Anticoagulation Prophylaxis with Weight-Adjusted Enoxaparin Reduces Rates of Venous Thromboembolism in Patients with Acute Lymphoblastic Leukemia Receiving Asparaginase-Based Intensification Therapy
Authors: Sibai Hassan , Chen Ruiqi , Liu Xing , Schimmer Aaron D , Schuh Andre , Law Arjun , McNamara Caroline J , Maze Dawn , Yee Karen W.L. , Minden Mark D. , Chan Steven M , Gupta Vikas , Murphy Tracy , Falcone Umberto , Sakurai Naoko , Brandwein Joseph M. , Seki Jack 
Published: October 2019

Abstract
Background Venous thromboembolism (VTE) is a well-known complication in adults receiving asparaginase (ASNase)-based intensification chemotherapy for acute lymphoblastic leukemia (ALL). The optimal preventative strategy is unclear. We previously reported high thrombosis rates during intensification without VTE prophylaxis. Our objective is to determine the effects of weight-adjusted enoxaparin as primary VTE prophylaxis in ambulatory adults receiving ASNase-based intensification chemotherapy for ALL.
Methods Patients who achieved complete remission following induction from 2011-2017 went on to receive ASNase-based intensification on the Dana Farber Cancer Institute (DFCI) 91-01 protocol. Patients already on therapeutic anticoagulation for prior VTE were excluded. VTE prophylaxis commenced on day 1, cycle 1 of intensification until the completion of the entire 21-30 week. From 2011 to 2014 patients received enoxaparin subcutaneously once daily, at a dose of 40 mg for patients weighing less than 80 kg, and 60 mg for those 80 kg and over for the first 3 years. Due to continuing occurrence of VTE from 2014-2017 patients received an escalated dose aiming at 1mg/kg daily (rounded to the nearest 20 mg). Results were compared to an historical patient cohort that received the same regimen without VTE prophylaxis prior to 2011.
Result: In our historical cohort of adult ALL that did not receive prophylactic anticoagulation (n=99), the rate of VTE was 27%. 124 patients received one of the above prophylactic anticoagulation schedules. The treated and control groups did not differ with respect to median age, gender, weight and number of ASNase treatment cycles per patient. 16 of 124 patients (12.9 %) in the prophylaxis groups developed symptomatic VTE. Sites of VTE in the prophylaxis group included lower extremity (10), sagittal sinus (2), subclavian line related (3), and pulmonary embolism (4). There were no major bleeding complications observed in the prophylaxis group.
In the first patient cohort (n=42), receiving fixed enoxaparin doses of 40 or 60 mg, dosing ranged from 0.39-0.69 mg/kg. The mean enoxaparin dose administered was 0.57 mg/kg. Seven (16.6 %) developed a symptomatic VTE, which was not significantly different from the historical non-prophylaxis cohort. In the second patient cohort (n=82), all patients received weight-adjusted enoxaparin > 0.7 mg/kg of enoxaparin. The mean enoxaparin dose administered was 0.88 mg/kg. Nine of 82 patients (10.9 %)) in this cohort had a symptomatic VTE, which was lower than the historical cohort (OR = 0.33 {95% CI, 0.15-0.77} and P< 0.01).
Conclusions: Weight-adjusted enoxaparin prophylaxis targeting 1 mg/kg/day reduced the incidence of symptomatic VTE in adult ALL patients receiving intensification chemotherapy with ASNase. This treatment is a viable VTE prevention option with no documented major bleeding.

Disclosures
Schimmer: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka Pharmaceuticals: Consultancy; Medivir AB: Research Funding; Jazz Pharmaceuticals: Consultancy. Schuh:Teva: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Amgen Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Shire: Consultancy; Otsuka: Consultancy. Maze:Novartis: Consultancy, Honoraria. Yee:Celgene, Novartis, Otsuka: Membership on an entity's Board of Directors or advisory committees; Agensys, Astex, GSK, Onconova, Genentech/Roche: Research Funding. Gupta:Incyte: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Brandwein:Pfizer: Consultancy; Celgene: Consultancy; Lundbeck: Consultancy; Novartis: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding.