Webinar: Understanding HCL Variant
September 10, 2019
Hosted by the Hairy Cell Leukemia Foundation with speaker, Dr. Farhad Ravandi from the University of Texas – MD Anderson Cancer Center
Note: The Q&A content is available through the transcript below.
Welcome and Introductions
My name is Anna Lambertson and I'm the executive director of the Hairy Cell Leukemia Foundation. Thank you for joining us today for a webinar about hairy cell leukemia variant.
I am absolutely thrilled to have Dr. Farhad Ravandi-Kashani as our guest speaker today. As you know, Dr. Ravandi comes to us from the University of Texas - MD Anderson Cancer Center, which is one of 28 HCL centers of excellence in the world.
He's the Janiece and Stephen A. Lasher Professor of Medicine and Chief of Section of Developmental Therapeutics in the Department of Leukemia. Thankfully, Dr. Ravandi chose hairy cell leukemia as an area of specialty.
So Dr. Ravandi thank you again for being with us today and I'm going to turn it over to you.
Thank you very much and good morning everyone. Good afternoon in many places.
So I'm just going to go over the topic of the variant form of hairy cell leukemia and clearly, that means that it's a leukemia that is very similar to hairy cell leukemia in some aspects, but different in others.
Just to give you a background: hairy cell leukemia itself is a very rare disease, as I'm sure many of you, unfortunately, have the leukemia.
But with the introduction of cladribine and pentostatin in front-line therapy, outcomes improved significantly.
Most people actually respond to subsequent therapy, but this just shows that many people relapse many years after initiation of therapy in some cases.
So this is why our group introduced the combination of cladribine and rituximab, both for hairy cell leukemia and hairy cell leukemia variant. However, many authorities still consider cladribine or pentostatin as the initial therapeutic strategies, as you see in this slide.
Now you also see in this slide that patients who are asymptomatic do not need initiation of therapy. That's very important, because despite the fact that both cladribine and pentostatin are relatively non-toxic agents, we really do not wish to start a patient on therapy just based on discovery of the fact that they have hairy cell leukemia or hairy cell leukemia variant.
That means, as long as they don't have any significant constitutional symptoms like fatigue, night sweats, weight loss or significant decline in their blood counts, particularly hemoglobin, platelet count or neutrophil count.
Another important thing for hairy cell leukemia and to some extent hairy cell leukemia variant, is now we have a number of different potential options for the unlucky patients who may get subsequent relapses or second relapses. That is very good because patients generally have a long life expectancy ahead of them, and the fact that we now have potential options for subsequent therapy is very important.
Now, if you look at this next slide with the combination of cladribine and rituximab, I just want to focus on the top two lines. These are either patients who were previously untreated or have had only one prior therapy and you can see that the lines are almost straight lines. And that means that this is a very effective therapy in our hands. We get close to 100% response and very few people relapse in terms of classical hairy cell leukemia. I will come back to this slide a little bit later as related to the variant hairy cell leukemia, which is the focus of our talk today.
Now, the variant form of hairy cell leukemia is even more rare. Classical hairy cell leukemia - we believe that there are about 1,000 new cases in the US every year. Variant is about 10% of that. So a hundred new cases and even that may be an over estimate, but it definitely does exist as you see in this slide.
The leukemia cells do have the projections or hairs that we see in classical hairy cell leukemia. They're a little bit different because they have a prominent nucleus. And I know that many of you will not appreciate what I'm saying. But, essentially the shape of the nucleus and the common components within the nucleus help the pathologist to make the distinction, to some extent, as opposed to the classical hairy cell leukemia. But again, both of these conditions, as well as a few other lymphoid malignancies, have these hairy projections and that's why they're called hairy cell leukemia or hairy cell leukemia variant.
So, again, to put a distinction between variant hairy cell and classical hairy cell, about 10% of the overall hairy cell population is variant.
