The frequency and management of asparaginase‐related thrombosis in paediatric and adult patients with acute lymphoblastic leukaemia treated on Dana‐Farber Cancer Institute consortium protocols

Abstract

SUMMARY The optimal management of asparaginase-associated thrombotic complications is not well-defined. We report the features, management, and outcome of paediatric (ages 0–18 years) and adult (18–50 years) patients with acute lymphoblastic leukaemia (ALL) with asparaginase-related venous thromboembolic events (VTE) treated at Dana-Farber Cancer Institute on clinical trials for newly diagnosed ALL between 1991–2008. Of 548 patients, 43 (8%) had VTE, including 27/501 (5%) paediatric and 16/47 (34%) adult patients. Sinus venous thrombosis occurred in 1.6% of patients. Age was the only significant predictor of VTE, with those aged >30 years at very high risk (VTE rate 42%). 74% of patients received low molecular weight heparin after VTE. Complications of anticoagulation included epistaxis (9%), bruising (2%), and, in two adult patients, major bleeding. 30 patients (70%) ultimately received at least 85% of the intended doses of asparaginase. 33% of patients experienced recurrent VTE (paediatric 17% vs. adults 47%, p=0.07). The 48-month event-free survival for patients with VTE was 85 ± 6% compared with 88 ± 2% for those without VTE (p=0.36). This study confirms that, after VTE, asparaginase can be restarted with closely monitored anticoagulation after imaging demonstrates clot stabilization or improvement. With this management strategy, a history of VTE does not appear to adversely impact prognosis.

Venous Thromboembolism Prevention During Asparaginase-Based Therapy for Acute Lymphoblastic Leukemia

“…In all, increased age has been identified as a risk factor for vte, the incidence being 34% in adults compared with 5% in pediatric patients treated with asparaginase-containing regimens 13 . In another singlecentre retrospective study, a 23% incidence of vte was reported during the intensification phase of the pediatricbased dfci 91-01 protocol in adults 8 .…”

The coagulopathy and thrombotic risk associated with L-Asparaginase treatment in adults with acute lymphoblastic leukaemia

“…A prospective study of 548 patients treated on Dana-Farber Cancer Institute (DFCI) ALL consortium protocols including L-Asp diagnosed a total of 48 symptomatic clots in 43 patients. 11 Overall, 5% (27) of 501 paediatric patients and 34% (16) of 47 adult patients experienced thrombotic events during treatment phases that included L-Asp. However, in this cohort the majority of events occurred post-induction with a median time of 3.5 months (0.5-10.1) from initiation of therapy to thrombosis.…”

“…10 Thrombosis is uncommon in children but the reported incidence in those receiving therapy for ALL ranges from 1.7 to 36.7%, depending on study design, treatment protocol and whether asymptomatic events are included. 10,11 The PARKAA (Prophylactic Antithrombin Replacement in Kids with ALL treated with Asparaginase) study reported a prevalence rate of thrombosis of 36.7% in 60 children during induction; however, the vast majority were asymptomatic, being diagnosed during extensive screening. 12 The prevalence of symptomatic thrombosis was 5%.…”

“…18 The more recently published data from both adult and paediatric patients treated according to DFCI consortium protocols identified 47 venous events, with 36% (17) being upper extremity/CVL related, 19% (9) lower extremity, 19% (9) CNS and 15% (7) pulmonary embolism. 11 The remainder were described as intra-cardiac (2%) and 'other' (8.5%). The sites of event were similar across adult and paediatric patients, but with a tendency for adults to experience more pulmonary embolism and children more CNS events.…”

Venous Thromboembolism in Cancer Patients

“…The incidence of ASNase -associated VTE complications is age-dependent, 3-5% in children (67,31) whereas the incidence reported from Dana-Farber Cancer Institute (1991-2008) in adult patients (≥ 30 years) was 34% and 42% (68). Less intensive ASNase regimen in adult patients have reported lower rates of thrombotic complications (69).…”