Thromboembolism in acute lymphoblastic leukemia: results of NOPHO ALL2008 protocol treatment in patients aged 1 to 45 years

Abstract

Thromboembolism frequently occurs during acute lymphoblastic leukemia (ALL) therapy. We prospectively registered thromboembolic events during the treatment of 1772 consecutive Nordic/Baltic patients with ALL aged 1 to 45 years who were treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol (July 2008-April 2017). The 2.5-year cumulative incidence of thromboembolism (N = 137) was 7.9% (95% confidence interval [CI], 6.6-9.1); it was higher in patients aged at least 10 years ( < .0001). Adjusted hazard ratios (HRas) were associated with greater age (range, 10.0-17.9 years: HRa, 4.9 [95% CI, 3.1-7.8; < .0001]; 18.0-45.9 years: HRa, 6.06 [95% CI, 3.65-10.1; < .0001]) and mediastinal mass at ALL diagnosis (HRa, 2.1; 95% CI, 1.0-4.3; = .04). In a multiple absolute risk regression model addressing 3 thromboembolism risk factors, age at least 10 years had the largest absolute risk ratio (RR, 4.7 [95% CI, 3.1-7.1]; RR, 2.0 [95% CI, 1.2-3.1]; RR, 1.6 [95% CI, 1.0-2.6]). Patients aged 18.0 to 45.9 years had an increased hazard of pulmonary embolism (HRa, 11.6; 95% CI, 4.02-33.7; < .0001), and patients aged 10.0 to 17.9 years had an increased hazard of cerebral sinus venous thrombosis (HRa, 3.3; 95% CI, 1.5-7.3; = .003) compared with children younger than 10.0 years. Asparaginase was truncated in 38/128 patients with thromboembolism, whereas thromboembolism diagnosis was unassociated with increased hazard of relapse ( = .6). Five deaths were attributable to thromboembolism, and patients younger than 18.0 years with thromboembolism had increased hazard of dying compared with same-aged patients without thromboembolism (both ≤ .01). In conclusion, patients aged at least 10 years could be candidates for preemptive antithrombotic prophylaxis. However, the predictive value of age 10 years or older, enlarged lymph nodes, and mediastinal mass remain to be validated in another cohort.

Disordered hemostasis associated with severely depressed fibrinolysis demonstrated using a simultaneous thrombin and plasmin generation assay during L‐asparaginase induction therapy in pediatric acute lymphoblastic leukemia

“…Although the THROMBOTECT trial reported that enoxaparin (LMWH) and activity‐adapted AT substitution were equally effective, a lower incidence of thrombotic events was shown in children aged over 6 years. In this context, several reports have also recently demonstrated that an onset age ≥10.0 years is a risk factor for L‐Asp‐associated thromboembolism . In our study, the T/P‐GA technique indicated that the P‐Peak ratios at T1 in the ≥10.0 years old group of BFM were significantly more decreased than in the younger age group, while T‐EP ratios at T1 and T2 in the ≥10.0 years old group of JACLS were significantly reduced.…”

“…In this context, several reports have also recently demonstrated that an onset age ≥10.0 years is a risk factor for L-Asp-associated thromboembolism. [29][30][31] In our study, the T/P-GA technique indicated that the P-Peak ratios at T1 in the ≥10.0 years old group of BFM were significantly more decreased than in the younger age group, while T-EP ratios at T1 and T2 in the ≥10.0 years old group of JACLS were significantly reduced. However, the statistical results regarding onset age in the JACLS group might have been misinterpreted because the ≥10.0 years old group of JACLS had a very small population (n = 4).…”

Thrombophilia screening and thromboprophylaxis may benefit specific ethnic subgroups with paediatric acute lymphoblastic leukaemia

“…Treatment-related risk factors for VTE in patients with ALL are L-asparaginase, steroids and central venous lines (Mitchell et al, 2010). Host risk factors include older age, mediastinal mass (Rank et al, 2018), high-risk ALL (Athale et al, 2005) and T-immunophenotype (Al-Aridi et al, 2011). Another host-related risk factor is inherited thrombophilia (Mitchell et al, 2010), which was first identified in association with VTE in healthy populations (Young et al, 2008).…”

Recurrent deep vein thrombosis in children with malignant blood diseases: literature review

“…Rank и соавт. [37]. Кумулятивная вероятность развития ТГВ была выше у пациентов в возрасте 10-18 лет, чем у пациентов 1-10 лет (15,5 и 3,7 % соответственно, р = 0,0001).…”

“…Кумулятивная вероятность развития ТГВ была выше у пациентов в возрасте 10-18 лет, чем у пациентов 1-10 лет (15,5 и 3,7 % соответственно, р = 0,0001). Риск симптоматических ТГВ повышают установка ЦВК [37] и применение L-аспарагиназы в дозах менее 10 000 ЕД / м 2 в течение более 9 дней [14].…”