There are typically older patients in the variant form. So the median age is about 70 whereas in the classical form of hairy cell leukemia, the median age is 50. Clearly, that means when the median age is 70, about half of the patients are older than 70 and half younger. But, in the classical, half of the patients are older than 50 and half are younger, so as a whole, the classical population is a younger population.
They do have large spleens and low blood counts depending on when they present.
We probably get less and less patients who present with very advanced disease, mainly because of the high availability of healthcare in the US. People now have routine blood checks and many patients are just discovered without having any symptoms on a routine blood test.
Now in the case of classical hairy cell leukemia, they tend to have typically low white cell counts, whereas in the variant, they actually have high white cell counts. You see here that the median number is 34. That's three times higher than the upper limit of normal.
One of the features of classical hairy cell leukemia is low monocytes. Monocytes are a type of white cells that help with specific types of infection. And they tend to be low in classical, but in the variant form, these numbers tend to be normal.
Flow cytometry is something that pathology uses to distinguish various lymphoid cancers such as hairy cell leukemia classical or hairy cell leukemia variant, and some of the other varieties that have some similar features. One is called splenic marginal zone lymphoma, which also has hairy projections. These markers on the surface of the cells help the pathologist make a distinction.
Variant hairy cell leukemia does have some of the markers of the classical such as CD11c and CD103. But, it's distinctively different because it lacks CD25, CD123 and CD200, which are present on classical hairy cell. So again, the pathologist uses these to make a distinction.
An important discovery a few years ago by the group in Italy, by Brunangelo Falini and Dr Tiacci, as well as others in Europe, was the discovery of this mutation in a gene called the BRAF, which occurs virtually in all cases of classical hairy cell leukemia, but is never present in variant hairy cell leukemia. That's a useful marker for the pathologist to make the distinction.
Also, more recently, people have looked at a small series of hairy cell leukemia patient samples and they've discovered that in about half of variant hairy cell leukemia, there's this other gene, MAP2K1, that is mutated.
Now, why do we want to make the distinction between variant and classical hairy cell? Because if they behave the same way, we really wouldn't go through all the trouble of making all this pathological differentiation and identifying the variant patients as opposed to classical. The reason is the variant patients tend to be less responsive to the historical treatment options for hairy cell such as cladribine and pentostatin.
As you see in this slide, the response rate is only about 50%. With classical hairy cell leukemia, with the single agent cladribine or pentostatin, the response rate is above 80% and in many publications up to 100%.
The other thing is small populations of variants can transform rapidly and become more aggressive and that's particularly specific to the variant form of hairy cell. But, despite that, and despite the fact that the therapy response and prognosis is a bit worse than classical, you can see the median survival is still close to 10 years. So it still continues to be a more indolent lymphoid malignancy. And it's not an acute leukemia.
This is what I mentioned about BRAF mutations. Again, that was a very important observation by Dr. Enrico Tiacci in Italy as well as Brunangelo Falini showing that this mutation of BRAFV600E is almost universally present in classical hairy cell, but not in variant hairy cell leukemia, as well as not in other lymphoid cancers.
What about treating variant hairy cell? Many people now agree that the combination of cladribine and rituximab is the best option for initiation of therapy in symptomatic patients. Again you can see in this slide that if you're completely asymptomatic and your blood counts are relatively normal, we don't recommend initiation of therapy, despite the fact that the treatment is generally well tolerated. It's still chemotherapy and, you know, you can have complications. So, the initial therapy for most people, based on the data published by us, as well as by Dr. Robert Kreitman, is combination of cladribine and rituximab.
You can see now for people who relapse, there are a number of potential other options available that I will go through.
So, just historically again I'm showing you that the response to single agent cladribine or pentostatin is only up to about 50%. It's still possible to treat variant hairy cell leukemia with single agent cladribine or pentostatin, but 50% response is not something we like to have.
So going back to the slide from us when we treated a few patients on our cladribine followed by rituximab study. The third line is the variant hairy cell. Most patients had a response. Again, these are very few patients, but all of them essentially had a response. But as you can see the responses have shorter duration. Now these are months and years, but you can see that patients relapse, many of them within a couple of years of initial therapy.
