Expanding the Horizon for Hairy Cell Leukemia - Episode 4

Promising Treatment Options in Hairy Cell Leukemia

Kristie L. Kahl
Kristie L. Kahl


Kristie L. Kahl: Can you explain what watch-and-wait is?

Dr. Robert Kreitman: When a patient gets diagnosed with hairy cell leukemia for the first time but doesn't need to be treated, that's called watch-and-wait. You just watch and you wait until the counts get bad enough or the spleen maybe gets big enough that causes symptoms and there's an indication for treatment. It’s rare – less then 10%, probably 5% of patients can escape treatment for their whole lives. It’s not quite as common as some other chronic diseases where you can avoid ever being treated but, in general, we don't jump into treatment until there are indications for treatment.

Generally, the normal blood counts have to be low, at least one of them, or the spleen has to be enlarged and painful. There are some other indications for treatment that can be used but those are the main ones.

Kristie L. Kahl: Can you discuss other standards of care for treatment?

Dr. Robert Kreitman: The most popular first-line treatment for hairy cell leukemia is single agent cladribine, and an equally good first-line treatment is pentostatin – these are purine analog chemotherapy drugs. They do have toxicities, but they're remarkably well tolerated. They can cause a range of different side effects: stem cell damage, neuropathies, nerve damage, normal blood counts to go down even lower than they were to begin with and that can cause fevers. Generally speaking, if patients start out with very low neutrophil counts the neutrophil count can go down very low with treatment. With either of these treatments, cladribine or pentostatin, patients have to be very careful to let their doctors know or come into the emergency room if they have fever because that means low neutrophil count and that means their infection-fighting ability is very low and it could there could be serious consequences if you don't get antibiotics. So that tends to be more common in patients who present with low neutrophil counts, but we see even patients with normal neutrophil counts when they start, can go down very low with even the first treatment with cladribine or pentostatin. So you have to careful about that. Pentostatin is given every other week for three months, up to six months sometimes. That’s a little bit more gradual, a more gentle treatment. Cladribine is generally given once a day for five doses or continuously for seven days. So it's a little bit more treatment packed into the first week and so we may see more side effects in terms of the bone marrow suppression, the low blood counts during that or just after that time, and it can take a month or more for the normal blood counts to come up.

Kristie L. Kahl: What is the standard of care in the relapsed/refractory setting?

Dr. Robert Kreitman: Patients are being treated with the same treatment as first-line treatment, however, they can combine it with (Rituxan [rituximab]), which is a CD20 monoclonal antibody that binds to CD20 and it gets the cells to commit suicide or get the immune system to kill the hairy cells and it works very well with the chemotherapy. It has some synergy, that means that two things that are used to treat work together to produce a very good response. We know that happens because rituximab makes the cells more sensitive to the chemotherapy. So, general speaking, if patients have had more than a two-year complete remission to the first-line treatment then one is more likely to be able to get away with the first-line treatment that they had before or maybe the alternative. In other words,if they started with cladribine they could get pentostatin the second time or vice versa. If, generally speaking, they got less than a two-year remission or they got a partial response, which means they didn't get a complete remission at all, then you'd be more likely to combine the purine analog treatment with rituximab.

I should say that there is new information from a randomized trial that if you give the cladribine

and rituximab together in first-line treatment then the results are extremely good. Not only do you have a higher complete remission rate but you eliminate minimal residual disease (MRD). Minimal residual disease is traces of hairy cells that are left behind by chemotherapy and they cause relapse over time, and given enough time they will grow into a relapse and patients will have to get treated again. So, if we can get rid of the MRD, then we can potentially prevent patients from relapsing.

So there is some new information that if you treat with cladribine and rituximab together early on for first-line treatment, you can eliminate the minimal residual disease. Over many years, median or average time of follow-up, around six-and-a-half years, very few if any of these patients need more treatment or they have no minimal residual disease. Their counts are excellent and if you compare that to a group of patients that were treated a long time ago with cladribine and then you wait for many years to relapse, about 28% of patients will relapse over about six years or so. This is being used more and more, but it’s not part of the official guidelines because the official guidelines in 2020 came out before the randomized trial was reported. But it's something that people are using more and more.

