Phosphoinositide 3-kinase Delta Research Articles

57 Development and Implementation of the TRIO Health Activated Phosphoinositide 3-kinase Delta Syndrome Characterization and Clinical Outcomes Immunologic Registry (APDS-CHOIR)

57 Development and Implementation of the TRIO Health Activated Phosphoinositide 3-kinase Delta Syndrome Characterization and Clinical Outcomes Immunologic Registry (APDS-CHOIR)

115 Off-label treatment with the selective PI3Kδ inhibitor leniolisib in 2 pediatric patients with activated phosphoinositide 3-kinase delta syndrome 2 (APDS2)

115 Off-label treatment with the selective PI3Kδ inhibitor leniolisib in 2 pediatric patients with activated phosphoinositide 3-kinase delta syndrome 2 (APDS2)

Long-term treatment with selective PI3Kδ inhibitor leniolisib in adults with activated PI3Kδ syndrome

AbstractActivated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity that manifests as immune deficiency and dysregulation; symptoms include frequent infections and lymphoproliferation. In our dose-finding and phase 3 placebo-controlled trials, treatment with the selective PI3Kδ inhibitor leniolisib reduced lymphoproliferation and normalized lymphocyte subsets. Here, we present 6 years of follow-up from the 6 adult patients in the original dose-finding trial receiving leniolisib. We used data from the ongoing open-label extension study, which was supplemented at later time points by investigators, including health-related quality of life (HRQoL) assessed through a clinician-reported questionnaire. We observed improvements in HRQoL: 5 of 6 patients experienced an increase in physical capabilities and socialization, and a decrease in prescribed medications. Immune subsets improved in all patients: mean transitional B-cell levels decreased from 38.17% to 2.47% and the CD4:CD8 T-cell ratio normalized to 1.11. Manifestations seen before and within the first year of leniolisib exposure, such as infections and gastrointestinal conditions, attenuated after year 2, with few new conditions emerging out to year 6. Thrombocytopenia or lymphopenia remained present in half of patients at year 6. Of 83 adverse events through year 5, 90.36% were grade 1; none were grade 4/5 nor deemed leniolisib related. Collectively, we saw an enhancement in HRQoL as well as durable changes in lymphocyte subsets and clinical manifestations, further supporting the use of leniolisib as a long-term therapeutic option for the treatment of APDS. This trial was registered at www.ClinicalTrials.gov as #NCT02859727.

APDS patients with immune-complex vasculitis and resolution with leniolisib

Activated phosphoinositide 3-kinase delta syndrome (APDS) is an inborn error of immunity with heterogeneous clinical manifestations of infections, immune dysregulation, autoimmunity; lymphoproliferation; and malignancy. Immune complex-mediated vasculitides have not yet been described in APDS patients. Here we offer a case series of three patients with APDS who have refractory IgA vasculitis (also called Henoch-Schönlein purpura), a form of immune complex-mediated vasculitis that activates complement and attracts neutrophils, macrophages and eosinophils to cause local tissue injury. Leniolisib is an inhibitor of PI3K p110δ and an FDA-approved treatment for APDS. IgA vasculitis resolved upon treatment with leniolisib. Patients with immune dysregulation including IgA vasculitis should be screened for APDS.

The highly selective and oral phosphoinositide 3-kinase delta (PI3K-δ) inhibitor roginolisib induces apoptosis in mesothelioma cells and increases immune effector cell composition