Again, this shows that variant hairy cell is more difficult to treat than classical hairy cell leukemia.
This is the strategy by Dr. Kreitman, who used cladribine and rituximab, but he used concomitant. So he started the rituximab on day one of cladribine. He also reported a very high response to virtually all of the patients and the duration was a little bit more durable.
Even in my opinion, I think the variant patients should be treated with concomitant cladribine and rituximab, with the rituximab starting on day one.
Other agents, as I mentioned, are available. This drug ibrutinib has been approved by the FDA for other lymphoid malignancies, most notably chronic lymphocytic leukemia. It's a very interesting drug that has really revolutionized the treatment of chronic lymphocytic leukemia. It has also been tested in hairy cell and variant hairy cell in a very small study that hasn't yet been published. We participated in it and I can tell you the patients do get response and clinical benefit.
It's an oral agent with limited toxicity and it's an option that can be used if the patient relapses.
This [moxetumomab] is another drug that has recently been approved by the FDA, both for classical and variant hairy cell. Although there are very few patients with variant who are treated on the study. This is what we call an immunotoxin. It's a fusion of a variable region of an antibody to the truncated region of the Pseudomonas toxin. Pseudomonas is a bacteria. They essentially make the toxin shorter. That makes it no longer toxic to the patient overall. This antibody binds to the surface markers on the surface of the hairy cells, gets internalized, and then the toxin is released and kills the leukemic cell.
So this has been approved for patients with second relapse of classical, but can be used with first relapse of variant hairy cell. Again, there's limited data, but it should be potentially effective.
Going back to the BRAF mutations, the other reason why there was a lot of interest in the discovery of these BRAF mutations in hairy cell leukemia was because a drug called vemurafenib was already being investigated in melanoma, which, as it happens, has the same BRAF mutation.
Melanoma, as you know, is a skin cancer, which is a very difficult disease to treat, but patients would respond to vemurafenib because they also had the BRAF mutation. And this led to the testing of this in classical hairy cell leukemia. Remember, variant patients do not have the BRAF mutation. I wanted to put this here because I frequently have patients asking me why we cannot use vemurafenib for variant, mainly because the target of the drug, vemurafenib, does not exist in variant hairy cell. So unfortunately, this is not an option for patients with variant hairy cell leukemia.
I think this is my last slide. I hope that I gave you a broad overview of variant hairy cell leukemia and if you have any questions, I'd be delighted to answer.
question & answer session
Thank you, Dr. Ravandi. So we did receive one question through the Q and A.
The patient asked, have you ever seen anybody with classic hairy cell transition to variant? This individual was diagnosed and treated as classic, but doesn't have the BRAF mutation.
No. These are two separate entities. So they don't progress from one to the other. There are some patients who don't have the BRAF mutation - in my opinion and many other people's opinion, based on the fact that the testing may be inadequate.
One of the things that we teach in medical school to medical students is that the bone marrow in hairy cell leukemia is a dry tap. You can't aspirate a lot of the fluid, unlike other leukemias. When you have a dry tap, you don't have a lot of specimen. And it's possible that you will get a negative BRAF mutation, just because you did not have an adequate sample.
Now, many places nowadays use other ways to try to identify the BRAF mutation. Our center users immunostaining of bone marrow biopsy specimens. So if you have classical hairy cell, and you don't have BRAF mutation, it may well be that the testing was inadequate, not because of anybody's fault, but because the sample was inadequate.
Thank you, Dr. Ravandi.
And for those of you who might have joined a little bit late, I'm receiving some questions through the Q and A portal. I also want to let people who want to ask a question live to do so. So if you do have a question and want to ask it live, go ahead and raise your hand and I will take a few of those.
I see that someone raised their hand.
[Patient name], would you like to ask a question?
Webinar Participant 1
When I was first diagnosed. I was diagnosed Non-Hodgkin's leukemia.
Then my spleen was also very big. So they took that out and at that time is when I was diagnosed with the hairy cell leukemia variant.
