A Retrospective Study of First and Recurrent Venous Thromboembolism in Patients with Acute Lymphoblastic Leukemia Treated on Total XV and Total Xvi Protocols
Authors: Jesudas Rohith , Kirkham Justin , Bryndziar Tomas , Inaba Hiroto , Jacobs Timothy , Jeha Sima , Okhomina Victoria , Kang Guolian , Cheng Cheng , Takemoto Clifford M. , Pui Ching-Hon , Karol Seth E. 
Published: December 2024

Introduction
Venous thromboembolism (VTE) is a common complication in patients with acute lymphoblastic leukemia (ALL), with an incidence rate of about 5%. The procoagulant state in ALL results from the underlying disease, central venous access devices (CVAD), and treatments (e.g., asparaginase, glucocorticoids). Despite the known risk of VTE, clinical factors predicting the utility, optimal timing, and duration of primary and secondary anticoagulation prophylaxis remain unclear. This study aims to identify clinical risk factors associated with the development of recurrent VTE events and to describe their timing and anatomical location.
Methods
We identified patients treated under the Total XV (NCT00137111) and Total XVI (NCT00549848) protocols who developed at least one VTE adverse event of severity grade 2 or greater. Using data from the Total XV and Total XVI studies, supplemented by medical record review when needed, we collected these patients' demographic and clinical data, dates of all VTE events, and start and end dates of asparaginase treatment. Wilcoxon rank-sum test was used to compare those with a single VTE and recurrent VTE. Fisher's exact test or Chi-square test was used to compare categorical variables between the two groups. Exact log-rank test was used to compare time to recurrent VTE between the two groups. Statistical analyses were conducted using SAS 9.4 and R 4.3.2.
Results
A total of 86 patients with a median age at ALL diagnosis of 12 years (range: 1 month - 18 years) were identified for this study; 75 (87%) patients had a single VTE and 11 (13%) recurrent VTEs (9 recurred once and 2 recurred twice). The clot resolved incompletely in 29 patients (43%) and completely in 28 (42%) at a median follow-up of 90 days (range: 4 - 283 days). Two patients died due to their VTE events (both with pulmonary emboli). Patients with a single VTE did not differ from those with recurrent VTEs in their age, gender, race, BMI, blood type (O vs. non-O), ALL lineage (B vs. T), or risk group (low vs. standard/high). There was no difference between the groups in whether the 1st VTE occlusion was partial, complete, or associated with a venous line, nor in the severity grade of the 1st VTE or the clot status at follow-up: clot progressed, stable, completely resolved, incompletely resolved, or fatal event. Overall, veins of the upper extremities were the most involved site (n=23; 27%), followed by cerebral veins (n=18; 21%), and multiple anatomical sites (n=15; 17%). Thirty-one (36%) of the initial VTEs, 2 (22%) of the 2nd VTEs, and both 3rd VTEs were CVAD related. The median time from the last asparaginase administration to the 1st VTE event was 11 days (interquartile range: 6 - 22 days), and the median time between the 1st and 2nd VTE events was 129 days (interquartile range: 45 - 325 days). Median time to recurrent VTE did not differ significantly between the low and the standard/high-risk patients (40 days vs. 274 days, exact log-rank test p=0.13).
Conclusions
In this study, no patient demographic, clinical characteristics, or the characteristics of the clot were associated with VTE recurrence. The times between asparaginase administration and 1st VTE development and between the 1st and 2nd VTE events ranged widely. A small number of VTE events is a limitation of this study. Ascertaining the utility of anticoagulant prophylaxis, its optimal timing and duration will require a larger data set from multiple institutions or a study group.