Prophylaxis with enoxaparin and antithrombin III in drug-induced coagulation alterations in childhood leukemia: a retrospective experience of 20 years.

BACKGROUND: Thromboembolic complications are well known in the treatment of childhood acute lymphoblastic leukemia. Over the years it has not been possible to reach a consensus on a possible prophylaxis of thromboembolic events during intensive therapy. Only the administration of enoxaparin was able to achieve evidence in the literature to date. METHODS: In this retrospective study, 173 childhood leukemia patients were treated over 20 years with a thromboembolic prophylaxis including enoxaparin and AT III during induction therapy with L-asparaginase and cortisone. RESULTS: We here report the effectiveness of administration of enoxaparin and AT III in childhood leukemia, showing a strikingly low prevalence of deep vein thrombosis (2.9%). Especially in adolescent patients, a particularly great need for AT III was demonstrated. CONCLUSIONS: We recommend thromboembolic prophylaxis with enoxaparin and AT III substitution during induction/reinduction therapy with L-asparaginase and glucocorticosteroids, especially from adolescence onwards.

A Quantum Double-or-Nothing Game: An Application of the Kelly Criterion to Spins.

A quantum game is constructed from a sequence of independent and identically polarised spin-1/2 particles. Information about their possible polarisation is provided to a bettor, who can wager in successive double-or-nothing games on measurement outcomes. The choice at each stage is how much to bet and in which direction to measure the individual particles. The portfolio's growth rate rises as the measurements are progressively adjusted in response to the accumulated information. Wealth is amassed through astute betting. The optimal classical strategy is called the Kelly criterion and plays a fundamental role in portfolio theory and consequently quantitative finance. The optimal quantum strategy is determined numerically and shown to differ from the classical strategy. This paper contributes to the development of quantum finance, as aspects of portfolio optimisation are extended to the quantum realm. Intriguing trade-offs between information gain and portfolio growth are described.

Stereotactic radiofrequency ablation of a variety of liver masses in children.

BACKGROUND AND AIMS: Surgical resection is currently the cornerstone of liver tumor treatment in children. In adults radiofrequency ablation (RFA) is an established minimally invasive treatment option for small focal liver tumors. Multiprobe stereotactic RFA (SRFA) with intraoperative image fusion to confirm ablation margins allows treatment for large lesions. We describe our experience with SRFA in children with liver masses. METHODS: SRFA was performed in 10 patients with a median age of 14 years (range 0.5-17.0 years) suffering from liver adenoma (n = 3), hepatocellular carcinoma (n = 1), hepatoblastoma (n = 2), myofibroblastic tumor (n = 1), hepatic metastases of extrahepatic tumors (n = 2) and infiltrative hepatic cysts associated with alveolar echinococcosis (n = 1). Overall, 15 lesions with a mean lesion size of 2.6 cm (range 0.7-9.5 cm) were treated in 11 sessions. RESULTS: The technical success rate was 100%, as was the survival rate. No transient adverse effects higher than grade II (Clavien and Dindo) were encountered after interventions. The median hospital stay was 5 d (range 2-33 d). In two patients who subsequently underwent transplant hepatectomy complete ablation was histologically confirmed. Follow-up imaging studies (median 55 months, range 18-129 months) revealed no local or distant recurrence of disease in any patient. CONCLUSIONS: SRFA is an effective minimal-invasive treatment option in pediatric patients with liver tumors of different etiologies.

Longitudinal assessment of peripheral blood BRAFV600E levels in patients with Langerhans cell histiocytosis.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a histiocytic disorder driven by a constitutive activation of the MAPK signaling pathway in myeloid cells. In 50-60% of cases, it is caused by the BRAFV600E mutation. There is evidence that levels of BRAFV600E in the peripheral blood of patients with LCH correlate with disease burden and could be used as marker for disease extent and response to therapy. However, there is currently no consensus on how testing for minimal disseminated disease should be performed. METHODS: Different approaches to determine the mutation load in patients with LCH were assessed and longitudinal evaluation of patient DNA during treatment with chemotherapy and/or the RAF inhibitor vemurafenib was performed. DNA was isolated from whole blood, different leukocyte subsets, and circulating cell-free DNA (ccf-DNA). RESULTS: We show that determining BRAF levels from whole blood is superior to using ccfDNA. Furthermore, it is important to identify the clinically relevant BRAF-mutated cellular subpopulations such as CD14+ monocytes or CD1c+ DCs, since other blood cells can also harbor the mutation and therefore confound whole blood or ccfDNA measurements. CONCLUSION: Our data support the view that single-agent treatment with an RAF inhibitor reduces disease activity but does not cure LCH.

High hyperdiploid acute lymphoblastic leukemia (ALL)-A 25-year population-based survey of the Austrian ALL-BFM (Berlin-Frankfurt-Münster) Study Group.