But they weren't sure. And it was during the spleen, I guess when they dissected that or whatever, that's when they came up with the hairy cell leukemia variant.
How do I ever know if I actually had the variant or not?
I mean the spleen is actually the best way that pathologists can make a diagnosis.
Where are you located?
Webinar Participant 1
Over by St. Louis, I go to Wash U Siteman Center.
Wash U is a very reputable place. So I would expect a pathologist would be expert.
And you know, unfortunately, sometimes in medicine things are not completely black and white, and there may be confusion because of that. But again, you're in a good center with very expert pathologists. They should make be able to make the diagnosis.
Webinar Participant 1
So when you're presenting with symptoms - like my lymph nodes are getting larger. Can they just stay large and you still stay asymptomatic? You know, can you hold there for a very long time?
Asymptomatic. That means that you're not having fever, fatigue, weight loss, loss of appetite.
And if your lymph nodes are very large, for example, the big lymph nodes in your neck that bother you in terms of your appearance, it can be an indication to start therapy.
Because that's a symptom.
Webinar Participant 1
Okay, that helps. Thank you.
[Patient name] - You have a question for us?
Webinar Participant 2
I was diagnosed in 2017 with the variant and had the cocktail. And after three and a half treatments of rituxin, it was a no go. It was like my body said no we're not doing this.
And then I relapsed a few months later and went to a different oncologist and she did the cladribine for five days. And then a month later, we started with the rituxin, and right at three and a half treatments that was it, my body was like, no go.
Well, they slowed it down to separate infusions over the course of two days to reduce the reaction. And I still reacted, so I was wondering what is the efficacy of rituxin given over the course of three days? Has that been done before?
You know, I don't think there's been studies looking at you know, splitting rituxin. I don't think there's any problem splitting the dose over three days. You're still getting the same dose.
Did they use any steroid premedication?
Webinar Participant 2
Yes, we used everything.
Yeah, you're a bit unlucky because most patients get a reaction with the first dose, but virtually no patient gets a reaction with subsequent doses. You're unlucky because you're obviously having problems with it.
Webinar Participant 2
Right. And the first time I took it as my initial treatment, I reacted super bad.
And then the second treatment went okay. Third treatment was a rapid infusion. Perfect. And then the fourth one after that it was like, nope, not doing it. This second time around I had the reactions, all through the treatments in spite of the pre meds.
Third time they gave you a rapid infusion?
Webinar Participant 2
Yeah, it went perfect.
Maybe that should stay on a slow infusion of several hours.
Webinar Participant 2
Yeah, that's what they did, they split it over two days, and I still reacted.
So I was trying to convince my oncologist to do a three day course and she's concerned about the efficacy of the drug, because I really want to get my six rounds in. I don't think four was enough for me. And that's why I relapsed so early.
Again, it's an unfortunate and unlucky situation. They can slow the process. Again, there is no data that I can refer to. I don't think there should be a problem.
Webinar Participant 2
Now if rituxin is a no go, what is the next best thing? I don't want to be back 18 months later and relapse.
If what you've received so far has produced a response, it is difficult for them to give you anything else at this point. And if it comes back, then you can try the other drugs that I mentioned, like ibrutinib.
Webinar Participant 2
Ibrutinib, okay. Well, we're discussing this with her in a couple of weeks. Well, thank you for your time.
Dr. Ravandi, we have another question. This is through the Q and A. This individual, [patient name], says she's currently in remission for hairy cell leukemia. Labs have come back normal, but she still feels so tired and gets sick a lot as well as bruises quickly. Why is this and what might cause these types of symptoms?
Bruising quickly. If her platelet counts have normalized, that should not happen. And if it does happen, there could be other reasons.
You should see a hematologist who is an expert in blood clotting disorders. But, when you say bruising quickly, if your platelet count has normalized, that should not be related to hairy cell leukemia.
Now, in terms of tiredness - There are many causes for tiredness. A patient can have low thyroid or sleep apnea or other reasons for tiredness that was all attributed to hairy cell leukemia.
