Objective To assess the incidence rate (IR), changes in IR over time, risk factors, treatment, and outcomes of pediatric noncerebral thromboembolism (TE). Study design The study included all patients ...aged 0 to 18 years diagnosed with first-ever noncerebral venous thromboembolism (VTE) and/or arterial TE in Denmark between 1994 and 2006. Patients were identified in national registries, followed by validation of diagnoses by medical records review. Results We confirmed 331 cases of VTE and 46 cases of arterial TE during 15.8 million person-years of observation, with corresponding IRs of 2.09 and 0.29 per 100 000 person-years. The IR peaked in infancy (age <1 year) for both VTE and arterial TE, with an additional peak among adolescents (age 15 to 18 years) for VTE. Boys predominated in IR of VTE in infancy, whereas girls did so in adolescence ( P < .01). The IRs of VTE and arterial TE remained stable during the study period, but with an trend toward increasing VTE in 2001 to 2006 ( P = .064). Underlying diseases/external triggers were present in 86.6% of the patients, and thrombophilia was present in 47.9% of the VTE cases. All-cause and TE-related 30-day case fatalities were 4.0% and 1.6%, respectively. Conclusions We found age- and sex-related disparities in the IRs of pediatric VTE and arterial TE, but insignificant changes in IR from 1994 to 2006.
Data on the validity of pediatric thrombosis diagnoses are missing. We aimed to examine the predictive value of a diagnosis of venous and arterial thrombosis using the Danish National Patient ...Registry (DNPR). We identified all first-time diagnoses among children and adolescents (aged 0-18 years) between 1994 and 2006 in DNPR. In total, 1138 potential cases of thrombosis were identified; the medical records were retrieved for 1112 (97.7%) and the positive predictive value (PPV) computed. Overall, the diagnosis of thrombosis was verified in 598 of the 1112 cases, corresponding to a PPV of 53.7% (95% confidence interval CI: 50.8-56.7). Diagnoses from wards had the PPV of 62.5% (95% CI: 59.4-65.6). The predictive value of a thrombosis diagnosis from wards was age-dependent, with a higher PPV (77.4%, 95% CI: 68.7-84.7) in neonates (<28 days) and adolescents (15-18 years) (68.2%; 95% CI: 63.2-72.5)) than in children (28 days-14 years) (51.2%; (95% CI: 46.0-56.4)). The PPV of a thrombosis diagnosis was improved by restricting the analysis to diagnoses from wards, primary diagnoses, and admissions with a length of stay of three or more days. The results indicate that an interpretation of nonvalidated hospital discharge data for pediatric thrombosis in a registry like DNPR should be made with caution.
Summary
We present a prospective multicentre cohort of 20 children with acute lymphoblastic leukaemia (ALL) and cerebral sinus venous thrombosis (CSVT). The study covers a period of 5 years and ...comprises 1038 children treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL 2008 protocol. The cumulative incidence of CSVT was 2%. Sixteen of the thromboses were related to asparaginase and 16 to steroids. Most CSVTs occurred in the consolidation phase. Nearly all were treated with low molecular weight heparin without bleeding complications. Mortality related to CSVT directly or indirectly was 10%, emphasizing the importance of this complication.
Cerebral atypical teratoid/rhabdoid tumors (AT/RT) of infancy are highly malignant and have a poor prognosis. The authors report on one case with long-term survival. The patient was a 1 year-old boy ...presenting with a large AT/RT in the right temporal lobe. He was treated with complete surgery, followed by multiagent chemotherapy. Later he had a second resection and intrathecal chemotherapy and Gamma knife radiosurgery was added to the treatment. Except for a well-controlled temporal epilepsy, the boy is doing well after 6 years follow-up. AT/RT should be treated in a multimodal way. Intrathecal chemotherapy and Gamma knife radiosurgery of single recurrent or residual tumors might increase survival.
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Introduction
Cerebral sinus venous thrombosis (CSVT) is potentially life-threatening thrombosis with mortality around 10%. Venous thromboembolism (VTE) is a common complication in children with ...cancer. These children have several thrombotic risk factors such as the malignancy itself, severe infections, prothrombotic medication and immobilization. The treatment of acute lymphoblastic leukemia (ALL) includes steroids and asparaginase (ASP), raising the VTE risk. In children with ALL the central nervous system (CNS) is a common localization for VTE. However, retrospective studies on small numbers of patients, larger studies and population-based data in children are scarce. The five Nordic countries, Estonia and Lithuania have a common treatment protocol for children with ALL between 1 and 18 years of age with prospective registration of toxicities, including CSVT offering a unique opportunity to study CSVT in this patient group. This is to our knowledge the largest report of children with ALL and CSVT describing the incidence, symptoms, treatment and the effect of CSVT on ALL treatment.
Methods
We assessed the symptoms, treatment, clinical risk factors and outcome of all children between ages 1 and 17 years at diagnosis of B-cell precursor or T-cell ALL between June 2008 and July 2013 and with CSVT. Data were collected from the patients’ medical records and the NOPHO leukemia registry.
