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PI3K Inhibitors in CLL
The Role of First-Generation vs Second-Generation PI3K Inhibitors in CLL

Released: September 13, 2018

Expiration: September 12, 2019

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Although the first-generation PI3K inhibitor idelalisib shows potent activity against relapsed chronic lymphocytic leukemia (CLL), concerns about its safety profile have limited its use in the clinic in favor of BTK inhibitors. However, promising clinical data for the investigational next-generation PI3K inhibitors umbralisib and duvelisib now prompt the question: What role could these new PI3K inhibitors play in managing CLL?

First-Generation vs Second-Generation PI3K Inhibitors
These 3 PI3K inhibitors are all very active in relapsed/refractory CLL, including patients with high-risk disease. As they have all shown efficacy in clinical trials, differences may emerge with regards to their safety profiles. Idelalisib, a PI3K delta inhibitor, was the first of this class that was evaluated and FDA approved in conjunction with rituximab in patients with relapsed CLL for whom rituximab alone would be considered appropriate due to other comorbidities. Adverse events that emerged and have limited its usage include grade 3/4 pneumonitis, colitis, and transaminitis. These toxicities are manageable but because this was a first-in-class agent, early awareness was needed regarding its toxicity profile, along with education on managing these side effects. Initial safety data suggest lower rates of these toxicities with both duvelisib, a dual inhibitor of PI3K delta and gamma, and umbralisib, a PI3K delta inhibitor with notable structural differences.

We currently lack any head-to-head data to guide us when choosing among PI3K inhibitors in relapsed/refractory CLL. Comparing the next-generation PI3K inhibitors, the data on duvelisib are currently more mature, and this agent was recently FDA approved for relapsed/refractory CLL after at least 2 previous therapies. In the phase III DUO trial in relapsed/refractory CLL, patients who received duvelisib experienced a significantly longer median PFS vs those who received ofatumumab (13.3 vs 9.9 months, respectively; P < .0001). Now that duvelisib is approved, I anticipate clinicians may favor duvelisib over idelalisib in their relapsed CLL patients if long-term data reveal it has a better safety profile. We will need to wait for more mature safety data on umbralisib before we can decide among the next-generation PI3K inhibitors.

Sequencing PI3K Inhibitors
Physicians should consider PI3K inhibitors for patients with relapsed CLL who need to switch therapy because of intolerable toxicity. For example, I would consider these agents for a patient responding to the frontline BTK inhibitor ibrutinib yet experiencing toxicity associated with this therapy, such as a major bleeding event or atrial fibrillation. In this case, the patient’s disease is already responding to a B-cell receptor pathway–targeting agent; thus, I would prefer to switch to a PI3K inhibitor, which acts on the same pathway. In a retrospective analysis conducted by Anthony Mato, MD, myself, and colleagues looking at sequencing of ibrutinib and idelalisib, patients who experienced toxicities with either agent could switch to the other and derive clinical benefit. Clinicians may further prefer PI3K inhibitors over venetoclax (an antiapoptotic Bcl-2 inhibitor) when there is a concern for high risk of tumor lysis syndrome (eg, bulky disease or high WBC count) and a logistic inability for those patients to be monitored appropriately while receiving venetoclax.

By contrast, for individuals progressing on a BTK inhibitor such as ibrutinib, switching to a PI3K inhibitor would likely lead to a shorter response duration. This was what we observed in the retrospective analysis described above. In this scenario, it would be reasonable to switch to venetoclax.

Notably, there are ongoing clinical trials such as UNITY-CLL evaluating next-generation PI3K inhibitors in the frontline CLL setting. Frontline studies of idelalisib were stopped due to an increase in death rates observed in previously untreated patients, which were mostly due to infectious complications. In other studies, there has also been a suggestion of higher rates of autoimmune-related events in younger untreated CLL patients, possibly due to differences in the function of regulatory T-cells in untreated vs multiply relapsed patients. Of course, only time and sufficient data will clarify, but because early data suggest the next-generation PI3K inhibitors may have more favorable safety profiles in the relapsed/refractory setting, these agents may also be safer in the frontline setting.

Combination Studies
Studies are also evaluating B-cell receptor–targeting agents combined with monoclonal antibodies, chemoimmunotherapy, and/or venetoclax. These trials are evaluating the potential of deeper remissions, time-limited duration therapy for some oral agents, and the possibility of prolonged response duration or survival for patients with CLL. Patients with Richter’s transformation and those with BTK- or venetoclax-refractory CLL remain a challenge for clinicians; combination studies may be beneficial in these settings. For example, an ongoing phase I/II study reported that umbralisib plus pembrolizumab plus the CD20-targeting antibody ublituximab is active in CLL, including BTK-refractory CLL, although we are waiting for mature safety data. This triplet may be more toxic because of immune-mediated events associated with PD-1 inhibition.

Your Thoughts?
How would you choose between the first-generation vs second-generation PI3K inhibitors? Please share your perspective in the comments box!

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If duvelisib receives FDA approval for relapsed/refractory CLL, in which scenario would you consider using this agent?
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