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Webinar Series: What's New in HCL?

Ibrutinib in Classic and Variant HCL

April 20, 2021

Hosted by the Hairy Cell Leukemia Foundation with expert speaker Dr. Kerry Rogers from The Ohio State University Comprehensive Cancer Center-The James. Moderated by Anna Lambertson, HCLF Executive Director.

Webinar Materials

Materials from the presentation and discussion with Dr. Rogers.

• View slides by Dr. Rogers.

Webinar Transcript

The following is a transcript of the 1.)Presentation given by Dr. Rogers and 2.) Question & Answer session with participants.

Presentation by Dr. Kerry Rogers, The Ohio State University Comprehensive Cancer Center-The James

Anna Lambertson:

Dr. Kerry Rogers is our speaker today. She's a hematologist oncologist at the Ohio State University Comprehensive Cancer Center, The James, in Columbus, Ohio. Many of you may already be familiar with Dr. Rogers, perhaps as a patient or because you joined past webinars or patient seminars where Dr. Rogers was a presenter. Dr. Rogers is deeply committed to helping patients with HCL and we see that in her research, her publications, and her willingness to contribute time and share her expertise with all of us. Dr. Rogers was also a member of our inaugural cohort of HCL Fellowship grant awardees in 2017 and she's been an active member of the HCLF network of specialists. Thank you Dr. Rogers for agreeing to speak with us today about your research.

Dr. Kerry Rogers:

Thank you and thank you very much for the really lovely introduction. Today I'm going to be talking about a study of Ibrutinib, which is an inhibitor of Bruton tyrosine kinase, in both classic and variant hairy cell leukemia. This is research describing the first use of this drug in hairy cell leukemia. I'm most excited to talk to you guys about this because this is really who we're doing this research for. So it's for people living with hairy cell leukemia and those that care about them.

Dr. Kerry Rogers:

Here’s the posting online in PubMed (which, if you're not familiar, is a website that indexes medical publications) of our report of the Phase 2 Study of Ibrutinib in Classic and Variant Hairy Cell Leukemia. I thought I’d post the website so you all can see that this is online for doctors and medical researchers around the world to start reading and learning from.

So this is the first study of a BTK inhibitor called Ibrutinib in hairy cell leukemia and in fact, it is the first study of any BTK inhibitor in hairy cell leukemia. This study opened in April of 2013 and is ongoing. I've been leading this study for the last several years, but really it's a team that made this study happen. As you can see, some of the people that worked on this study are authors and you can see them listed on the screen, but there's many more people who put time and effort into making this research possible, including the people that participated in the study.

So the results that we're presenting and that we've published are from the first 37 patients. We have fully recruited now to 44 patients, but the reason we wanted to publish it when we had results for 37 patients is that the study had been open for so long and we'd learned so much about the drug, we didn't want to wait any longer to make this information available, both to people with hairy cell leukemia and their doctors. So to make sure that people can start benefiting from Ibrutinib, we wanted to make sure that these results got put into the scientific community. 

Dr. Kerry Rogers:

I want to frame a little bit why this study is important or what role we think Ibrutinib might fill and why we're studying this. As most of you know, hairy cell leukemia is a chronic B-cell leukemia. So it's a leukemia people live with for many years and the cell that transformed to become a leukemia cell is a B-cell or B-lymphocyte. People with hairy cell leukemia can expect to live many years with it. So in most cases, their full lifespan. Part of what's driven the very good outcomes for people with hairy cell leukemia is purine analog chemotherapy. So those are cladribine and pentostatin. 

I'm sure most of you have heard of those drugs before. They're highly effective and some people can take a single course of cladribine or pentostatin and not have any more problems from hairy cell leukemia for a decade or more. That's outstanding and that's not the group that we feel really needed something new in terms of treatment. Taking one course of something and being in remission for decades or a decade or more is great. But we are really looking at the group of people with hairy cell leukemia who didn't benefit from these purine analogs in the way that we would want.

