Prophylaxis with apixaban (Eliquis) failed to reduce the rate of venous thromboembolism (VTE) in children with newly diagnosed acute lymphoblastic leukemia or lymphoma, according to results from the phase III randomized PREVAPIX-ALL study.
During a median follow-up of 27 days, 12% of patients receiving the direct oral anticoagulant had a composite VTE compared with 18% of those receiving no systemic anticoagulant (relative risk [RR] 0.69, 95% CI 0.45-1.05, P=0.080), reported Sarah H. O’Brien, MD, of Nationwide Children’s Hospital and the Ohio State University in Columbus, and colleagues.
Notably, two major bleeding events occurred in each group, and clinically relevant non-major bleeding, primarily grade 1 or 2 epistaxis, occurred more frequently in the apixaban group versus the standard-care group (4% vs 1%; RR 3.67, 95% CI 1.04-12.97, P=0.030), they wrote in Lancet Haematology.
The results of this study “do not support uniform use of pharmacological thromboprophylaxis in pediatric patients with acute lymphoblastic leukemia or lymphoma, and the safety of apixaban during induction chemotherapy requires continued study in patient subsets such as children younger than 2 years, those with central nervous system disease, and those with hyperleukocytosis,” O’Brien and colleagues noted.
“However, 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,” they added.
It is well known that children diagnosed with acute lymphoblastic leukemia or lymphoma are at increased risk of VTE while undergoing induction chemotherapy. However, the authors observed that while VTE is preventable, using anticoagulants in children is problematic because the disease — as well as induction chemotherapy — can increase the risk of bleeding, and low-molecular-weight heparin (the preferred anticoagulant for children) requires daily injections.
Apixaban represents a potential solution to these issues since it is given orally, has anticoagulant activity independent of antithrombin, and does not require monitoring, “which are clear advantages in a pediatric population,” O’Brien and colleagues noted. “In addition, direct oral anticoagulants have few drug-drug interactions, which make the anticoagulant especially favorable in children with acute lymphoblastic leukemia or lymphoma, a patient population on complicated chemotherapy regimens during induction.”
In a commentary accompanying the study, Uma H. Athale, MD, of McMaster Children’s Hospital in Hamilton, Ontario, noted that older age is an independent risk factor for ALL-associated VTE, with the lowest incidence in children younger than 5 years and the highest incidence in those ages 15 to 18. In PREVAPIX-ALL, children younger than 10 had a higher bleeding rate with apixaban versus standard of care, while those ages 10 and up had similar bleeding rates in both groups.
“These observations beg the question: why subject younger children to the potential harm of bleeding? Why not give the intervention to only patients aged 10 years or older, or patients categorized as having high-risk acute lymphoblastic leukemia (who receive more intensified therapy)? Such an approach would certainly reduce the number needed to treat (NNT) or to harm (NNH),” she wrote.
According to the study, the NNT is 33 to prevent one thromboembolism event in children younger than 10, and 10 for children 10 and older, while for major and clinically relevant non-major bleeding, the NNH to prevent one bleed is 33 for children younger than 10 and 100 for those 10 and older.
“These numbers make a strong case for future pediatric trials of acute lymphoblastic leukemia thromboprophylaxis to target only patients aged 10 years and older,” Athale noted.
PREVAPIX-ALL was an open-label trial conducted across 74 pediatric hospitals in 10 countries and included 512 patients ages 1 to 17 with newly diagnosed acute lymphoblastic leukemia (pre-B cell or T cell) or lymphoblastic lymphoma (B cell or T cell immunophenotype), with a new central venous line inserted between days -7 and 4 of induction that was planned to remain in place until at least day 29 of therapy.
These patients were randomly assigned 1:1 to weight-adjusted twice-daily apixaban during induction (median age 6, 55% boys, and 76% white) or standard of care (median age 6, 58% boys, and 76% white).
The most frequent grade 3-5 adverse events in the apixaban and standard-care groups were thrombocytopenia (28 and 20 patients, respectively) or platelet count decreased (49 and 45), anemia (77 and 74), febrile neutropenia (27 and 20), and neutropenia (16 and 17) or neutrophil count decreased (22 and 25).
O’Brien and colleagues also reported that 77% of patients in the apixaban group — compared with 96% in the standard-of-care group — completed the treatment period, with adverse events as the most common reason for discontinuation.
The study was funded by the Bristol Myers Squibb-Pfizer Alliance.
O’Brien reported that her institution received salary support from the Children’s Oncology Group.
Several co-authors are employees of Bristol Myers Squibb.
Athale has received consulting fees for participation on an advisory board from Jazz Pharmaceuticals and Servier Pharmaceuticals.
Source Reference: O’Brien SH, et al “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” Lancet Haematol 2023; DOI: 10.1016/S2352-3026(23)00314-9.
Source Reference: Athale UH “Thromboprophylaxis in paediatric acute lymphoblastic leukaemia” Lancet Haematol 2023; DOI: 10.1016/S2352-3026(23)00339-3.