NYMC Faculty Publications

Apixaban versus No Anticoagulation for the Prevention of Venous Thromboembolism in Children With Newly Diagnosed Acute Lymphoblastic Leukaemia or Lymphoma (Prevapix-All): A Phase 3, Open-Label, Randomised, Controlled Trial

Sarah H. O'Brien, Division of Pediatric Hematology and Oncology, Nationwide Children's Hospital, Columbus, OH, USA; The Ohio State University, Columbus, OH, USA. Electronic address: sarah.obrien@nationwidechildrens.org.
Vilmarie Rodriguez, Division of Pediatric Hematology and Oncology, Nationwide Children's Hospital, Columbus, OH, USA; The Ohio State University, Columbus, OH, USA.
Glen Lew, Bristol Myers Squibb, Lawrenceville, NJ, USA.
Jane W. Newburger, Department of Cardiology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Corinna L. Schultz, Nemours Center for Cancer and Blood Disorders, Nemours Children's Health, Wilmington, DE, USA.
Etan Orgel, Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Kimberly Derr, Department of Pediatric Oncology, Geisinger, Danville, PA, USA.
Mark A. Ranalli, Division of Pediatric Hematology and Oncology, Nationwide Children's Hospital, Columbus, OH, USA; The Ohio State University, Columbus, OH, USA.
Adam J. Esbenshade, Monroe Carell Jr Children's Hospital at Vanderbilt, Vanderbilt University Medical Center, Nashville, TN, USA.
Jessica Hochberg, Department of Pediatrics, New York Medical College, Valhalla, NY, USA.Follow
Hyoung Jin Kang, Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Wide River Institute of Immunology, Seoul National University Children's Hospital, Seoul, South Korea.
Yulia Dinikina, Department of Chemotherapy for Oncohematological Diseases and Bone Marrow Transplantation for Children, Almazov National Medical Research Centre, Saint Petersburg, Russian.
Donna Mills, Bristol Myers Squibb, Lawrenceville, NJ, USA.
Mark Donovan, Bristol Myers Squibb, Lawrenceville, NJ, USA.
Joshua L. Dyme, Bristol Myers Squibb, Lawrenceville, NJ, USA.
Nicholas A. Favatella, Bristol Myers Squibb, Lawrenceville, NJ, USA.
Lesley G. Mitchell, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.

Author Type(s)

Faculty

DOI

10.1016/S2352-3026(23)00314-9

Journal Title

The Lancet. Haematology

First Page

e27

Last Page

e37

Document Type

Article

Publication Date

1-1-2024

Department

Pediatrics

Abstract

BACKGROUND: Paediatric patients with acute lymphoblastic leukaemia or lymphoma are at increased risk of venous thromboembolism resulting in increased mortality and morbidity. We hypothesised that apixaban, a direct oral anticoagulant, would safely reduce venous thromboembolism in this patient population. METHODS: PREVAPIX-ALL was a phase 3, open-label, randomised, controlled trial conducted in 74 paediatric hospitals in 9 countries. Participants aged 1 year or older to younger than 18 years with newly diagnosed acute lymphoblastic leukaemia (pre-B cell or T cell) or lymphoblastic lymphoma (B cell or T cell immunophenotype) and a central venous line in place throughout induction were randomly assigned 1:1 to standard of care (SOC, ie, no systemic anticoagulation) or weight-adjusted twice-daily apixaban during induction. Randomisation was performed centrally and stratified by age (those <10 years or those ≥10 years). Participants weighing 35 kg or less were administered 2·5 mg twice daily of apixaban as a 2·5 mg tablet, 0·5 mg tablets, or 0·4 mg/mL oral solution, while those weighing more than 35 kg were administered weight-adjusted prophylactic doses using 0·5 mg tablets or the 0·4 mg/mL oral solution twice daily. Primary outcomes were assessed by a blinded central adjudication committee. The primary efficacy outcome for the intention to treat population was the composite of symptomatic or clinically unsuspected venous thromboembolism, the primary safety outcome was major bleeding, and secondary safety outcomes included clinically relevant non-major (CRNM) bleeding. Patients were screened for venous thromboembolism by ultrasound and echocardiogram at the end of induction. The trial was registered with ClinicalTrials.gov (NCT02369653) and is now complete. FINDINGS: Between Oct 22, 2015, and June 4, 2021, 512 participants were randomly assigned and included in analyses (222 [43%] female and 290 [57%] male; 388 [76%] White, 52 [10%] Asian, 24 [5%] Black or African American, and 48 [9%] other races; and 122 [24%] Hispanic or Latino ethnicity). During a median follow-up period of 27 days (IQR 26-28), 31 (12%) of 256 patients on apixaban had a composite venous thromboembolism compared with 45 (18%) of 256 participants receiving SOC (relative risk [RR] 0·69, 95% CI 0·45-1·05; p=0·080). Two major bleeding events occurred in each group (RR 1·0, 95% CI 0·14-7·01; p=1·0). A higher incidence of CRNM bleeding, primarily grade 1 or 2 epistaxis, occurred in the apixaban group (11 [4%] of 256 participants) compared with the SOC group (3 [1%] of 256; RR 3·67, 95% CI 1·04-12·97, p=0·030). The most frequent grade 3-5 adverse events in both groups were thrombocytopenia (n=28 for the apixaban group and n=20 for the SOC group) or platelet count decreased (n=49 and n=45), anaemia (n=77 and n=74), febrile neutropenia (n=27 and n=20), and neutropenia (n=16 and n=17) or neutrophil count decreased (n=22 and n=25). Five deaths occurred, which were due to infection (n=3 in the SOC group), cardiac arrest (n=1 in apixaban group), and haemorrhagic cerebral sinus vein thrombosis (n=1 in the SOC group). There was one apixaban-related death (coagulopathy and haemorrhage after cardiac arrest of unknown cause). INTERPRETATION: PREVAPIX-ALL is, to our knowledge, the first trial assessing primary thromboprophylaxis using a direct oral anticoagulant in paediatric patients with acute lymphoblastic leukaemia or lymphoma. No statistically significant treatment benefit was identified in participants receiving apixaban. Major and CRNM bleeding were infrequent overall, but a higher incidence of CRNM bleeding (primarily epistaxis in younger children) occurred in participants receiving apixaban. For patients deemed to be at particularly high risk of thrombosis, PREVAPIX-ALL provides encouraging safety data for the use of apixaban in clinical settings in which the potential benefits are thought to outweigh the risk of bleeding. FUNDING: Bristol Myers Squibb-Pfizer Alliance.

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