Jacqueline C. Barrientos, MD, MS, Explains the Rationale for Using Combination Therapies in CLL

Jacqueline C. Barrientos, MD, MS, Associate Professor, The Feinstein Institute for Medical Research, Northwell Health, Long Island, New York, explains why combining therapies is beneficial for the treatment of patients with chronic lymphocytic leukemia (CLL).

Jacqueline C. Barrientos, MD, MS:  We know that these drugs that are not always targeted agents they work really well as monotherapy. However, the majority of them are not able to get to a complete remission or MRD undetectable state.

As such, you really are not in a deep remission. It can cause or lead to a selection of a clone that is no longer responding. For example, if you're on Ibrutinib after several years, you can develop BTK mutation or PLC Gamma mutation.

If you're on Venetoclax, you can develop BCL-2 mutation. When that happens, you no longer respond to the drug. The idea of combining is trying to avoid the emergence of these resistant clones. That's one.

The other idea is that maybe by achieving a very deep remission with MRD undetectable disease, you can potentially shorten the three-month duration. Some of these drugs, as you know, are approved for continuous dosage until progression.

If you have a patient that is young, you have the perspective of taking a drug for the rest of your life. That can be 40 years of taking the same drug. With time, you may develop side effects or toxicities that mean you no longer are able to take the drug.

By combining, you may be able to achieve a more significant response, a deeper remission with complete remissions, and including undetectable MRD state, which can allow you to maybe discontinue the drug and therapy.

We saw that in combination of Venetoclax with Rituximab in the MURANO trial. That's a phase III trial that led to the approval of the combination.

Patients that achieved undetectable MRD state, they had the remission that was longer than people that had MRD-positive disease. More importantly, this therapy was only given over two years. Even after discontinuation of the regimen, they were still in remission.

There are several new combination strategies. If you can achieve that with Venetoclax in combination with Rituximab, what would happen if you do Venetoclax in combination with Ibrutinib?

That data is emerging. Peter Hillmen from the UK presented data on the CLARITY trial in patients with relapsed refractory disease. He showed that the majority of patients not only do achieve a response but they also achieve a complete remission, and many of them achieved an undetectable MRD state.

This same combination regimen was tested in patients in the front line setting and presented by Bill Wierda in the CAPTIVATE trial. The patients also achieved complete remission.

Several of them were able to achieve undetectable MRD, including in patients with 17b. The goal is that if you achieve this MRD-negative state, you might be able to discontinue both drugs. Then when the time comes and you relapse, you may reintroduce these drugs.

Instead of giving the drug forever, both of them, you are able to allow the patient to have a therapy-free holiday, which is the goal in a young fit patient. You don't want to develop any of the toxicities, which include financial toxicity.

That's the reason why we are doing combination strategies, to see if maybe in some patients, including patients with high-risk disease, by giving the combination, you might be able to avoid the emergence of this selection of clones that will lead for you to stop responding to the drugs.