Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients

Abstract

The risk of thrombosis in children with acute lymphoblastic leukemia (ALL) reportedly ranges between 1% and 37%. Epidemiologic studies have usually been hampered by small numbers, making accurate estimates of thrombosis risk in ALL patients very difficult. The aim of this study was to better estimate the frequency of this complication and to define how the disease, its treatment, and the host contribute to its occurrence. We made an attempt to combine and analyze all published data on the association between pediatric ALL and thrombosis, by using a meta-analytic method. The rate of thrombosis in 1752 children from 17 prospective studies was 5.2% (95% CI: 4.2-6.4). The risk varies depending on several factors. Most of the events occurred during the induction phase of therapy. Lower doses of asparaginase (ASP) for long periods were associated with the highest incidence of thrombosis, as were anthracyclines and prednisone (instead of dexamethasone). The presence of central lines and of thrombophilic genetic abnormalities also appeared to be frequently associated with thrombosis. In conclusion, the overall thrombotic risk in ALL children was significant, and the subgroup analysis was able to identify high-risk individuals, a finding that will hopefully guide future prospective studies aimed at decreasing this risk. IntroductionAcute lymphoblastic leukemia (ALL) is more frequent in children than in adults; indeed, two thirds of all cases occur at pediatric age. 1 The risk of thrombosis is increased in ALL patients, 2 and its occurrence may complicate the treatment course with a negative prognostic impact. Its frequency reportedly ranges between 1.1% and 36.7%, a quite large variation related to several factors, such as different definitions of thrombosis (symptomatic vs asymptomatic), diagnostic methods for its detection, study design (prospective vs retrospective), and differences in treatment protocols. 2 The pathogenesis of this increased thrombotic risk is not fully understood, but includes a combination of variables related to the disease itself, its treatment, and the host. [3][4][5] Although many clinical and epidemiologic studies were performed in this field, the majority were either retrospective or prospective observations on small numbers of subjects. Thus, the results are contradictory and inconclusive, mainly due to lack of statistical power. However, a careful assessment of risk factors would be useful to improve the quality of treatment and to identify subgroups in which prophylactic interventions would be beneficial.The objective of the present study was to quantitatively combine and analyze the available data, by a meta-analytic approach, to obtain accurate estimates of the thrombotic risk in pediatric patients with ALL.Several subgroup analyses were carried out to control for possible biases arising from heterogeneous pieces of information and to sort out subpopulations at higher risk of thrombosis. Materials and methods Meta-analysisIn the PubMed database, all available articles were searched usin...

Risk factors of central venous lines-related thrombosis in children with acute lymphoblastic leukemia during induction therapy: a prospective study

“…[1][2][3][4][5][6][7] We found no association between VT and characteristics of patients at diagnosis (Table 1). CVL-VT were reported being associated with left body side, subclavian vein placement and percutaneous technique insertion in children with ALL.…”

“…6 As reported in a meta-analysis based on 1752 children with ALL, L-Asp given at doses less than 10 000 U/m 2 for more than 9 days and PDN versus DXM increased the risk of thrombosis. 4 Our study did not show a statistically significant increased rate of VT after PDN (ALL 95 and ALL 2000-PDN random arm) compared to DXM (ALL 2000-DXM random arm) ( Table 1). In the multivariate model, the PDN further increased the OR of the CVL diameter/body surface ratio as the most predictive risk factor of CVL-VT, from 6.3 to 7.6 (95% CI: Table 1 Distribution of CVL-VT in 56 children with ALL after the end of induction, according to demographic and clinical characteristics at diagnosis, ANC at time of CVL insertion and treatment protocol Letters to the Editor 1.6-35.9) ( Table 3).…”

“…In the multivariate model, the PDN further increased the OR of the CVL diameter/body surface ratio as the most predictive risk factor of CVL-VT, from 6.3 to 7.6 (95% CI: Table 1 Distribution of CVL-VT in 56 children with ALL after the end of induction, according to demographic and clinical characteristics at diagnosis, ANC at time of CVL insertion and treatment protocol Letters to the Editor 1.6-35.9) ( Table 3). Inherited prothrombotic factors may exacerbate the risk of thrombosis in children with ALL; [4][5][6][7] however, thrombophilia screening before starting chemotherapy is not considered a must at this time 3 . In our study no association was found between VT and at least one inherited prothrombotic factor, as persistent high level of lipoprotein(a) 430 mg/dl, 5,10-methylenetetrahydrofolate reductase (MTHFR) homozygous, factor V Leiden or prothrombin gene mutation, persistent lower Letters to the Editor activity of protein So60% , of protein Co65% and of factor XIIo70%.…”

“…[1][2][3] Data on occurrence, risk factors and outcome of CVL-VT, as well as the gold-standard imaging test, are either limited or controversial. [1][2][3][4] A recent meta-analysis on thrombotic events in childhood ALL could not thoroughly evaluated the role of CVL as the proportion of patients bearing a CVL was reported by few prospective studies. 4 Recognizing the risk factors of CVL-related complications is important for assessing the benefit/risk ratio of these devices.…”

Personal practice: How we manage the risk of bleeding and thrombosis in children and young adults with acute lymphoblastic leukaemia

“…Thrombocytopenia and low fibrinogen levels may increase the risk of bleeding whilst ineffective regulation of excess thrombin generation, mainly due to anti-thrombin (AT) III deficiency, predisposes to thrombosis. The risks are highest in the first few weeks of treatment when the haemostatic abnormalities are at their worst (Caruso et al, 2006;Qureshi et al, 2010). These have been comprehensively described elsewhere (Mitchell et al, 1995;Payne & Vora, 2007) and we don't intend to recapitulate them here.…”