ALBERT

Description: 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.

Description: 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)

Description: Introduction DVT incidence ranges from 3 to 15% in cancer patient. Nevertheless there are only few data about DVT in lymphoma. Aim of our study is to define the real DVT risk and incidence in lymphoma patients. Patients and Methods Our study is a retrospective study including patients of two haematology centers. We considered the age of the patients, sex, histological type of lymphoma (indolent -IL- vs aggressive -AL), localization over or under diaphragm, extranodal localizations, vascular compression, stage of disease, IPI, LDH level, chemotherapy type and timing of administration (weekly vs every 2wks or 3 weeks), the use of chemotherapy regimen containing methotrexate as potential risk factors in DVT onset. Data regarding 567 NHL patients, observed from 2001 to 2006, were collected. 400 patients had indolent NHL (IL) and 167 Aggressive NHL (AL). Median age was 59 years (R 13–94), M/F ratio was 300/267. DVT was diagnosed by ultrasound or CT scan. The statistical analysis was conducted with Yates corrected chi square test, Odds Ratio (OR), Log-rank test (to compare Kaplan-Meier curves). Results 87 patients (15%) showed DVT. Of these, 37(43%) were localized at legs and 19(22%) involved abdominal veins (especially iliac veins, 10% of total). DVT onset median time was 3 months from NHL diagnosis (Range 0–156 months). Sex, histological type of lymphoma (IL vs AL), localization over or under diaphragm, extranodal localization, stage of disease, IPI, LDH level, and use of chemotherapy regimen containing methotrexate were not related to an increased risk to develop DVT. Vascular compression was the most significant risk factor for DVT development with OR 3.1 (CI95%:1.9–5), Chi Square22.7(p〈 0.0001). Patients receiving weekly chemotherapy showed an increased risk to develop DVT (OR 1.8; CI95%:1.1–2.8), Chi Square5.1, p0.024. Patients aged ≥60 presented increased risk of DVT with OR 1.7(CI95%: 1–2.7), Chi Square 4.28 (p 0.04). Patients with DVT within 3 months from NHL diagnosis had an higher risk of disease relapse or non response at first line chemotherapy: OR 3.7 (CI95%: 1.8–7.3), Chi Square 13.4 (p 〈 0.0001), positive predictive value 0.71(CI95%: 0.57–0.82), specificity 0.95(CI95%: 0.93–0.97). However DVT had no impact on mortality and survival, also in the subgroup of patients with DLBCL. Discussion In our study vascular compression by enlarged lymphonodes, patient age ≥60 y.o., and weekly administration of chemotherapy seem to be the main risk factors to develop DVT in NHL patients. Further studies, concerning genetic conditions and other disease-related parameters, are ongoing to individuate other risk factors for thrombosis in NHL patients. The DVT development within 3 months from NHL diagnosis seems to be a risk factor for non response/relapse. An antithrombotic prophylaxis could be considered in the patients with higher thrombotic risk.