Dr. Kerry Rogers:

People with a short remission duration - say you take cladribine and then two years later, your hairy cell leukemia is back and you need treatment again, and then you take cladribine again, two years later you're in the same spot. So if you're really getting just a few years out of cladribine or pentostatin, that's not a good benefit. Some people have already had three or four treatments of cladribine or pentostatin and you say, "Should I really take four or five treatments of this?" And then of course, some people can't tolerate those drugs. I've met people that have had neuropathy, which is nerve pain, from them or other side effects. Some people have infections that make them dangerous. So there's people that just aren't able to tolerate them. And so this is really the group of patients where there's a need for different treatments for hairy cell leukemia and that's the need that we're looking at trying to meet with this study.

So, there are some alternatives to purine analogs.

There's Vemurafenib, which is the brand name Zelboraf, that inhibits the mutant protein, BRAF V600E, so it's a oral-targeted drug. It's a pill. And that's been studied in two phase two studies in hairy cell leukemia and there's ongoing investigation with Vemurafenib to learn how to use it better and how to combine it with some other drugs to increase the effectiveness. It is only suitable for people that have the BRAF mutation.

There's moxetumomab pasudotox, the brand name for that is Lumoxiti. That's actually FDA approved for people that have had at least two prior treatments, including purine analog. And it's an antibody drug conjugate. So that can be effective for a group of people with hairy cell leukemia.

There's Interferon, which is a very old treatment. That's an immune stimulant.

And then rituximab, or Rituxan is the brand name, and that's an anti-CD20 monoclonal antibody. So it's an antibody that targets the CD20 marker on hairy cell leukemia cells. That is frequently combined with cladribine or pentostatin. There’s a study combining rituximab with Vemurafenib, so it's something that can be used in combination with other treatments. And it can be given by itself in some cases.

Dr. Kerry Rogers:

So these are the existing drugs for hairy cell leukemia in this space I'm talking about, the more established ones. So we designed a study of Ibrutinib for patients who are not expected to have a large benefit from purine analogs. So these are people that have had at least one prior treatment for hairy cell leukemia, including a purine analog if they had classic. And because folks with a variant of hairy cell leukemia don't get the same benefit from pentostatin and cladribine, we allowed people to enroll in this study as a first treatment if they had the hairy cell leukemia variant.

So for people with classic hairy cell leukemia, you either had to have had a purine analog or be unable to take it or if you had the variant, you could enroll in this study, because the purine analogs don't have the same benefit for most people in that group. And then the people we were enrolling in this study were folks that needed treatment. So people who had symptoms from the hairy cell, had low blood counts, some people had large lymph nodes or spleen from it. So you had to have some issue from the hairy cell leukemia that you needed to improve with a treatment in order to be in this study.

Dr. Kerry Rogers:

So, just to give a little bit of brief background on the drug. Ibrutinib is FDA approved for four other types of cancer. It's not FDA approved for hairy cell leukemia, it's FDA approved for chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, and Waldenstrom’s macroglobulinemia. Those are all B-cell cancers, so it's very effective in this group of B-cell cancers and hairy cell leukemia is also a cancer of B-cells, which is why we thought that Ibrutinib would work in hairy cell leukemia.

It is an oral-targeted agent. So it's a kinase inhibitor that gets into the cells and targets a protein called BTK. The long name for BTK is Bruton's tyrosine kinase. BTK, or Bruton's tyrosine kinase, is a protein that's in a signaling cascade. So those are signaling pathways within B-cells. And BTK gets activated, hits another one downstream, so it's kind of like dominoes within the cell. And blocking BTK interrupts that domino string within the cell and actually causes B-cells that are leukemia or lymphoma cells to die off over time. So it changes the biology of leukemic B-cells in these different cancers.

So it's really an outstanding drug in more diseases than just hairy cell leukemia. I put on this slide too the packaging and what the drug looks like just so people can get a better understanding of what it is.

So it's pills that are given once a day.

Dr. Kerry Rogers:

This is a multi-site study. So this study was open and available to patients more places than just the Ohio State University. It was also open at the NIH, MD Anderson, Mayo Clinic in Minnesota, and Karmanos Cancer Institute in Detroit.

So it enrolled a total of 44 people across all the sites. And again, this is the experience of the first 37 people, that's who we had results for when we were publishing this study and wanted to get this information available.

