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2021 Hairy Cell Leukemia Patient Seminar Session
Panel Discussion: Frequently Asked Questions
October 10, 2021
Hosted by the Hairy Cell Leukemia Foundation with guest speakers Dr. Michael Grever from the Ohio State University, Dr. Robert Kreitman from the National Cancer Institute, NIH, Dr. Kerry Rogers from The Ohio State University and Dr. Clive Zent from The University of Rochester. Moderated by Anna Lambertson, HCLF Executive Director.
Session Materials
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Transcript of Panel Discussion
Anna Lambertson:
Today, we have really an incredible panel. Our panelists, we have Dr. Kerry Rogers from the Ohio State University. Many of you may have listened to her outstanding presentation given last year's virtual patient seminar. You may have also participated in, it was April when she presented her research on Ibrutinib. So I'm grateful that she's joining us today. Dr. Clive Zent from the University of Rochester in New York. He has also very graciously done patient webinars for us in the past. Dr. Robert Kreitman, who is from the National Institute of Health in the US, has done many different presentations like this for us in the past and we're always grateful for all of these individuals and their contributions to these patient programs.
And then our moderator today is Dr. Michael Grever from the Ohio State University whose name, I think, is veryfamiliar to many of you. Some of you may even be a patient of his. He's been involved in HCL research and treatment for decades. Having worked actually with Dr. Bertha Bouroncle at the Ohio State University who is credited with really discovering and identifying HCL. So without further ado, I'm going to turn it over to you. Dr. Grever. I will, as I said,relay questions to you as they come up from patients.
Dr. Michael Grever:
Anna thank you very much for the introductory comments and thank you to the panelists who are here to answer your questions and discuss your questions with us. We also want to thank the patients for participating and for the Hairy Cell Leukemia Foundation for supporting all these opportunities to do research to continue to improve the lives of the patients and also to help educate patients and their families about this disease. I'd also like to point out that Dr. Kreitman worked with Dr. Bouroncle at Ohio State University when he was a medical student too. So we both had the opportunity of working with the individual who wrote one of the most definitive papers on this disease back in 1958.
So let us not waste any more time and get right to the patients and try and help answer of their questions.
Anna Lambertson:
Dr. Grever, I think we were going to kick it off with a question to the panelists about managing hairy cell leukemia in the context of COVID. And so we were curious to hear from you all about how the ongoing pandemic has affected treatments and how does HCL and the HCL therapies impact patient's response to the virus and to the vaccine.
Dr. Michael Grever:
Well, maybe why don't we ask Dr. Zent to maybe give us some comments on the management of hairy cell leukemia during this terrible pandemic?
Dr. Clive Zent:
Thank you (Dr. Mike Grever) and thanks for the opportunity to be on this panel. It's a big question. We could probably spend the hour and a half on there. But I'd just like to start off with a summary that I think is important for all patients and their families. So first of all, this (COVID-19) is a disease we didn't really know about two years ago that has changed our lives at every level and is especially pertinent for patients with any sort of lymphoma or leukemia and hairy cell leukemia is no exception. So for people that have hairy cell leukemia and have been treated and done well, it's a disease that does affect your immune competence, and you are at probably higher risk of getting the disease and possibly higher risk of getting into serious complications from it.
But we really can't quantify that very well and so we just sort of have to generalize from the risk of the population with low grade B cell malignancies. Probably most of the data we have is from the disease known as chronic lymphocyticleukemia, but we know that that data is not completely appropriate because it's a different disease. So it's really hard to be specific. And I think that being careful about avoiding exposure, getting the vaccinations as recommended and being cognizant of the risk of having the infection when you have a fever and taking appropriate action, especially with the availability of the antibody therapies would be really important.
The bigger concern for everybody really is patients who are diagnosed during this time and patients that are needing treatment during this time. And I think the biggest concern there is that the therapy that we've all used for a long time that is highly effective, gives most people a durable response, is also highly immunosuppressive. And these drugs like cladribine and pentostatin, not only do they decrease your normal blood production and therefore decrease your neutrophils, which are your general purpose immune cells that protect you from infection, but they really do suppress your adaptive immune system, both your T-cell mediated and your B- Cell mediated response,s so you can't respond to specific infections and therefore you're much more likely to get unusual infections and possibly have a worse course.
So we've been really careful about trying to avoid these drugs during this time. And the Hairy Cell Leukemia Foundation group has put out a paper, which was published at the end of last year with a lot of suggestions which are still mostly pertinent, but the disease has changed with the Delta variant coming up. And we now really have to think about whether some of our recommendations have to change, but the basic principles are that if you can, you want to avoid cladribine and pentostatin as first line therapy in patients who can possibly safely avoid treatment for a little bit longer and hopefully make it through to the end of the pandemic, whenever that is that might be reasonable. Otherwise we've been trying to use more targeted therapies like Vemurafenib and other BRAF inhibitors and it is something that has to be done on a person to person basis.
And this is something that is very individual depending on what your needs are. But I think anybody who needs treatment for hairy cell leukemia today has to really take the risks of COVID and its complications as a serious concern before getting treated and discuss it with their physician and ask their physician to seek input from colleagues if they feel they need it. So I think that's enough for me for the moment and give some of my colleagues an opportunity to talk about us as well.
Dr. Kerry Rogers:
I was hoping to build on that last point, because I think it's a really good one. And I think Dr. Zent summarizes really nicely the main kind of themes or considerations. And I think the choice of selecting a treatment, if someone needs treatment during this pandemic, is a really important thing and can be very individual. So drugs like cladribine and pentostatin are expected to suppress not only B cells and, you know, obviously treat the leukemia, but also T cells, and really in terms of viral immunity, we expect that this will lower it quite a bit, not multiple years necessarily after someone's taken it, but certainly in the months after receiving it. However, we have the most data to support long term remissions with that. Use of things like BRAF inhibitors, which are now being studied, especially in combination with drugs like antibodies like rituximab or obinutuzumab as a first treatment, we don't know that the remission is quite as long, and there's not as much data with this.
Certainly as a single agent, we don't expect the remissions or the time until people need treatment again to be as long, but the immunosuppressive effects are much less. So just thinking about those two things, if you have people, like I've taken care of some people that reduced their risk of COVID exposures by wearing masks, washing their hands, but have either occupational or family obligations that mean that they can’t just stay at home and avoid all potential exposure to COVID; people that are healthcare workers, teachers, or have small children that leave the home to do things. And so it might make more sense to pick something that's less immunosuppressive, but the remission might not be as long.
