Leading the Field

THIS YEAR ALONE, chronic lymphocytic leukemia (CLL), the most common type of leukemia in adults in the United States, will affect more than 20,000 Americans.

As investigators learn more about the disease, such as associated gene changes, they can better determine the best treatment and likely outcome for a given patient. In an interview with CURE®, Jacqueline Barrientos, M.D., M.S., an associate professor at the Feinstein Institute for Medical Research in Manhasset, New York, discussed the most recent advances and where these treatments stand in clinical trials.

CURE®: Please describe the types of therapy available to treat CLL.

Barrientos: CLL has been a disease where we take a watch and- wait approach because many of our patients don’t have symptoms. Back in the day when people needed therapy, we just had chemotherapy. Then investigators found out that a combination of chemotherapy and immunotherapy was the goal. Unfortunately, chemo-immunotherapy approaches available 10 years ago were very toxic and unable to be tolerated by patients, because this is a disease of the elderly.

Starting in 2010, we saw the first clinical trials with novel targeted agents that targeted pathways affected by these cancers. The first clinical trial was with the drug Zydelig (idelalisib). Shortly after came clinical trials with a BTK (Bruton tyrosine kinase) inhibitor called Imbruvica (ibrutinib). We found out that these drugs work really well but in a different way. In CLL, the white blood cell counts started to go up very quickly and the lymph nodes shrunk immediately, but at the time, because we did not have any prior idea that these drugs would work this way, the first patients were taken off trial. If you have leukemia and your white blood cells go even higher, that’s a bad thing. With chemotherapy, that never happens. (In this case), experts had to get together to say, “No, this is actually working.”

It brings the white blood cell count up because it’s being moved out of the lymph nodes. It affects the way the cells interact with one another, until the (cancer) cells die off.

We know that this pathway works, but how do we make it better? There are a couple of other agents in the pipeline. A second-generation BTK inhibitor, Calquence (acalabrutinib), is approved by the Food and Drug Administration (FDA) in relapsed/refractory mantle cell lymphoma. It’s currently being tested in patients with CLL against Imbruvica, and the same (is happening) with Zydelig. (In June), the FDA approved Venclexta (venetoclax), which works in a different pathway. It behaves like a chemotherapy that tells CLL cells to die by enhancing a cellular suicide pathway known as “programmed cell death,” or apoptosis.

A lot of patients can access these drugs, which is very encouraging. These are much better tolerated for the most part, and patients don’t have to spend their entire day sitting in an infusion chair; they can (sometimes) take a pill.

Are these newer anticancer agents being tested in clinical trials?

The field is moving toward combination strategies to see if maybe the combination approaches might be best (i.e., chemotherapy and novel agents, novel agents with biologics, or novel agents with biologics with another novel agent).

Two major trials are ongoing currently, one in young people and another in the elderly. Other trials are also in the pipeline. For example, patients with high-risk disease are being studied in Germany. (Investigators) are testing Imbruvica against placebo, which is the watch-and-wait standard of care, to see which is better. This may change our management if we find out that giving therapy at the time of diagnosis is better, but we don’t know that right now.

The other area where the field is moving is that maybe instead of (putting patients on) a drug forever, such as Imbruvica, we can do combination studies to see if we can allow patients to have a drug holiday and resume when the disease starts (producing) symptoms again.

(In some cases), patients stop responding to these agents. For those patients, there is a promising new strategy using chimeric antigen receptor T cells. This is when T cells are taken out of a patient, reengineered and then reinfused into the body. This strategy is still early in its infancy, and because of that, you can still have severe toxicities.

How important is molecular testing for determining the sequence of treatments?

For us, it is very important to at least test the 17p deletion or TP53 mutation, because those patients should not be given chemotherapy. Also, patients with mutated IDHV tend to have a worse outcome in terms of earlier relapses if they have been exposed to chemo-immunotherapy regimens.

What should patients know about having a chronic disease?

I would want patients to see a specialist at least once to know that there are promising clinical trials. Sometimes by the time a patient comes to see us, they have had so much prior therapy; it pains us to know they could have been given something different if they saw a specialist sooner.

You have to listen to your body. If there is something that you don’t agree with, don’t hesitate to seek a second opinion. We encourage it.

JACQUELINE BARRIENTOS, M.D., M.S., an associate professor at the Feinstein Institute for Medical Research.