Results
In total, 20 (1.9%) of the 1038 children with ALL treated according to the NOPHO ALL 2008 protocol developed CSVT. The cumulative incidence of CSVT was 2.0%. All the thromboses occurred within the first 5 months of treatment. The most common symptoms at the diagnosis of CSVT were headache, convulsions, weakness/fatigue and cerebral nerve palsy/hemiparesis/hemiplegia. The most frequent localizations for CSVT were sinus sagittalis (n=16) and sinus transversus (n=10). However, in most cases multiple cerebral veins were involved ( 70%). Median D-dimer at time of the CSVT diagnosis was 0.85 mg/L (range 0.19-4.7 mg/L) with 5 patients having normal D-dimer. We could not identify any clinical risk factors for CSVTs. CSVT was associated with steroids (treatment within 2 weeks before the diagnosis of CSVT) in 16/20 and with Pegylated asparaginase in 16/20. Fifteen patients were later screened for the inherited thrombophilic factors; one child had heterozygous prothrombin G20110A mutation and another heterozygous factor V (R506Q) Leiden mutation.
Most patients (19/20) were treated with anticoagulants: mostly low molecular weight heparin (LMWH). The median treatment with LMWH was 26 weeks (range 14-119 weeks). No bleeding complications were observed in connection with LMWH.
Two deaths were directly related to CSVT. Asparaginase was omitted from the treatment in 7 and delayed or reduced in 5 of the cases raising the risk for subsequent suboptimal leukaemia treatment. Of the surviving 18 patients, follow-up imaging revealed complete recanalization in 7 and partial recanalization in 7 cases. No imaging was available for the remaining 4 patients.
Conclusions
The incidence of CSVT in children with ALL was approximately 2%. No statistically significant clinical predictors for CSVT were identified. The mortality related to CSVT was 10%. Anticoagulation with LMWH was the treatment of choice in most cased and was well tolerated.
No relevant conflicts of interest to declare.
Introduction
Children with acute lymphoblastic leukemia (ALL) are at high risk for VTE due to several thrombotic risk factors such as the disease itself, central venous line (CVL), immobilization, ...infections and treatment with asparaginase and steroids, leading to increased morbidity and mortality. Identifying the clinical risk factors and high risk treatment phases for VTE is important and can lead to a better outcome and quality of life for these children. We conducted this prospective study on symptomatic VTE in children with ALL to characterize the prevalence, the clinical characteristics, and potential clinical predictive factors for symptomatic VTE and the impact of thrombosis on treatment delays.
Methods
All patients (n=1083), age 1-18 years, diagnosed with B-cell precursor or T-cell ALL between June 2008 and July 2013 and enrolled in the NOPHO ALL 2008 treatment protocol in the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden), Estonia or Lithuania were included in the study.
Thrombotic events (TE) were prospectively recorded until the end of December 2013. TE was defined as objectively confirmed symptomatic TE. Main questions were: time of VTE occurrence, impact on treatment delay, type of CVL, dysfunction of the CVL, blood samples including D-dimers and thrombophilia screening, family history of TE, type and duration of antithrombotic therapy, and major bleeding during anticoagulation.
Results
The cumulative risk of symptomatic VTE was 6.0% (CI 95% 4.7-7.7) for children treated with the NOPHO- ALL 2008 protocol. No arterial TE was found. VTE occurred in median 80 (IQR 43-118) days in the SR and 104 (IQR 39-127) days in the IR protocol and were in majority of cases associated with asparaginase treatment (84.5%, 49/58). See figure 1 for the localization of the VTE. VTE had a high impact on the treatment in the patients. Treatment with asparaginase was shortened in half of patients with VTE and chemotherapy treatment delayed in 25%. Age ≥ 15 years and residual disease ≥ 5% after induction therapy was significantly associated with VTE in the multivariate analysis (Table 1).
Conclusions
Our findings indicate that Venous Thromboembolism (VTE):
- is a major complication of ALL treatment
- may lead to reduced intensity of the ALL treatment and
subsequently possible long term impact on the EFS
- risk is dependent on the patients age and residual disease after leukemia induction
The possibility of identifying patients with elevated risk of VTE needs to be studied further and thromboprophylaxis for such patients during high-risk treatment phases can be considered in future ALL protocols.
Table 1Multivariate Cox regression analysis of the risk for VTEFactorHR (95% CI)P valueAge category, years1-78-1415-17Ref1.9 (1.0-3.7)6.2 (3.4-11.3)<0.0000.0440.000GenderMale1.6 (0.9-2.8)0.074ALL phenotypeB-precursorT-cellBilineageRef2.3 (1.2-4.2)4.2 (1.0-17.4)0.0190.0100.047Residual disease ≥ 5% day 294.1 (1.9-9.0)0.001
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No relevant conflicts of interest to declare.
We present a very late onset relapse of PTLD 10 yr after allogeneic HSCT in a patient in third remission for ALL, nine yr after the first episode of PTLD. The recipient was conditioned with ...fractionated TBI 12 Gy, cyclophosphamide, and horse ATG. The first episode of PTLD with a large retroperitoneal tumor occurred one yr after transplantation; a residual tumor infiltrating spleen and colon was resected one yr later. Due to continual pathological signals in liver and lungs, persistent fever, and an M‐component in peripheral blood, a new course of four rituximab doses was given, after which the fever settled, the PET scan normalized, and the M‐component disappeared. Without any ongoing immunosuppressive therapy, PTLD relapsed nine yr later with large intra‐abdominal lymph node masses causing ureteric obstruction with bilateral hydronephrosis. Pathological features were identical to the primary PTLD tumor: EBV related, of donor origin, positive for CD138 and CD79 alpha, but negative for CD20 and CD19. The transcription factor PAX5 was negative but BOB1 and OCT2 were positive, consistent with plasmablastic lymphoma. The relapse was successfully treated with a combination of low dose chemotherapy and rituximab. Five yr after end of treatment, the girl has moderately reduced renal function but otherwise remains well without evidence of disease.
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