Outcome of Thrombosis in UKALL 2003- Anticoagulation and Re- Exposure to Aspariginase Is Feasible and Safe.
Authors: Qureshi Amrana , Richards Sue , Vora Ajay J. , Mitchell Christopher D , Wade Rachel , Goulden Nicholas 
Published: October 2019

We report the incidence and outcome of thrombosis in UKALL 2003. In this study NCI low risk patients receive 3 drug induction (Vincristine, Dexamethasone and Asparaginase), NCI high risk (upper age limit 20) receive additional Doxorubicin. Morphologic slow early responders (SER) are assigned “augmented BFM” therapy. In non SER, post induction treatment is randomly allocated by day 28 MRD; all patients receive at least one standard CCG modified BFM delayed intensification (DI) and monthly pulsed Vincristine and Dexamethasone during two (girls) or three (boys) years of maintenance. Pegylated E. Coli Asparaginase (Peg-ASP) (Oncospar, Medac UK) 1000 units/m2 is used throughout the protocol. Standard and Intermediate risk patients receive two doses Peg-ASP in induction at days 4 and 18 and a single dose on day 4 of each of two delayed intensifications. High risk patients receive an additional 8 doses during consolidation, interim maintenance and 2 delayed intensification courses. Thrombotic events were reported in 60 or 3.3% (37 male, median age 7 years) of the 1824 patients enrolled in ALL 2003 between October 2003 and June 2008. Of these, 52 or 87% occurred during a period of Asparagine depletion (38 induction, 12 in Delayed Intensification and 2 in Capizzi). Thrombosis was rare during maintenance although many patients retain central venous access throughout their therapy. A higher incidence of thrombus was seen during 4 rather than 3 drug induction 21/744 (2.8%) v 17/1082 (1.6%). This likely reflects increased age and greater use of central venous lines (CVL) in induction in this regime. The site of thrombus was reported in 51 patients: 25 were CVL related, 4 limb DVT independent of CVL, 18, involved cerebral venous sinuses (CerVS), 2 cerebral arteries (CerA), 1 portal vein,1 renal vein Outcome data is available for 38 patients with a minimum of 6 months follow up. No patient died due to thrombosis. 2 children were treated with aspirin after a cerebral arterial thrombus; both have on going mild hemiplegia. 2 children with active bleeding at the time of CVL associated venous clot were not anticoagulated. The remaining 34 who suffered venous thrombosis were anticoagulated (34 LMWH, 1 UFH & Warfarin, I Danaparoid) for a median of 3 months (range 1–17). None experienced significant bleeding or protocol delay. All patients (including 10 with CerVS) who suffered venous thrombus recovered fully. To date, 25 children (including 5 CervS thrombosis) received further therapy with Peg-ASP following a thrombotic episode. 13 received prophylactic heparin during Asparagine depleteion. No recurrence of thrombus was seen.

Modern paediatric ALL protocols rely heavily on profound Asparagine depletion, high dose steroids and the presence of central venous catheters. Consequently strategies for effective management of thrombosis are integral to such regimes. In ALL 2003 thrombosis occurred in 3% of patients over 95% of whom tolerated anticoagulation without bleeding or delay in therapy. All those suffering venous thrombosis made a full recovery. Importantly, re exposure to Asparaginase was feasible and safe even after CerVS thrombus.