Targeting aberrantly expressed kinases in malignant pleural mesothelioma (MPM) is a promising therapeutic strategy. We here investigated the effect of the novel and highly selective Phosphoinositide 3-kinase delta (PI3K-δ) inhibitor roginolisib (IOA-244) on MPM cells and on the immune cells in MPM microenvironment.To this aim, we analyzed the expression of PI3K-δ by immunohistochemistry in specimens from primary MPM, cell viability and death in three different MPM cell lines treated with roginolisib alone and in combination with ipatasertib (AKT inhibitor) and sapanisertib (mTOR inhibitor). In a co-culture model of patient-derived MPM cells, autologous peripheral blood mononuclear cells and fibroblasts, the tumor cell viability and changes in immune cell composition were investigated after treatment of roginolisib with nivolumab and cisplatin. PI3K-δ was detected in 66/89 (74%) MPM tumors and was associated with reduced overall survival (12 vs. 25 months, P=0.0452). Roginolisib induced apoptosis in MPM cells and enhanced the anti-tumor efficacy of AKT and mTOR kinase inhibitors by suppressing PI3K-δ/AKT/mTOR and ERK1/2 signaling. Furthermore, the combination of roginolisib with chemotherapy and immunotherapy re-balanced the immune cell composition, increasing effector T-cells and reducing immune suppressive cells. Overall, roginolisib induces apoptosis in MPM cells and increases the antitumor immune cell effector function when combined with nivolumab and cisplatin.These results provide first insights on the potential of roginolisib as a therapeutic agent in patients with MPM and its potential in combination with established immunotherapy regimen.

Systematic review of mortality and survival rates for APDS

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma, and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants in PIK3CD and PIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function variants in the PIK3CD gene, while loss of function variants in PIK3R1 have been reported to cause APDS2. We conducted a review of the medical literature and identified 256 individuals who had a molecular diagnosis for APDS as well as age at last report; 193 individuals with APDS1 and 63 with APDS2. Despite available treatments, survival for individuals with APDS appears to be shortened from the average lifespan. A Kaplan–Meier survival analysis for APDS showed the conditional survival rate at the age of 20 years was 87%, age of 30 years was 74%, and ages of 40 and 50 years were 68%. Review of causes of death showed that the most common cause of death was lymphoma, followed by complications from HSCT. The overall mortality rate for HSCT in APDS1 and APDS2 cases was 15.6%, while the mortality rate for lymphoma was 47.6%. This survival and mortality data illustrate that new treatments are needed to mitigate the risk of death from lymphoma and other cancers as well as infection. These analyses based on real-world evidence gathered from the medical literature comprise the largest study of survival and mortality for APDS to date.

Optimization of virtual screening against phosphoinositide 3-kinase delta: Integration of common feature pharmacophore and multicomplex-based molecular docking

Extensive research has accumulated which suggests that phosphatidylinositol 3-kinase delta (PI3Kδ) is closely related to the occurrence and development of various human diseases, making PI3Kδ a highly promising drug target. However, PI3Kδ exhibits high homology with other members of the PI3K family, which poses significant challenges to the development of PI3Kδ inhibitors. Therefore, in the present study, a hybrid virtual screening (VS) approach based on a ligand-based pharmacophore model and multicomplex-based molecular docking was developed to find novel PI3Kδ inhibitors. 13 crystal structures of the human PI3Kδ-inhibitor complex were collected to establish models. The inhibitors were extracted from the crystal structures to generate the common feature pharmacophore. The crystallographic protein structures were used to construct a naïve Bayesian classification model that integrates molecular docking based on multiple PI3Kδ conformations. Subsequently, three VS protocols involving sequential or parallel molecular docking and pharmacophore approaches were employed. External predictions demonstrated that the protocol combining molecular docking and pharmacophore resulted in a significant improvement in the enrichment of active PI3Kδ inhibitors. Finally, the optimal VS method was utilized for virtual screening against a large chemical database, and some potential hit compounds were identified. We hope that the developed VS strategy will provide valuable guidance for the discovery of novel PI3Kδ inhibitors.