Meanwhile if you have someone who really wants to get what we have the most data for being most effective, which would be a drug like cladribine or pentostatin and really is in a position in their life where they can reduce exposures dramatically for a period of time and doesn't have family or occupational or other obligations, it might make sense to say, okay, you know, the thing that is potentially more effective, hairy cell treatment is better, but I understand that this means a lot more in terms of what I'm not going to be able to do during this pandemic for a while.
So I think it's very difficult to make these decisions without really having a direct conversation with a person about what their life is like, what their obligations are like and what their considerations are for doing this. And then one thing I was hoping maybe Dr. Kreitman would comment on, is this study he's been working on that's a combination of cladribine or rituximab as an initial therapy, which was beginning to be used more before the pandemic. The anti CD20 monoclonal antibodies like rituximab, we know, not only in people with hairy cell or blood cancers, but also in people taking them for autoimmune disease, very much suppress the ability to form antibodies, so will decrease the ability to form antibody response to vaccines very dramatically for a period of time, months, usually six months to a year. And also in lymphomas, which again is not exactly the same as hairy cell, but where we have data, seem to worsen outcomes for people that actually got COVID.
So if you're thinking about doing this antibody combination with any other therapy, I think the risk of adding that when we're not having a pandemic seems low, but during a pandemic, I think that's more. So I was hoping maybe Dr. Kreitman had some thoughts on that combination in the context of the COVID-19 pandemic. I just wanted to highlight that you really have to kind of take into account the patient's goals, not only for treatment, but also what their life is like when making decisions about what to do.
Dr. Robert Kreitman:
So yeah, so these comments are very, very important and well taken. So we have sort of a similar approach but I'll tell you what our approach is at the NIH. So when we started out, we thought COVID was going to last a couple months, maybe three months, and that's what the predictions were from the experts and we now know that this is a long term process. We really don't know how far the light is at the end of the tunnel. And in talking to patients the message really hits home, that the patients don't want their response to treatment to be compromised in any way. They really want the best treatment for hairy cell that they can possibly get.
So one of the points that the consensus document led by Dr. Grever on COVID and hairy cell made was to not assume that patients are going to have a good antibody response to the vaccine. Fortunately now that we have the vaccine there are also many tests available to determine how good the antibody response is and that the recommendation is to test patients to make sure that they have good antibody levels. And I think that is a very important thing that we do practice at NIH. And one of the things that we approach patients who get recently diagnosed with hairy cell and want definitive treatments is to look at their antibody level after they've been vaccinated. We very much encourage the patients to who get vaccinated first of all.
And we find that some patients have very good antibody levels and that's good. In patients with medium antibody levels or low antibody levels, they can often respond very well to an additional vaccine dose. If they've had three doses, a fourth dose, if they've had two doses a booster, and we find that they can achieve very high levels with repeated vaccine dosing, particularly if they have normal B cells in addition to the hairy cells that they invariably have when they get diagnosed.
And so before starting a treatment, which is immunosuppressive to both T cells and B cells, say they get cladribine alone which is an immunosuppressive to both, or if they get cladribine plus rituximab which is immunosuppressive to both, but the rituximab immunosuppression lasts a lot longer. It may last a year after the last dose of the rituximab. It could even last longer before they can make antibodies. We want to make sure that they have high enough levels of antibodies. And when they do, and when they receive treatment, we find that their antibody levels stay positive during the time so far that we've been following them. They do go down a little bit, but we want to make sure, and therefore we want to make sure that they start out at a very high level.
And so that is a strategy that we practice. Now that doesn't work for some patients because they have so many hairy cells when they start in the blood. And it may not be a very high percentage of the lymphocytes, but it's a very high percentage of their B cells are hairy cells. And they may not have any normal B cells that you can find. And these patients may not respond to the COVID vaccine at all.
So in these patients, we sometimes recommend a single agent, a BRAF inhibitor, like Vemurafenib, or a combination like dabrafenib and trametinib. The latter was presented at a meeting that the former Vemurafenib has been published many times. And what that does is it may not get rid of the minimal residual disease, which we'll talk about in this conference, but it will get patients into remission often into good partial response or a complete remission, and it will bring their normal B cells up. And then once they have a good remission, we follow those patients. And many of them may do very well for many months, even more than a year, but when treatment is needed. And during that time, of course, they can receive the COVID vaccines if their antibody levels up. And then once they need treatment, because that response runs out, then we can start definitive treatment and we find that those patients are very well protected.
So that's our experience in general, in treating patients that we don't have to compromise definitive therapy, but we may need to delay it and use a BRAF inhibitor to try to improve the normal B cell so that response to the vaccine can be achieved.
Dr. Michael Grever:
Well, thank you very much for all these valuable comments. This is really a complicated question and deserves some careful discussion because when we wrote the recommendations last spring, one of the things that we pointed out was that if somebody is in danger of serious complications from the hairy cell leukemia but they're not actively infected, you shouldn't omit effective therapy because you're afraid they might get some other complication. However, when you look at the patients who have hairy cell leukemia at the time of diagnosis, there is an assessment that needs to be made on how low their counts are and how much danger they're in from the hairy cell leukemia. For example, many years ago Dr. Harvey Golomb from University of Chicago, pointed out that about 10% of patients who are newly diagnosed with hairy cell leukemia clearly have the disease, but their blood counts are not low enough that they absolutely need to be treated right away. And they could be followed without therapy. If you follow them carefully and closely.
You can't just say, well, you need to be followed and then not pay attention because they may come back and the counts are definitely lower. So we wrote some guidelines. And if the neutrophil count is less than a thousand, or if the platelets are less than a hundred thousand or the hemoglobins less than 10, then many of us would agree that therapy is necessary. On the other hand there are some people who have a absolute neutrophil count of 900 or 850, and they may not be in as much immediate danger as somebody whose absolute neutrophil count is 500 or less. So these are just general statements, but it's important to make a decision about how urgent the therapy is. And if you are going to say that you're not going to treat the person at that time, then you do have to set out a plan where you're not going to lose the patient to follow up.