BACKGROUND: Approximately 30% of childhood acute lymphoblastic leukemia (ALL) cases are high hyperdiploid (HD). Despite their low relative recurrence risk, this group accounts for the overall largest relapse proportion. PROCEDURE: To evaluate potential risk factors in our population-based cohort of patients with HD ALL enrolled in four Austrian ALL-BFM (Berlin-Frankfurt-Münster) studies from 1986 to 2010 (n = 210), we reviewed the clinical, laboratory, and cytogenetic data of the respective cases in relation to their outcome. RESULTS: The 5-year event-free (EFS) and overall survival (OS) of the entire group was 83.1 ± 2.7% and 92.0 ± 1.9%, respectively. Univariate analysis revealed that trisomy 17 was significantly associated with a better EFS and OS, whereas trisomy 10 and a modal chromosome number (MCN) > 53 chromosomes were significantly associated with a better OS. Except for the latter, findings remained valid in multivariate analysis. CONCLUSIONS: In line with previous studies, our retrospective analysis shows that MCN and specific trisomies are relevant prognostic indicators in an ALL-BFM cohort of patients with HD ALL. However, considering the current dominant role of minimal residual disease monitoring for prognostic stratification in ALL, including this particular subgroup, it is unlikely that this information is compelling enough to be utilized for refined risk classification in future ALL-BFM treatment protocols.

Hemophagocytic lymphohistiocytosis after allogeneic bone marrow transplantation during chronic norovirus infection.

Hemophagocytic lymphohistiocytosis (HLH) is a macrophage activating syndrome that is known to develop in patients with autoimmune disease, malignancies or infection, for example with Epstein-Barr virus, cytomegalovirus or varicella zoster virus. We describe a 24-month old boy with acute myelogenous leukaemia relapse and allogeneic bone marrow transplantation, who developed HLH on day +40 during chronic infection with norovirus. Here, we report for the first time the development of HLH in combination with chronic norovirus infection after allogeneic bone marrow transplantation in a hematopoietic malignancy.

Computed tomography guided percutaneous lung biopsies and suspected fungal infections in pediatric cancer patients.

BACKGROUND: The spectrum of potential fungal pathogens known to cause invasive pulmonary infections has grown as a result of intensified immunosuppressive therapy and the emergence of antifungal resistance. PROCEDURE: In a retrospective single center study, we investigated computed tomography guided percutaneous lung biopsies in 16 childhood patients with suspected fungal infections. Microbiological analysis consisted of microscopic examination, culture, and a broad-range fungal polymerase chain reaction for detection of either Aspergillus or Mucorales species. RESULTS: In 14 patients (88%), invasive fungal infection with Aspergillus species including A. terreus, Mucormycetes, and Saccharomyces cerevisiae being the main pathogens was confirmed, including patients with a double infection (19%). In two cases, the most likely diagnosis of primary bronchiolitis obliterans organizing pneumonia was established based on the results of typical histopathologic features, negative culture results, and symptoms resolved after treatment with high-dose cortisone. Diagnosis of invasive fungal pneumonia led to an immediate interruption of antineoplastic treatment in 100%, reduction of antibiotic drugs in 76%, and change of empirical to targeted antifungal therapy in 63%. The safety of lung biopsy was guaranteed by lack of any complications, such as bleeding or pneumothorax. CONCLUSIONS: The increased detection of rare fungal infections by computed tomography guided biopsy supports the need for a rapid and precise diagnosis, as most of the fungal pathogens are at least partially resistant to available antifungal therapy and proper treatment is essential for best practice in patient management.

The inferior prognosis of adolescents with acute lymphoblastic leukaemia (ALL) is caused by a higher rate of treatment-related mortality and not an increased relapse rate--a population-based analysis of 25 years of the Austrian ALL-BFM (Berlin-Frankfurt-Münster) Study Group.

Adolescents aged 15-18 years with acute lymphoblastic leukaemia (ALL) have been historically reported to have a poorer prognosis than younger children. We retrospectively analysed the characteristics and outcome of 67 adolescents included in a population-based series of 1125 non-infant cases that were enrolled into four Austrian ALL-BFM (Berlin-Frankfurt-Münster) multicentre trials at paediatric institutions within a 25-year period. Five-year event-free survival (EFS) and overall survival (OS) were 66 ± 6% and 76 ± 5% respectively, and thus lower than in younger children (83 ± 1%, 91 ± 1%; P < 0·001). This was not due to an increased cumulative incidence of relapse (CIR) (5-year CIR: 19 ± 5% vs. 13 ± 1%; P = 0·284), but due to an increased incidence of treatment-related death [5-year cumulative incidence of death (CID): 15 ± 4% vs. 3 ± 0%; P < 0·001] as a first event. Furthermore, while 44/67 (66%) non-high-risk adolescents had favourable 5-year EFS and OS rates (76 ± 7%, 89 ± 5%), 18/67 (27%) high-risk adolescents had an inferior outcome (5-year EFS: 56 ± 12%, OS 61 ± 11%, P < 0·05). Among the latter patients the CID was significantly higher than in younger high-risk children (22 ± 10% vs. 6 ± 2%; P = 0·020). Given that adolescent age is an independent risk factor for death as a first event, this specific age group may need particular vigilance when receiving intense BFM-type chemotherapy, as relapse-free survival is similar to younger children.