Two isomorphous series of 2′-(2,5-dichlorothiophene-3-carbonyl)-1′-(aryl)-1′,2′,5′,6′,7′,7a'-hexahydrospiro[indoline-3,3′-pyrrolizin]-2-one derivatives: X-ray structures, intermolecular interactions, Hirshfeld analysis and molecular docking

Two isomorphous series of 2′-(2,5-dichlorothiophene-3-carbonyl)-1′-(aryl)-1′,2′,5′,6′,7′,7a'-hexahydrospiro[indoline-3,3′-pyrrolizin]-2-one derivatives are reported. The first series contains namely, 1′-(2-bromophenyl)-2′-(2,5-dichlorothiophene-3-carbonyl)-1′,2′,5′,6′,7′,7a'-hexahydrospiro[indoline-3,3′-pyrrolizin]-2-one, C25H19BrCl2N2O2S, (I), 2′-(2,5-dichlorothiophene-3-carbonyl)-1′-(o-tolyl)-1′,2′,5′,6′,7′,7a'-hexahydrospiro[indoline- 3,3′-pyrrolizin]-2-one, C26H22Cl2N2O2S, (II), and (1′R,2′S,7a'S)-2′-(2,5-dichlorothiophene-3-carbonyl)-1′-(m-tolyl)-1′,2′,5′,6′,7′,7a'-hexahydrospiro[indoline-3,3′-pyrrolizin]-2-one, C26H22Cl2N2O2S, (III), are isomorphous in space group P1¯. The second series of 2′-(2,5-dichlorothiophene-3-carbonyl)-1′-(4-methoxyphenyl)-1′,2′,5′,6′,7′,7a'-hexahydrospiro[indoline-3,3′-pyrrolizin]-2-one, C27H26Cl2N2O4S, (IV), 2′-(2,5-dichlorothiophene-3-carbonyl)-1′-(p-tolyl)-1′,2′,5′,6′,7′,7a'-hexahydrospiro[indoline-3,3′-pyrrolizin]-2-one, C27H26Cl2N2O3S, (V) and 1′-(3-bromophenyl)-2′-(2,5-dichlorothiophene-3-carbonyl)-1′,2′,5′,6′,7′,7a'-hexahydrospiro[indoline-3,3′-pyrrolizin]-2-one, C26H23BrCl2N2O3S, (VI) are isomorphous in space group P21/c. In each of compounds (I–III), a combination of N—H∙∙∙O and C—H∙∙∙O hydrogen bonds generates a chain of an alternating centrosymmetric edge-fused rings of R22(8) [(π)N—H∙∙∙O—C(π)] and R42(14) [(π)C/N—H∙∙∙O—C(π)]. These chains are further linked along the b-axis by π∙∙∙π stacks of the thiophene rings. Inter-sheets C—H∙∙∙π contacts propagate along [100] contributing to the supramolecular assembly. In the series (IV–VI), both N—H∙∙∙O and C—H∙∙∙O hydrogen bonds generate sheets in cb plane, composed of centrosymmetric dimers of molecules linked through (π)C—H∙∙∙O—C(π) hydrogen bonding into R22(24) [in (IV)] or R22(14) [in (V and VI)] ring motifs. The dimers are further connected by the solvent MeOH molecules by another ring motif R32 (8) rings through (π)C—H∙∙∙O—C(π), (π)N—H∙∙∙O—(MeOH) and CH3OH∙∙∙O—C(π) hydrogen bonding. Intermolecular interactions were visualized using Hirshfeld surface analysis and the major contacts found to be delineated into H∙∙∙H, H∙∙∙Cl/Cl∙∙∙H, H∙∙∙C/C∙∙∙H and H∙∙∙O/O∙∙∙H in the triclinic series and H∙∙∙H, H∙∙∙Cl/Cl∙∙∙H, H∙∙∙C/C∙∙∙H and H∙∙∙O/O∙∙∙H in the monoclinic derivatives. Docking results reveal that derivatives (II) and (III) bind to the lipophilic pocket of the phosphoinositide 3-kinase delta PI3Kδ, androgen receptor SARMs, epidermal growth factor receptor EGFR kinases, and apoptosis regulator BCL-2 with high affinities. In addition, compound (III) formed a very stable complex with phosphoinositide 3-kinase delta PI3Kδ with the lowest binding free energy of –10.02 kcal/mol, and the results demonstrated that phosphoinositide 3-kinase delta PI3Kδ complex (4xe0-4c) and epidermal growth factor receptor complex (1xkk-4b) promoted higher stability than the androgen receptor complex (5t8e-4c) and the apoptosis regulator BCL-2 (2w3l-4b). The docking study suggests that these derivatives have the potential to be further evaluated in vitro and in vivo for cancer drug discovery.