The main goals of the study - the big one was to determine how effective Ibrutinib is in treating hairy cell leukemia. So the primary endpoint was the overall response rate at 32 weeks after starting the drug. We also looked at the overall response rate which is how many people responded to the drug at 48 weeks and at any time during treatment. We looked at how long people remained in remission, or what their leukemia controlled while taking Ibrutinib. And of course, we looked at what we call overall survival, which is, if people are still alive after starting the study and how long.

Dr. Kerry Rogers:

We also characterized the side effects of Ibrutinib. So you always want to know what side effects this is causing people, we call them adverse events for clinical trials.

This study was sponsored by the Cancer Therapy Evaluation Program, or CTEP, at the National Cancer Institute. So this is a NCI-sponsored study. And Ibrutinib, the drug used in this study was actually provided by the manufacturer, which is a company called Pharmacyclics, through an agreement with CTEP. So that's who provided the funding for the study and who provided the drug for the study. And those are very important things because you can't do research without this.

Dr. Kerry Rogers:

So the treatment in the study is very straightforward. You take Ibrutinib once a day every day. And people just take it until either their leukemia progresses or it's not controlling the leukemia anymore, they develop a side effects or side effects and need to stop taking it, or they choose to stop taking it. Sometimes people's lives change or their health changes and it doesn't make sense to continue a particular treatment. Of course, patients will have to stop taking it when the study ends, but I don't foresee that happening in the near future.

There were two doses because this study was also to determine the correct dose of Ibrutinib. 420 milligrams is the approved dose for most of the diseases it's approved in. And at the time this study was designed, we didn't know what the approved or best dose would be in basically any form of cancer or disease we were using it in. So both 420 milligrams and 840 milligrams were studied and because of this trial, we decided 420 milligrams, which is the approved dose in most other cancers, was the correct one to use. And like I said, we assessed response at two pre-specified times. Then later the treating physician could reassess response to find out how well their patients were doing in terms of the treatment.

Dr. Kerry Rogers:

So, these are some characteristics of who was in this study. These are the 37 people whose experience we're reporting in this paper. The median age was 64. Median isn't exactly average, but you can think of them as similar if you're trying to understand what median is. And then the range is the range between the youngest and the oldest person. So the youngest person entering the study was 43 and the oldest person was 78. About 20% of people in this study were women, so it was 19% were women.

And then this is really important, the median time between being diagnosed with hairy cell leukemia and entering the study was 9.8 years. So that means that people were getting treatment in this study after having hairy cell leukemia for nearly a decade. But of course, that's not everyone, so there's a range. So the shortest amount of time between diagnosis and enrolling in the study was .2 years and the longest amount of time was actually 42 years. So, that's someone that was diagnosed with the hairy cell 42 years before joining the study.

Dr. Kerry Rogers:

The number of prior treatments - the median was four. So again, we had a couple people that had the variant. We had two people with the variant who had not received a treatment previously and took Ibrutinib as a first treatment. And then the most treatments anyone had received before receiving Ibrutinib in this study was 12. But I like to look at this kind of information about the median time between diagnosis and entering the study and the median number of treatments to confirm that we did actually have in the study who we wanted to have in the study, which is people that weren't necessarily benefiting from purine analogs and who had taken a relatively high number of treatments in the amount of time they had hairy cell leukemia.

The main goal of studies like this are to pick a really new treatment method for people who aren't getting the benefit we'd like out of our current treatments. So I think we actually did that, looking at these numbers. 76% of people in the study had the classic form of hairy cell leukemia, and 24% had the variant. And then I showed the BRAF status here. There was one person where it was unknown, but 54% were BRAF positive and 43% were BRAF negative.

Dr. Kerry Rogers:

This is a slide I made just for this group. I put the number of prior treatments, how many had a splenectomy, and then this middle section, "Agents received," is to show you what people had taken before being in the study. And some of them actually received multiple treatments. So 92% of people in the study had taken cladribine before. That's almost everybody. 32% had taken pentostatin. In fact, some people had taken multiple treatments of cladribine. You have 11% having taken Vemurafenib before and 14% having received moxetumomab pasudotox. So you can see that most people in this study had received cladribine or pentostatin.

