Apixaban Is Effective and Safe in Reducing Venous Thromboembolism (VTE) in Obese Patients with Newly Diagnosed Pediatric Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma (ALL/LL) a Sub-Study Analysis of the Prevapix-ALL/Children's Oncology Group ACCL1333 Trial

Background: Pediatric patients with ALL/LL are at increased risk for VTE and obesity further increases VTE risk. Pediatric ALL/LL patients experiencing VTE have increased risk for mortality as compared to ALL/LL patients without VTE. Therefore, effective and safe pharmacologic VTE prevention options are urgently needed. The PREVAPIX-ALL trial was a multi-center, multinational, randomized, open-label, controlled trial assessing the safety and efficacy of primary prophylaxis using apixaban for the prevention of VTE in pediatric patients with ALL/LL. PREVAPIX-ALL was a collaboration between the Bristol Myers Squibb/Pfizer Alliance and the Children's Oncology Group. Patients with ALL/LL undergoing induction chemotherapy containing asparaginase therapy were randomized to either apixaban or standard of care (SOC - no anticoagulation). The objective of the current study was to separately analyze obese patients as a subgroup of the PREVAPIX-ALL trial. Aims: To assess the efficacy and safety of prophylactic apixaban vs. SOC for VTE prevention during induction chemotherapy in obese pediatric patients with ALL/LL. Methods: Obesity was defined as ≥ 95 th percentile for age and sex specific body mass index as per the Centers for Disease Control and Prevention childhood obesity definition. Patients newly diagnosed with ALL/LL, ages ≥ 1 to < 18 years, with a central venous line, and on induction chemotherapy with asparaginase were randomized to apixaban vs. SOC. Apixaban thromboprophylaxis was administered at a fixed dose per body weight until the end of induction when participants were screened for VTE. The primary efficacy outcome was a composite of symptomatic and asymptomatic VTE. The primary safety outcome was major bleeding, and the secondary safety outcome was a composite of major and clinically relevant non-major (CRNM) bleeding. Results: Out of 512 PREVAPIX-ALL participants, 498 (97.2%) were age 24 months or older with weight and height available. Of those, 82 were obese. Forty-two were randomized to apixaban and 40 were randomized to SOC (Table 1). For the primary efficacy outcome there was a statistically significant decrease in VTE events in the apixaban arm, 1/42 (2.4%) compared to the SOC arm 10/40 (25%) [RRR 91% (95% CI 3%, 99%) p 0.0067] (Table 2). No statistically significant difference was observed in bleeding between the two groups (Table 2). The mean apixaban exposure was similar among the obese and non-obese groups: obese apixaban mean exposure (SD) 23.4 days (5.55) and non-obese 23.5 days (6.44). No statistical difference was observed in the median steady-state area under the curve (AUC-TAU ng.h/mL) drug exposure between obese and non-obese categories stratified by age group on a linear scale: obese (n=38) 686.94 ng.h/mL (95% CI 397.8-1314.6) and non-obese (n=186) 663.50 ng.h/mL (95% CI 319.1-1090.9). Conclusion: Apixaban VTE prophylaxis in obese ALL/LL patients receiving asparaginase during induction chemotherapy resulted in a statistically significant 91% RRR in VTE compared to SOC. No statistical difference was observed in apixaban exposure days and AUC/TAU between obese and non-obese patients. Bleeding events were not increased in the apixaban arm as compared to SOC. Primary prophylaxis using apixaban safely reduces VTE in obese ALL/LL pediatric patients receiving induction chemotherapy containing asparaginase. References: https://www.cdc.gov/obesity/index.html. Mitchell, L.G., et al., Definition of clinical efficacy and safety outcomes for clinical trials in deep venous thrombosis and pulmonary embolism in children. J Thromb Haemost, 2011. 9(9): p. 1856-8. O'Brien S, Rodriguez V, Lew G, Newburger J, Schultz C, Orgel E, Derr K, Ranalli M, Esbenshade A, Hochberg J, Kang H, Dinikina Y, Crevar C, Donovan M, Dyme J, Favatella N, Mitchell L. PREVAPIX-ALL: Phase 3 Study of the Safety and Efficacy of Apixaban for Thromboprophylaxis versus Standard of Care in Newly Diagnosed Pediatric Acute Lymphoblastic Leukemia or Lymphoma (ALL/LL) [abstract]. https://abstracts.isth.org/abstract/prevapix-all-phase-3-study-of-the-safety-and-efficacy-of-apixaban-for-thromboprophylaxis-versus-standard-of-care-in-newly-diagnosed-pediatric-acute-lymphoblastic-leukemia-or-lymphoma-all-ll/. Accessed July 17, 2023.

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