Webinar: Understanding Hairy Cell Leukemia
March 2020
Hosted by the Hairy Cell Leukemia Foundation with Dr. Robert Kreitman from the National Institutes of Health (NIH)
Presentation Materials
View a recording of Dr. Kreitman’s presentation (audience Q&A is in the transcript only). >>
Transcript
The following is a transcript of the 1.) Presentation given by Dr. Kreitman and 2.)Question & Answer session with participants.
Presentation by Dr. Kreitman
Dr. Kreitman:
So it's a tense day in the world. I know everyone is concerned about coronavirus. Unfortunately, I'm not an expert in infectious disease. But we'll focus today on hairy cell leukemia, but I anticipate some questions about this new problem that we have might interact with the patient's plans for treatment, et cetera. So we're going to focus on an update on the treatment of hairy cell leukemia today but first let's introduce hairy cell leukemia. Many people are already aware of this, it's a B-cell disorder, it comprises 2% of all leukemias, it amounts to 1,200 new cases per year in the US, similar number in Europe. Patients present with low blood counts, large spleens, the cells have these cytoplasmic projections; they are bright positive for certain antigens like CD22 and CD20.
Classic hairy cell expresses CD25 and carries a BRAF-V600E mutation. And the treatment, standard treatment includes Purine analogs; they are either cladribine or pentostatin. They can induce long-term complete remissions, but they're not known to be curative and they have decreased efficacy with each repeated course. And there are variants of hairy cell that lack CD25; we call that HCL-V for hairy cell variant or that express unmutated IGHV4-34, it's an immunoglobulin rearrangement that all B cells, including hairy cells have. But if they have the unmutated IGHV form these patients usually respond very poorly to treatment. But even classic hairy cell patients can become resistant.
Now, the diagnosis is done by flow cytometry of the blood or bone marrow. And this is done to rule out other disorders. We can often make the diagnosis before the bone marrow, but we need the bone marrow to rule out other things. And it's just very important in the diagnosis process to determine if patients have classic or variant hairy cell. This really summarizes the difference between classic and variant hairy cell, where the classic form, which is most of the patients, has a mild spleen enlargement compared to a variant where it's severe. The lymph nodes usually are absent in classic, but present in variant hairy cell.
CD25 typically is negative in hairy cell variant, positive in hairy cell classic. And the BRAF mutation is unmutated. So we call that negative usually in hairy cell variant. It's positive in classic hairy cell. And the response to cladribine or pentostatin is good in classic and poor in variant. But this variant that I talked about with the IGHV4-34, it has features that are similar to both. For example, the spleen enlargement tends to be severe, but the lymph nodes are high and the leukemic cells are high in the blood. But these patients have often low normal counts and they're positive for CD25. So these patients are mistaken for classic hairy cell, but like variant, they are unmutated BRAF and they have a poor response to standard treatment. It's really important for determining how to treat the patients.
So how do you treat patients with hairy cell variant? So we find that cladribine alone has a very poor, complete remission rate. Only 9% of 39 reported cases. But if you combine cladribine with rituximab, and this is five daily doses of cladribine (in green) with eight weekly doses of rituximab (in orange), the patients have a 95%, complete remission rate. And so single agent cladribine or pentostatin should no longer be used for a hairy cell variant; this is why it's so important to get a good diagnosis.
Now, what does complete remission mean? So it means that there's no hairy cell visible by standard stains, this is hematoxylin and eosin or H&E stain or Wright stain of the bone marrow and blood.
You could see here there's this monotonous appearance of hairy cells that are replaced by normal blood cell making cells in the bone marrow. And you also have to have resolution of enlarged spleen, lymph nodes, hairy cell counts have to go down, and the normal blood counts have to be resolved. In other words, neutrophil count of at least 1.5, hemoglobin at least 11, platelet count at least 100. Compared to those counts that patients should have to need treatment. To need treatment for hairy cell, you should have either an ANC neutrophil count less than one, immunoglobulin less than 10, platelet count less than 100. This is a 1, 10 and a 100 rule. If all of these numbers are greater, then you may not need treatment and it may be more appropriate to wait until you really need treatment unless you have other indications like a large painful spleen or multiple infections. And there's some other indications.