At the time of the analysis for this paper, we had 40% of people still taking Ibrutinib, so that's 15 of the 37 people that we were reporting. And 60% then stopped taking Ibrutinib. Nine was because their hairy cell leukemia progressed or came back while they were taking the Ibrutinib and it was no longer controlled. Seven stopped due to side effects. Four stopped because either the patient or their doctor thought that it was the right thing to do to stop taking the treatment, even though they were doing well on it. And then two people died of pneumonia while they were taking the study treatment. The median follow-up, so the amount of time we have that we've followed people for, is 3.5 years and the longest we had was almost six years. And this data is from between April 1st of 2013 to September 9th of 2019.

Dr. Kerry Rogers:

So, here is the overall response to Ibrutinib. I want to show you a couple of things about this bar graph. You can see there at 32 weeks, you have only 24% of people having a response, so that's a complete or partial response. And you see there's a very large section of people in green. Those are people with stable disease. So their leukemia didn't get worse, but it didn't meet the cut off for saying that this is a response. And you can see that at 48 weeks, more people have a complete or partial response and fewer people have stable disease. And if you look at the last column, which is the best response achieved by someone in the study, you have 54% of people, so over half of the people in the study, got either a complete or partial response.

This is very typical for Ibrutinib in other cancers too. So, what we see is people benefit from the drug and their leukemia won't get worse, but it can take much more than a year, so 48 weeks is still less than a year, to see these responses develop. So, they'll get an objective response but it will take a relatively long time. So people feel well, go about their lives, and aren't sick from the hairy cell during that time, but they don't meet the criteria that physicians and researchers used to say that this is a remission or response. Within that, we had seven complete remissions and 13 partial remissions.

Dr. Kerry Rogers:

This slide is a better indicator of how well this drug can work in hairy cell leukemia and what the benefit is to patients. So if you haven't seen this before, this is a Kaplan–Meier curve and the line along the bottom is time in months. You can think of that as a timeline and it goes all the way out to about 65 months there on the bottom. And then on the side it says survival probability. So that's the probability that someone is still alive. 

So the PFS, which is the progression-free survival, so that's alive without their leukemia returning is always going to be fewer people than those that are alive because some people had their leukemia come back and went on to receive other treatments and be well taking those treatments.

Dr. Kerry Rogers:

So there's a couple things about this that's really important. And the first thing I want to say is that these are pretty flat. So you can see within the first year of treatment, you have some people that died and some people had their leukemia return, but actually after about the first year, it was relatively fewer people that had their leukemia return. And this is actually people that died for any reason, so if you had a heart attack unrelated to the treatment, that also counts as a death in the study. I just want to make the point that it's not just people who died specific to the leukemia.

Dr. Kerry Rogers:

So, you see that's pretty flat, so that's a whole group of people who are alive and doing well. So even though the overall response rate is only 54%, at three years, 73% of people were alive and with their leukemia controlled. And that's actually pretty good. So you're saying that almost three quarters of the people who started this treatment are alive and doing well from a hairy cell perspective three years into the study.

So the median progression-free survival and progression-free survival is the amount of time that people are alive without their leukemia worsening was not reached. If you look carefully, overall survival, that blue line kind of falls off at the end pretty sharply. No, that's not because everyone in the study died at once, that's because there were very few people out that far. So if you have two people who you're following and one of them dies, you get a huge step off like that. It actually has to do with statistical modeling, so please don't panic.

But yeah, so these are very flat progression-free overall survival curves, meaning people are doing very well in this study. And I think this is really showing what a benefit this drug can be to people with hairy cell leukemia.

Dr. Kerry Rogers:

I don't want to spend too much time on this, but this is the adverse events. That's what we call them in studies, but you can think of them as side effects. And then this table is the most common side effects people had. And I tried to put in parenthesis the more common way to think about what these side effects are. We break them down in grade one or two, which is mild side effects, ones that might need a medication, but won't result in you being hospitalized or impairing your daily functioning much. Grade three or four side effects are ones that actually impair daily life, result in a hospital stay, things like that. And then this is this last column is just any side effect.

