The Frequency and Management of Asparaginase-Related Thrombosis in Pediatric and Adult Patients with Acute Lymphoblastic Leukemia Treated On the Dana-Farber Cancer Institute (DFCI) Consortium Protocols.
Authors: Grace Rachael F. , Dahlberg Suzanne E. , Neuberg Donna , Sallan Stephen E. , Neufeld Ellis J. , DeAngelo Daniel J. , Silverman Lewis B. 
Published: October 2019

Abstract
Abstract 3073
Poster Board III-10
An increased risk of thrombotic complications during asparaginase (ASP) therapy has been described, but few studies report the management and outcome of these individuals.

METHODS
We retrospectively reviewed the medical records of patients (pts) ages 0-50 years (y) with ALL who developed venous thromboembolic events (VTE) while receiving ASP. Pediatric (ped) cases (age 0-17 y) were identified from 501 pts treated between 1991-2008; adult cases (age 18-50 y) were identified from 47 pts treated between 2001-2008. All pts were treated on DFCI ALL Consortium trials (including 20-30 consecutive weeks of ASP) at a single academic center (Boston, MA). VTE was diagnosed by symptoms and confirmed by diagnostic imaging in all pts.

RESULTS
Of 548 pts treated for ALL, 44 (8%) developed VTE, including 27/501 (5.4%) ped pts and 17/47 (36.2%) adults. The sites of VTE included upper extremity (n=18), lower extremity (n=9), and sinus venous thrombosis (n=9). 7 pts experienced a pulmonary embolism. 15 VTE were line-related. 8 VTE occurred during induction and 36 post-induction. Median time to VTE was 3.5 months (mos) (0.5-17.8 mos) with no difference in timing between adult and ped pts. Univariate predictors of VTE are shown in Table 1. There were no differences by sex, race, or ethnic group. In the multivariate model, age was the only significant predictor of VTE with the odds ratio (OR) of VTE increasing with age. Using the 0-5 y age group as a reference (VTE rate 2%), OR were as follows: ages 5-10 y, OR 4.0 (VTE 7%, p=0.02); ages 10-20 y, OR 12.2 (VTE 19%, p<0.01); ages 20-30 y, OR 23.7 (VTE 31%, p<0.01); ages >30 y, OR 37.9 (VTE 42%, p<0.01).

Management
Of the 44 patients with VTE, 76% were treated with low-molecular weight heparin (LMWH) and 21% with warfarin. Antithrombin III (ATIII) levels were checked at least weekly in 17 of 32 pts treated with LMWH and ASP. 11 of 32 pts received ATIII replacement at least once. Most ped pts were anticoagulated until completion of ASP (60% ped pts vs. 29% adults), whereas adults were more often anticoagulated until all chemotherapy was completed (41% adults vs. 8% ped pts, p=0.02). Complications of anticoagulation included bruising (2%) and epistaxis (10%). Two pts (both adults) experienced major bleeding (one intracranial hemorrhage, one compartment syndrome). ASP was held in all pts after diagnosis of VTE. ASP was restarted in 75% of pts, with no difference between ped and adult pts. Ped pts were more likely to be reimaged prior to restarting ASP (56% vs. 6%, p=0.01). In the 33 patients restarted on asp after VTE, 11% experienced a recurrence of VTE (ped pts 17% vs. adults 47%, p=0.07). 31/44 (71%) pts with VTE received at least 85% of intended doses of ASP.

Outcomes
Median follow-up was 52 mos. The 48-month EFS and overall survival (OS) for pts with VTE was 76% +/-7% and 83% +/-6%, respectively. For ped pts with VTE, EFS was 91% +/-6% and OS 92% +/- 7%, and for adults with VTE, EFS was 57% +/- 12% and OS 61% +/- 13%.

CONCLUSIONS
Thrombotic complications are more frequent in adult than pedi pts with ALL. After VTE, ASP can be safely resumed with concurrent anticoagulation. The incidence of recurrent VTE after restarting ASP in ped pts is low, which may be due to differences in age-related predisposing factors or differences in management. Despite VTE, EFS did not appear to be adversely impacted. Large, prospective studies are needed to optimize management of pts with ASP-associated VTE.

Disclosures
Sallan: Enzon Inc.: Contributed to support of an investigator meeting, Research Funding. DeAngelo:EUSA Pharma: Consultancy; Enzon: Consultancy, Speakers Bureau.