If you actually have had a good response, a lot of the tiredness related to hairy cell leukemia should disappear, but if it's still there it could be because of other things and other factors.
Okay. Thank you, Dr. Ravandi.
Looks like we have a live question from [patient name]. Do have a question for us?
Webinar Participant 3
Yes. Hi. I was wondering, how do we find out what is FDA approved?
I'm my doctor's first patient, and I have hairy cell classic. It's very, "This is what the FDA has approved." She won't even think about rituxin or any other options because she says, "If this is what the standard treatment is." So I'm just curious. I see so many people trying these other treatments with these concurrent treatments.
Webinar Participant 3
How do we get that information, or how do you have a conversation to present that to your doctor?
The only thing that's recent that is preapproved for hairy cell is moxetumomab and that's only for patients in second relapse or beyond.
So the standard continues to be cladribine and pentostatin. And they do produce very good responses, so I understand why they are reluctant to do anything else. Now again, our center believes the standard should be cladribine plus rituximab, as does the NIH.
But unfortunately, because hairy cell is an uncommon disease, it's unlikely that we can get organized to do a large randomized trial to show that the combination is better than single agent.
Webinar Participant 3
So my best bet is to find a doctor who is willing...
Well it's not the doctor, the insurance company has to be willing to pay for the rituximab. The doctor should be willing, no problem, but you know we have patients coming to us and the insurance company does not pay for rituximab. Rituximab is an expensive drug.
Webinar Participant 3
Ok that makes sense. Thank you.
Thank you, [patient name].
So we have another question through the Q and A portal.
This individual was diagnosed with variant hairy cell leukemia and later was diagnosed with large B cell lymphoma. Do you feel, Dr. Ravandi, that the combination of cladribine two times and R-CHOP - do you feel it's that combination that led to such a long remission for this patient? Do you have any other insight into what might have helped this patient stay in remission for so long?
So remember when I presented the slides, I said that a certain proportion of patients can transform to more aggressive lymphoma. And diffuse large B cell lymphoma is an aggressive lymphoma. R-CHOP is a very standard therapy for diffuse large B cell lymphoma.
So they have provided the appropriate therapy.
Okay, great. And thank you for responding to that question Dr. Ravandi.
So this is a question that you did touch a bit on, flow cytometry, during your presentation. This individual is asking this question through the Q and A.
This individual was diagnosed with variant hairy cell leukemia through flow cytometry, but the bone marrow biopsy was a dry tap. Is this typical for the variant form of hairy cell leukemia?
It is more common for the classical hairy cell to be a dry tap. Actually, variant tends not to be a dry tap.
But if the pathologists are convinced that he has variant - in medicine, nothing is 100% so it could be a variant patient who does have a dry tap. But generally classical is dry tap, variant tends not to be dry tap.
Okay, thank you.
Dr. Ravandi. There was an individual who had asked about the combination of cladribine and rituximab, with regards to the variant. Do you feel that there's a difference between starting cladribine and rituximab at the same time, as opposed to doing rituximab after the cladribine? You had mentioned during your presentation using them concurrently. Do you feel that there's a preference, one way or the other, for hairy cell leukemia variant?
For the variant, I would say concurrent is the preferred way. Even for classical, giving concurrent strategies is a very good strategy. We've been doing sequential, but concurrent even for classical. For variant, I would definitely do concurrent.
Great. Thank you, Dr. Ravandi. So there was an individual who reached out prior to the webinar and had a question about his treatment. This individual is in Nepal, so he might experience barriers to certain treatment protocols there as opposed to if he were a patient here in the US.
He was diagnosed with variant hairy cell leukemia in 2006, received treatments in 2007, again in 2008, and then a third time in 2018. Each time he received treatment with cladribine only. He was in a pretty long remission the first time and as you might suspect, a shorter remission the second time. Following the third round of treatment with cladribine, he's now been in remission for about a year. Now for the third round, he did try receiving rituximab, but unfortunately he had a pretty severe adverse reaction to the rituximab. So he stopped and completed the cladribine only.