So you can see here, especially with diarrhea, a lot of people having diarrhea, but actually no one had severe enough diarrhea that it was a real problem for them. So, some of these things occur but they're not reaching the severity that's impacting people's lives as much. I put in red some of the hematologic side effects, so ones that are related to your blood or blood counts. So you can see how many people had anemia or low platelet count in the study. And then some of these side effects are actually really common with Ibrutinib in other diseases, such as diarrhea, myalgia, which is muscle pains; atrial fibrillation down here at the bottom, which is very common abnormal heart rhythm.

So we are actually are seeing the same spectrum in types of side effects in hairy cell leukemia as we do with Ibrutinib in other diseases, which is really nice because this drug's been given to thousands of people with cancers like chronic lymphocytic leukemia. So I think that experience of what side effects those people with other cancers get with Ibrutinib applies to people with hairy cell.

Dr. Kerry Rogers:

We did some scientific studies with this. So we looked at drug levels at both the doses. We looked at mechanisms of drug resistance in hairy cell leukemia, which not too many people had resistance to it so it's kind of exploratory. And then we actually looked at antibody levels during treatment. You can see that's what graphed there at the bottom, showing that IgG levels decrease from base line. Not a huge amount, but they definitely go down. IgG is a certain type of infection-fighting antibodies and we see this with Ibrutinib in other cancers too.

So just to summarize, what we learned from the study is that Ibrutinib is effective in both classic and variant hairy cell leukemia. And the progression-free survival was long. I was talking about that flat area of progression-free survival curve. At three years, you have 73% of people alive and with their leukemia controlled. And that's a really great thing and compares very favorably to drugs like Vemurafenib where the average time before your leukemia comes back is less than two years, even if you have a complete remission.

And then side effects with Ibrutinib were similar to other cancers. One of the things we wanted to do when we published this was to make it clear that Ibrutinib is a good option for specific hairy cell leukemia patients. So this isn't something that needs to replace cladribine or pentostatin for people who are healthy enough to get it. But for people who aren't benefiting from purine analogs, this is a very good option and should be considered. Because it's approved in other cancers, it can be prescribed from a pharmacy for people with hairy cell off label.

Dr. Kerry Rogers:

What we want to do in the future is look at treatment with Ibrutinib in combination with other drugs to improve the response rate and how effective it is for people. 

This can't include everyone that worked on the study, just because there were so many people, but I wanted to make sure I made a slide just so you get some idea of people that were involved in this. I have the sub-sites on there, of course CTEP and Pharmacyclics, the Hairy Cell Leukemia Foundation for supporting me, and also allowing me to present results from this study at the scientific meeting. And then most importantly, the patients that chose to participate in the study and those people who supported them, because that is who we are doing this study for, is people with hairy cell leukemia and this research is obviously not possible unless people are willing to participate in this research study.

Question & Answer Session with Dr. Kerry Rogers

Anna Lambertson:

I am going to jump quickly into the Q&A. There were some questions that came up that I thought could help clarify a few things for some of the participants. Earlier on in your presentation, you were pointing out the percentage of patients who were BRAF positive or BRAF negative and it seemed to several participants that the percentage of BRAF negative was higher than what you might expect since we have this general understanding that virtually everybody who is classic is BRAF positive. Can you clarify that? The somewhat high percentage of BRAF negative patients in the study?

Dr. Kerry Rogers:

This was a question with this study raised by other people in the hairy cell leukemia community and the peer reviewers at Blood, which is the journal where this is published. So, as we know, most people with classic hairy cell leukemia have the BRAF mutation, so it's around 98%. However, what you'll see from our data here. 

If you have more people that are BRAF negative than you have variants, then you have a substantial fraction of people who are BRAF negative but have classic hairy cell leukemia.

So, that is something that happens biologically, and while it's only maybe a couple percent of people with classic hairy cell leukemia that are BRAF negative, this study was looking to enroll people with more difficult to treat or more unusual cases of hairy cell that didn't benefit from purine analogs, so we selected for this population of less common hairy cell leukemia that is classic, but BRAF negative. 

