Combination Strategies in CLL

Thomas J. Kipps, MD, PhD: There are a number of studies now that are ongoing that look at combination therapy. I think oncologists want to combine A plus B plus C, and clearly this is borne out of the findings from the early days of oncology when they used a drug that was effective and then used a different drug that has a different toxicity profile. You can then use them together, and together you might have greater responses than if you used either drug alone.

And this is something that is being explored with the targeted therapies — either targeted therapies with other targeted therapies or targeted therapies with traditional chemoimmunotherapy. I know there have been some studies to look at this in the past by using targeted therapies with chemoimmunotherapy. And I think we have to look at the data critically to ask the question of whether the chemoimmunotherapy is actually helping out in terms of the response that we get with these newer targeted therapies.

Another study that was being discussed here was to use bendamustine, ibrutinib and Gazyva, or obinutuzumab, the so-called Big Regimen. And I think the data indicate that patients have a high response potential, but we know that treatment with bendamustine and Gazyva gives a high response potential, and treatment with ibrutinib gets a high response potential. So, I think it’s only after we look at all the data from a number of patients that allow us to say that this is truly offering a benefit to the patient. We shouldn’t necessarily assume that piling on more, with more, is going to necessarily be better.

I will say this, there’s also not only the kinase inhibitor therapy but the therapies that involve inhibition of key proteins such as BCL-2. BCL-2 is a protein that can protect leukemia lymphoma cells from dying, and this is like a shield. And with the advent of specific drugs that can inhibit BCL-2, we can render the leukemia cell or the lymphoma cell more susceptible to dying spontaneously. So, it’s really quite exciting. These drugs have offered tremendous advances because we now are contending with a problem of giving a drug to a patient who has a large tumor burden, they take the drug, and there’s so much in the way of tumor lysis that they can get into trouble. The level of potassium inside cells is quite high. If a lot of cells die right away, then you can get a very high level of potassium in the blood, and that can be very harmful to, for example, the heart in being able to function.

So, I think we have to be very careful when we start these medications. And for that reason, we have been able to adopt strategies where there’s a ramp-up dose escalation where patients start with a very small dose, they graduate 1 week later to a higher dose, and 1 week later to a higher dose. It takes about 5 weeks to get up to the dose that’s going to be maintained over time. Once they achieve that dose that’s maintained over time, you don’t have the risk of the tumor lysis, but it’s with every incremental increase.

Now there are some strategies that are being considered to try and treat patients who have what is termed “high tumor burden," and who then are at very high risk for this type of complication with other agents before they get treated with venetoclax, which is the BCL-2 antagonist. To combine therapies with venetoclax, such as ibrutinib or another drug such as Gazyva, or obinutuzumab, I think is all going to be quite exciting because these drugs are all very active individually by themselves. When we combine them, we’re hoping that we can get higher rates of remission. But, I do think we have to look critically at the potential toxicities when we combine all these drugs and ask the question — are we truly getting the bang for the buck? Are patients really getting the benefit that we would anticipate from the increased complexity and the increased cost of using all these newer agents together?

So, I would advocate that this meeting here at the ASH 2016 is starting to indicate what type of combination protocols are being developed or being considered. But, I think it’s premature right now for us in clinical practice to pile on with different regimens just because it has been done in the clinical trials. I do believe looking at the data and the longer term follow-up data would be very important to help govern our practice in the future.

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