So trying to make a decision about how urgent the therapy is based on the blood counts is important. And then you can decide about whether or not the patients are already vaccinated. I've encountered a number of individuals right now who are already vaccinated, fully vaccinated, and they have detectable antibodies. And so one of the concerns that you have in somebody who's not been vaccinated is if you choose a regimen that's very immunosuppressive, you may make it very difficult for them to develop antibodies for anywhere from six to 12 months. So it's a question about how low the counts are and whether or not the patients have been already fully vaccinated, and you have to have a long discussion with the patient because some of these other alternatives, for example, using Vemurafenib alone, it is effective if somebody's got really low counts, even if they have an active infection. We've published results, where we've been able to show that if you use Vemurafenib alone, you can get the counts up, you get the infection under control, and then maybe at a slightly later date you could do more definitive long term therapy.
Although some of the recent reports coming out with Vemurafenib used in conjunction with rituximab have a really close to a hundred percent response rate, and that's very attractive. But it's really the combination of Vemurafenib plus rituximab. And as you've already heard, rituximab can significantly impair your ability to respond to vaccines for six to 12 months. So there's a lot of complexity in making this decision. And I found that the most important thing is to involve the patient and explain the options, and then try and come up with a decision about what therapy you're going to use.
Hopefully if the patients are already vaccinated, you can treat the hairy cell leukemia if it's in a situation where you're concerned that there may be further deterioration in the counts, and that puts you in a more dangerous position to start therapy. So these are really complicated individualized decisions and there's no one formula that fits all patients. So one of the other things that is important is there are a number of different institutions that will tell you if you have detectable antibodies, but they don't really report out the titer. So we know the patients with hairy cell leukemia in general, tend to have normal immunoglobulin levels. And this is important because patients with CLL, which is a completely different disease, many of those patients have difficulty responding to vaccines because they have impaired immunoglobulin levels. So we're hoping that patients who have hairy cell leukemia are going to respond well to these vaccine strategies. And then we have to assess the levels of the blood counts and the patient's overall condition to make a reasonable decision about when and how to treat. So that's complicated, a very important question.
Anna Lambertson:
Dr. Grever, we've received quite a few questions through the Q&A in the chat about this topic. And thank you already for the information that the four of you provided. Some of the questions are about how do you, or can you quantify the antibody result? Whether a patient and their doctor can decide whether they had a good response to the vaccine based on the antibody result? And then how are you, or are you using that result to determine whether or not the patient should get the booster?
Dr. Michael Grever:
Let’s ask (Dr. Bob Kreitman) since he's done a lot of work. We're trying to collect this information right now. I know Dr. Rogers and Dr. Zent and myself and, and many other individuals that work with us are trying to acquire the information about patients who have had the vaccine and whether or not they have detectable antibodies. (Dr. Bob Kreitman), did you want to give some insight into how the antibody titers are determined or what to do if you can or can't get that information?
Dr. Robert Kreitman:
I know Labcorp and Quest do have semi quantitative antibody levels. And at the NIH we have semi quantitative assays. They're pretty good. The spike antibody is the one that you're interested in when you're looking at the response to the vaccine. There's another type of antibody called the nuclear capsid antibody. That's only positive when you have infection with the virus. And so that's not so much your interest when you're looking at your response to the vaccine. So it's important to know which antibody test you're looking at because they don't always actually say on the test which test it is. If you want to know your response to the vaccine, you have to look for the spike antibody tests.
And we do these routinely in patients. In general we find that when patients have good levels of normal B cells, they will make high levels or at least adequate levels of spike antibodies and that's what you want to see. These are the antibodies that will protect you in case of an exposure to COVID. They protect patients from being infected and even more, they protect patients from being sick with COVID and being sick to the point that they might be hospitalized.
There is also a less well defined immunity called T-cell immunity. And this is part of the antibody response. This is part of the immune response to the vaccine. And it's something that's less well defined both in terms of the amounts. It's not easy to get a test for that. And there's also not a clear idea of exactly how well it protects patients. But there is good evidence that the higher levels of antibodies that you have the better you'll be protected against COVID if you were to get exposed. So this is something that we do follow.
Dr. Kerry Rogers:
I've not yet seen like a firm cut off for, if your antibodies hit this level, you'll never get COVID or if your antibodies hit this level you definitely will get COVID. So while we know that higher levels of antibodies are more protective against infection, I don't have an exact number where it's like, oh, hey, you're good. You hit like X amount. And also antibodies aren't everything. You can still get COVID even if you have antibodies although it majorly reduces your risk of severe infection, hospitalization, and death if you've been vaccinated. But you can still get infected, even if you have antibodies and not having antibodies doesn't guarantee that you're going to get really severe disease because of that T cell and other types of immunity that we can't measure.
The discussion around antibodies is mostly because we can measure them well and we know that antibodies with other vaccines and with this one there's emerging data that it protects you at all. The other thing that I really want to point out is that these vaccines, I highly recommend all my patients get even if you don't make antibodies you still might be benefiting from it. This is an important thing to do. If you're actively getting treatment, it might be good to have a conversation about when during treatment it might be best to do it, but even if you're not going to get optimal protection, we are having a major public health crisis where people are exposed. Vaccination is good, people around you that you interact with getting vaccinated will help you. And just because you're vaccinated doesn't mean that you go somewhere without a mask on. All these things have to be used in combination to protect yourself.
I would definitely not for anybody say, oh, hey, you have high antibodies. You don't need to wear a mask, go out and interact with whoever you want and don't worry about exposure. I've had people ask me this and say like, oh no, I'm not wearing a mask anymore I have antibodies. And personally, that's not the way I think about it for any of my patients or myself and I'm immunocompetent and vaccinated.
I also do recommend boosters regardless of the antibody levels because I think it will help boost, you know, antibody levels and other parts of the immunity. And for people with immune compromise, like people living with hairy cell leukemia, it's really considered like the third shot in the series to protect you as opposed to a booster, which is more the conversation for adults in this country that don't have any immune compromise. And since people with hairy cell leukemia are immune compromised and we're considering it kind of like the third shot in the theories, you could get both a Pfizer or a Moderna booster depending on what your original shots were.
And if the other people in the panel have other things to add, I'm open to hearing that. I just wanted to make sure that I added that information to this discussion.
Dr. Robert Kreitman:
I'd like to echo what (Dr. Kerry Rogers) said about the booster. That even if you do have high levels of antibodies, there may be an improvement in the quality of the antibodies that a booster can provide. And this has to do with some of the mechanisms of boosting that it produces something called somatic hypermutation. And this produces a more wide variety or breadth of the types of antibodies that can be made, each of the antibodies coming from memory B cells. And even though you're boosting with the same vaccine that was developed over a year ago to the original strain of COVID, boosting can actually give you antibodies that bind better to the Delta variant and the beta variant even. And so this is something that has been shown recently in the New England journal and other places that is a benefit of boosting. And so I echo, that despite antibody levels, you can get an improvement in the quality of antibody with boosting.