So there's a small group of people who have classic hairy cell leukemia that are BRAF negative. They usually don't have as much benefit from purine analogs as people who are BRAF positive and since we're selectively trying to get people in this study who aren't going to benefit from purine analogs, we have a higher portion of people who have classic hairy cell leukemia and are BRAF negative. 

Anna Lambertson:

You talked a bit about side effects. Are those side effects lasting side effects or just during treatment?

Dr. Kerry Rogers:

The majority are just during treatment - expected to go away within hours, days, or weeks of stopping treatment. So things like headaches, high blood pressure, acid reflux stop after you stop taking the drug. Things like the abnormal heart rhythm, atrial fibrillation, this increases your risk for that developing. But once you develop it, it can go away when you stop the drug, but there's a few things like that that can remain even after you stop taking the treatment. But the vast majority of these go away in a very short timeframe after you stop taking Ibrutinib.

Anna Lambertson:

With regards to FDA approval or approval in Europe - do you see this moving forward towards approval for patients with HCL?

Dr. Kerry Rogers:

We would really like that and we have had discussions with both the investigator, Dr. Ivy, at CTEP, and with the company Pharmacyclics about filing for FDA approval. How drugs get approved is mostly a scientific process, but also there's regulations and more government agency aspects to that, which are very important. The FDA's trying to look at the right drugs for a whole variety of diseases, so while it would be great to get this FDA approved, I don't know if that's something that we will be able to do based on this study or not.

The good news is, in rare cancers like hairy cell leukemia, if you have a publication like this one we have in Blood, and there's no standard therapies or people have already gotten standard therapies, it's usually fairly easy to get your insurance company to provide these off label, so something that's prescribed for an indication other than it's approved. And I imagine the situation at the EMA, which is the European agency, is similar but potentially more complex in this case because this was a US trial.

So I'd like to see this approved by the US FDA. I don't know if that will happen based on this trial or not. But the fact that this is published now will help people get access to it even if it's not approved. This drug also is in the NCCN, which is the National Comprehensive Cancer Network guidelines, which are the guidelines that oncologists and hematologists use to figure out how to treat cancers. Usually if things are in the NCCN, insurance companies are likely to approve. This study got Ibrutinib in the NCCN guidelines, which will also improve patient's ability to get it.

Anna Lambertson:

Earlier on in your presentation, you included a list of alternatives to the purine analogs. You listed Vemurafenib, moxetumomab pasudotox, Interferon, and rituximab. One individual pointed out you hadn't listed Bendamustine and is that just because it's a chemotherapy drug or is there another reason?

Dr. Kerry Rogers:

That's a good point. I could have listed Bendamustine and I didn't, one, because it's a chemotherapy drug and I was trying to list things that are alternatives to chemotherapy. Bendamustine is a partial alkylating agent, partial purine analog. So I left it off the list for that reason. It can be very helpful for people, particularly with the variant of hairy cell leukemia, but I did leave it off the list because it's a partial purine analog and a chemotherapy.

Anna Lambertson:

You also spoke a bit about how when it comes to progression-free survival, Ibrutinib may be more effective than, for example, Vemurafenib in terms of the number of years that the patient can be without his or her leukemia worsening. Is that correct?

Dr. Kerry Rogers:

Yes. That's correct. So, we have at three years 73% still alive without their leukemia progressing. Vemurafenib is generally given for a shorter time period. There were two phase two studies of Vemurafenib, one by the group in New York and one by the Italian group published in the same publication in the New England Journal of Medicine. And they used something called relapse-free survival, which is how long you were alive without your leukemia returning, which is just slightly different than progression-free survival. It's a technical matter. But for people with a complete remission, the median was less than two years, so that's less than 50% at two years, which is shorter than 73% at three years.

So there's been a great effort to combine Vemurafenib with other drugs like rituximab or another antibody called Obinutuzumab that might boost the time people remain in remission after it. I have also seen some people get repeat treatments with Vemurafenib after their leukemia returned. But yes, based on phase two studies, the amount of time you can expect to not have your leukemia return is shorter with Vemurafenib the way it's given in those studies.

