Webinar: Understanding HCL Variant
June 18, 2024
Speaker: Dr. Farhad Ravandi, MD Anderson Cancer Center
Hosted by the Hairy Cell Leukemia Foundation (HCLF) with guest speaker Dr. Farhad Ravandi, MD Anderson Cancer Center. Moderated by HCLF Executive Director Anna Lambertson.
Webinar Materials
View a recording of Dr. Ravandi’s presentation >>
Transcript of Dr. Ravandi’s Presentation
Dr. Farhad Ravandi, MD Anderson Cancer Center:
Thank you for organizing this and thanks to the Hairy Cell Leukemia Foundation that has done a lot of work in this rare disease.
I have been given the task to focus on an even more uncommon disease, which is hairy cell leukemia variant.
We have had excellent therapeutic options now for almost 25 or 30 years; these have been the nucleoside analogs, cladribine and pentostatin, that were developed in the 1990s. They were quite revolutionary in leukemia therapy because in the 1990s, very few leukemias could be treated with anything to achieve a response rate. With these drugs, patients with HCL achieved response rates as high as 90%. This was quite a big event in those days and many institutions around the world started using these agents for treating classical HCL.
But the work has not been done completely because if you follow these patients over the years, even with that high response rate, you can see that disease-free survival, which means patients relapsing, falls with the years of follow-up. I always tell my patients that of course, if this was a disease of the very elderly, as in patients in their 80s and 90s, we probably wouldn't be as concerned. But the median age at diagnosis is 55, so at least half of the patients are diagnosed before their 50s. And so you really want to improve this long-term disease-free survival.
Because of that, there have been efforts to improve that initial therapy. The standard therapy has continued to remain single agent cladribine or pentostatin. Most institutions and physicians have tended to go towards cladribine, but when the patient needs therapy, and that's important to emphasize because not every patient needs immediate initiation of therapy and there are some criteria for indication for therapy including significant lowering of the blood counts or significant symptoms including night sweats, weight loss, and significant fatigue. But when the patient needs therapy, the cladribine and pentostatin have remained as what is considered a standard, although with the introduction of rituximab in the early 2000s and with the development of regimens that combined cladribine either concomitantly or sequentially with rituximab, the use of rituximab in the frontline setting has increased. And there have been a number of studies that have suggested that patients’ responses would be more durable.
At our center, we developed the sequential cladribine followed by rituximab regimen, which we've been using for 20 years with excellent disease-free survival duration. We recently looked at this data of about 150 patients, and we've only had a few patients relapsing in 20 years. So, this regimen does improve the duration of response in classical hairy cell leukemia.
Now, the National Institutes of Health (NIH) group has looked at the concomitant administration of cladribine and rituximab in these patients, and they have also shown that this is a relatively safe and effective combination and can produce deeper responses. The only downside of the combination is Immunosuppression. Both agents suppress the immune system, so the patients are at more risk of infections, and particularly viral infections. In the COVID era, there was understandably some anxiety about using these drugs in patients with HCL.
We have been doing this combination in the sequential manner for a long time, and we first reported this data in mid 2000s and more recently in this publication. As you see, for patients who were untreated for classical HCL and a few patients that we did treat in first relapse, the outcomes are excellent. A few patients relapsed and the overall survival of patients with classical HCL is the same as the data of an age match population.
So, this is not a leukemia that is, at least these days, is going to lead to death of the patient even in long-term follow-up.
Variant hairy cell unfortunately has less success with this or other regimens. There are people who relapse fairly quickly after even this combination, and there are unfortunately still some patients who don't do well, even as related to their variant hairy cell leukemia survival. In general, patients with HCL and variant HCL, if they pass, they usually pass from other causes, but variant hairy cell is a more difficult population.
Difference in presentation
HCL Variant presents differently than classic HCL. Patients with classic HCL tend to present with significant pancytopenia. That means their blood counts are all low. On the other hand, patients with HCL variant have a higher white count at presentation and an elevated lymphocyte count.
Both HCL cells and variant HCL cells are lymphocytes. Now, in classical HCL, they tend to be low, but in variant HCL, abnormal lymphocytes increase in the peripheral blood. That’s a generalization, but in general, the distinction between variant and classical HCL is where in the variant the patients have higher blood count at presentation, higher than normal, whereas in classical it's lower.
HCL is rare with about 1,000 new cases in the US each year. HCL variant is even rarer, about 10% of HCL patients.