So what about complete remission with minimal residual disease? We can detect this by methods that were not available in 1958 when hairy cell was first discovered and people were calling patients in complete remission based on these criteria. But now we have the ability to detect minimal residual disease. So instead of changing the definition for CR, complete remission, we say whether a patient has CR with or without minimal residual disease. We can detect this by special stains in the bone marrow biopsy, by flow cytometry of the blood or bone marrow, by molecular studies like PCR, and the complete remission may last longer if minimal residual disease, MRD, is negative. So you'll hear MRD a lot.
Now, we did a study to look at treatment of untreated hairy cell; this is frontline or first-line treatment. And what we did was we randomized patients between getting cladribine by five daily doses shown in green. Both arms got that. And half the patients, we gave concurrent rituximab weekly for eight doses. And it's a little bit more complicated, but let's focus on this first, to avoid getting too complicated. What we found by the six-month time point is that the cladribine and rituximab together, which we call CDAR, gave a complete remission rate of 100% versus 88%, this isn't that much different. But if you look at the MRD free rate there was a huge difference at six months; 97% versus 24% with cladribine alone.
And if you look at six and a half years down the line in a median time point for patients being treated you get an even greater difference. 94% of these patients stayed MRD free in complete remission, where only 12% after cladribine alone were MRD free. So, this is a very important difference. Now, this is more complicated because after the six-month time point, if patients had MRD in the blood, they could get delayed rituximab by eight weekly doses and this could be either in the first group or the second group. And so in other words, in the second group, the patients who originally had cladribine alone, they could get delayed rituximab. And then if more than six months later, they had MRD in the blood, they could get another course of delayed rituximab. And we found that cladribine plus delayed rituximab, this is the third line here, we could get this 12% up to 47%. In other words, if 40% of the patients at a median of six and a half years are MRD free; however, the majority of these patients had MRD and it wasn't close to the group that got cladribine and rituximab alone.
However, by either approach, by the approach of getting immediate rituximab or delayed rituximab, only zero to 3% of these patients needed more treatment so far. This is at a median of 6.5 years. And if you compare this historically to patients treated with cladribine alone and then just waiting to see when the patients need more treatment, when they relapse, already 28% of those patients have already relapsed. So what it shows us is that either of these approaches could keep patients from needing more treatment as early as they will otherwise.
But if you really want to stay MRD free, then the cladribine and rituximab immediate treatment, seems to be the best. And this was just published online in Journal of Clinical Oncology. Now, rituximab can be given also with either bendamustine or pentostatin for multiple relapsed and refractory hairy cell. This is a trial that we've had at the NIH going on for many years. And we compare patients getting bendamustine (in green) with pentostatin (in blue). And in either case, we're giving the rituximab, again shown in orange, given every two weeks.
It's a little bit different in bendamustine; it's given on days one and two. Pentostatin is given on days one and 15. There's a very high complete remission rate. Most of the complete remissions are MRD free, but while highly effective, this approach may be toxic due to the fact that it's chemo.
So can MRD-free complete remission be achieved without chemo and what's the benefit of being MRD free? So we can target CD20 or CD22 without chemo in relapsed hairy cell either with rituximab that kills cells after binding to CD20, has a CR rate of only 13% without chemo in patients with relapsed hairy cell. But there was a new agent for hairy cell that we've been developing for many years called moxetumomab pasudotox; we just call it moxe. And it's an engineered protein. It has an antibody fragment that binds to CD22. It's connected to a toxin (shown in yellow and red), and it kills cells after getting inside.
It has this complete remission rate of 41-73%. And most of these complete remissions are MRD free. This was approved in 2018 for relapsed hairy cell. It's called Lumoxiti; that's a trade name. And this shows the importance of MRD-free CR from moxe. So in the phase one trial, 11 patients had MRD-free CR shown in green and over time, these are the number of months, only one of these patients relapsed while nine had MRD-positive complete remission shown in blue, and eight of these patients relapsed. The patients still in MRD free CR or still in complete remission are shown by these vertical orange bars.
And so moxe is given by 30-minute infusion on days one, three, and five repeated every four weeks. Seven patients who got one to four extra cycles after complete remission did not relapse. And of 14 patients who did not get extra cycles, most of these patients, shown in blue. And so CR duration is longer if moxe can clear MRD and this seems to require extra cycles. And this is just to show that there are some toxicities that we can get into with moxe and it's called hemolytic uremic syndrome or capillary leak syndrome. And either of these seem to be preventable by making sure that patients have plenty of fluid.
