Combinations Have Potential to Shift CLL Treatment Paradigm

Richard R. Furman, MD

The combination of venetoclax (Venclexta) and ibrutinib (Imbruvica) could possibly change the treatment landscape for patients with chronic lymphocytic leukemia (CLL).

In results presented at the 2017 ASH Annual Meeting, the combination elicited a complete response (CR) or CR with incomplete hematologic recovery (CRi) rate of 47% for patients with relapsed/refractory disease.1 The findings, which were from the TAP CLARITY study, showed that all 38 efficacy-evaluable patients experienced at least a partial response to ibrutinib and venetoclax, with an objective response rate of 100%.

Of these patients, 37% who were treated with the combination were negative for minimal residual disease (MRD) in the peripheral blood at 8 months. When testing the bone marrow, the MRD-negative rate was 32%.

OncLive: Can you please provide an overview of your presentation on CLL at the 35th annual CFS?

What combinations with ibrutinib have been successful?

In an interview prior to ASH conducted at the 35th annual CFS®, Richard Furman, MD, director of the CLL Research Center at Weill Cornell Medicine, discussed the current management of CLL and the future of combinations, including venetoclax and ibrutinib, for this patient population.Furman: The main point of my talk was to identify where our patients’ current therapy is failing. I used ibrutinib as the paradigm for what I believe is the best upfront treatment for patients. I identified the patients who are not going to be able to enjoy the long-term progression-free survival of ibrutinib with the hope of being able to predict who those patients are ahead of time.Ibrutinib is being combined with everything. The study that is going to be the most important to changing the treatment paradigm is the ibrutinib plus venetoclax trial. The patients are receiving 3 months of ibrutinib as a single agent and then are going to receive venetoclax in combination for 12 months.

What other agents is venetoclax being explored with?

What are your expectations for the combination of venetoclax and rituximab?

What are the most pressing unmet needs for patients with CLL?

Patients who have stopped venetoclax and are MRD-negative are randomized to stop treatment with ibrutinib or continue it. If they are MRD-positive, they stay on ibrutinib. The hope is that, with the limited duration of our therapy, we might be able to make the MRD-negative patients stay on ibrutinib. There is the obinutuzumab (Gazyva), venetoclax, and ibrutinib study. There is also a cyclophosphamide, rituximab (Rituxan), and ibrutinib study. Moreover, there is also the head-to-head comparison of venetoclax and rituximab to bendamustine and rituximab.When we look at rituximab and venetoclax versus bendamustine and rituximab, rituximab is just an add-on and venetoclax is doing a vast majority of the work. The data for venetoclax and rituximab will be the same for venetoclax alone. The most pressing needs are the patients who are going to be at risk for developing Richter’s transformation. We have identified risk factors for Richter's transformation and prior chemotherapy is one of them with a 17p deletion. However, there are still many patients who transform simply because of the biology.

Is the future of the CLL field poised to include more combinations?

How do you decide which patients to treat with single-agent ibrutinib or which ones to try one of the combination regimens that are in development?

What factors play a role in choosing therapy overall for your patients?

We have a lot of patients transforming early on, as well. When patients are transformed, their survival is quite poor. It would be important to either identify novel tumor predictors or different interventions we can do that might help prevent this for patients.We have always been interested in combinations. Combinations have been the main state since 1990. Ibrutinib and venetoclax are enabling us to have success or [beneficial] outcomes even earlier. We like doing combination therapy but, in essence, we have been doing that for a while. In a group of newly identifiable patients, you can give them ibrutinib with nothing else and they will do extraordinarily well. With everyone else, it is important to recognize who those people are so you can treat them differently.Ibrutinib is my first choice for everyone because of the tolerability and efficacy. There are some patients who benefit from a more rapid reduction in the tumor burden. You are going to need the people who are at risk of developing Richter’s transformation or are at risk of developing resistance to ibrutinib. For those patients, I treat them with venetoclax.

Hillmen P, Munir T, Rawstron A, et al. Initial Results of Ibrutinib Plus Venetoclax in Relapsed, Refractory CLL (Bloodwise TAP CLARITY Study): High Rates of Overall Response, Complete Remission and MRD Eradication after 6 Months of Combination Therapy. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 428.