PCR30 Benefits and Challenges of Different Qualitative Approaches in Rare Disease: A Case Study in Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) Using a Narrative Exercise and Qualitative Interviews

PCR30 Benefits and Challenges of Different Qualitative Approaches in Rare Disease: A Case Study in Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) Using a Narrative Exercise and Qualitative Interviews

Interim analysis: Open-label extension study of leniolisib for patients with APDS

Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS; or p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency) is an inborn error of immunity caused by PI3Kδ hyperactivity. Resultant immune deficiency and dysregulation lead to recurrent sinopulmonary infections, herpes viremia, autoimmunity, and lymphoproliferation. Leniolisib, a selective PI3Kδ inhibitor, demonstrated favorable impact on immune cell subsets and lymphoproliferation over placebo in patients with APDS over 12weeks. Here, we report results from an interim analysis of an ongoing open-label, single-arm extension study. Patients with APDS aged 12 years or older who completed NCT02435173 or had previous exposure to PI3Kδ inhibitors were eligible. The primary end point was safety, assessed via investigator-reported adverse events (AEs) and clinical/laboratory evaluations. Secondary and exploratory end points included health-related quality of life, inflammatory markers, frequency of infections, and lymphoproliferation. Between September 2016 and August 2021, 37 patients (median age, 20 years; 42.3% female) were enrolled. Of these 37 patients, 26, 9, and 2 patients had previously received leniolisib, placebo, or other PI3Kδ inhibitors, respectively. At the data cutoff date (December 13, 2021), median leniolisib exposure was 102 weeks. Overall, 32 patients (87%) experienced an AE. Most AEs were grades 1 to 3; none were grade 4. One patient with severe baseline comorbidities experienced a grade 5 AE, determined as unrelated to leniolisib treatment. While on leniolisib, patients had reduced annualized infection rates (P= .004), and reductions in immunoglobulin replacement therapy occurred in 10 of 27 patients. Other observations include reduced lymphadenopathy and splenomegaly, improved cytopenias, and normalized lymphocyte subsets. Leniolisib was well tolerated and maintained durable outcomes with up to 5 years of exposure in 37 patients with APDS. gov identifier: NCT02859727.

Monogenic forms of common variable immunodeficiency and implications on target therapeutic approaches.

Common variable immunodeficiency (CVID) is the most common symptomatic inborn error of immunity. The disorder is characterized by variable clinical and immunological manifestations, and, in a small minority of patients, a monogenic cause may be identified. In this review, we focalized on three different monogenic forms of CVID-like disease. Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare disorder characterized by hyperactivated class I phosphatidylinositol-3 kinase (PI3K) pathway. Affected patients present with respiratory infectious episodes, impaired viral clearance and lymphoproliferation. Recently, a direct PI3K inhibitor has been approved and it showed encouraging results both in controlling clinical and immunological manifestations of the disease. On the other hand, patients with defects in CTLA-4 or LRBA gene present with life-threatening immune dysregulation, autoimmunity and lymphocytic infiltration of multiple organs. Abatacept, a soluble cytotoxic T lymphocyte antigen 4 (CTLA-4) fusion protein that acts as a costimulation modulator, has been widely implemented for affected patients with good results as bridge treatment. Understanding the biological basis of CVID is important not only for enriching our knowledge of the human immune system, but also for setting the basis for potential targeted treatments in this disorder.