Anna Lambertson:

Thank you for that comparison. I'm sure that's interesting to a lot of individuals on the webinar. How does Ibrutinib compare within the same scope to moxetumomab for example?

Dr. Kerry Rogers:

That's a great question and the way I think about this for patients is that we have these tools, Vemurafenib, Ibrutinib, moxetumomab pasudotox, that all can, for an individual, result in very good remissions and they all have their different spectrum of side effects and advantages and disadvantages. Vemurafenib is a shorter term treatment. It's given for usually a matter of weeks and not indefinitely. Ibrutinib's given indefinitely. Moxetumomab is given three days a week one week out of the month for six months. So it's a IV treatment and it's given for a a six cycle course. So one of the reasons people might prefer to do that one is that it's an IV treatment that you're over with in six months. And also has very different side effects compared to something like Ibrutinib. So, you see something called capillary leak syndrome. You can see something call hemolytic uremic syndrome which is not actually as bad as it sounds, but it's something that has to be monitored for, so there's different groups of people that are best suitable to take these different drugs. So it's really great as someone that takes care of people with hairy cell leukemia to sit down and look at what their preferences are regarding treatment, what their other health conditions are, and which side effects might not be good for them and to choose within these available drugs which one might be best for them as an individual. In terms of the efficacy of moxetumomab pasudotox compared to Ibrutinib, that's a hard comparison to make just based on the way the clinical trials were done.

Anna Lambertson:

So, we did receive a question from someone who is asymptomatic, they have variant hairy cell leukemia, they have been speaking with their doctor since last year about potentially looking at, they've been talking about Ibrutinib. While this patient, is asymptomatic now, as his diseases progresses and treatment is deemed necessary, he's been talking to his doctor about trying Ibrutinib as the first option, rather as salvage following what you might otherwise do using a purine analog and rituximab. What are your thoughts on Ibrutinib as a first-line treatment option for an asymptomatic variant HCL patient?

Dr. Kerry Rogers:

First, sometimes people have no symptoms from their hairy cell, either classic or variant, and still need treatment for other reasons, but I don't think this is something that should be started in someone that doesn't have a need to improve something related to their hairy cell. So that doesn't have some lymph nodes enlarging, low blood counts for some reason that you need to do something to make the leukemia better. None of these treatments I'm aware of in this category will cure hairy cell leukemia. So you really want to wait until you have something you need to improve to take any treatment.

I do think though that Ibrutinib can be a very appropriate first treatment for the variant of hairy cell leukemia. People living with the variant of hairy cell leukemia can't expect to get a decade out of cladribine or pentostatin, that's not how effective those drugs are for them. Drugs like Bendamustine, rituximab can be effective, but you don't get the same duration of benefit. I think that the reason we allowed people to take Ibrutinib as a first treatment if they had the variant was just because the other treatments for people with the variant of hairy cell leukemia aren't as effective as we have for classic hairy cell leukemia. When you sit down with them to look at how well these things work, what the side effects are, it might be the best choice to take this as a very first treatment for the variant of hairy cell leukemia.

So I'm showing you the progression-free and overall survival curves and we did actually do an exploratory statistical analysis to look, to answer the question, “did people with the variant or classic do better?” Meaning, was the progression-free survival longer in people with the variant or with classic or was there a difference in overall response in people with the variant or with classic? And what we found was there was no difference in how well Ibrutinib seemed to be working for both those groups of people.

So it actually looks like, as far as we know, and again we only have 37 people so this isn't a trial with hundreds of people, but it looks like people with the variant do as well with people with classic hairy cell leukemia with Ibrutinib. So I think that really suggests that this can be very effective for that group of people and could be used as a first treatment.

Anna Lambertson:

And to conclude, since we're still in the midst of COVID and this global pandemic, what should patients who are either taking Ibrutinib or considering Ibrutinib keep in mind with regards to the vaccine? Any risks related to antibodies or in terms of timing with the COVID vaccine? Any guidance that you might offer in that regard?