I know that other patients have similar questions and that is for patients who have such a negative reaction to rituximab, are you recommending those other treatments such as ibrutinib or moxetumomab? What would be your recommendation for this patient if they relapse again?
Typically people who get subsequent cycles of cladribine or pentostatin, their remission is typically shorter the second time or third time. But if you don't have a lot of options to other strategies such as rituximab. Obviously, this patient, for example, did very well after his second course. So as I mentioned, ibrutinib is very expensive, so I'm not sure if it's easy to obtain. But personally I think I would switch perhaps to pentostatin to see if you can get a response with a different purine analogue rather than go to ibrutinib.
Okay. Thank you, Dr. Ravandi. I appreciate that.
So there's an individual who through the Q and A is asking about longitudinal studies regarding remission. So this individual does have classic HCL, as opposed to the variant. What are you seeing with regards to long-term permission for patients? You did reference this a little bit. So if you might touch on that quickly again.
Well, again, with the single agent nucleoside analogues, pentostatin or cladribine, a significant proportion of patients do get long term remissions. But as you saw with the curves that I showed you, many people relapse after about four or five years. And some people relapse more quickly. This is why we did the cladribine and rituximab regimen, and so far we have seen excellent long term responses. And this is not just by us, but also by other groups like the NIH group - Dr. Kreitman - and the Royal Marsden group - Dr. Dearden.
So the whole point of adding rituximab is improving the long term duration of response.
Great. Thank you, Dr. Ravandi.
With regards to ibrutinib, you've mentioned ibrutinib for the treatment of variant hairy cell leukemia. What response rates are you seeing with ibrutinib for variant and is there a higher response rate for patients with classic hairy cell leukemia who were treated with ibrutinib?
I mean, complete response rate is not very high for either of them. But again, patients get a lot of clinical benefit and many patients can stay on it for several years. But it's a daily oral pill that you have to continue to take for several years.
Okay, thank you very much. I do have an individual, [patient name], who wanted to share some of his experience receiving rituximab. [patient name], would you like to share?
Webinar Participant 4
I just went through this. I started this journey in January and I wasn't sure whether I had classical or variant because of the BRAF mutation. And one of the things I'd like to share with people is just making sure that the first thing they do is educate themselves and read all the studies.
And the biggest thing that I wanted to share, though, was that even though I wasn't available to get into a trial, I did go through several doctors and found that universities that have more of a research component to them are more willing to fight to get the rituximab. And while I was denied at several doctors the rituxin, because of the cost and because of the protocol, the research university Michigan State University specifically did treat me with rituxin. They were able to get that authorized with the insurance company. They had to fight a little bit. I'd be willing to, I'm sure my doctor would be willing, to share what he was able to do to get me the rituxin, because that was a critical thing for me. After reading the research, I knew I wanted rituxin concurrently with my cladribine.
I'm near the end of my treatment now and if there's any way that I can help anybody, I'd be happy to do that.
And so we do have another question, Dr. Ravandi. This is from the Q and A portal. Is it typical in variant hairy cell leukemia for someone to become anemic, despite an iron infusion? So this patient with variant hairy cell leukemia is experiencing anemia, despite having an iron infusion. Is that typical?
Was the variant treated?
That I don't know. I would imagine so, but I'm not entirely sure from this question.
I mean, iron infusion is a completely separate subject. The reason why patients with this leukemia or other leukemias become anemic is because the bone marrow is replaced by the leukemic cells and doesn't produce normal red cells.
Iron deficiency is usually related to blood loss, so unfortunately, people can have two different pathologies. So you can have a leukemia and unfortunately, you can also have a bleeding stomach ulcer. Ladies, for example, that could be premenopausal bleeding.
But iron does not help hairy cell leukemia anemia.
I want to thank you, Dr. Ravandi, for taking the time to share your expertise today.
Thank you to everybody who to joined us. And I hope you all enjoy the rest of your day.
Thank you, have a nice day. Bye everybody.
Transcript has been edited for clarity.