And this shows a bucket as an analogy that the bucket's constantly leaking. This actually allows the moxe to get out of the blood vessels. It's not necessarily a bad thing, but it's important for patients to keep drinking. And we try to get patients to drink orally so that they don't have to get IV fluid and get overloaded. And one cup per hour works very well, it's very well tolerated, keeping lapses and drinking to less than two to three hours at night works well. And if patients get nausea or a headache after moxe, we find that a low dose of steroid, dexamethasone, works very well, allows patients to keep drinking. So we can now target CD20 and CD22 together with moxe and rituximab. We call that regimen moxe R; this is experimental, we're testing this at the NIH. First goal, is to reduce normal B cells to prevent antidrug antibodies that could neutralize the moxe. Our second goal is to reduce the amount of hairy cell so that moxe can achieve CR more quickly. And then we're testing moxe R in multiply relapsed hairy cell.
And we're giving four cycles past the MRD-free CR, maximum of eight cycles. And our goal is to get MRD free CR in after two cycles in only four more cycles. And we've been able to do this in so far, a couple patients, in just four patients so far.
I want to briefly mention the BRAF inhibitors, this includes not only Vemurafenib that can produce complete remissions. These are MRD positive, and same is observed with dabrafenib and trametinib and which inhibits not only BRAF, but the trametinib also inhibits MEK. And to eliminate MRD, you can combine Vemurafenib and either rituximab or obinutuzumab. And that's being done with the obinutuzumab in Memorial Sloan Kettering and rituximab in Italy.
And so these agents do have side effects. They can cause skin rashes, skin cancer, fever and chills; so you have to be under good supervision.
Ibrutinib is an agent which has a low complete remission rate. They're mostly MRD positive but you can use this in hairy cell variant. It doesn't require the BRAF mutation. It can cause atrial fibrillation and bleeding and infections. But in general, it's actually better tolerated than the BRAF inhibitors. It can take many months and even years to work. And so this is a good chronic treatment. It's not a good treatment for patients who have really low counts and they need something to work right away.
So, in conclusion, the first-line treatment is still a single agent purine analog. But at least combining with rituximab can be an option with the publication of cladribine rituximab regimen. And hairy cell variant should not be treated with purine analog alone. Purine analogs, those include pentostatin and bendamustine, can be combined with rituximab. Although these have chemo toxicity. Moxe is approved for hairy cell. It's the only chemo free regimen with a high rate of MRD-free CR. And moxe and rituximab is highly effective and we're testing this at the NIH. The BRAF and or MEK inhibitors can rapidly achieve complete remission, but they appear to need rituximab to eliminate MRD. And the oral inhibitor ibrutnib works very slowly but can also achieve CR, generally MRD positive.
And I want to encourage everyone to participate in clinical trials. I think you'd get a better care that way, and we can all improve the care of hairy cell leukemia. And these are the clinical trials that are mentioned on the Hairy Cell Leukemia Foundation website. And they're being done at the NIH and in different parts of the world as I mentioned during the talk.
2. Question & Answer Session
Anna Lambertson (relaying questions from webinar participants):
I know that there are many patients with similar questions in this regard. So if someone is currently in remission, so they've received treatment with cladribine, maybe even cladribine and rituximab, they'd been in remission for a while, maybe even years, their blood counts are stable. Is there any reason as far as you know for them to consider themselves to be at greater risk with coronavirus?
Dr. Kreitman:
So we really don't know a lot about coronavirus, but we do know that patients are at risk, even if their blood counts are normal, for different infections, opportunistic infections, particularly if they're a CD4 count is low. The median time to recover a normal CD4 count after a single agent purine analog, cladribine or pentostatin, is about four years. This was demonstrated back in the late 80s and actually, in 1993-1997 by Seymour et al. So those counts, the CD4 count, can be measured; your doctor can measure that for you if you're interested the next time you get a CDC. And then you can see what your risk is for infections.