Outcome of children and adolescents with a second or third relapse of acute lymphoblastic leukemia (ALL): a population-based analysis of the Austrian ALL-BFM (Berlin-Frankfurt-Münster) study group.

We analyzed outcome of a population-based cohort of 74 children with second and third acute lymphoblastic leukemia (ALL) relapse and aimed to identify prognostic factors. Duration of previous remission and site of relapse appeared of prognostic relevance as patients with a second remission duration >1.5 years and isolated extramedullary relapse did better. Neither patient with a second bone marrow relapse who underwent previous allogeneic transplantation nor patients with T-cell ALL survived. Overall, 7 of 74 (9%) patients are in long-term remission. Stem cell transplantation seemed to be the only curative option for systemic relapse of B-cell precursor ALL as all 4 surviving patients with a second/third relapse involving the bone marrow received a transplant. Conclusively, patients with a second ALL relapse are ideal candidates for phase I/II trials exploring new innovative drugs.

Immature platelet fraction predicts early marrow recovery after severe chemotherapy associated neutropenia.

Febrile neutropenia secondary to chemotherapy is one of the most critical complications in cancer treatment. The aim of this study was to determine if an increase in the percentage of immature platelet fraction (IPF%) might predict early neutrophil recovery following cytostatic-dependent aplasia. A retrospective cohort study compared serial complete blood counts and the level of C-reactive protein (CRP) following induction chemotherapy for Ewing sarcoma and Non-Ewing sarcoma patients. The measurements were taken on a Sysmex XE-2100 instrument. A total of 287 paired samples from 28 children after the first cycle of chemotherapy were analyzed to test if an increase in the IPF% anticipated the CRP peak and recovery of neutrophil count. The chemotherapy associated nadir of neutrophils, reticulocytes and platelets was reached at 9.7 ± 1.5, 11.0 ± 1.7 and 11.9 ± 0.9 days (mean ± SD) respectively, in Ewing sarcoma patients. Still in severe neutropenia, IPF% was the first parameter that significantly increased and anticipated the CRP peak (11.9 ± 1.6 days, mean ± SD). The IPF% continuously increased (maximum = 6.56% ± 2.8%, mean ± SD) and peaked at 12.2 ± 1.4 days (mean ± SD) after commencement of chemotherapy. Compared to neutrophil recovery (14.6 ± 1.4 days, mean ± SD), the IPF% peak was anticipated by 2.4 days (p = 0.0085). Although variably treated, in non-Ewing sarcoma patients the effect was similar and the IPF% peak anticipated neutrophil recovery by 6.8 ± 4.7 days (p < 0.01). IPF% increased significantly at > 48 h before neutrophil recovery in patients treated with chemotherapy. IPF% is an inexpensive parameter and may be valuable in the management of febrile neutropenia.

Recommendations for Nutritional Supplementation in Pediatric Oncology: A Compilation of the Facts.

BACKGROUND: As one of the few modifiable risk factors, the importance of dietary patterns for both disease prevention and treatment outcome in pediatric oncology has gained increasing popularity. Malnutrition is associated with lower survival rates, tolerance to treatment, and quality of life. Yet, especially in children with malignancies, nutritional deterioration is common, and pediatric cancer patients often present with inadequate intake of micro- and macronutrients alike. Despite the reported widespread use of dietary supplements, few empirical data provide a basis for clinical recommendations, and evidence for their efficacy is inconsistent. Current literature lacks a systematic approach as to how and which supplements should be recommended for specific patients, types of cancer, or during specific treatments. The aim of this review is to highlight the role of the most frequently used nutrients in pediatric malignant diseases and to give a practical guide based on current scientific evidence. METHODS: A comprehensive literature search was conducted on PubMed through April 2023 to select meta-analyses, systematic reviews, observational studies, and individual randomized controlled trials (RCTs) of macro- and micronutrient supplementation in pediatric oncology. The search strategy included the following medical subject headings (MeSH) and keywords: "childhood cancer", "pediatric oncology", "nutritional status", "dietary supplements", "vitamins", "micronutrients", "calcium", "magnesium", "vitamin D", "zinc" "glutamine", "selen", and "omega-3 fatty acids". The reference lists of all relevant articles were screened to include potentially pertinent studies. RESULTS: The present review provides a comprehensive and updated overview of the latest evidence about the role of nutrition and diet in pediatric oncology, also focusing on different nutritional interventions available for the management of the disease. We summarize evidence about the importance of adequate nutrition in childhood cancer and the role of several micronutrients and critically interpret the findings. Possible effects and benefits of supplementation during chemotherapy are discussed, as are strategies for primary and secondary prevention. CONCLUSIONS: We here describe the obvious benefits of dietary supplementation for childhood cancer. Further large-scale clinical trials are required to verify the impacts of deficiencies and the possible benefits of supplementation and optimal dosages. (337 words).