Dr. Clive Zent:
So I'm going to have a slightly different opinion. I think we really don’t know how important T cell immunity is, but I think that based on our knowledge of a lot of other vaccines for viruses, it is important and it may be more important than antibodies. I think that we have to be very careful about using the antibody levels as a surrogate for the risk of infection and the risk of getting serious infection because of many things, first of all the Delta variant is much more infectious. In orders of magnitude, much, much higher levels of virus that people are exposed to and enough virus can overcome immunity even if it's good and certainly, humoral immunity, which requires the antibodies to bind onto the spike proteins and prevent the viruses from infecting initially or later.
And so I don't really advise my patients that if they have a high level, they are safe and I don't tell them if they have a low level that they're not safe because we really don't know. There's almost no published data about T cell responses to the virus. And I haven't seen anything that's been published and I might have missed it to the Delta variant. And so I think I agree with both Dr. Kreitman and Dr. Rogers that we need to maintain physical barriers. We need to stay away from unvaccinated people, get people vaccinated if they’re spending a lot of time with us. And we’re certainly not over, at any time we could have a variant that doesn't respond to the vaccine and produce immunity. And so I think we really got to consider this to be a serious ongoing condition that is not over and might not be over for a while. And we have to keep that in mind in looking after patients who were previously treated and are doing well, and the patients that need treatment for the first time.
Coming from Africa, where we've been exposed to a lot of epidemics like malaria and TB, I think we are just at the beginning of this epidemic and we need to be very careful about thinking that there are simple solutions to a very complex problem.
Anna Lambertson:
If you don't mind, I'd like to jump in with a question that we've been getting through the Q&A from patients. We're actually receiving some really interesting questions from patients about the possible reaction or connection between the vaccines and the treatment for hairy cell leukemia. And by that I mean, one patient is curious - they were vaccinated before treatment, then they received cladribine, does the cladribine kill off or destroy the antibodies that the body produced? And then on the other side, can these vaccines affect the bone marrow biopsy results, for example? So I think patients are really curious about the interaction between the vaccines, that you are all encouraging your patients to get, and these treatments for the hairy cell leukemia.
Dr. Michael Grever:
I'd just like to say that we've already heard how important being able to generate antibodies seems to be for keeping you healthy. And I advise all my patients to try and get adequately immunized. And the thing though that we have to understand is that the T-cells are important. And when we use the purine nucleoside analogs, either pentostatin or cladribine, we have the hope and we have a lot of evidence that that's going to improve the bone marrow function in terms of getting the hairy cells to go down and the normal cells to come back. But one of the consequences of using either cladribine or pentostatin is that the T cells take a very strong hit. And we've known this for quite some time and T cells will go quite low after either pentostatin or cladribine. And it takes quite a while for them to recover. It may be a year or longer for the absolute numbers of T cells to even come back to the lower limit of normal.
Yet we have people after cladribine and after pentostatin that have done very well. But nevertheless, we have to understand that the treatment to improve the bone marrow and to get people out of trouble from hairy cell leukemia does have that effect. And that effect will last for quite some time. And we have arbitrarily selected certain T cell levels where we think patients are beginning to have enough recovery to be out of immediate danger. But actually I've seen people still reactivate their herpes Zoster or shingles, even when the T-cells are only slightly on their way to recovery. So the T cell recovery is important. And sometimes people tend to forget that the T cells are down and they think well the hairy cell leukemia is in remission, I've had my vaccine, so I have a detectable antibody, so I should be okay to mix and mingle and do what I used to do and what I want to do.
And I would echo what the others have said, and that is we still need to exert precaution because that T-cell defect is important in terms of your immune response. One of the things that we routinely do is we quantitate the recovery of the T cells and that's routinely done in a lot of different labs. But we don't have routine testing for T cell function. So this cells may be coming back, but we still don't know how long it's going to take for them to fully recover. So caution that once these numbers start to get near normal, you still need to be considering getting the vaccine and the booster or the third dose, however we want to call it.
Dr. Kerry Rogers:
But I also think just use all the tools at your disposal to avoid getting COVID. And that's vaccines is one tool, but also I think everyone agrees, wear masks. Please just don't go out and be around a bunch of people, just because you have antibodies.
Anna Lambertson:
Dr. Grever, we might in the interest of time, want to move on to another topic, comparing chemotherapy versus non chemotherapy treatment options. Why different drugs are being combined? What useful results those combinations are having for patients and then also the treatment recommendations that you are offering to your patients at relapse or if they don't respond to other treatments?
Dr. Michael Grever:
Well, we've all looked at different ways and many different ways of treating this disease. So some of the most important research yet remains to be done and that is to try and get the longest absolute duration of remission. We have very effective therapies. When Dr. Kreitman and I first worked with Dr. Bouroncle back in the 1980s, which wasn't that long ago, she predicted that with hairy cell leukemia, the average survival was only four to five years. And we've made tremendous progress. We can now get the overwhelming majority of patients with classic hairy cell leukemia to go into a remission. And many of these are very durable.
And one of the things that we became aware of was that when the bone marrow looks like it's in a complete remission, if you use special stains called immunohistochemical stains, you can see that there still is a fair amount of residual disease in a number of these patients. Despite that, we did a study with over 350 patients with hairy cell leukemia in the 1990s that showed that with pentostatin at least 67% of the patients did not need to be retreated for their hairy cell leukemia when we are out to over nine years of follow up. And cladribine has equally impressive responses. But nevertheless, there are patients who have early relapse. 40 to 50% of patients will relapse. And there's probably a relationship to the extent of residual disease that's left, so many of the investigators, including Dr. Kreitman, here have worked very hard to try and find ways to reduce the amount of residual disease. We still need to get a better handle in my opinion, as to the value in terms of pushing the therapies, if they are suppressing the immune system and trying to balance that against reducing the amount of residual disease, because when patients do relapse we still have effective therapy for them.
And so fortunately patients with hairy cell leukemia can now live almost as long as they would've lived, if they didn't get the disease. And so we have made a lot of progress. But the way we probably are going to continue to see continued progress is to see how we can rationally combine targeted therapy and try to get even longer prolonged duration of remission. (Dr. Bob Kreitman), you've done a lot of thinking about this. What would you say to somebody about the rationale with combined therapies and trying to get rid of the residual disease? What is your opinion on that?