In patients who have very low CD4 count, it's often because they've gotten several courses of purine analog; maybe it might be less than 100. Normal would be above around 400. But let's say it's below 200, there may be an increased risk of opportunistic infections. And if it's below 150, we typically ask those patients to go on an antiviral drug, which is called valacyclovir or valtrex or a cyclovir to prevent shingles or herpes simplex. Even in patients who have higher CD4 counts, we find that those patients can have shingles and things. But what we don't know is whether a high CD4 count protects against the coronavirus or conversely, whether patients who have a low CD4 count are at higher risk for coronavirus and that we don't know.
What we do know about the flu, which is similar to coronavirus, influenza, and is also dangerous, can kill people, is that if you've had rituximab in the past six months, you may not respond to the flu shot. And if you only get one flu shot per year and you've gotten rituximab in the last six months and it's in the fall, you might want to wait for a few months for your B cells to recover from the rituximab before you get a flu shot. Unfortunately, right now there is no flu shot for coronavirus. And so the best policy is to isolate and prevent getting exposed.
Anna Lambertson (relaying questions from webinar participants):
Thank you, Dr. Kreitman. And if someone is currently undergoing treatment, which is going to be the case for many patients who are joining today's webinars. Perhaps they've completed cladribine and they're still completing their rounds of rituximab, there's one individual who sent in a question saying they were planning to travel tomorrow to come to NIH for treatment or some type of consultation. What are you telling your patients right now if they're in the process of receiving treatment? Should they continue their treatment or delay their treatment? What guidance do you have in that regard?
Dr. Kreitman:
I think patients who are getting treatment should not compromise their treatment, because there may be very serious consequences if they don't get the best response possible. And right now, we have reported about 3000 cases (of coronavirus) in the country and about 30 cases in Maryland. And this works out to be about five out of a million people in the country and about five out of a million people in the state of Maryland. However, that seems like a very low risk. I think the risk is much higher than that because there's so many people who have not been tested and will be diagnosed in the coming days. But you have to balance that in patients who are now getting treated that have a very good option to get a very long possibly MRD-free complete remission, and you don't want to compromise that possibility.
So people who are now under treatment, I would caution them against compromising their treatment. What I would say is that it's very important to keep your hands clean and to avoid direct contact with people. In other words, to be very close, to be touching people, it seems that the virus is spread that way. And there is a question about whether viruses can be spread by touching surfaces. We do know that the virus is viable on surfaces for several days. So it's important that you keep your hands clean. I know that there is shortage of hand cleaners. We do have these at the NIH that patients can stock up on and we're very careful to prevent transmission of the virus in that, we just can't know who has it, any of us could have it at any point in time. So, we do have to be careful even though we think the risk is extremely low.
Anna Lambertson (relaying questions from webinar participants):
And I would just say if you agree with this that if someone is currently undergoing treatment or coming to NIH for participation and to have a consultation, I think it would be wise for them to reach out to their doctor or to your office if they're coming to NIH, just to make sure that there aren't any issues with receiving that treatment or with them traveling. So just kind of encouraging everyone to also consult with their doctor if they are planning to travel for treatment. Do you think that's an okay recommendation?
Dr. Kreitman:
I think that's fine. The NIH is open. We are actively treating patients with all kinds of different diseases. I think that there are some patients who are doing extremely well and they're being followed up in long-term follow up. We are currently making some arrangements with those patients to delay them from coming in just to avoid unnecessary travel. But the key word is unnecessary, and if you are now under treatment then that may be very necessary. But if you're just having a routine follow up once a year or something like that, that may not be so necessary. Or a follow up once every three months, or something and you're doing very well, that may be not so necessary. I think all doctors right now are making arrangements to try to avoid people traveling.
Webinar participant:
From your past webinars or any research that I have done, your initial protocol for rituximab and moxe was a six month duration, every 28 days. In your presentation just now, you said that it's been showing better results with an additional two cycles for a total of eight, is that correct?
Dr. Kreitman:
Right, so we haven't gotten there yet to the eight cycles. And the reason why is that, the way that this protocol is set up if you can still see your screen. So what we're doing is, our goal is to get four cycles past it, MRD-free CR. And that's because the patients who really did the best over here, you can see this green line, if they had one to four consolidation cycles, which means extra cycles, past complete remission they did not relapse. And so we want to give everyone four consolidation cycles if we can.
