Promising Therapies and Clinical Trials for Chronic Lymphocytic Leukemia

Farrukh Awan, MD, University of Texas Southwestern Medical Center, spoke with the Journal of Clinical Pathways about some of the most promising therapies and clinical trials within the field of chronic lymphocytic leukemia (CLL).

Please introduce yourself by stating your name, title, organization, and relevant professional experience.

I'm Farrukh Awan, and I'm a professor of medicine in the Department of Internal Medicine at the University of Texas (UT) Southwestern Medical Center in Dallas, Texas, where I also lead the lymphoma program and focus my clinical care on patients with CLL.

Are there any promising emerging therapies or ongoing clinical trials in the field of CLL that you believe may have a significant impact on future treatment approaches?

There are multiple options for clinical trials right now in the CLL field. The first important advancement in the field, or efforts that have been underway for a long time, is early intervention.

Historically, we have not treated patients right after diagnosis because chemotherapy early intervention did not result in prolonging survival. Yes, the cancer went into remission, but sometimes the toxicity of the treatment from 20, 30 years ago was worse than watching patients for a while. That's why historically, we've been following this principle that early treatment does not prolong life. So, we usually start treating the patients if the disease bothers them clinically or based on accounts or symptoms and so on.

That's been the mantra of the field. This approach is called watchful waiting and active surveillance. It is difficult for patients to understand why we are watching the cancer. It's been stress provoking and anxiety provoking for our patients when we have to say, "You have a malignancy and we will not intervene unless it causes problems." That's what we're trying to change.

There have been multiple efforts more recently to intervene early for patients who have high-risk disease, using some of the newer molecules. Hopefully this will result in them living longer because we control the disease at an early stage. We strongly recommend that any patient who has high-risk disease at the time of diagnosis seek out these options for early intervention.

A lot of these trials are ongoing nationally, and they will hopefully determine if there is any role for early treatment in patients with CLL right after diagnosis. Maybe not for all patients, but maybe for a small subset of patients.

The next big question in the field is, can we combine some of the agents that we have in order to improve remission rates, which will result in longer remission. Also, can we stop treatment after a set time point.

For example, maybe we can treat patients for 12 months and 24 months or whatever time point we decide is appropriate and that duration would be enough for them to get into deep remissions. That will result in better outcomes for them in the long run because then they will not have to take a pill forever. Also, the toxicities will be less. All of these efforts are being explored in various clinical trials.

The field is slowly heading toward an era where we will move away from indefinite therapy to a time limited therapy. How will we get there? What's the best approach that is being discussed in various clinical trials of various combinations? There are pill only combinations, pill and IV formulation combinations, etc. It depends on what will give us the best outcome.

There are ongoing comparative trials, which are trying determine whether combination time-limited therapy of the two most active compounds—BTK inhibitors and the BPL2 inhibitors—will result in a better outcome for our patients in the long run. That's another approach that is being evaluated in clinical trials. I highly recommend all our patients to participate in those trials.

The next area being investigated is second-generation, third-generation, or  fourth-generation drugs. These drugs are more specific, and they may have less side effects. They may also work even if patients fail the first-generation drugs that are currently available and approved for use.

There's a lot of work being done in developing newer molecules that are more potent, more active, and also hopefully less toxic. I strongly encourage patients, especially those in which their disease has relapsed after the initial treatment, to participate in those trials to explore the outcomes of these newer agents. A lot of those agents have gone through their initial dose-finding clinical trials, so we know which are effective. Hopefully they will continue to improve outcomes for our patients.

Lastly, I think one thing we're all excited about is the cellular therapy, the CAR T therapy that is approved. Those trials will keep happening and they will slowly move up the line and patients with less severe disease or less refractory disease will be able to participate. Hopefully, they'll result in better outcomes.

Another treatment modality that is looking very promising but is still in clinical trials is the use of bispecific antibodies. Bispecific antibodies have already been approved for patients with diffuse large B cell lymphoma and follicular lymphoma, which are basically cousins of CLL in the lymphoid malignancy space, and they have had some promising side effects. We're also getting more comfortable in managing them in outpatient care. Some of those are intravenous drugs and some of them are subcutaneous options.

There's a lot of excitement that maybe we can use these bispecific antibodies to enhance the immune system and to direct the immune system of the patient to fight against the CLL cells without necessarily having to go through the more cumbersome procedure of CAR T-cell therapy.

Will bispecific antibodies replace CAR T-cell therapy? Will they be an alternative to CAR T-cell therapy? Will they be used as a bridge to CAR T-cell therapy? All of these are questions can only answered by active participation by physicians and patients in those exciting new clinical trials.