Dr. Robert Kreitman:
So the clinical data that we have, looking at first line cladribine plus rituximab, shows that it's very effective in preventing MRD, and getting patients into complete remission without MRD. We call these MRD-free complete remissions or MRD-free CR. And our study showed that out of 34 patients randomized to getting cladribine and immediate rituximab, 97% of patients were MRD free at the six-month time point. And in following those patients a median of 6.5 years, we had only one additional patient. So 94% of patients were still MRD free after that time. Compared with about 10% of patients who get cladribine alone, after six months after cladribine about 24% of the patients had MRD free complete remission. Really compared to 97%, that's a huge difference.
There were three additional patients, so maybe 32% patients will get complete remission, MRD free, after cladribine alone. But the durability of the MRD, the MRD comes back. And these patients may go many years without relapse. But what we looked at is long term follow up done by many experts. And we find that after about six and a half years, in patients who need treatment due to low blood counts, the kind of patients that we're enrolling in our clinical trials, about 28% of patients will relapse about six and a half years after cladribine alone or after pentostatin alone. And in our experience, when we use cladribine plus rituximab, we find that less than 5% of patients will relapse to the point where they need more treatment compared to 28%.
So we think that there's a big difference in terms of relapse requiring treatments, not just minimal residual disease. Patients that talk to us tell us that it's a quality of life issue that they want to remain in remission. They don't want to have to relapse and get more treatment, even though that treatment might be effective, it might also be toxic and they'd rather not get it, they'd rather have the best response possible to their first treatment.
So what we also did in our study was in patients who got cladribine alone, and then maybe six months later or years later had MRD, which is traces of hairy cells visible in the peripheral blood by flow cytometry, we treated those patients with delayed rituximab. And again, the rituximab is not given for actually needing treatment, it's given for MRD. And rituximab made most of those patients, two thirds, MRD free. In other words, it achieved MRD free complete remission in these patients who had complete remission, but they became MRD positive.
And most of those patients over the years have stayed in MRD free CR, complete remission after cladribine with delayed rituximab. So what we find is that if you compare long term patients who got rituximab early versus patients who got rituximab delayed, there's better, in terms of MRD free, complete remission, in the patients who got rituximab early. But in terms of lack of relapse, it appears to be the same. And so either method of using rituximab early at the same time as cladribine, or using cladribine with rituximab given later, even years later, can prevent or delay patients from needing more treatment. It’s just that they may have more MRD in the latter group.
But there's no indication that there's a difference in survival in these two groups. But we think that either method, either method of first line treatment, is better than getting cladribine and then waiting for full relapse. And so that's what we would conclude from the randomized study that we did that really either method, either using rituximab front or using delayed rituximab may be helpful compared to the standard care. And we note that the NCCN guidelines now give cladribine with immediate rituximab as an option for first line treatment of hairy cell.
And I don't want to downplay the importance of the research going on now in chemo-free options that are now being developed for firstline treatment of hairy cell leukemia, including the obinutuzumab and vemurafenib study that was done at Sloan Kettering. There's some advantage to trying to achieve this kind of response, MRD free CR, without chemotherapy about something that is coming along.
Dr. Michael Grever:
There's a lot of research going on. (Dr. Clive Zent) what are your thoughts? We have to consider what we're doing right now in the midst of this pandemic as to what we might do, even as the pandemic comes under better control, but the getting rid of residual disease probably has some impact on terms of how long it might be to the next treatment. On the other hand, it carries with it, the risks of further suppressing the immune system, not for one month, but probably for six to 12 months. So what are your thoughts about that?
Dr. Clive Zent:
So I think that it would be very nice to develop chemotherapy free, highly effective therapy for treating classical hairy cell leukemia. We now have the ability to block a lot of pathways. Some of them are pathological, some of them are non pathological. So the classical feature, most people with hairy cell leukemia is that they have the activated BRAF protein. You can inhibit that with drugs like Vemurafenib and dabrafenib and then you can also block non pathological proteins like BTK with drugs, like Ibrutinib and acalabrutinib and get an effect. We don't really fully understand that, but it certainly seems to have some clinical value.
And we can use a whole range of antibodies, whether they be conjugated or unconjugated to treat as well. The basic principle in treating low grade lymphomas is that we still consider them incurable, but it's possible that if we can treat these people with multiple drugs that have different mechanisms of action with non-overlapping resistance, that we will be able to get the clone level down to such a low level that would either be able to control it with immunological modulation going forward, or it might be low enough that the patient's own immune system might be able to control it for a long time.
So I agree completely that minimal residual disease testing at very low levels, like one in 10,000 or one in 100,000 is a very good surrogate testing mechanism for determining how well drugs work, as Dr. Kreitman has so eloquently described. Because one of the fortunate problems we have in treating hairy cell leukemia today is that patients do so well that we can't use overall survival as the endpoint anymore. And if we did, we'd all have to live hundreds of years to be able to get neat, decent clinical results. So that's good. But we got to develop surrogate markers for outcome and I think that minimal residual disease is a good objective and probably a clinically and biologically meaningful marker.
So I agree. I think this is a very good way to go. I think that we need to be incremental in our targeted therapy. So I think using a BRAF inhibitor plus an antibody would be a good start. I think it would be reasonable to compare that to cladribine in the post pandemic world. Cladribine and rituximab would be even a better comparison because then we are actually determining whether vemurafenib has the ability to replace cladribine under these circumstances or to be at least equally effective and less toxic. So I think this is the way to go. I think that this is the first good step, and I think that it's very reasonable to use minimal residual disease. However, the role of minimal residual disease in clinical practice is far less easy to understand because we all want to be able to give people one treatment that's the last treatment they ever get. That is the goal; that's called cure or near cure. And we can't always achieve that. And we can't predict always or getting better at it who's likely to get into long term remission and who isn't.
So using MRD to direct treatment outside of a clinical trial is hazardous, because as we all know, there are many people who didn't get minimal residual disease negative status and who've done very well. And I think that's just my last point is that it's very important to remember that there are probably three factors, which determine how long before you get your next treatment. One is how much disease you have and how much that's reduced by treatment. Two, how fast your disease grows back because of its intrinsic biology and three, and we really haven't explored this very much, is how much does any recovery of immune function against your tumor help you to keep that disease from coming back? And so MRD is only one part of that equation, and we don't even really know how important it is. So I think there's lots of more work to be done. And I think we should be careful not to make mistakes in clinical care based on MRD testing.