And so what we're doing is with the first cycle, we're giving rituximab three days before the moxe to get the normal B cells and the hairy cells down before the moxe starts. At four week intervals, we use these repeat cycles where we can start the moxe and the rituximab on the same day. And then we restage patients prior to cycle three, in other words, after two cycles. And our goal is to get an MRD-free CR after two cycles and then to get four more cycles. And where we are now is a couple of these patients have already had MRD-free CR after two cycles. And so they'll get four more cycles, a total of six and they won't need those last two cycles.
But there may be a patient who just has a lot more disease and needs a total of eight cycles. So we allowed, in the protocol, to give two more cycles and I think that will be important to be able to get the best outcome. On the phase three trial, we had patients who were doing great. They got their six cycles, almost no toxicity, and they certainly could have had more cycles. And we saw that their bone marrow after six cycles was almost a complete remission. Very, very close to complete remission. In fact, we waited some months or a year after and indeed it did show a complete remission but it didn't stay there. And so we really think that a couple more cycles in those patients who need it may be important. So, we're giving those extra cycles just to patients who need it, that's the answer.
Anna Lambertson (relaying questions from webinar participants):
I'm going to share another question from the Q&A box. This individual recently completed his third round of cladribine in the past 16 years. He completed that third round of cladribine about three weeks ago. Last remission was for 11 years; his cancer recovering nicely. However a little over a week ago, about 10 days ago, his platelets shot up to 350. It's about the highest that they've ever been. And now for the past three tests, they've been falling. So shot up to 350, now they'd been falling down to 230. Is this a bad sign despite the fact that the white blood cell count and the absolute neutrophil count are going up?
Dr. Kreitman:
Okay, so let me just say one thing before answering the question. In a patient who's had two courses of purine analog - although the recommendations, which are I think a little outdated, say that if the last complete remission was very long, you could go with another course of purine analog. I think a lot of people now are trying to avoid that third course of purine analog because there is a higher incidence of side effects and cumulative toxicity, stem cell damage, nerve damage.
And so I think that now that we have all these non-chemo options that I mentioned, a lot of people are going more with something other than a third course of cladribine. But if you've had a third course of cladribine or any other effective treatment, and you find that your platelet count shoots up after the treatment, it could be because your spleen, which was enlarged prior to the treatment, and it may not be enlarged enough to feel it, but it might be enlarged, may shrink very quickly with the treatment. And that may evict platelets from the spleen, and that causes the platelet count to go up.
And it's not that the body's necessarily making more platelets, it may be that the spleen's shrinking and pushing those platelets out into the bloodstream. Now, if there's a good response, the bone marrow will start making more platelets. That happens a little later, maybe about three or four weeks later after the treatment's given. And so you'll tend to see the platelet count go down. It may go down to the low hundreds, and then it'll come back up again, possibly. And so the answer is no, it's not a bad thing, it's quite typical.
Webinar participant:
I had classic hairy cell about three and a half years ago. Had a week long, a seven day drip of cladribine in full complete remission, no MRD. So my immune system, my white blood cell counts, used to be 7,500, that's the ANC count, now they're down to 2,500. So I'm concerned that a repeat treatment of cladribine would completely destroy my ability to make white blood cells. So it's looking like rituximab and the other drug or maybe a better treatment that won't further wreck my immune system, is that what I should take away from this presentation?
Dr. Kreitman:
So you've had one course of cladribine before, is that right?
Webinar participant:
Yes, three and a half years ago.
Dr. Kreitman:
Yes, so in patients who need more treatments… So obviously in patients who need more treatment, the first step is to actually make sure that you actually do need more treatment. That usually requires a bone marrow, requires blood counts. Some patients have low blood counts that go below these limits, the 1, 10 and 100, but then they go right back up. Maybe the patient had a viral infection or something and they were just transiently low, the patient really doesn't need treatment again.
It's important in patients whose treatment was relatively recent in the last four years, to make sure that you really do need treatment. But we find that in patients with one prior cladribine that the highest responding regimen is actually this one, the protocol that we have with the cladribine and rituximab, either delayed or concurrent because we get a complete remission in either group of 100% in that setting. And if you were to get another course of cladribine alone, you're expected complete remission rate would only be about 65%. And if you're saying that you need to be treated now less than four years after the first course, it might be even lower than 65% by itself. So I would encourage, we have a trial open here, but I would encourage something other than cladribine alone.