Deconvolution of bulk RNA sequencing in activated phosphoinositide 3-kinase δ syndrome.

Many gaps remain in our understanding of the immune and molecular characteristics that underlie activated phosphoinositide 3-kinase delta syndrome (APDS). We performed RNA sequencing of peripheral blood leukocytes obtained from a child with APDS and his healthy parents and deconvoluted bulk transcriptional data to assess immune cell status. Pathway enrichment analysis suggested signaling pathways enriched in virus infection as well as the PI3K, mitogen-activated protein kinase (MAPK), natural killer cell-mediated cytotoxicity, and nucleotide-binding oligomerization domain (NOD)-like receptor signaling pathways. The proportion of B cells memory, T cells CD4 memory resting and dendritic cells activated were reduced, whereas B cells naïve, T cells CD8, NK cells resting, monocytes and macrophages M2 were increased in the child. Top 10 hub genes were screened and showed moderate to strong relatedness with immune cell proportions. Deconvolution of bulk RNA sequencing to assess immune cells status can provide further insight into the alterations in immunological features underlying APDS and other rare diseases.

Immunodeficiency due to a novel variant in PIK3CD: a case report

BackgroundPrimary immunodeficiencies are immunological disorders caused by gene mutations involved in immune system development and activation. Recently, activated phosphoinositide 3-kinase delta syndrome (APDS) due to mutations in the phosphoinositide 3-kinase (PI3K), phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit delta gene (PIK3CD), and phosphoinositide 3-kinase regulatory subunit 1 (PIK3R1) genes have been reported to induce a combined immunodeficiency syndrome leading to senescent T cells, lymphadenopathy, and immunodeficiency. The exact diagnosis of these deficiencies is essential for treatment and prognosis. In recent years, targeted treatment with selective PI3Kd inhibitors has had a significant effect on controlling the symptoms of these patients.Case presentationIn this case report, we represent a 27-month-old girl with recurrent fever, an increased level of inflammatory markers, and erythema nodosum, who was referred to the rheumatology clinic. In the course of evaluations, because of the lack of clinical improvement with usual treatments, and a history of frequent respiratory infections, combined immunodeficiency was diagnosed in the immunological investigations. Moreover, whole-exome sequencing was performed for her.ConclusionThe genetic analysis found a novel variant of PIK3CD (c.1429 G > A) in the patient. Following daily antibiotic prophylaxis and monthly IV therapy, the patient’s frequent infections and fevers were controlled.

Genomic characterization of lymphomas in patients with inborn errors of immunity

Patients with inborn errors of immunity (IEI) have a higher risk of developing cancer, especially lymphoma. However, the molecular basis for IEI-related lymphoma is complex and remains elusive. Here, we perform an in-depth analysis of lymphoma genomes derived from 23 IEI patients. We identified and validated disease-causing or associated germline mutations in 14 of 23 patients involving ATM, BACH2, BLM, CD70, G6PD, NBN, PIK3CD, PTEN, and TNFRSF13B. Furthermore, we profiled somatic mutations in the lymphoma genome and identified eight genes that were mutated at a significantly higher level in IEI-associated diffuse large B-cell lymphomas (DLBCLs) than in non-IEI DLBCLs, such as BRCA2, NCOR1, KLF2, FAS, CCND3, and BRWD3. The latter, BRWD3, is furthermore preferentially mutated in tumors of a subgroup of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) patients. We also identified five genomic mutational signatures, including two DNA repair deficiency-related signatures, in IEI-associated lymphomas and a strikingly high number of inter- and intrachromosomal structural variants in the tumor genome of a Bloom syndrome patient. In summary, our comprehensive genomic characterization of lymphomas derived from patients with rare genetic disorders expands our understanding of lymphomagenesis and provides new insights for targeted therapy. The research was funded by: Swedish Cancer Society (Cancerfonden), the Swedish Research Council, the Swedish Childhood Cancer fund, NSFC (81670184), the Radiumhemmet research fund, CIMED, the Knut and Alice Wallenberg Foundation Keywords: Aggressive B-cell non-Hodgkin lymphoma, Genomics, Epigenomics, and Other -Omics, Tumor Biology and Heterogeneity No conflicts of interests pertinent to the abstract.