Dr. Kerry Rogers:
Actually I don't have much more to add to that discussion. But I completely agree with the point that I'd like to make is that I think we need to keep discussing MRD and to use it to try to decide what treatments might be more effective when we're doing research studies to develop new treatments or to learn more about how they work, especially with treatments that are given for like a fixed duration of time. But it is much, much less clear what it means for an individual or when you're treating someone in clinic and not looking at results of a research study. And beginning in hairy cell leukemia and definitely in another disease that we've mentioned a couple times, which is chronic lymphocytic leukemia, I just worry when people are planning an individual treatment for a person living with hairy cell leukemia and are focused on MRD not just kind of like the data from studies when picking a treatment, but for them individually, you could potentially expose an individual to more treatment than is right for them to try to achieve something that we don't know is meaningful for that particular individual. So I think it's an excellent tool and something we need to keep using to understand our treatments better and to develop new treatments, but it is very difficult to know for an individual person what to do with MRD.
Dr. Michael Grever:
I would agree with that. I think that for a long time now we've known that we have effective therapy, you know, for hairy cell leukemia. We've often emphasized that you have to take into consideration how far you're pushing the patient in terms of immunosuppression, because it's not only the risk for infection but there's also the potential that if you push the immunosuppression too heavily, more than you need to, you may increase long term risks of secondary cancers. Because the immune system's important, not only for maintaining safety against coronavirus but it's also important to prevent us from getting second malignancy. So this is an important area of research. It's an important area of research, but whether or not this is extrapolated into every hematology office for routine care really needs to be carefully considered.
Anna Lambertson:
I think that the individuals on the webinar have a variety of questions relevant to the discussion. I did want to pull out a few questions from the Q&A and then I'm going to take a live question. There's an individual who said that they were diagnosed, they first received cladribine five years ago, then had another treatment of cladribine combined with rituximab. Their doctor is now considering a third round of cladribine in six months, if they don't achieve absolute remission. I felt like that was important to give to this panel given the guidelines that many of you helped to write years ago.
Dr. Michael Grever:
Well, one of the points that we have made when we wrote guidelines in 2017 on how to manage hairy cell leukemia, we pointed out at that time that the standard of care was to either use cladribine or pentostatin. And then at the time of making that decision about when you should start therapy, we gave some very specific guidelines in terms of making the decision to start therapy with either cladribine or pentostatin based on the blood counts. And then we gave recommendations for patients who clearly relapsed not only relapsed, but needed to be retreated using those same guidelines of the blood counts. And we pointed out that going with a second course of cladribine or pentostatin would probably be also based on how long the first remission lasted.
So if it was a very short remission, then you might even consider taking a completely different approach. If it was a really long remission, 10 years or more, you might reconsider using the same agent. But in relapse a lot of the hematologists have found that adding a second agent like rituximab to the purine analog will give you a longer second remission. There have been some studies that looked at the duration of the second remission in relationship to the time to first relapse, and it gets shorter if you just go with the same agent without doing something a little bit different, unless it was a really prolonged initial remission.
So I think the other thing that has to be discussed is, if you have an assessment of the patient after the combined use of cladribine and rituximab, we would need to know when that assessment was made, because we know that the bone marrow can get better after cladribine and cladribine and rituximab, the bone marrow can get progressively better as you get out to the four month or longer period. If you do it too soon, you may make an assessment that the effective therapy wasn't as good as you had hoped. But we don't usually try and do that assessment until we've given the treatment enough time to really have the maximal effect. And that's in my opinion, somewhere around four months. And it depends on what the marrow shows. I know if there was a lot of hairy cell leukemia, easily detectable at that point, then you might consider some additional therapy. So the timing is important.
And one of the other things that there's also not uniform agreement on is how many patients get a bone marrow to assess this response? In my opinion, I think it is important to do a bone marrow to assess response, because we want to know how much residual hairy cell leukemia was left, so we'll have a better idea about what to project for the patient. So if somebody had cladribine and then they relapsed five years later and they got cladribine and rituximab, I would need to know how far out are they from that second remission? Have they had peripheral blood count recovery, and how much residual disease was left? I know (Dr. Claire Dearden in the United Kingdom) has given more than one cycle of cladribine but for the most part, you know, we have to be careful about giving cladribine too many extra cycles, because there is a cumulative effect on the bone marrow reserve when you use cladribine in particular. And so you have to be careful you don't end up with very low cellularity in the bone marrow with repeated cycles. So I would need to know what the bone marrow showed at what time point than what the peripheral blood recovery was. Does anybody else want to comment on that?
Dr. Clive Zent:
Yeah, I'd like to comment if possible. (Dr. Mike Grever), I agree with you completely. And I think it's always very important to remember that there are other reasons why people can have pancytopenia. It's not always hairy cell leukemia, and you really shouldn't treat hairy cell leukemia again unless you know that hairy cell leukemia is causing the next problem that the patients have.
Dr. Kerry Rogers:
Can I add too that I'm not sure if they mean like, oh, not in remission, that there's just hairy cell in the bone marrow and if their blood counts are normal. Because sometimes even if you get the cladribine plus rituximab, the blood counts are normal, the person feels well, but there's still like just a little bit of hairy cell in the marrow, I don't know that that's a reason to go for another cycle of cladribine. So kind of like Dr. Grever was saying, it's important to know exactly how much is left in the marrow. And then also if people are doing well and their blood counts are normal, there might not be a reason to pursue a new treatment right then. So I think there's a lot more information we'd need to give more specific recommendations than that.
Anna Lambertson:
There may be more questions come in about MRD and the combination therapies. We frequently receive questions from patients about the timing of the rituximab. And I know that the four of you may have different opinions about this, some of which you've expressed, but really the question is the research, some of which is from Dr. Kreitman, shows that there may be some greater synergy if cladribine and rituximab are given at the same time, but can a patient still have benefit from the Rituximab even if they get it years later, or if they completed their cladribine. There was for example, a patient who joined the webinar this morning; their doctor decided to give the cladribine and do rituximab on day one of the cladribine. Now they're trying to figure out is it worth administering more rituximab for another five days now that the cladribine has been completed? I know that this is not kind of a black and white concrete answer, but if you could spend just a few minutes on that, because that is an incredibly frequent question that we get from patients; the timing of the rituximab. Is there a point after which there's just no benefit of getting the rituximab?
