In patients with activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS), the use of the oral PI3Kδ inhibitor leniolisib reduced lymphadenopathy and normalized immune cell subsets, according to results from a study published in Blood.1
“Overall, leniolisib was well tolerated, and significant improvement over placebo was notable in the co-primary endpoints, reducing lymphadenopathy and increasing the percentage of naïve B cells, reflecting a favorable impact on the immune dysregulation and deficiency seen in patients with APDS,” according to the researchers, led by V. Koneti Rao, MD, of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland.
APDS is an inborn error of immunity caused by hyperactive PI3Kδ signaling. Clinical manifestations include infections, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. The treatment of APDS is mainly empirical, although leniolisib was shown to be efficient and well tolerated in an earlier six-patient study.2
This phase III, randomized, triple-blinded, placebo-controlled, fixed-dose study included 31 patients with APDS (median age = 20 years; 51.6% female). Participants were randomized 2:1 to receive 70 mg leniolisib or placebo twice daily for 12 weeks. The co-primary outcomes were the differences from baseline in index lymph node size and in the percentage of naïve B cells in peripheral blood, representing immune dysregulation and deficiency. All patients completed treatment and were included in the safety analysis set, with fewer patients included in the efficiency analyses.
The primary outcomes were met. The difference in the adjusted mean change for lymph node size between leniolisib (n=18) and placebo (n=8) was -0.25 cm2 (95% CI -0.38 to -0.12 cm2; p=0.0006). The difference between leniolisib (n=8) and placebo (n=5) for percentage of naïve B cells was 37.30% (95% CI 24.06-50.54%; p=0.0002).
For secondary outcomes, leniolisib reduced spleen volume compared with placebo (adjusted mean difference = -186 cm3, 95% CI -297 to -76.2; p=0.0020) and improved lymphocyte subsets and cytopenias. Immunoglobulin M levels decreased to normal limits in most patients receiving leniolisib over 12 weeks. The changes in health-related quality of life measures were not statistically significant, but investigators reported that 70% of patients receiving leniolisib and 44.4% of those receiving placebo had improvements in energy levels and activity.
Compared to patients taking placebo (30%), fewer patients receiving leniolisib (23.8%) reported treatment-related adverse events (AEs), which were mostly grade 1-2. Five patients reported a serious AE, with none judged as being related to the study medication. No deaths were reported within 30 days of the end of trial.
“We hypothesize that the AEs commonly associated with PI3Kδ inhibitors in other populations may be minimized in patients with APDS as their baseline hyperactive PI3Kδ is brought within a physiologic range and not inhibited completely by leniolisib,” the authors noted.
Limitations of the trial include the small sample size, especially for the naïve B-cell analysis. While the characteristics were similar between the groups, bronchiectasis and gastrointestinal complications were more prevalent in the placebo group. Another limitation was the short evaluation period for outcomes, which was insufficient to assess clinically meaningful measures such as decreases in the frequency of infection, hospitalization, and antimicrobial use. However, the authors noted it is unethical to withhold treatment for patients with APDS for longer than necessary.
The authors plan to complete further study, including trials in younger children with APDS.
Any conflicts of interest declared by the authors can be found in the original article.
- Rao VK, Webster S, Sediva A, et al. Randomized, placebo-controlled, phase 3 trial of PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome [published online ahead of print, 2022 Nov 18]. Blood. doi: 10.1182/blood.2022018546.
- Rao VK, Webster S, Dalm V, et al. Effective “activated PI3Kδ syndrome”-targeted therapy with the PI3Kδ inhibitor leniolisib. Blood. 2017;130(21):2307-2316.