Dual inhibition of phosphoinositide 3-kinases delta and gamma reduces chronic B cell activation and autoantibody production in a mouse model of lupus.

Phosphoinositide 3-kinase delta (PI3Kδ) plays key roles in normal B cell activation and is chronically activated in malignant B cells. Targeting of PI3Kδ using FDA-approved drugs Idelalisib or Umbralisib has shown efficacy in treatment of multiple B cell malignancies. Duvelisib, an inhibitor targeting both PI3Kδ and PI3Kγ (PI3Kδγi) has also been used for treatment of several leukemias and lymphomas and was suggested to offer potential additional benefits in supressing T cell and inflammatory responses. Transcriptomics analyses indicated that while most B cell subsets predominantly express PI3Kδ, plasma cells upregulate PI3Kγ. We thus assessed whether PI3Kδγi treatment can impact chronic B cell activation in the context of an autoantibody-mediated disease. Using the TAPP1R218LxTAPP2R211L (TAPP KI) mouse model of lupus-like disease driven by dysregulated PI3K pathway activity, we performed 4 week PI3Kδγi treatments and found significant reduction in CD86+ B cells, germinal center B cells, follicular helper T cells and plasma cells in multiple tissues. This treatment also significantly attenuated the abnormally elevated serum levels of IgG isotypes observed in this model. The profile of autoantibodies generated was markedly altered by PI3Kδγi treatment, with significant reductions in IgM and IgG targeting nuclear antigens, matrix proteins and other autoantigens. Kidney pathology was also impacted, with reduced IgG deposition and glomerulonephritis. These results indicate that dual inhibition of PI3Kδ and PI3Kγ can target autoreactive B cells and may have therapeutic benefits in autoantibody-mediated disease.

Development of phosphoinositide 3-kinase delta (PI3Kδ) inhibitors as potential anticancer agents through the generation of ligand-based pharmacophores and biological screening

Development of phosphoinositide 3-kinase delta (PI3Kδ) inhibitors as potential anticancer agents through the generation of ligand-based pharmacophores and biological screening

Up-regulation of miR-192-5p inhibits the ELAVL1/PI3Kδ axis and attenuates microvascular endothelial cell proliferation, migration and angiogenesis in diabetic retinopathy.

Diabetic retinopathy (DR) is a common complication of diabetes mellitus that poses a threat to adults. MicroRNAs (miRNAs) play a key role in DR progression. However, the role and mechanism of miR-192-5p in DR remain unclear. We aimed to investigate the effect of miR-192-5p on cell proliferation, migration and angiogenesis in DR. Expression of miR-192-5p, ELAV-like RNA binding protein 1 (ELAVL1) and phosphoinositide 3-kinase delta (PI3Kδ) in human retinal fibrovascular membrane (FVM) samples and human retinal microvascular endothelial cells (HRMECs) was assessed using RT-qPCR. ELAVL1 and PI3Kδ protein levels were evaluated by Western blot. RIP and dual luciferase reporter assays were performed to confirm the miR-192-5p/ELAVL1/PI3Kδ regulatory networks. Cell proliferation, migration and angiogenesis were assessed by CCK8, transwell and tube formation assays. MiR-192-5p was decreased in FVM samples from DR patients and high glucose (HG)-treated HRMECs. Functionally, overexpressed miR-192-5p inhibited cell proliferation, migration and angiogenesis in HG-treated HRMECs. Mechanically, miR-192-5p directly targeted ELAVL1 and decreased its expression. We further verified that ELAVL1 bound to PI3Kδ and maintained PI3Kδ mRNA stability. Rescue analysis demonstrated that the suppressive effects of HG-treated HRMECs caused by miR-192-5p up-regulation were overturned by overexpressed ELAVL1 or PI3Kδ. MiR-192-5p attenuates DR progression by targeting ELAVL1 and reducing PI3Kδ expression, suggesting a biomarker for the treatment of DR.