Dr. Robert Kreitman:
Yeah, so we have to rely on the clinical data sets that we have, and I can just go through those real quick. So before we started our studies, (Dr. Farhad Ravandi) at MD Anderson did a non-randomized study where patients were treated with cladribine and then started the eight weekly doses of rituximab, four weeks after the first dose of cladribine. I believe about 22% of those patients were MRD free at the three month time point by bone marrow studies and thereafter the bone marrow wasn't assayed for MRD. So it's a little bit difficult to compare with our studies where we check the bone marrow; he also checked the bone marrow at the one month time point this was before rituximab was started.
We checked bone marrow at the one month or four week time point and the six month time point. And then at 1.5 years, 2.5 years, and then every other year after that, and we have patients now that are 12 and a half years out. And so what we are finding is the MRD free complete remission rate; if you use the rituximab upfront is 97% as I mentioned. And in those patients who got the delayed rituximab, two thirds of those become MRD free. So the reason that we talk about synergy is not from our laboratory studies; there was a group, Chou, et. al reported two studies where the synergy between rituximab and cladribine depend on the rituximab making the cells more sensitive to the cladribine.
And the fact is that the body gets rid of the cladribine very quickly within a day or two. Whereas it takes many weeks to months to get rid of the rituximab. And so if the rituximab is started a month or even a week after the cladribine is over, there would not be a possibility of synergy based on that theoretical mechanism, that mechanism that was found in the lab. And so when we use rituximab early we try to start it on the same day as the cladribine. When the rituximab is started delayed - as I mentioned it's very effective; two thirds of patients who are MRD positive in the blood can become MRD free, not only in the blood, but also in the bone marrow with delayed rituximab. There that we may not be dealing with synergy, but we may be dealing with the fact that rituximab is highly effective when targeting isolated hairy cells, in other words no large clumps of hairy cells that you would get in a patient who needs treatment due to overt disease, but a patient who only has MRD, the rituximab may have a much easier time eradicating those cells. And so that may be why it works very well in achieving two thirds of patients who are MRD positive, getting them MRD free in the blood and the bone marrow.
And so these are the data sets that we've seen. And as I mentioned in our studies, we have data so far out to six and a half years where the need for next treatment is only about 3% either way. And compared to historical about 28%, we think this is a very large difference whether patients develop relapse to the point where they need more treatment. But this is something that needs further follow up.
But I don't think that what we're going to have to make this decision will be a randomized trial between getting a combination type treatment versus patients getting cladribine alone. That trial is something that really is not realistic. It's not something that patients would agree to join. And so we have to use other methods to determine which is the best treatment approach for patients. And then of course, this totally ignores the issue of is there a benefit for a chemo free regimen? And I think this is where a lot of emphasis is now looking at things like obinutuzumab and vemurafenib. Moxetumomab plus rituximab is another chemo free regimen that is not being used yet in the first line setting. It's being tested in the multiple relapse setting. And this was reported at ASCO (American Society of Clinical Oncology) this year to achieve 78% MRD free complete remissions in patients who are multiply relapsed. So some of these chemo free regimens are also quite interesting.
Dr. Kerry Rogers:
I don't think I could do a better job summarizing all that data than Dr Kreitman did for you. But one way to think about this, just taking away some of the complexity is, as he was saying you can give these together, if you give them in the same timeframe and get synergy, but rituximab does have activity by itself, so it will treat the hairy cell leukemia. So you can get rituximab like eight years after cladribine but it's really a separate treatment and not a combination treatment.
So for anyone asking like, oh, gosh, it's been five years, can I take this? You can, but it's really a separate treatment. And I've not seen any really large scale data to say what to expect, or how long that will last, but it can be an option for specific circumstances that there might be something going on with an individual that they would choose that over some of the other therapies for hairy cell that we've been discussing. So it doesn't mean that rituximab is worthless if it's not given in combination with cladribine or pentostatin which it can be used after pentostatin. But it's really just a separate treatment at that point and not a combination treatment. I don't know if anyone else has something to add on that, I just thought that might help some of the patients.
Dr. Clive Zent:
I would like to comment that I don't think we really get true synergy between antibodies and cladribine because antibodies don't really interact with cells in a way that's similar to cladribine. I think we need to say, you know, additive effect of some sort, but it's not true synergy in the pharmacological sense of it. The fact that we understand antibody function much better than we did 10 years ago; it's immune mediated. And there could be an argument that you'd want to wait some time after cladribine to give rituximab because you've got loss of macrophages and natural killer cells, which are the effector cells. But I don't think that's really that important because giving antibody with rituximab gives you three months of effective therapy, just one dose.
It's very reasonable to give them together because cladribine will probably clear out the bone marrow, get macrophages back into the bone marrow and those are your effector cells. And the other thing is that if you split the two treatments, you get very severe decreases in your B cells and T-cells from your cladribine and then as soon as those B cells are coming back after cladribine and a recovery of immune function, you’re wiping out all your B cells again with rituximab. So I think it's best to give them together. And I really don't see the point of waiting after cladribine to give rituximab later. I agree completely with Dr. Rogers, that giving rituximab a few years later is different therapy. And we need to be cognizant of the fact that these antibodies aren't completely benign and there can be seriouscomplications with their use.
Dr. Michael Grever:
No, I would just add one thing and then you can add to it (Dr. Robert Kreitman). But one of the things that you have to be careful about when you give them simultaneously upfront is that you can have a more profound, immediate thrombocytopenia in those patients. And I've had really serious drops in the platelet count when we were giving a purine analog simultaneously with the rituximab. So I know others have seen the same thing, so you just need to be aware of it. If you're giving them simultaneously to somebody who has a very marginal platelet count, you're going to need to follow them very carefully. It doesn't last all that long, but we've had one patient who actually had some bleeding associated with a severe thrombocytopenia.
Dr. Clive Zent:
But that can happen if you give it a month later as well. And it's worse with obinutuzumab which is actually one of the reasons why we have to be careful about combining that with cladribine.
Dr. Michael Grever:
Well, I've seen it more in the few patients we've used them both on early on, but I guess it could come as a result of the antibody itself, but when we've given them together, there’ve been pretty dramatic decreases in those patients.
