New Approvals Transform CLL Treatment, More Advances on the Horizon

Thomas Kipps,

MD, PhD

Treatment options for patients with chronic lymphocytic leukemia (CLL) have significantly expanded over the past several years. In 2013/2014, four new therapies for CLL were approved—obinutuzumab, ibrutinib, ofatumumab, and idelalisib—prompting ASCO to name the vastly improved outlook for patients with CLL as its inaugural “Cancer Advance of the Year.”

For additional insight on these new agents and other emerging CLL therapies, OncLive spoke with Thomas Kipps, MD, PhD, professor of Medicine in the Division of Hematology-Oncology, and Deputy Director for Research at the UC San Diego Moores Cancer Center.

OncLive: What recent advances in the treatment of patients with CLL are you most excited about?

Dr. Kipps: Ibrutinib and idelalisib in particular represent very exciting advances in that they are orally active and seem to be well tolerated. They appear to block the signaling through the B-cell receptor. I think it is very important to understand clearly how these drugs actually do work so that we can manage clinical responses that we see, as well as try to improve upon them by combining them with different agents.

Although these agents are very effective at inhibiting B-cell receptor signaling, they do more than that. They actually inhibit the ability of these leukemic cells to migrate and go to the sites that they need to go to in order to survive. These are the lymph nodes and the spleen. So what actually happens are the leukemic cells empty out from the lymph node compartments and the white cell count can rise quite substantially. It is that activity, the ability to deprive the leukemic cells from getting back into the lymphoid tissue, that may be the greatest case for why these drugs function in the way that they do.

Within the lymphoid tissue there are other cells and factors which really sustain the leukemic cell and they keep it alive and they also allow it to grow. I think that this is a very exciting concept because you can achieve these by other tools too such as blocking the homing receptors so there could be a possibility of combining this with other therapies, or at least having other strategies that do the same thing.

What is very important with these new agents is that we have to understand how they work and what kind of toxicities they may have. We understand that if we combine them together, sometimes there may be unforeseen toxicities, and so it is important that clinical trials happen to understand how to best use these agents.

I also think they can be combined with other agents as well. We’ve been working with this drug called venetoclax [ABT-199], which is a BCL-2 inhibitor. Oncologists for a long time have actually been inhibiting BCL-2 by the use of chemotherapy or radiation therapy. What that does is induces p53 which then induces the proteins that are like the BCL-2 inhibitors. So they kill the cell by that mechanism. However, when you do that repeatedly, you lose p53 and the drugs lose the activity that we’d like them to have. And I think this advent of using drugs that directly inhibit BCL-2, kind of circumvents that defect and can actually induce the killing of leukemic cell directly, without having to engage p53.

What impact could a better understanding of BCL-2 inhibitors and how they work have on treatment?

Understanding how these drugs work allows us to anticipate how the patient may respond to these drugs. Mainly the patient may have an increase in their white cell count we’d expect that, and would not be alarmed by that. We’d be able to counsel the patient to continue with therapy despite the fact that the blood count is getting larger.

I think it is also important to understand that there may be differences between patients and how well they are likely to respond to these therapies. Understanding what the mechanism is should help us find the factors that really identify patients that will be good responders from ones that will be so-so responders. Everyone seems to respond well, but some patients may not respond with as much of a therapeutic benefit than some others, and trying to understand the mechanism of the drug will allow us know who will respond the most successfully.

What other side effects are you worried about with these new agents?

What is interesting is that these inhibitors can over time induce an inflammation, almost like autoimmune state, we have many patients that may develop arthritic symptoms, or skin rashes. With idelalisib, after many months of therapy, one out of seven patients may develop colitis, similar to an inflammatory bowel disease. So what we are seeing is although there cancer is improved, we are seeing this autoimmune disease that we have to recognize so we can stop therapy and render therapy for what might be an autoimmune disease.

The other complications that we’ve noted with kinase inhibitors are kind of quirky. For ibrutinib, because the drug inhibits enzymes that are also found in platelets, it may make the platelets function less effectively, so it may be a problem if the patients have a very low platelet count. This increases the risk of bleeding, it is also not uncommon for patients to bruise easily and have to be very careful. It can be also be very dangerous if patients require anticoagulation therapy. That could result in serious bleeding complications.

I am thankful for other agents out there that could be used for patients that can’t tolerate these agents because of these toxicities. We are going to improve our understanding of how these drugs work and how they can result in complications. These are important question to address to learn how to better use these drugs.

How have advances in targeted therapies impacted CLL treatment?

This is a very exciting time because we have a lot more targets to go after. If we choose our targets wisely and go after targets that activate the leukemic cell through different pathways by inhibiting all of these pathways we leave the leukemic cell no escape. By combining these therapies, either on top of each other or in sequential therapy, we can create a therapy that can eradicate the disease.

Are there any particular trials in this space that you are most excited about?

We are looking at a targeted agent called cirmtuzumab, or UC-961, in a trial at the Moores Cancer Center at the University of California of San Diego. This agent is an antibody that is directed against this protein that we identified as being on the leukemic cells but not on other cells. We are excited about the ability of this antibody to direct and eradicate the ability of the leukemic cell that expresses this protein. So we will have to wait and see how this is tolerated and how effective it is. But it is possible that this, in addition to some of these other tools, will hopefully achieve a cure, at least for some of our patients.