PIK3R1 mutation associated with primary immunodeficiency: a case of a 14-year-old male and review of the literature: case report

We report a rare case of a 14-year-old boy diagnosed with Activated phosphoinositide 3-kinase delta syndrome Type 2 (APDS2). Based on a typical clinical presentation (Delayed teething, Prominent lymphadenopathy and recurrent characteristic infections started early in life and including multiple episodes of bilateral conjunctivitis, an extensive herpes skin infection in addition to recurrent upper sinopulmonary infections) along with suggestive laboratory immunological findings, and positive confirmatory genetic testing. After diagnosis, the patient was commenced on prophylactic antibiotics which resulted in a reduction in the frequency of his infections and hospitalizations. The targeted therapy of mTOR inhibition with Sirolimus and the possibility of hematopoietic stem cells transplantation are considered and discussed with the family, and he is on regular follow-up with the Allergy/Immunology team. APDS is a rare but increasingly reported inborn error of immunity. Gain-of-function and loss-of-function mutations in phosphoinositide 3-kinase (PIK3CD (encoding P 110 δ ) and PIK3R1 (encoding p 85 α , p 55 α , a n d p 50 α )) lead to APDS1 and APDS2, respectively. Our aim in reporting our case is to allow room for more elaboration of the different genotypes and clinical presentations of both types of APDS, in which early and accurate diagnosis will subsequently help in the initiation of outcome-improving therapy.

A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome

AbstractActivated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity with clinical manifestations including infections, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. Hyperactive PI3Kδ signaling causes APDS and is selectively targeted with leniolisib, an oral, small molecule inhibitor of PI3Kδ. Here, 31 patients with APDS aged ≥12 years were enrolled in a global, phase 3, triple-blinded trial and randomized 2:1 to receive 70 mg leniolisib or placebo twice daily for 12 weeks. Coprimary outcomes were differences from baseline in the index lymph node size and the percentage of naïve B cells in peripheral blood, assessed as proxies for immune dysregulation and deficiency. Both primary outcomes were met: the difference in the adjusted mean change (95% confidence interval [CI]) between leniolisib and placebo for lymph node size was −0.25 (−0.38, −0.12; P = .0006; N = 26) and for percentage of naïve B cells, was 37.30 (24.06, 50.54; P = .0002; N = 13). Leniolisib reduced spleen volume compared with placebo (adjusted mean difference in 3-dimensional volume [cm3], −186; 95% CI, −297 to −76.2; P = .0020) and improved key immune cell subsets. Fewer patients receiving leniolisib reported study treatment-related adverse events (AEs; mostly grades 1-2) than those receiving placebo (23.8% vs 30.0%). Overall, leniolisib was well tolerated and significant improvement over placebo was notable in the coprimary 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. This trial was registered at www.clinicaltrials.gov as #NCT02435173.

Rapid Tumor Debulking of Relapsed/Refractory CLL Patients By PI3Kδ Inhibition and Anti-CD20 Monoclonal Antibody Treatment

