Upfront Duvelisib Plus FCR Shows Promise in Younger Patients With CLL

Matthew S. Davids, MD, MMSc

The combination of duvelisib and fludarabine-cyclophosphamide-rituximab (FCR) demonstrated efficacy as a frontline treatment for younger patients with chronic lymphocytic leukemia (CLL), according to results of a phase Ib/II study presented at the 2018 European Hematology Association Congress.

Of 32 patients enrolled on the study, 31 were evaluable at the time of report. The 2-year overall response rate and progression-free survival were both 94%, with 52% achieving complete response (CR) or CR with incomplete blood count recovery. Additionally, 42% of patients achieved a partial response.

Overall, the regimen proved to be an effective therapy for younger patients with CLL, with an MRD negativity rate in the bone marrow of 76%, says lead author Matthew S. Davids, MD, MMSc.

There were some infectious and immune-mediated toxicities, including thrombocytopenia, neutropenia, and anemia. Davids says that pulling back on the chemotherapy may lessen the toxicity of the regimen moving forward.

OncLive: Can you begin by giving an overview of the study?

What have been the findings thus far?

What was the toxicity profile?

In an interview with OncLive during the meeting, Davids, associate director, Center for Chronic Lymphocytic Leukemia, Dana-Farber Cancer Institute, discussed the findings with duvelisib plus FCR, as well as the potential future for this agent in the treatment of patients with CLL.Davids: This is an investigator-initiated, phase Ib/II study of a drug called duvelisib, which is a dual PI3K inhibitor that targets both the delta and the gamma isoforms of PI3K. It is given in this study in combination with FCR, which is our gold standard of therapy for younger, fit patients with CLL.Initially as a phase I component, we found the correct dose of duvelisib, which we identified to be 25 mg twice daily, which is the same dose that duvelisib is being developed with in the relapsed/refractory setting as a monotherapy. We then moved onto the phase II portion, and we found that this combination was highly efficacious. We found that about 76% of patients got to the deepest level of response in the bone marrow, which is MRD negativity. That is much higher than what we would expect from FCR alone with historical studies.We did see some toxicities with this approach, including some immune-mediated toxicities, which may have been related to duvelisib. There were also some cytopenia and infections, which we typically see with FCR.

What are the challenges in treating this population?

One of the next steps that we are considering is to see if we can dial back the number of cycles of chemotherapy while still preserving the efficacy. We hope that it will have some advantages in terms of improving the tolerability of the regimen.With these younger patients with CLL, we want to give them a normal life span. If a patient is in their 40s or 50s, that might mean decades of life. Some of the new drugs that have come along, like ibrutinib (Imbruvica), for example, are very promising. However, we could not necessarily imagine putting a patient on it for 30 or 40 years. It is certainly possible, but we worry about resistance mutations and long-term toxicities.

What would you like clinicians to take away from the study so far?

The idea with our study, as well as a lot of others being presented at this meeting, is to combine these agents for a time-limited period. For the younger patients in particular, this is going to be very beneficial, as it will allow them to at least have drug holidays, if not a curative potential.We know that FCR is still the gold standard for patients who are young and fit, particularly if they have the mutated form of IGHV. We have also presented data previously on a study combining ibrutinib with FCR. In the United States, duvelisib is likely to get a label as monotherapy in the relapsed/refractory setting.

Duvelisib has been granted a priority review by the FDA for CLL, small lymphocytic leukemia, and follicular lymphoma. If approved, what impact will the agent will have on the landscape?

I would encourage community oncologists to start thinking about these types of combination approaches moving forward. It is not something where our study could define a new standard of care yet, but we are hopeful that with larger studies, we may be able to do so.If duvelisib is approved, it is going to be impactful in the relapsed/refractory patient population. If you take CLL for example, this is a population that can benefit from the new drugs, like ibrutinib and venetoclax (Venclexta). Often though, we see these patients progress on both of those agents.

Is there anything else that you would like to highlight?

Therefore, having a new PI3K inhibitor is helpful. It is true that we have idelalisib (Zydelig) already in this space, but duvelisib is now likely being approved as a monotherapy, whereas idelalisib has the label with rituximab (Rituxan). [Duvelisib] would give a nice oral regimented option for these patients. The toxicity profile of duvelisib does look favorable, particularly in the relapsed population.One other aspect of our study that is important to understand is that our regimen with duvelisib plus FCR seems to particularly benefit patients with the unmutated IGHV form. This is a group that typically does not have a durable benefit from FCR alone. As we look to approach treating younger patients with unmutated IGHV in the future, this type of combination approach with novel agents, either with chemotherapy or other novel agents, is going to be really important.

Davids M, Fisher D, Tyekucheva S, et al. A phase Ib/II study of duvelisib in combination with FCR (DFCR) for frontline therapy of younger CLL patients. In: Proceedings from the 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S807.

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