Dr. Kerry Rogers:

I know that most people want to get vaccinated so that they can go back to doing some things that they like doing and seeing people that they like seeing. And I think that's really important. In hairy cell leukemia specifically, there is not a lot of information on how well vaccines work in general. We would like to get that information related to these COVID vaccines, but we don't have it now. And there's actually not a lot of information on how other vaccines work for people with hairy cell leukemia.

However, people with other B-cell leukemias, like I was discussing on the earlier slide, other diseases where Ibrutinib is approved, have decreased vaccine responses compared to other individuals. So these B-cells are immune system cells and they interfere with the way the immune system works and so, people living with hairy cell leukemia probably have lower immune responses after vaccines because they have hairy cell leukemia. And that's not just the COVID vaccines, it's probably all vaccines.

So the group where there is the most information on this is actually a group of people with a disease called chronic lymphocytic leukemia, or CLL, and those folks have much worse vaccine responses to things like flu shot, Pneumovax, Shingrix, any other vaccine you can think of, compared to healthy individuals or even other people with B-cell cancers. So this is a group of people that have low vaccine responses in general and what we've seen there is Ibrutinib makes some aspects of vaccine response better and some aspects worse.

So, we don't know that Ibrutinib or BTK inhibitors as a class interferes with vaccine responses, but the only data that we have in this area that I'm aware of comes from CLL where people just have terrible vaccine responses in general. What I've been telling people living with hairy cell leukemia is that even if your vaccine response isn't as good as individuals without any sort of blood cancer or immune-modulatory condition, you'll probably still get a benefit from the vaccine. We have not seen increased side effects in patients with any forms of blood cancers and so it is still worth getting vaccinated even if you don't get a maximal response and hopefully that is still enough to keep you from getting very sick or being hospitalized or dying from COVID-19.

Like I said, for BTK inhibitors, we're not sure, it looks like might help the response a little, might hurt it a little. It's unclear. When you look at drugs like Vemurafenib, that's not something that's really immunosuppressive so I wouldn't expect that to change vaccine responses much. But when you look at drugs like rituximab, we know for sure that in other vaccines, the COVID vaccines we're still working on it. These are very new vaccines, but in all other vaccines where it's been studied, drugs like rituximab even in people without cancers that get them for other conditions can't really form a vaccine response with any efficacy in terms of making an antibody response for six months after taking. So it really drops antibody responses.

Cladribine and pentostatin interfere with the same immune system cells that produce antibodies and probably reduce vaccine responses pretty substantially themselves. And I don't know that that's true, but I would think that it is based on the mechanism. So really, these treatments all have slightly different effects on vaccine response.

The last thing I'll say, because this is really important, is after getting vaccinated, you can check your antibody response to the spike protein, which is the antigen that's in the vaccine that you form an immune response against. As an individual with no immune system conditions, I got vaccinated and of course have no interest in checking my antibody response, I'm sure it worked great. But in a lot of my patients, they've wanted to know what their antibody response is and that's a test you can get, if that's something that people choose to do. If you have antibodies then people are usually pretty happy. If they don't have antibodies after the COVID vaccine, the things to realize is there's no scheme right now to get people revaccinated. There might be something to do for that group of people in the future, and that it doesn't mean you have no immune response, it just means you don't have an antibody response. So other parts of your immune system still could have responded.

So I think to summarize this for people with hairy cell leukemia, just having hairy cell might decrease your immune system's ability to make a nice response to a COVID vaccine. And that also, BTK inhibitors, we're not exactly sure what effect is has on COVID vaccines, but we don't think it's all bad, but it's potentially not all good. Drugs like rituximab or anti-CD20 monoclonals definitely impair vaccine responses for all vaccines we're aware of. Purine analogs likely do the same. And then for Vemurafenib, I would guess that they don't hurt vaccine responses, but I don't know that for sure because it hasn't been looked at yet.

Hopefully that's a nice summary and just to be clear, I've recommended all of my patients get vaccinated.

Anna Lambertson:

Dr. Rogers, thank you so much for that very comprehensive response. Thank you for the time that you took today. This was a wonderfully informative and very fast-paced webinar. And thanks to everyone who joined to listen in and to ask questions.

This transcript has been edited for clarity.