But I think that my first point was that make sure you really do need treatment because some patients, their counts are low just temporarily and then they go back up.
Anna Lambertson (relaying questions from webinar participants):
We frequently receive questions about shingles. If the patient has stable counts or otherwise, are you recommending that your patients get Shingrix, the shingles vaccine?
Dr. Kreitman:
Yeah, so we are recommending the patients to have the Shingrix. We make sure that their B cells are detectable in the blood. We get a flow cytometry and we can determine that. Generally these patients have gone way past six months after their last course of rituximab, which decreases the B cells, normal B cells. So the Shingrix is a killed virus, it's not a live virus. There's an older viral vaccine for shingles that should not be used. But nowadays, the one that everyone's using is Shingrix, which is killed. I will say that the vaccine is about 90% effective. We have seen patients get annoying cases of shingles after getting the Shingrix vaccine. It's not quite as effective as valtrex or acyclovir in preventing shingles but it's pretty effective. So if patients really don't want to take those drugs then the Shingrix is a good option.
Anna Lambertson (relaying questions from webinar participants):
Another question from the Q&A box. This individual has hairy cell leukemia variant, he has the variant for hairy cell leukemia. He's been on rituximab for 4-5 months and he's also been on imbruvica. And it might be important for you to know that he's had a splenectomy. How long do you generally recommend that patients be on imbruvica?
Dr. Kreitman:
So I think if imbruvica, the ibrutinib, is working, I wouldn't stop it. And there is some thought that rituximab and ibrutinib may not work well together as a doublet.
Rituximab is usually not given with ibrutinib. That combination may antagonize the activity a little bit of... the ibrutinib may antagonize activity of the rituximab. It's not definite for sure but at least in other diseases like CLL, that combination as a doublet. It doesn't seem to work well unless you use a chemotherapy drug with it. But we're really talking about hairy cell now and ibrutinib as a single agent looks quite effective. So I think if a hairy cell variant patient is responding well to ibrutinib, it's not clear to me that the rituximab is doing it or that the ibrutinib is doing it. Maybe that one... only one of those two is necessary. Generally speaking rituximab alone doesn't have a very high response rate. And I think that in these patients it's important to get good follow up, to get flow cytometry of the blood and really see what's happening sometimes, otherwise it's hard to know how good the response is.
Webinar participant:
Okay, I had a treatment, I think it was the chemo drug cladribine 15 years ago and I'm still in remission. And I'm just wondering, is that normal remission rate or can I expect something to start happening or what have you, sometime in the future here?
Dr. Kreitman:
So that is pretty much a normal remission rate. I think that other people are seeing that kind of remission. In fact, the median time to relapse in patients after cladribine is about 16 years. So really a patient being in remission 15 years later is really expected. It's more the rule not the exception. But you might find that you have minimal residual disease at this point but that doesn't necessarily mean that you need to be treated.
Anna Lambertson (relaying questions from webinar participants):
What is the best time to repeat a bone marrow biopsy after cladribine treatment?
Dr. Kreitman:
So the guidelines say four to six months and we wait for six months. We do find that sometimes patients will not reach their best response in the bone marrow until at least the six month time point. And there's a few patients that even later will have a very good response. One of the biggest errors that I see local doctors do in hairy cell is to get a bone marrow too soon, maybe at two months or three months and they see that there are hairy cells there, and the normal counts have not yet recovered from the cladribine, and they'll decide that the patient hasn't responded to the first course of cladribine and they'll give another course of cladribine. This is very harmful because it exposes the patients to a lot of toxicity and that patient if left to themselves, may have gone into complete remission on their own at the sixth month or later time point and really should not get that second course of cladribine.
And so again, this is really the most common mistake that I see and patients should be aware that it can take a long time to reach a complete remission in hairy cell. Don't get so concerned if the blood counts are low and a bone marrow shows hairy cells after two or three months. We try to avoid doing a bone marrow that soon because we will not treat patients that soon.
Anna Lambertson (relaying questions from webinar participants):
If you're planning to treat the patient with cladribine and then either concurrently or with delayed rituximab, do you wait until after the rituximab is administered to do the bone marrow biopsy as well or do you generally do a biopsy in between the cladribine and rituximab?