In both of these disorders, the cells have these projections from what we call cytoplasm; this is why they're called hairy because of these what we call projections.
There are other lymphoid malignancies or lymphoid cancers that can have these hairs and we rely on the pathologist to tell us whether this is hairy cell or variant hairy cell. Other uncommon blood cancers can have these hairs; one is splenic marginal zone lymphoma, which is another disorder where the cells have these projections.
But again, this can be easily clarified by the pathologist by a number of features. They look at expression of these markers on the surface of the cells. So in the classical hairy cell leukemia, you have some markers such as the ones mentioned here that do not exist on the surface of variant hairy cell. And as I mentioned, there was other difference that in the variant hairy cell, usually you have a high white cell count and lymphocyte count, whereas it's the opposite in the classical hairy cell.
Now, an important distinction is this thing that has been more recently described in hairy cell leukemia. About seven years ago, our Italian colleagues describe this mutation in a gene that is present in virtually every case of classical hairy cell leukemia called the BRAF mutation. And this mutation does not happen in the variant hairy cell. So that's one way that we can be quite certain in addition to these surface markers that a patient has variant rather than the classical hairy cell leukemia.
There are some papers that I've looked at other genetic abnormalities in variant hairy cell. For example, mutations in this MAP2K1 gene has been described in about half of cases with variance hairy cell leukemia.
Importance of accurate diagnosis
Why do we need to distinguish HCL variant from classic? Classic HCL responds very well to nucleoside analogs, which are cladribine and pentostatin. Whereas, HCL variant responds less well to the single agent nucleoside analog therapy.
Interferon was a drug that was used in the early 90s. It's no longer used in either of these disorders to that extent, but interferon was more likely to respond in a classic HCL patient than a variant patient.
The HCL variant patients unfortunately tend to have a worse prognosis than classic. Even after the standard therapies, the duration of remission tends to be lower, although they still live a very long time.
HCL is not a rapidly fatal disease. Of course, every patient who hears ‘leukemia’ gets very anxious, but if you don't respond very well to initial therapy, the duration of remission can be very long. And in patients with HCL variant, there are patients who don't start therapy immediately and you can wait and watch some of these patients for a while before you need to start therapy.
The indications for therapy are based on the number of and features in the blood counts. For example, if the white cell counts rapidly double, this is probably an indication to start therapy; if you have a significant anemia or low platelet count, there would probably be more indication to therapy; or if you have significant ‘constitutional symptoms’ (fatigue, night sweats, weight loss, et cetera.)
The BRAF mutation is an excellent marker for classic HCL. In this seminal paper by the Italian group, they described these BRAF mutations in almost 100% of patients with classic HCL; hey also looked at a number of other lymphoid cancers like lymphoma or variant HCL and they did not find this mutation. So again, this is a good marker to identify classic, and if you have a patient who has variant, it’s a good marker to show that it is not the classic and is a variant HCL.
So how do we treat these patients? If you are asymptomatic and don't have a lot of blood count abnormalities, you can watch. In a patient who does have symptoms, the combination of cladribine and rituximab is now standard. It's clear that this combination is definitely better than single agent therapy. So myself and most other HCL experts do recommend initiation of therapy with combination. And in fact, in HCL variant, I recommend concomitant administration of cladribine and rituximab.
Important precautions before, during and after treatment
This is an immunosuppressive regimen; for the first month, the blood counts will go down because cladribine is a chemotherapy agent, and then they go back up. But when you give it in combination with rituximab and even as a single agent, these drugs suppress the immune system and make you more predisposed to infections, particularly viral infections. So, I always suggest and recommend to my patients to be up to date in their vaccinations, such as COVID-19 as well as pneumonia and flu vaccines before initiation of therapy.
HCL is not a disease that you have to always rush to start therapy, so you may have some time to get yourself up to date with your vaccines. Also, because the disease can sometimes be watched and not initiate therapy, I generally, if I can, try to avoid initiating therapy during winter months when there are a lot of viruses going around, although that does not mean that I would never start therapy. Of course, if the patient needs therapy because of their significantly low blood counts or symptoms, we do start therapy anytime.
Another virus that can be a problem is shingles. Many people are now vaccinated for shingles. Patients who are not vaccinated, I tend to start on a prophylactic drug called valacyclovir or Valtrex. I tend to use that as a prophylactic measure against the development of shingles during therapy and for about six months to a year after the completion of therapy. So that's true for both classic and variant HCL.
