PMID- 35226723 OWN - NLM STAT- MEDLINE DCOM- 20220502 LR - 20220607 IS - 1528-0020 (Electronic) IS - 0006-4971 (Linking) VI - 139 IP - 17 DP - 2022 Apr 28 TI - A randomized, placebo-controlled, double-blind trial of canakinumab in children and young adults with sickle cell anemia. PG - 2642-2652 LID - 10.1182/blood.2021013674 [doi] AB - Excessive intravascular release of lysed cellular contents from damaged red blood cells (RBCs) in patients with sickle cell anemia (SCA) can activate the inflammasome, a multiprotein oligomer promoting maturation and secretion of proinflammatory cytokines, including interleukin-1beta (IL-1beta). We hypothesized that IL-1beta blockade by canakinumab in patients with SCA would reduce markers of inflammation and clinical disease activity. In this randomized, double-blind, multicenter phase 2a study, patients aged 8 to 20 years with SCA (HbSS or HbSbeta0-thalassemia), history of acute pain episodes, and elevated high-sensitivity C-reactive protein >1.0 mg/L at screening were randomized 1:1 to received 6 monthly treatments with 300 mg subcutaneous canakinumab or placebo. Measured outcomes at baseline and weeks 4, 8, 12, 16, 20, and 24 included electronic patient-reported outcomes, hospitalization rate, and adverse events (AEs) and serious AEs (SAEs). All but 1 of the 49 enrolled patients were receiving stable background hydroxyurea therapy. Although the primary objective (prespecified reduction of pain) was not met, compared with patients in the placebo arm, patients treated with canakinumab had reductions in markers of inflammation, occurrence of SCA-related AEs and SAEs, and number and duration of hospitalizations as well as trends for improvement in pain intensity, fatigue, and absences from school or work. Post hoc analysis revealed treatment effects on weight, restricted to pediatric patients. Canakinumab was well tolerated with no treatment-related SAEs and no new safety signal. These findings demonstrate that the inflammation associated with SCA can be reduced by selective IL-1beta blockade by canakinumab with potential for therapeutic benefits. This trial was registered at www.clinicaltrials.gov as #NCT02961218. CI - (c) 2022 by The American Society of Hematology. FAU - Rees, David C AU - Rees DC AD - King's College London and King's College Hospital NHS Foundation Trust, London, United Kingdom. FAU - Kilinc, Yurdanur AU - Kilinc Y AD - Cukurova University Medical Faculty, Adana, Turkey. FAU - Unal, Selma AU - Unal S AD - Department of Pediatric Hematology, Mersin University Medical Faculty, Mercin, Turkey. FAU - Dampier, Carlton AU - Dampier C AUID- ORCID: 0000-0002-7738-2620 AD - Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA. FAU - Pace, Betty S AU - Pace BS AD - Department of Pediatrics, Augusta University, Augusta, GA. FAU - Kaya, Banu AU - Kaya B AD - Barts Health NHS Trust, Royal London Hospital, London, United Kingdom. FAU - Trompeter, Sara AU - Trompeter S AUID- ORCID: 0000-0002-7099-8449 AD - Cancer CT Unit, University College London Hospitals NHS Foundation Trust, and NHS Blood and Transplant, London, United Kingdom. FAU - Odame, Isaac AU - Odame I AD - Hemoglobinopathy Program, The Hospital for Sick Children (SickKids), Toronto, ON, Canada. FAU - Mahlangu, Johnny AU - Mahlangu J AUID- ORCID: 0000-0001-5781-7669 AD - Haemophilia Comprehensive Care Centre, Faculty of Health Sciences, University of the Witwatersrand and NHLS, Johannesburg, Gauteng, South Africa. FAU - Unal, Sule AU - Unal S AD - Department of Pediatric Hematology, Hacettepe University, Ankara, Turkey. FAU - Brent, Julie AU - Brent J AD - New Cross Hospital/The Royal Wolverhampton NHS Trust, Wolverhampton, United Kingdom. FAU - Grosse, Regine AU - Grosse R AD - Clinic of Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, Hamburg, Germany. FAU - Fuh, Beng R AU - Fuh BR AD - Brody School of Medicine At East Carolina University, Greenville, NC. FAU - Inusa, Baba P D AU - Inusa BPD AUID- ORCID: 0000-0003-2643-765X AD - Evelina London Children's Hospital, London, United Kingdom. FAU - Koren, Ariel AU - Koren A AD - Pediatric Hematology, Ha'Emek Medical Center, Afula, Israel. FAU - Leblebisatan, Goksel AU - Leblebisatan G AD - Cukurova University Medical Faculty, Adana, Turkey. FAU - Levin, Carina AU - Levin C AUID- ORCID: 0000-0002-7774-3529 AD - Pediatric Hematology Unit, Emek Medical Center, Afula, Israel. FAU - McNamara, Elizabeth AU - McNamara E AD - Novartis Pharma AG, Cambridge, MA; and. FAU - Meiser, Karin AU - Meiser K AD - Novartis Pharma AG, Basel, Switzerland. FAU - Hom, Douglas AU - Hom D AUID- ORCID: 0000-0003-4477-9135 AD - Novartis Pharma AG, Cambridge, MA; and. FAU - Oliver, Stephen J AU - Oliver SJ AD - Novartis Pharma AG, Basel, Switzerland. LA - eng SI - ClinicalTrials.gov/NCT02961218 PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Biomarkers) RN - 37CQ2C7X93 (canakinumab) SB - IM CIN - Blood. 2022 Apr 28;139(17):2578-2580. PMID: 35482344 MH - *Anemia, Sickle Cell/complications/drug therapy MH - *Antibodies, Monoclonal/adverse effects MH - Antibodies, Monoclonal, Humanized/adverse effects MH - Biomarkers MH - Child MH - Double-Blind Method MH - Humans MH - Inflammation/drug therapy MH - Young Adult EDAT- 2022/03/01 06:00 MHDA- 2022/05/03 06:00 CRDT- 2022/02/28 17:11 PHST- 2021/09/12 00:00 [received] PHST- 2022/02/07 00:00 [accepted] PHST- 2022/03/01 06:00 [pubmed] PHST- 2022/05/03 06:00 [medline] PHST- 2022/02/28 17:11 [entrez] AID - S0006-4971(22)00282-8 [pii] AID - 10.1182/blood.2021013674 [doi] PST - ppublish SO - Blood. 2022 Apr 28;139(17):2642-2652. doi: 10.1182/blood.2021013674.