Dr. Kreitman:
So in the clinical trial, if anyone reads that paper, we did do a one month bone marrow on patients, but it was really done for research purposes and the patients also were interested in how they were doing, whether they were already getting MRD free one month after starting the five daily doses of cladribine plus eight weekly doses of rituximab. And that one month bone marrow was done right in the middle of the rituximab actually, and many of the patients were already MRD free, but the patients who weren't, they also became MRD free at the six-month time point. So in practice, there really is no practical need for a bone marrow before treatment is finished. And so we would wait... if we were going to give rituximab upfront, in other words, the first eight weeks we would wait until four months later to do the bone marrow or six months after starting the treatment.
Anna Lambertson (relaying questions from webinar participants):
And if you could clarify the cladribine and rituximab, is that available to patients as front-line treatment or is that currently only available in the clinical trial?
Dr. Kreitman:
So patients are now getting that through their insurance companies. Most insurance companies are approving that. And this was before the online publication of our clinical trial. Part of the reason for that is Dr. Ravandi at MD Anderson published many years ago the high efficacy of delayed rituximab, in other words, when you start these eight weekly doses one month after the cladribine. He found that about three quarters of patients were MRD free at the three-month time point.
It's a little bit hard to compare those results to ours, but based on that alone, patients are getting approval for cladribine plus rituximab for newly diagnosed hairy cell and I think with our randomized trial, I think it'll be much easier to get that drug approval. For patients who were once relapsed, we are still enrolling patients on our clinical trial. And like other investigators of clinical trials I would encourage patients to look into those because I think you get more care, you get more assessments and the outcomes may be better in that case. Also, the people running the clinical trials are experts wherever they happen to be.
Anna Lambertson (relaying questions from webinar participants):
Let’s take one more question through the Q&A. So there were a few questions about CD4, you had been talking about CD4. So when patients receive their printout from their doctor and it shows what their blood counts are. Will they see CD4 in their materials from their doctor?
Dr. Kreitman:
Not in an ordinary CBC. It also goes by the name of T4 count, T4 instead of CD4, but it's commonly tested but is not part of the routine CBC. In a flow cytometry that we would do here at the NIH for research purposes, if patients are sending in samples to us to ask us to comment by mail, we always do that. But most flow cytometries don't automatically contain a CD4. So you would need to ask for it if you were interested. In some cases I think it's relevant because if patients have very, very low CD4 counts they may be at more risk for infections and may need some prophylactic antibiotics in that case. And this really is mainly patients who've had multiple courses of purine analog.
Anna Lambertson (relaying questions from webinar participants):
For the final question, you've talked quite a bit about how adding rituximab to cladribine can help eliminate MRD. How long after completion of cladribine can the addition of rituximab help in eliminating minimal residual disease?
Dr. Kreitman:
So it depends what the use of rituximab is aimed for. So rituximab can eliminate minimal residual disease more easily if the cells are individualized and there are cells that are scattered and it's not hard for the rituximab to reach every single cell. And in that case it gets rid of MRD. But in the way that we give rituximab upfront, we are taking advantage of synergy. And synergy between cladribine and rituximab relies on the rituximab making the cells more sensitive to cladribine. And the problem is that the cladribine gets out of the system very quickly and within about a day or two. And so if the rituximab has started one month after the cladribine starts, then that means that rituximab has started about 23 days after the last dose of cladribine there's not going to be any synergy. And we think that that's an issue that separates patients who get the rituximab upfront versus the patients who get the rituximab delayed.
But it's fair to say that rituximab delayed is effective. And so it's just that if you want that synergy, you really need to start the rituximab within a day or so of the cladribine or else it won't have synergy. But again, this is something that we can test for synergy in laboratory systems. It doesn't necessarily mean that synergy is important in patients, but we are finding this difference if you compare the immediate rituximab where you can see synergy versus the delayed rituximab where you don't have synergy, the latter is effective, it's not quite as effective though.
Anna Lambertson:
I want to thank again, everybody who's joined the webinar. Please stay safe and Dr. Kreitman we really appreciate you sharing your expertise today.
Dr. Kreitman:
Thank you for listening and I want to echo, to wish everyone the best of health and to stay safe, especially during this time.
This transcript has been edited for clarity.