making that determination, how do you decide whether the rituximab should be concurrent or delayed? Finally, what do you mean by delayed rituximab?

Dr. Robert Kreitman:

Concurrent means that the rituximab can start on day one of the cladribine and then, that's the first day of eight weekly doses of rituximab. Delayed means delayed at least six months from the dose of cladribine. We would start delayed rituximab when the hairy cells were visible in the blood by flow cytometry. I mentioned blood because you can see them in the bone marrow aspirate, but you're not sure unless you see them in the blood, whether they're really going to take hold. Sometimes we see it in the bone marrow aspirate, and it goes away on its own gradually. Those patients may not need delayed rituximab to get rid of their MRD.

Now, you can give delayed rituximab to patients who have MRD coming back even after CDAR. Even if they got rituximab early, they could get it later delayed by six months. The other thing I should mention is that even before we started our CDAR trial, Dr. Ravandi at MD Anderson tested delayed rituximab where all the patients got eight weekly doses of rituximab starting 28 days after the cladribine. Delayed could be delayed by six months or it could be delayed by four weeks. Either way, we have complete remission rates, whether the rituximab is given upfront or delayed by six months or one month, the complete remission rates are about a hundred percent, but the MRD-free rates are a little bit different.

Anna Lambertson:

Can you talk a bit about toxicity related to cladribine? A concern that some patients have is they've been treated with cladribine, perhaps they've relapsed after only a year, or they've had HCL for 20 years and they've been treated several times with cladribine. What do you say to these patients who are looking at their options and considering the risks associated with another round of cladribine?

Dr. Robert Kreitman:

I think that the main concern is if you get chemotherapy a second time, you'd like to not have to get it a third time, so you really want that second remission to be better than the first remission. Usually, the way to do that is to add rituximab to the chemotherapy the second time around. In fact, the official guidelines by the NCCN, they don't list cladribine alone or pentostatin alone for relapsed hairy cell but would recommend adding rituximab to the cladribine. But the hairy cell experts feel that there are some patients, particularly with long remission durations after the first course of cladribine, and that might be reasonable to use cladribine alone again, particularly if the patient or the doctors don't think giving rituximab is a good idea. But I would go as far as to say that the second time around, many patients now are trying to avoid chemotherapy altogether and going with options like BRAF inhibitors with or without rituximab to try to eliminate the toxicity of chemotherapy.

I don't think that there are features that you can use to determine, "Yes, this patient should definitely get cladribine alone," or "This patient should definitely get cladribine with rituximab." I think it's more of an individual decision on the part of the patient and the physician. We don't unfortunately have definitive guidelines where we can say, "Yeah, there are differences that we could detect in patients that can lead us to make a hard and fast decision."

Anna Lambertson:

The data is quite good in showing the rituximab's effectiveness in eliminating MRD and we believe, based on the data, in potentially extending a patient's remission. Why are some patients concerned about rituximab? What are the downsides?

Dr. Robert Kreitman:

Well, the rituximab toxicity is frontloaded. In other words, the first day that you get rituximab you usually have chills and there can be fevers, there could be rashes, there can be high blood pressure, low blood pressure, shaking chills. We find that for early hairy cell first line treatment of hairy cell, you must give steroids prophylactically. Otherwise, we can't even get patients through their first day of rituximab without steroids. We give that prophylactically to make it as smooth as possible. But some patients have a rough time getting the rituximab. It usually gets better though the second or third dose. Usually, by the third or fourth dose, patients are not having any toxicity. It has to do with how many hairy cells are present. In fact, if you give delayed rituximab, because there's so few hairy cells present, you generally don't find toxicity from rituximab.

Some patients are allergic to rituximab, that's rare, but it does happen. We've been able to get patients through their rituximab even if they're allergic to it by using desensitization.

Anna Lambertson:

Just to clarify, rituximab and obinutuzumab are not chemotherapy. That was a question that came through the Q&A.

Dr. Robert Kreitman:

That's important to state. One of the things about chemotherapy for hairy cell, cladribine, pentostatin, even bendamustine, they kill normal T cells and they can deplete normal CD4 positive T cells for a median of four years before they come up to the normal levels. Some patients have chronically low normal T cells. This can cause long-term opportunistic infections. There's some debate about whether those could cause secondary malignancies in patients with low CD4 cells. This is one of the reasons why people want to try to avoid chemotherapy, but most patients get through chemotherapy just fine.

The other thing to mention about secondary malignancies is that many people believe that hairy cell itself is a risk factor for secondary malignancy, so you must be careful about getting screened for colon cancer and breast cancer, prostate cancer, melanoma, things that are easy to detect early and avoid dying from.

Anna Lambertson:

In general, what does the data say about blood counts improving after cladribine and rituximab (CDAR)? How long does it take? Are there different blood counts, white, red platelets, et cetera, that come back first? What does that look like for most patients?

Dr. Robert Kreitman:

That's a very good question, and it turns out that the platelet counts come back first. Assuming someone's going to get a good response to their treatment, the platelet counts come up within about three weeks. It takes a little bit longer, about five or six weeks, for the neutrophil counts to become normal. When you use concurrent cladribine and rituximab, you find that on day two of the rituximab, in other words, a day after the first dose of rituximab, when patients have a lot of hairy cell present, the platelet count drops by about 50 points. That's important because some patients could need a platelet transfusion.

We haven't had any serious bleeding, but we do give transfusions if we see a platelet count below 8. Some doctors are not comfortable with that. They want to give platelet transfusions if it's below 10 or even 15 or 20. But nevertheless, if you compare patients who get CDAR versus patients with cladribine alone, even the platelet count at four weeks is better after CDAR than the platelet counts after cladribine alone. I think that is because the cladribine plus rituximab, it cleans out the bone marrow quicker and allows the normal cells to grow in more quickly than if you just give cladribine alone. That's what we find as far as the time course of how long it takes to get improvement in the bone marrow.

