• Je něco špatně v tomto záznamu ?

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

VK. Rao, E. Kulm, A. Šedivá, A. Plebani, C. Schuetz, A. Shcherbina, VA. Dalm, A. Trizzino, Y. Zharankova, S. Webster, A. Orpia, J. Körholz, V. Lougaris, Y. Rodina, K. Radford, J. Bradt, A. Relan, SM. Holland, MJ. Lenardo, G. Uzel

. 2024 ; 153 (1) : 265-274.e9. [pub] 20231004

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, Research Support, N.I.H., Intramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc24007824

Grantová podpora
Z01 AI000732 Intramural NIH HHS - United States

BACKGROUND: 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. OBJECTIVE: Leniolisib, a selective PI3Kδ inhibitor, demonstrated favorable impact on immune cell subsets and lymphoproliferation over placebo in patients with APDS over 12 weeks. Here, we report results from an interim analysis of an ongoing open-label, single-arm extension study. METHODS: 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. RESULTS: 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. CONCLUSIONS: Leniolisib was well tolerated and maintained durable outcomes with up to 5 years of exposure in 37 patients with APDS. CLINICALTRIALS: gov identifier: NCT02859727.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc24007824
003      
CZ-PrNML
005      
20240423160311.0
007      
ta
008      
240412s2024 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1016/j.jaci.2023.09.032 $2 doi
035    __
$a (PubMed)37797893
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Rao, V Koneti $u National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: korao@niaid.nih.gov
245    10
$a Interim analysis: Open-label extension study of leniolisib for patients with APDS / $c VK. Rao, E. Kulm, A. Šedivá, A. Plebani, C. Schuetz, A. Shcherbina, VA. Dalm, A. Trizzino, Y. Zharankova, S. Webster, A. Orpia, J. Körholz, V. Lougaris, Y. Rodina, K. Radford, J. Bradt, A. Relan, SM. Holland, MJ. Lenardo, G. Uzel
520    9_
$a BACKGROUND: 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. OBJECTIVE: Leniolisib, a selective PI3Kδ inhibitor, demonstrated favorable impact on immune cell subsets and lymphoproliferation over placebo in patients with APDS over 12 weeks. Here, we report results from an interim analysis of an ongoing open-label, single-arm extension study. METHODS: 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. RESULTS: 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. CONCLUSIONS: Leniolisib was well tolerated and maintained durable outcomes with up to 5 years of exposure in 37 patients with APDS. CLINICALTRIALS: gov identifier: NCT02859727.
650    _2
$a lidé $7 D006801
650    _2
$a ženské pohlaví $7 D005260
650    _2
$a mladý dospělý $7 D055815
650    _2
$a dospělí $7 D000328
650    _2
$a mužské pohlaví $7 D008297
650    _2
$a fosfatidylinositol-3-kinasy třídy I $x genetika $7 D058534
650    _2
$a fosfatidylinositol-3-kinasy $x genetika $7 D019869
650    _2
$a kvalita života $7 D011788
650    _2
$a mutace $7 D009154
650    12
$a syndromy imunologické nedostatečnosti $x genetika $7 D007153
650    12
$a lymfadenopatie $x komplikace $7 D000072281
655    _2
$a časopisecké články $7 D016428
655    _2
$a Research Support, N.I.H., Intramural $7 D052060
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Kulm, Elaine $u Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Bethesda, Md
700    1_
$a Šedivá, Anna $u Department of Immunology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
700    1_
$a Plebani, Alessandro $u Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy
700    1_
$a Schuetz, Catharina $u Department of Pediatric Immunology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
700    1_
$a Shcherbina, Anna $u Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
700    1_
$a Dalm, Virgil A $u Division of Allergy & Clinical Immunology, Department of Internal Medicine, Rotterdam, The Netherlands; Department of Immunology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
700    1_
$a Trizzino, Antonino $u Department of Pediatric Hematology and Oncology, ARNAS Civico Di Cristina Benfratelli Hospital, Palermo, Italy
700    1_
$a Zharankova, Yulia $u Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus
700    1_
$a Webster, Sharon $u National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
700    1_
$a Orpia, Alanvin $u National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
700    1_
$a Körholz, Julia $u Department of Pediatric Immunology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
700    1_
$a Lougaris, Vassilios $u Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy
700    1_
$a Rodina, Yulia $u Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
700    1_
$a Radford, Kath $u Novartis Pharmaceuticals UK Ltd, London, United Kingdom
700    1_
$a Bradt, Jason $u Pharming Healthcare, Inc, Warren, NJ
700    1_
$a Relan, Anurag $u Pharming Healthcare, Inc, Warren, NJ
700    1_
$a Holland, Steven M $u National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
700    1_
$a Lenardo, Michael J $u National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
700    1_
$a Uzel, Gulbu $u National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
773    0_
$w MED00002505 $t Journal of allergy and clinical immunology $x 1097-6825 $g Roč. 153, č. 1 (2024), s. 265-274.e9
856    41
$u https://pubmed.ncbi.nlm.nih.gov/37797893 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y - $z 0
990    __
$a 20240412 $b ABA008
991    __
$a 20240423160308 $b ABA008
999    __
$a ok $b bmc $g 2081678 $s 1217591
BAS    __
$a 3
BAS    __
$a PreBMC-MEDLINE
BMC    __
$a 2024 $b 153 $c 1 $d 265-274.e9 $e 20231004 $i 1097-6825 $m Journal of allergy and clinical immunology $n J Allergy Clin Immunol $x MED00002505
GRA    __
$a Z01 AI000732 $p Intramural NIH HHS $2 United States
LZP    __
$a Pubmed-20240412

Najít záznam

Citační ukazatele

Možnosti archivace