Duvelisib Provides CLL Patients With a Later Line of Therapy

Ian W. Flinn, MD, PhD

There is a need for new agents in the second and third line for patients with relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL), according to Ian W. Flinn, MD, PhD. In September 2018, the FDA helped fill the void, approving duvelisib (Copiktra) for adult patients with r/r CLL who have received at least 2 prior treatments.

OncLive: How does duvelisib affect the treatment paradigm for CLL?

How is duvelisib different from other PI3K inhibitors?

In an interview with OncLive, Flinn discussed the agent’s potential impact on patients with CLL. Flinn is director of lymphoma research at Sarah Cannon and the Sarah Cannon Center for Blood Cancer at Tennessee Oncology and TriStar Centennial Medical Center, based in Nashville, Tennessee. He serves as the lead investigator of the DYNAMO and DUO studies in duvelisib.Flinn: The CLL treatment paradigm has changed significantly over the past few years. We’re seeing use of targeted therapies, such as BTK and BCL2 inhibitors, earlier in the course of disease and getting away from the chemotherapy of old. As a consequence, we need new therapies and we need new treatments for patients who have received those therapies but have relapsed. This is where duvelisib comes in. There’s a need in the second and third line for patients to receive new agents, and, because of its mechanism of action, duvelisib is ideally suited for this setting.Duvelisib is an inhibitor for both the delta and gamma isoforms of PI3K. The only other currently approved PI3K inhibitor for CLL is idelalisib [Zydelig], which is a pure delta isoform inhibitor. We know that the delta isoform is important because it is expressed in the malignant cells, but the gamma isoform is important in the microenvironment that is supporting the growth and proliferation of CLL cells.

What is the optimal patient population for this drug?

Duvelisib is an inhibitor of both of these isoforms, and it has a direct effect on the malignant cells, as well as the microenvironment and, therefore, may have greater efficacy in this patient population.The optimal patient population for duvelisib consists of patients with CLL who have had 2 prior therapies. We know from the DUO trial [NCT02004522], a phase III trial that randomized patients to receive either duvelisib or ofatumumab [Arzerra], an anti-CD20 antibody, that patients with 2 prior therapies had significant improvement in response rate, the depth of remission, and progression-free survival. We also saw a very tolerable safety profile.

What are the dosing considerations?

How well do patients tolerate duvelisib?

For patients who are intolerant to some of the other therapies, such as ibrutinib [Imbruvica] or venetoclax [Venclexta], [and physicians’] choices are limited, then I think duvelisib is also an important choice.The normal dose of duvelisib is 25 mg twice per day. It is given orally, and it is given continuously as long as the patient is benefiting from the treatment and not having significant adverse effects. You do have to be careful if someone is receiving the drug with a CYP3A inhibitor, in which case you have to dose-reduce duvelisib to 15 mg twice a day. And, of course, if someone has adverse events, then you want to dose-reduce the drug as well.Doctors and patients have several safety considerations to think about. There are risks of increased liver function tests within the first 8 to 12 weeks. By and large, if the drug is held and [the event] gets to be grade 3 or higher, the liver function test will resolve, and the patient can be restarted back on that drug. That’s a very easy adverse event to manage.

Other adverse events include autoimmune complications. This was predicted from laboratory study results that show that inhibition of the delta isoform produces diarrhea or colitis. Patients and their physicians need to be aware of colitis that can occur with duvelisib. It generally happens later, after 5 or 6 months on treatment and, if it gets severe, [physicians] need to withhold the drug and potentially use oral nonabsorbable steroids like budesonide or systemic steroids to treat the colitis.

Finally, the infectious complications need to be considered. We recommend that everyone receive PCP [pneumocystis pneumonia] prophylaxis while on duvelisib and I certainly would consider using prophylaxis against herpes viruses such as acyclovir for patients.