A group at MD Anderson, previous to that trial, studied cladribine followed a month later by rituximab, and also found a 100% complete response rate and also a good removal of minimal residual disease. There is some controversy now about whether this should be part of the first-line treatment of hairy cell leukemia.

Now, I want to back up and say that after that, if patients have a very poor response to their first course of cladribine, there is a drug called a BRAF inhibitor that could be used in the second-line and that's called (Zelboraf [vemurafenib]) and that's recognized as a legitimate second-line treatment, or in other words after the first relapse, that can be used providing the complete response to the first-line chemotherapy was less than two years or if patients had no complete remission. But in order to use this drug, you have to demonstrate that you have the BRAF V600E mutation…This mutation was discovered by a group in Italy in 2011 in hairy cell leukemia. It was shown in a trial in 2015 to be very effective in relapsed hairy cell leukemia. This is a recognized treatment in the second-line and it's certainly one of the treatments that is recognized in the third-line and beyond, that means relapsed several times. Vemurafenib has been combined with rituximab and it has much better complete remission rate. It eliminates the minimal residual disease as well, so about two-thirds of the patients have no evidence of minimal residual disease. But we don't have long-term data on it.

The other treatment that was just approved in 2018 for relapsed hairy cell leukemia is a drug called (Lumoxiti [moxetumomab pasudotox]). This is a drug that is very different than chemotherapy. It is made out of an antibody that binds to CD22, which is on the surface of hairy cells. It goes inside and then the toxin kills the cell and this drug is quite unusual in that it can eliminate minimal residual disease and cause complete remission as a single agent, and it's not chemotherapy. It doesn't cause chemotherapy toxicities. The problem with this drug is that you have to be careful when giving it. It kills cells that it gets inside so it pokes holes in the blood vessels and it makes the blood vessels leaky so patients have to drink lots of water when they're taking it…It’s very well tolerated. If you don't hydrate well that drug could cause some kidney damage and so you have to be very careful.

There’s another recommended drug in the third-line and beyond, (Imbruvica [ibrutinib]). Ibrutinib is a great drug. It's approved for chronic lymphocytic leukemia and mantle cell lymphoma and some other hematologic tumors. But in hairy cell leukemia, it works very slowly but surely. We’re waiting for a full report of a clinical trial. It has some excellent effects and one of the advantages of this drug is that it you don't need the BRAF mutation and sometimes it's very helpful even in patients who don't have the BRAF mutation.

…Lumoxiti is a drug which was specifically approved for hairy cell leukemia. There are insurance companies that will pay for ibrutinib and rituximab, but generally speaking these drugs were not approved for hairy cell leukemia. Whereas lumoxiti is a drug that works especially for hairy cell leukemia, so it is approved for hairy cell leukemia.

Kristie L. Kahl: What do patients with hairy cell leukemia have to look forward to?

Dr. Robert Kreitman: There's so many more treatments now. They can look forward to having treatments that work very well – not only that work but can be given orally for those patients who want to avoid getting IV treatments. Intravenous treatments allows patients to get out and avoid having to go back to the doctor. We find that the oral treatments by themselves tend to spare the minimal residual disease. The patients will continue to have minimal residual disease which means that if you stop the oral drugs, the disease will come back. Although sometimes it takes more than a year for the for the disease to come back. If a patient really wants to have a treatment that makes it so the patient will not need any treatment in the future and, therefore, not have any side effects from treatment, then you really need a treatment that can eliminate the minimal residual disease.

Those treatments include moxetumomab pasudotox as a single agent and vemurafenib plus rituximab can do that. Although we don't have long-term data on that combination. One thing we do have long-term data on is the cladribine plus rituximab given in the first-line, but we also have data on other purine analogs like pentostatin…that can give very high complete remission rates without minimal residual disease. There is a lot more that we know now that has not been published and will be published soon. Those kinds of combinations with the rituximab generally offer the possibility of elimination of minimal residual disease. Many patients are happy not having the minimal residual disease eliminated but being able to be treated chronically with treatments that they can tolerate, providing they can tolerate them well, including the ibrutinib and the BRAF and MEK inhibitors.

Transcription edited for clarity.