Anna Lambertson:

How do you evaluate the response? When do you do the post-treatment bone marrow biopsy? What is your approach? What do the guidelines recommend? What is the best way to know how the blood counts have improved and what the patient's response has been to treatment?

Dr. Robert Kreitman:

The only way you can determine if you're in complete remission is to do a bone marrow, because the complete remission is defined by not seeing those hairy cells in the bone marrow, at least by the regular stain. The best time to do a bone marrow is at the 6-month time point; some people go as early as four months. We like to stick with six months to make sure that you have enough time to achieve a complete remission. We follow patients with bone marrow closely even after six months. But most patients, I would say, they get a bone marrow at six months, they get followed by blood afterwards. There are some patients that just don't like bone marrows at all, and they can be followed by the blood count. In that case, you don't know if you're in complete remission, but you at least know that you have an improvement in the blood count.

Anna Lambertson:

I want to quickly ask a question about BRAF inhibitors, particularly vemurafenib. As you know and as many individuals who may be considering vemurafenib know, there are different doses that are used. Why are we seeing 960, 480, and 240? Is there a difference in outcomes for patients? What can you share with those listening regarding the different doses of vemurafenib?

Dr. Robert Kreitman:

I think that higher doses of these agents are probably more effective, but there are no data that show that dose matters. That's because we don't have enough patients to test different doses and to randomize patients to have a group get one dose and another group get another dose. We find that even the lowest dose of vemurafenib, 240 milligrams twice a day instead of 960, can be very effective and can give you complete remission. I think that it's good to go down on the dose. Patients have toxicities and many times you can get more drug and you can be treated for longer if you go down on the dose than if you try to push through with doses that are too toxic.

Different patients can tolerate different doses of vemurafenib. You can say the same thing for the other drugs, the combination of dabrafenib and trametinib and encorafenib and binimetinib.

Anna Lambertson:

You and your colleagues have recently published a study regarding patients with HCL and their response to COVID. There's an ongoing concern about COVID among people with HCL, before treatment, during treatment and after treatment. What are their risk factors for getting sick?

Many patients reach out to the Foundation and let us know their lymphocytes are still low, even though they were treated with CDAR a few years ago. They're concerned that they could become severely sick if they come down with COVID or other viruses. There's also an ongoing concern about vaccines, including the COVID vaccine and flu vaccine, and when those vaccines should be timed with treatment for the patient to have the best outcome. What information can you share with webinar participants based on your study and your own experience?

Dr. Robert Kreitman:

COVID vaccines are not effective in increasing the antibody levels in patients who have had rituximab within the last year. In general, very few of those patients made antibodies even to COVID, for about a year.

After about a year and a half, we see some patients start to recover their normal B cells, to be able to respond to getting COVID, and then, after one and a half years, most of the patients, but not all, are able to respond to vaccines. That's one of the reasons why it's recommended that patients check antibody levels. It's not a general recommendation for the community. You'll see that the CDC doesn't recommend that everyone check antibody levels, but it is a recommendation for hairy cell patients because the treatment and even the disease can cause low normal B cells. That can prevent good immunization and even a good response to the COVID.

But it's fortunate though, the good news is that doesn't mean you die of COVID. There are good treatments for COVID. I mentioned paxlovid and remdesivir; there are good treatments that can be used even when you don't have antibodies. We don't find that the vaccine is a problem for hairy cell patients. It's not a toxic vaccine. There are toxicities for the vaccine that are extremely rare and we think they're similar for patients with hairy cell and patients who do not have hairy cell and patients. Fortunately, those patients can rely on the COVID drugs, especially Paxlovid and Remdesivir, when they get infected with COVID.

Anna Lambertson:

A final question: You mentioned secondary cancers. Are there secondary cancers specifically associated with vemurafenib that you are seeing in patients with HCL being treated with vemurafenib? You mentioned the importance of screenings for colon cancer, and we know the experts recommend patients with HCL receiving annual skin checks. What else can you advise or share with our patients listening?

Dr. Robert Kreitman:

The cancer risk after chemotherapy seems to be related to the low CD4 counts. Those cancers, secondary cancers, can be the common cancers, it can be other hematologic malignancies that are more deadly than hairy cell. It's important to screen early for those things that you can prevent dying from by catching them early. Like I said, breast cancer, colon cancer, melanoma. The cancers that are caused by vemurafenib, those are totally different. They may be squamous cell carcinomas. They're not benign, they're malignant, but they don't tend to kill people. They may require you to stop the drug. Vemurafenib can cause cancers related to the skin that are totally different than the secondary malignancies that we worry about with chemotherapy. That's important to understand the difference there.

Anna Lambertson:

Dr. Kreitman, thank you so much. Over the course of today's presentation, you've talked not only about purine analogs like cladribine and pentostatin that have been around for a very long time and have resulted in long remissions from many patients. You've shared some of the more recent data that you and investigators at MD Anderson have brought forward about cladribine with rituximab, which is exciting in terms of the ability of that combination to extend remissions. Then, the BRAF inhibitors, as well as CAR T. I want to say before we wrap up, it's incredible that there are investigators such as you and your team who continue to commit time and resources in your lab to finding new therapies and improving existing treatments for patients with HCL, helping to extend remissions and ultimately to improve quality of life.

We are at the end of our time. I want to thank you, Dr. Kreitman, for doing the presentation today and taking time to answer the questions. And thank you to everybody who joined us for today’s discussion.

This transcript has been edited for clarity.