UNLABELLED: In order to identify reasons for treatment failures when using targeted therapies, we have analyzed the comprehensive molecular profiles of three relapsed, poor-prognosis Burkitt lymphoma cases. All three cases had resembling clinical presentation and histology and all three patients relapsed, but their outcomes differed significantly. The samples of their tumor tissue were analyzed using whole-exome sequencing, gene expression profiling, phosphoproteomic assays, and single-cell phosphoflow cytometry. These results explain different treatment responses of the three histologically identical but molecularly different tumors. Our findings support a personalized approach for patient with high risk, refractory, and rare diseases and may contribute to personalized and customized treatment efforts for patients with limited treatment options like relapsed/refractory Burkitt lymphoma. SUMMARY: The main aim of this study is to analyze three relapsed Burkitt lymphoma patients using a comprehensive molecular profiling, in order to explain their different outcomes and to propose a biomarker-based targeted treatment. In cases 1 and 3, the tumor tissue and the host were analyzed prospectively and appropriate target for the treatment was successfully implemented; however, in case 2, analyses become available only retrospectively and his empirically based rescue treatment did not hit the right target of his disease.

• Keywords
• Burkitt lymphoma, pediatric oncology, precision medicine, targeted therapy, theranostics,
• Publication type
• Journal Article MeSH

Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase δ (PI3Kδ) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kδ syndrome [APDS]). Knowing the genetic etiology of APDS afforded us the opportunity to explore PI3Kδ inhibition as a precision-medicine therapy. Here, we report in vitro and in vivo effects of inhibiting PI3Kδ in APDS. Treatment with leniolisib (CDZ173), a selective PI3Kδ inhibitor, caused dose-dependent suppression of PI3Kδ pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110δ variants and in T-cell blasts derived from patients. A clinical trial with 6 APDS patients was conducted as a 12-week, open-label, multisite, within-subject, dose-escalation study of oral leniolisib to assess safety, pharmacokinetics, and effects on lymphoproliferation and immune dysregulation. Oral leniolisib led to a dose-dependent reduction in PI3K/AKT pathway activity assessed ex vivo and improved immune dysregulation. We observed normalization of circulating transitional and naive B cells, reduction in PD-1+CD4+ and senescent CD57+CD4- T cells, and decreases in elevated serum immunoglobulin M and inflammatory markers including interferon γ, tumor necrosis factor, CXCL13, and CXCL10 with leniolisib therapy. After 12 weeks of treatment, all patients showed amelioration of lymphoproliferation with lymph node sizes and spleen volumes reduced by 39% (mean; range, 26%-57%) and 40% (mean; range, 13%-65%), respectively. Thus, leniolisib was well tolerated and improved laboratory and clinical parameters in APDS, supporting the specific inhibition of PI3Kδ as a promising new targeted therapy in APDS and other diseases characterized by overactivation of the PI3Kδ pathway. This trial was registered at www.clinicaltrials.gov as #NCT02435173.

• MeSH
• Lymphocyte Activation drug effects   MeSH
• Chemokines blood   MeSH
• Molecular Targeted Therapy * MeSH
• Demography MeSH
• Child MeSH
• Phenotype MeSH
• Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors   immunology   metabolism   MeSH
• Immunoglobulin M blood   MeSH
• Protein Kinase Inhibitors pharmacology   MeSH
• Infant MeSH
• Rats MeSH
• Humans MeSH
• Lymph Nodes drug effects   pathology   MeSH
• Mutation genetics   MeSH
• Child, Preschool MeSH
• Primary Immunodeficiency Diseases MeSH
• Pyridines pharmacokinetics   pharmacology   MeSH
• Pyrimidines pharmacokinetics   pharmacology   MeSH
• Spleen drug effects   pathology   MeSH
• Immunologic Deficiency Syndromes drug therapy   enzymology   immunology   pathology   MeSH
• T-Lymphocytes drug effects   immunology   MeSH
• TOR Serine-Threonine Kinases antagonists & inhibitors   metabolism   MeSH
• Transfection MeSH
• Organ Size MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Rats MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Chemokines MeSH
• Class I Phosphatidylinositol 3-Kinases MeSH
• Immunoglobulin M MeSH
• Protein Kinase Inhibitors MeSH
• leniolisib MeSH Browser
• Pyridines MeSH
• Pyrimidines MeSH
• TOR Serine-Threonine Kinases MeSH

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.

• Keywords
• Activated phosphoinositide 3-kinase δ syndrome, PIK3CD gene, bronchiectasis, hematopoietic stem cell transplantation, immunodeficiency, p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency, phosphoinositide 3-kinase inhibitor, phosphoinositide 3-kinase δ,
• MeSH
• Survival Analysis MeSH
• Antibiotic Prophylaxis MeSH
• Child MeSH
• Adult MeSH
• Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors   genetics   MeSH
• Herpesviridae Infections genetics   mortality   therapy   MeSH
• Respiratory Tract Infections genetics   mortality   therapy   MeSH
• Enzyme Inhibitors therapeutic use   MeSH
• Immunoglobulins, Intravenous therapeutic use   MeSH
• Cohort Studies MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Lymphoproliferative Disorders genetics   mortality   therapy   MeSH
• International Cooperation MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation genetics   MeSH
• Mice MeSH
• Child, Preschool MeSH
• Surveys and Questionnaires MeSH
• Recurrence MeSH
• Immunologic Deficiency Syndromes genetics   mortality   therapy   MeSH
• Hematopoietic Stem Cell Transplantation MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Mice MeSH
• Child, Preschool MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Class I Phosphatidylinositol 3-Kinases MeSH
• Enzyme Inhibitors MeSH
• Immunoglobulins, Intravenous MeSH
• PIK3CD protein, human MeSH Browser