Thrombotic Complications in Acute Lymphoblastic Leukemia. A Meta-Analysis of Prospective Studies Comprising 1,920 Patients.
Authors: Caruso Vanesa , Di Castelnuovo Augusto , Storti Sergio , Mariani Guglielmo , Iacoviello Licia , Donati M. Benedetta 
Published: October 2019

Abstract
Thrombosis may occur in patients affected by acute lymphoblastic leukemia (ALL), complicating the course of treatment with impact on the prognosis of the disease. Its frequency has been described to range between 0 and 36.7%, depending on the study design. A combination of conditions related to the disease, treatment and host could be involved in the pathogenesis of this prothrombotic state.
Methods: We performed a meta-analysis of all prospective studies evaluating the incidence of symptomatic thrombosis in patients with ALL, published in English, since 1977. Subgroup analyses were performed to evaluate the influence of patient characteristics and treatment strategies on thrombotic complications. Pooled incidence rates and 95% confidence intervals were calculated using exact method, that account for sparseness of individual studies.
Results: From a total of 105 articles, 53 were initially excluded. Reasons for exclusion were: case reports without reference to the population at risk (15), no data about incidence of thrombosis (22), reviews (9), duplicated data (5), no clear definition of the endpoints (2). Retrospective (15) and small prospective studies designed for the evaluation of laboratory parameters (14) were also not considered. Each arm from a randomized clinical trial or a comparative study was considered as a different group. Twenty three studies (33 groups) were included, comprising 1,920 patients and 100 thrombotic events (Incidence Rate (IR): 0.052, 95%CI 0.043–0.063). The table describes the IR of thrombosis for the overall population, and for subgroups formed according to patient and treatment characteristics.
Conclusions: Factors that seem to increase the incidence of thrombosis are: recent year of publication (which could reflect a more accurate diagnosis or differences in treatment with time), adulthood, induction phase of treatment, use of anthracyclines and of lower daily doses of asparaginase given for a long period of time. Extensive studies of the kinetics of inhibition of coagulation proteins by asparaginase are required to confirm the latter finding.
Groups Size Events IR (95% CI) (%) P Total thrombosis 33 1920 100 5.2 (4.3–6.3) Central nervous system (CNS) thrombosis 32 1838 50 2.7 (2.1–3.6) Non-CNS thrombosis 32 1838 49 2.6 (2.0–3.5) At diagnosis 2 118 1 0.8 (0.1–6.0) Induction 24 1428 69 4.8 (3.8–6.1) Post-induction 13 775 12 1.5 (0.9–2.7) 0.00012 Children 14 1175 51 4.3 (3.3–5.7) Adults 10 253 18 7.1 (4.5–11.0) 0.069 Daily dose of asparaginase (at induction) ≤ 6000 U/Kg 10 591 48 8.1 (6.1–11.0) ≥ 10000 U/Kg 14 837 21 2.5 (1.6–3.8) < 0.0001 Days of asparaginase (at induction) < 9 days 16 904 43 2.7 (1.8–4.0) ≥ 9 days 8 524 45 8.6 (6.4–11.0) < 0.0001 Use of anthracyclines Yes 21 933 56 6.0 (4.6–7.7) No 3 495 13 2.6 (1.5–4.4) 0.0057 Year of publication < 1989 5 810 26 3.2 (2.2–4.7) 1990–1999 21 432 22 5.1 (3.4–7.7) 0.008 ≥ 2000 7 678 52 7.7 (5.8–10.0)