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Genetic Sequencing in Chronic Lymphocytic Leukemia

Lee Greenberger, chief scientific officer at the Leukemia and Lymphoma Society, discusses the differences in subtypes of chronic lymphocytic leukemia and why genetic sequencing is important.
BY Kristie L. Kahl and Lee Greenberger
PUBLISHED February 11, 2020


Transcript:

Kristie L. Kahl: What is CLL and how does it develop?

Lee Greenberger: Chronic lymphocytic leukemia is regarded as an indolent disease. It’s a disease of the blood cells. The white blood cells undergo certain mutations as they are developing the bone marrow and they can go out throughout the body depending on the stage of the CLL. They typically will go to lymph nodes, so you will see patients who walk in with enlarged lymph nodes. It could also be fatigue. As the bone marrow becomes compromised and the white blood cells that are produced in CLL are immature and not as effective as mature cells, so infections can manifest, fatigue, you can also see other blood counts go out of range as these cells begin to take over the bone marrow and compromise the entire blood system.

Kristie L. Kahl: What is the difference between slow-growing and fast-growing CLL?

Lee Greenberger: So, typically CLL patients have a slow-growing disease and in rare cases, the CLL will transform into an aggressive disease. At that point, it requires treatment that, honestly, we have a difficult time to control. CLL is typically a slow-growing disease. It might manifest in average age of about a 70-year-old and it can require simply no treatment. This is low-grade, watch-and-wait, come back in three to six months and we’ll keep an eye on it.

If in the event the CLL becomes advanced enough, the lymph nodes are swelling and there is enough fatigue, we can see a lot of CLL cells in the bone marrow or the blood, a biopsy is taken, and the therapy will begin.

Therapies have evolved considerably in CLL. It’s one of those areas where precision medicine has really played a big role in the last 10 years, where you’ve had a number of drugs that have been approved for CLL and we’ve changed over from cytotoxic therapy in combination with immunotherapy, in particular (Rituxan [rituximab]). It would be a cytotoxic therapy, which has toxic side effects, and Rituxan, something called FCR, that is migrated over to oral therapies in the last 10 years. The oral therapies, which began as an observation 20 years ago with now an oral therapy that is highly effective, that has become the mainstay for many CLL patients. So, what you typically use a BTK inhibitor, like {Imbruvica [ibrutinib]), now there are three approved BTK inhibitors.

BTK is a protein within the CLL cells and when it is activated it will cause these CLL cells to proliferate. So, you can shut down BTK with ibrutinib, and it can be highly effective. It’s not completely effective, and while some patients will have a good response, some patients will not and ultimately develop resistance to BTK inhibitors. That is where the next drug comes into place.

(Venclexta [venetoclax]) can control CLL. What is being done now is to use ibrutinib and venetoclax combinations. Those are even more effective, so we’re getting to a stage with CLL treatments where we can say, “Here are two oral medications, take these.” And this will be highlight effective in controlling disease.

The disease will be under control, the nodes will shrink and we can’t even find the disease and the disease is eradicated essentially. If that doesn’t work there are still alternative therapies to that, in particular, CAR-T cell therapy, this immunotherapy that allows the T cells to recognize these CLL cells and selectively kill them.

We have multiple alternatives for CLL. It’s really one of the best examples of how precision medicine and immunotherapy have advanced in blood cancers.

Kristie L. Kahl: We see FDA approvals for CLL, but also small lymphocytic lymphoma, what is the difference?

Lee Greenberger: SLL is a type of CLL and basically a less aggressive form of CLL. There is not as many CLL cells that are detected. It is typically a watch-and-wait scenario and it mar or may not progress to CLL.

Kristie L. Kahl: You mentioned precision medicine, how do genetics play a role in CLL?

Lee Greenberger: There are multiple ways to define what is the status of a tumor. We have now characterized all 20,000 genes in the genome. You can easily sequence these genes and find out whether there are mutations. It is very clear for all of these blood cancers, and cancer in general, that there are mutations that cause these cancers. Some of these mutations are actionable, there are drugs for them, some of them there are not. It is very important, when a sample is done of the lymph node or the bone marrow, to send this out for sequencing. Sequencing will tell you what mutations exist in those patients.

That is important for a couple of reasons. We know that certain mutations are poor prognosis, and others are not. So, you can begin to tell a patient, you are likely to respond or you’re likely to not respond. It may dictate whether you go to more aggressive therapies or less aggressive therapies.

Kristie L. Kahl: What is your biggest piece of advice for someone who is newly diagnosed with CLL?

Lee Greenberger: These days the most important thing for a newly diagnosed patient is to make sure that they get a full work up, that includes the bone marrow biopsies, the mutational sequencing, the analysis of the cells (what do the chromosomes look like), and lay out all the options. It could be simply watch and wait, you don’t need to do anything. In fact, doing nothing can be quite beneficial because it’s not toxic, you just simply wait. And some of these patients can progress and it does require coming into the doctor’s office. And some may require extensive therapy. Going to a major medical center that is an expert in dealing with this disease and making it a differential diagnosis of whether it’s CLL or not is very important, and then designing the therapies and carefully watching these therapies. It’s not just simply going to the pharmacy and taking a drug, is the drug working, is it failing, is it developing resistance and we know that by mutational analysis, if you have a certain mutation you are not going to respond.

Having someone sophisticated who can do that analysis is important. Once you go on a drug, it’s not simply taking the pill, this requires careful follow up by an expert in the field.

Transcript Edited for Clarity

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