The PI3K inhibitors have taken a back seat to the Bruton tyrosine kinase (BTK) inhibitors and to the BCL-2 inhibitor venetoclax in the management of CLL. Early and late-onset immune-mediated toxicities that are associated with PI3K inhibitors include infections, hepatotoxicity, diarrhea and/or colitis, and pneumonitis. Additionally, studies have shown decreased circulating levels of regulatory T cells with the use of PI3K inhibitors, which potentially points to an immune-mediated component to some of these toxicities.

Attempts to mitigate these toxicities have been undertaken, more so in lymphoma than in CLL, and some studies have shown improved adverse-event profiles with staggered dosing and adjusted treatment schedules. Copanlisib, for example, is an intravenous PI3K inhibitor that is US Food and Drug Administration (FDA) approved for use in patients with lymphoma but not CLL, and it is administered in an intermittent schedule. This drug appears to be linked to fewer of the autoimmune issues that are observed with the oral PI3K inhibitors.

In the phase 3 UNITY-CLL trial, the oral PI3K inhibitor umbralisib was administered in combination with the anti-CD20 monoclonal antibody ublituximab. Umbralisib plus ublituximab was compared with obinutuzumab plus chlorambucil in patients with treatment-naive and relapsed/refractory CLL. The umbralisib-plus-ublituximab regimen was clearly superior to the obinutuzumab-plus-chlorambucil regimen. However, it is not known whether umbralisib monotherapy is superior to the already FDA-approved PI3K inhibitors idelalisib and duvelisib, and it was recently announced that there are potential safety concerns with umbralisib that are being monitored by the FDA. In my view, I do not think that there would be much change in terms of the overall treatment paradigm in CLL even if umbralisib plus ublituximab were to be approved, since patients generally have such a good experience with the BTK inhibitors and with venetoclax.

The current role of PI3K inhibitors in CLL is mainly limited to situations in which the other available treatments are not an option (eg, contraindications or intolerance), although intolerance to first-line therapies is becoming less of an issue. And, unfortunately, the durations of remission with PI3K inhibitors to date have not been high in patients who have failed treatment with BTK inhibitors and venetoclax. For instance, if a patient is refractory to a BTK inhibitor, the duration of remission will be rather short with a PI3K inhibitor, perhaps less than 1 year.