Newer agents for treating HCL
There are of course other agents available. There have been studies using B-cell receptor inhibitors. A number of these drugs are now FDA approved for other chronic leukemias such as chronic lymphocytic leukemia. That's a disease that shares a lot of features with HCL. And we do borrow a lot of the knowledge for therapy of HCL and variant HCL from other lymphoid malignancies, mainly because they are much more common. Because of that, there have been more clinical research, activity, and drug development in those diseases.
In chronic lymphocytic leukemia or CLL, there are a number of drugs that are now approved, such as Ibrutinib and similar second and third generation drugs such as pirtobrutinib and other B-cell receptor inhibitors. These do have activity in both HCL and variant HCL. So, if we have patients who have relapsed from prior similar therapy, we use these drugs with good success. They tend not to produce complete remission, but they do control the disease for a protracted long-term period of time.
There are many other drugs that are now available for other lymphoid malignancies, other lymphomas and chronic lymphoid leukemias, and these drugs may be effective in variant HCL. Because of the disease being rare, there are not huge clinical trials of these drugs and agents in variant HCL, but there are always anecdotal single patient reports of these drugs being useful.
If a patient responds to therapy and relapses after a few years, there's a possibility of retrying the same strategy, for example, cladribine and rituximab, or for example, bendamustine plus rituximab.
In classic hairy cell leukemia, the BRAF mutation also exists in other cancers, for example, melanoma (a skin cancer), thyroid cancer and other cancers. And because of that, drugs that target these BRAF mutations have been developed and are FDA approved for other cancers. We have used these drugs in HCL with a lot of success. One of them is Vemurafenib, where in combination with rituximab has been useful in classic HCL. Unfortunately, variant HCL does not have this mutation and as such, these drugs are not going to be highly effective in variant HCL. Vemurafenib or dabrafenib, these drugs unfortunately are not useful for variant HCL.
The response to therapy for variant HCL in the original studies of pentostatin and cladribine was lower than what it was for classic HCL. For classic, it approached 90%, but it was as low as only about 50% for variant. But this response improves when you combine it with rituximab, and this is sequential. There is a recent publication from the NIH group combining cladribine and rituximab concomitantly in variant HCL, which is quite more effective.
Because of this resistance, many of us don't tend to use single agent cladribine or rituximab.
Again, to go over the B-cell receptor inhibitors: Ibrutinib and others, such as pirtobrutinib, which have been approved for chronic lymphocytic leukemia, do have activity in HCL as well as in variant HCL patients. So, they are useful drugs to consider, particularly after a relapse in patients who have previously received cladribine and rituximab.
Moxetumomab pasudotox is an antibody-based therapy or immune-based therapy that was developed by Dr. Robert Kreitman in the NIH and has significant activity both in variant and in classic HCL, but at the moment is not available in the market.
One interesting thing, and this was reported by the Italian group who were pioneers in the development of vemurafenib and the BRAF inhibitors in classic HCL; they showed that using this molecularly targeted agent against BRAF mutations, you change the shape of these hairy cells. So, the hairy cells, when they respond, they lose their hairs. This clearly shows that the BRAF mutation is important in the development of classic HCL; the drug is effective by moving these cells back towards their normal shape.
Importance of clinical trials to advance new therapies
The more we know about the molecular or the genetic basis of these leukemias, the more we can develop and try to have even more effective drugs. Again, in classic HCL, Vemurafenib is very effective, especially when combined with rituximab and is used commonly in the relapse setting. But it is also useful because these drugs don't cause the chemotherapy associated suppression of the blood count, so they can be a bit safer in specific situations.
And of course, in variant HCL, there's been studies looking at the molecular pathogenesis or the molecular changes and there are some molecular aberrations. I mentioned to you the MAP2K mutations that can happen in about 50%, but because this is a disease that is uncommon and quite rare all over the world, we do need to rely on clinical trials. So if one is diagnosed with the classic and particularly with variant HCL, it's very useful for you as well as for the development of the knowledge base to be participating in these clinical trials, because there is a lot of science that is going on in the research labs all around the world, and this is leading to better identification of what causes these leukemias on the genetic basis. And this leads to development of more effective therapies.
Especially in rare diseases, we need to collate all the information. Participating in trials and at least having therapy in centers who do treat HCL will help us develop and get more insights into the management of patients with both classic and variant HCL.
Transcript has been edited for clarity.