Introduction Effective multi-targeted drug combinations could rapidly achieve deep remissions in CLL allowing for defined duration treatment. The combination of a novel highly-specific phosphoinositide 3-kinase delta (PI3Kδ) inhibitor and casein kinase 1 epsilon (CSK1ε) inhibitor, umbralisib (UMB), and a glycoengineered chimeric monoclonal antibody (mAb) targeting a unique epitope on CD20, ublituximab (UBL), with the BCL2 inhibitor venetoclax (VEN) may decrease drug resistance, reduce risk of tumor lysis syndrome (TLS) and achieve higher levels of undetectable minimal residual disease (MRD). This triple agent therapy is being evaluated in relapsed or refractory CLL patients (U2-VEN, ClinicalTrials.gov NCT03379051). Patients received oral 800 mg UMB once-daily. For Cycle 1, UBL was given via IV on Day 1 (150 mg), Day 2 (750 mg), Day 8 (900 mg), Day 15 (900 mg), and then on Day 1 in Cycles 2 and 3 (900 mg); for 3 cycles of 28 days, followed by consolidation with UMB and VEN for cycles 4 to 24. Patient (n = 25) blood samples were collected Pre- and Post-treatment on days of UBL administration during cycles 1-3. Our studies focused on UMB and UBL treatment effects on: 1) The decrease in the circulating CLL tumor burden and thus the subsequent risk of TLS from the addition of VEN to the regimen; and 2) CD20 antigen loss on CLL cells, a major mechanism of anti-CD20 mAb resistance. Methods Blood was analyzed by clinical laboratory automated cell counter and then stained with antibodies against CD3, CD5, CD19, and CD20 for flow cytometry analysis. CLL cell counts were calculated from flow cytometry and clinical laboratory results. To quantitate CD20 surface molecules, peripheral blood mononuclear cells were isolated and stained for flow cytometry analysis with the addition of a Molecules of Equivalent Soluble Fluorochrome standard curve. All human specimen collection and usage was conducted with written informed consent after approval of our Institutional Research Subjects Review Board according to the ethical guidelines of the Declaration of Helsinki. Results Average CLL cell counts (47 x 109/L) decreased rapidly after administration of the first dose of UMB and UBL (C1D1 Post, 26 x 109/L), which rebounded the next day (C1D2 Pre, 43 x 109/L) and then decreased after the second treatment (C1D2 Post, 24 x 109/L). By Day 15, the average CLL cell count had dropped to 9 x 109/L, which decreased further to 5 x 109/L by the start of cycle 3 (Fig. 1). Notably, the variation in CLL cell counts (error bars) decreases over treatment time, suggesting that most CLL patients' tumor burdens are decreasing to a similar low level independent of starting CLL cell count. The change in average CLL cell count between Pre and Post measurements is initially very high (45% decrease C1D1) with decreasing effectiveness over treatment time (8% decrease C3D1). This change could be due to the loss of CLL cell membrane CD20 levels leading to mAb resistance. Pre-treatment (C1D1 Pre) average CLL cell membrane CD20 levels (n=18) were 29,000 CD20 molecules/cell. This decreased to 9,000 molecules/cell after the first treatment (C1D1 Post), stabilized at 9,100 molecules/cell on the next day (C1D2 Pre) and then decreased further after the second treatment (C1D2 Post) to 1600 molecules/cell. After day 8 treatment, CD20 levels remained at 1,000 molecules/cell or less until the end of this study (C3D1). Discussion UMB and UBL rapidly decrease circulating CLL counts over three cycles of treatment, reducing most CLL patient tumor burden to similar low levels. This clinical response could facilitate addition of VEN in the 4thcycle of therapy by decreasing the risk of TLS. The rapid loss of surface CD20 from CLL cells to 1,000 CD20 molecules/cell or less by C1D8 Post has the potential to cause acquired resistance to anti-CD20 mAb therapy. This rapid and sustained loss of CD20 levels is consistent with that reported at standard doses for other anti-CD20 mAbs. However, an effect of concomitant UMB on CD20 levels cannot be ruled out. Previous work suggests that lower anti-CD20 mAb doses can prevent these large decreases in CD20 levels and increase UBL efficacy. In conclusion, our initial data show that treatment with a selective PI3Kδ and CSK1ε inhibitor (UMB) combined with an anti-CD20 mAb (UBL) is effective in decreasing CLL cell counts in all patients assessed in the U2-VEN clinical trial. However, treatment efficacy could be limited by large decreases in the CLL surface CD20 levels. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal