Abstract
Introduction: Homeostatic PI3Kδ signaling is essential for healthy lymphocyte development. Dysregulated PI3Kδ signaling can promote the survival, proliferation, and accumulation of aberrant lymphocytes. Pathogenic germline variants in the genes encoding PI3Kδ cause the inborn error of immunity (IEI) activated PI3Kδ syndrome (APDS). Gain-of-function variants in PIK3CD or loss-of-function variants in PIK3R1 result in kinase hyperactivity, causing dysregulated B and T cells that lead to frequent infections, lymphoproliferation, enteropathy, autoimmune cytopenias, and increased risk of lymphoma. Other lymphoid malignancies have been treated with PI3Kδ inhibitors, despite those tumors typically lacking activating genetic variants in that isoform.
We previously reported use of targeted inhibition of hyperactive PI3Kδ signaling with orally bioavailable, selective PI3Kδ inhibitor leniolisib in 6 patients with APDS in a 12-week, open-label, within-subject dose-escalation Phase 2/3 clinical trial (Part 1 of NCT02435173; Rao VK, et al. Blood. 2017), as well as an interim analysis of the open-label extension study (Rao VK, et al. Blood. 2018). Results from a 12-week randomized placebo-controlled trial of 31 patients with APDS were reported earlier this year (EHA abstract LB2369). Here we describe interim analysis outcomes from the ongoing open-label, single-arm, long-term extension study (NCT02859727).
Methods: Thirty-seven patients with APDS aged ≥12 years were enrolled globally; 20 patients have been on leniolisib for nearly 2 years and 5 patients were exposed to it approximately 5 years. Thirty-five patients rolled over from NCT02435173; 2 patients were new to the study. The primary objective was to evaluate long-term safety of leniolisib. Spleen and index lymph node size were measured at either extension day (ED) 168 or 252. Presence of lymphoma, cytopenias, and infections were also assessed across multiple time points.
Results: In patients with APDS, lymphoproliferation is variable and includes lymphadenopathy, hepatosplenomegaly, and nodular lymphoid hyperplasia; the first 2 were measured here. Lymph node size decreased at ED168/252 with a mean change from baseline (CFB) (standard deviation [SD], n) in the sum of product diameters of index nodes (cm2) at ED168 of -7.73 (6.47, 15) and at ED252 of -11.70 (15.97, 11). Spleen 3D volume (cm3) also decreased: mean CFB (SD, n) ED168, -198.48 (124.23, 16); ED252, -236.64 (165.20, 11). See Figure 1 for a representative image. Decreases were also observed in spleen bi-dimensional size.
Three patients had a history of B-cell lymphoma prior to the trial: stage IV diffuse large B-cell lymphoma (2010), Hodgkin lymphoma with nodular sclerosis (2001), and extranodal marginal zone non-Hodgkin's lymphoma (MALT; 2005). All 3 remained in remission.
There was a statistically significant decrease of -0.351 (p=0.0040) in infection rates with each additional year of leniolisib treatment, despite a concomitant reduction in immunoglobulin replacement therapy usage.
This cohort had a range of autoimmune multilineage cytopenias; 17/31 improved or resolved (Table 1). Three patients who had normal absolute neutrophil count at baseline experienced transient neutropenia during the study, one had concomitant infections.
Leniolisib was well tolerated; 32/37 patients experienced adverse events (AEs) Grades (Gr) 1-3. The majority were Gr 1 (55%), with no Gr 4 AEs and 1 Gr 5 AE. One patient with significant baseline comorbidities (pneumonia, necrotizing lymphadenitis, bronchiectasis, pancytopenia, disseminated mycoplasma infection, liver disease, edema, and cardiomyopathy) suffered cardiac arrest resulting in death at extension day 794 determined not related to study drug. This was the only discontinuation. No serious AEs were suspected related to leniolisib. Study drug related AEs occurred in 13.5% of patients.
Severe gastrointestinal (GI) AEs are known to occur with use of other PI3Kδ inhibitors. On leniolisib 85.3% of GI AEs were Gr 1-2. Fifteen patients experienced GI AEs (excluding dental caries), 10 of whom had a history of GI disease. No GI AE was reported as related to study treatment.
Conclusion: Long-term PI3Kδ pathway modulation with leniolisib administration was well-tolerated in patients with APDS, with continued improvement in lymphoproliferation and cytopenias and no recurrence of lymphoma following study drug exposure up to 5 years.
Disclosures
Sediva:Takeda: Consultancy; Octapharma: Consultancy, Honoraria. Dalm:Pharming: Consultancy, Honoraria; Pfizer: Honoraria; CSL Behring: Consultancy, Honoraria; Glaxo Smith Kline: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Kulm:Leidos Biomedical Research, Inc.: Current Employment; Brightspot: Current Employment. Orpia:Westat, Inc: Ended employment in the past 24 months; Ultimate Health School: Other: Independent contractor (nursing instructor). Kucher:Novartis Pharma AG: Current Employment, Current equity holder in publicly-traded company. Radford:Novartis Pharma AG: Current Employment. Bradt:Pharming Group NV: Current Employment, Other: Current holder of stock options in a publicly-traded company; Neoclone: Current equity holder in private company.
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