Anna Lambertson:
Could you as a panel, briefly address prognosis and outcomes for those with the variant form of hairy cell leukemia? Are some of the new therapies that are being examined or researched perhaps going to improve outcomes for patients with the variant? Probably out of the over a hundred people who are on the webinar today, we might have one or two who doesn't have classic and often their situation gets pushed aside as we talk about the BRAF mutation and other things. So, could you as a panel, take few minutes to talk about the variant?
Dr. Michael Grever:
(Dr. Kerry Rogers), why don't you start off and talk about the Ibrutinib and then (Dr. Bob Kreitman) can give his thoughts on it with the combined therapy that he's developed for the variant.
Dr. Kerry Rogers:
So I do think the short answer to this is yes, that the treatment outcomes and expected disease course for people with the variant of hairy cell leukemia is expected to be better with these newer therapies. Although, again, we're talking about a small number of people, so it's very hard to use scientific data to demonstrate it's better, but I fully expect that this is true. And the more treatments we have, the better, I would expect people with a variant to do.
Also like anything, even with people with the variant of hairy cell leukemia, some people do well and some people don't, so individual disease factors still matter. The thing I was really excited about that I'd like to share is we did a phase two study of Ibrutinib in hairy cell leukemia and allowed people with classic hairy cell leukemia that had previously been treated with purine analogs to join the study. But people were actually allowed to be in the study if they had the variant of hairy cell leukemia, whether or not they've been treated before and that's in recognition of the fact that these chemotherapies don't work as well with the variant. And a lot of them have something called a P53 mutation, which predicts chemotherapy doesn't work as well.
So we reported results of the first 37 people in this study recently in a journal called Blood. And we had nine patients with a variant and two that had never received a treatment before that decided to take Ibrutinib as a first treatment. Just to get some idea, the data from the study, the overall response rate was right around 54% and at three years almost three quarters. So I think it was 74% of people or 73% were still alive and didn't have their leukemia relapse. That's really good for the population of people that were in this study. Obviously that doesn't compare with taking cladribine as a first treatment for classic hairy cell leukemia, but when we did an analysis to ask the question, “Did people with a variant do better worse or the same as people with classic?”, we couldn't find any difference between how people at the variant did or people with classic. Granted we're only talking about nine people with the variant and 37 people total, but I find this really encouraging because I think it means that Ibrutinib is helping people with a variant of hairy cell leukemia and this is an appropriate option. Anna sort of alluded to this, but people with the variant don't have the BRAF V600E mutation and do not benefit from Vemurafenib so that's not an option for this group.
But I was very encouraged by this data with Ibrutinib, which is a once daily oral medication that's taken long term or indefinitely either until it stops working or you develop side effects and have to stop. So it's kind of a different scheme than some of the chemotherapies, but it was nice to see that this newer therapy does really seem to be benefiting people living with a variant of hairy cell leukemia. And so I would definitely say that supports that treatment outcomes and survival are expected to be better with the development of these newer agents.
Dr. Robert Kreitman:
So one of the problems with hairy cell variant is that the clinical data with it is less. The dataset with Ibrutinib as (Dr. Kerry Rogers) said was, I guess, nine patients. Dr. Ravandi tested seven patients in his trials of cladribine plus rituximab where the rituximab was delayed by four weeks. We recently published an analysis of 20 patients in Blood Advances where patients were treated with cladribine with immediate rituximab. And we achieved a complete remission rate of 95%, in other words 19 out of 20 patients. And this is as compared with 42 historical patients with hairy cell variant that we could find published, where they were treated with cladribine alone and the complete remission rate was about 8%.
So we feel, based on that, that patients really should not be treated with purine analog alone, if they have variant hairy cell. And moreover, it really highlights the importance of getting a good diagnosis of hairy cell leukemia, making sure that you don't have the variant, because it will probably not respond well to cladribine alone or pentostatin alone. Now what happens after complete remission with cladribine and rituximab is important, because we find that we had enough patients in the 20 that we studied that if the patients got a MRD free complete remission at the four week or the six month time point, those patients had a longer progression free survival as well as overall survival. In other words, the chance that they could stay in remission and the chance that they could stay alive was better if they got MRD free.
And so while being MRD free is still debated in classic hairy cell, there's no question that it's crucially important in variant hairy cell that the patients achieve MRD free complete remission. Also, we found that if patients had the P53 mutation, which we know makes these patients less responsive to chemotherapy, and cladribine is the chemotherapy in cladribine rituximab, that these patients had a shorter progression-free survival as well as overall survival. And so we think that the cladribine/rituximab regimen was very good; patients generally stayed in complete remission for five years or more, but many patients after five years would relapse and they can sometimes be salvaged by delayed rituximab. There are several patients we still have now that for years after delayed rituximab, meaning a second course of rituximab, they're still MRD free and doing well.
But in patients who relapse after that point, we found that their overall survival is only about 30 months median. So we really have a lot more to do in hairy cell variant. I think that there's an interest in combining some of the newer agents to treat that disease. But I think the take home point is that the cladribine rituximab regimen is very effective at least for getting patients into a good remission for many years. So that's what we found in our study of hairy cell variant.
The other thing I wanted to just real briefly mention is when you talk about delayed rituximab, so when you have a patient who needs treatment with hairy cell leukemia because of low blood counts and they have a lot of tumor, their spleen is enlarged, they have a lot of tumor in the bone marrow. That's not what we're using delayed rituximab for. So when patients need treatment for overt disease, they relapse. The data from Dr. Saven’s studies show that 13% of those patients can achieve complete remission with rituximab alone, which is not very high. But when rituximab is given before MRD, and this is what we call delayed rituximab, then patients are already in complete remission but it can get them MRD free. So we're really talking about two different things when rituximab is used late. So I wanted to make that clarification. That's more talking about classic hairy cell, but we also use delayed rituximab in our treatment of patients with hairy cell variant.
Anna Lambertson:
Dr. Grever, we've reached our time. There are a number of people who I know had some questions around the topics that were discussed today. We weren't able to get to everyone's questions which is always the case, but I just want to say thank you to the four of you for taking time on your weekend to come and speak to patients who joined. And I also want to say thank you to the patients who were open in bringing their questions, which I know are sometimes tough to share.
As a reminder, we do have a virtual coffee chat at 2:45 Eastern time for individual patients who would like to join and kind of interact with other patients. And then there are two other sessions that remain in this patient seminar for those of you who would like to join.
So thank you again Dr. Grever, Dr. Kreitman, Dr. Zent and Dr. Rogers. We're incredibly grateful to you.
This transcript has been edited for clarity.