Prospective use of molecular minimal residual disease for risk stratification in children and adolescents with acute lymphoblastic leukemia : Long-term results of the AIEOP-BFM ALL 2000 trial in Austria.

Since 1979 Austrian children and adolescents with acute lymphoblastic leukemia (ALL) have been treated according to protocols of the Berlin-Frankfurt-Münster (BFM) study group. The Associazione Italiana di Ematologia e Oncologia Pediatrica and BFM (AIEOP-BFM) ALL 2000 study was designed to prospectively study patient stratification into three risk groups using minimal residual disease (MRD) on two time points during the patient's early disease course. The MRD levels were monitored by detection of clone-specific rearrangements of the immunoglobulin and T­cell receptor genes applying a quantitative polymerase chain reaction-based technique. The 7­year event-free survival (EFS) and overall survival rates for all 608 Austrian patients treated between June 1999 and December 2009 within the AIEOP-BFM 2000 study were 84 ± 2% and 91 ± 1%, respectively, with a median observation time of 6.58 years. Event-free survival for patients with precursor B­cell and T­cell ALL were 84 ± 2% (n = 521) and 84 ± 4% (n = 87; p = 0.460), respectively. The MRD assessment was feasible in 94% of the patients and allowed the definition of precursor B­cell ALL patients with a low, intermediate or high risk of relapse even on top of clinically relevant subgroups. A similar finding with respect to MRD relevance in T­ALL patients was not possible due to the small number of patients and events. Since this pivotal international AIEOP-BFM ALL 2000 trial, molecular response to treatment has been continuously used with additional refinements to stratify patients into different risk groups in all successive trials of the AIEOP-BFM ALL study group.

The anti-apoptotic protein BCL2L1/Bcl-xL is neutralized by pro-apoptotic PMAIP1/Noxa in neuroblastoma, thereby determining bortezomib sensitivity independent of prosurvival MCL1 expression.

Neuroblastoma is the most frequent extracranial solid tumor in children. Here, we report that the proteasome inhibitor bortezomib (PS-341, Velcade) activated the pro-apoptotic BH3-only proteins PMAIP1/Noxa and BBC3/Puma and induced accumulation of anti-apoptotic MCL1 as well as repression of anti-apoptotic BCL2L1/Bcl-xL. Retroviral expression of Bcl-xL, but not of MCL1, prevented apoptosis by bortezomib. Gene knockdown of Noxa by shRNA technology significantly reduced apoptosis, whereas Puma knockdown did not affect cell death kinetics. Immunoprecipitation revealed that endogenous Noxa associated with both, Bcl-xL and MCL1, suggesting that in neuronal cells Noxa can neutralize Bcl-xL, explaining the pronounced protective effect of Bcl-xL. Tetracycline-regulated Noxa expression did not trigger cell death per se but sensitized to bortezomib treatment in a dose-dependent manner. This implies that the induction of Noxa is necessary but not sufficient for bortezomib-induced apoptosis. We conclude that MCL1 steady-state expression levels do not affect sensitivity to proteasome-inhibitor treatment in neuronal tumor cells, and that both the repression of Bcl-xL and the activation of Noxa are necessary for bortezomib-induced cell death.

Omega-3 Fatty Acids and Their Role in Pediatric Cancer.

BACKGROUND: Malnutrition is common in children with cancer and is associated with adverse clinical outcomes. The need for supportive care is becoming ever more evident and the role of nutrition in oncology is still not sufficiently understood. In particular, the consequences of macro- and micronutrient deficiencies require further research. As epidemiological data suggest anti-tumoral properties of omega-3 (n-3) polyunsaturated fatty acids (PUFAs), we reviewed the role of nutrition and n-3 supplementation in pediatric oncology. METHODS: A comprehensive literature search was conducted on PubMed through 5 February 2021 to select meta-analyses, systematic reviews, observational studies, and individual randomized controlled trials (RCTs) on macro- and micronutrient supplementation in pediatric oncology. The search strategy included the following medical subject headings (MeSH) and keywords: "childhood cancer", "pediatric oncology", "nutritional status", "malnutrition", and "omega-3-fatty-acids". The reference lists of all relevant articles were screened to include potentially pertinent studies. RESULTS: We summarize evidence about the importance of adequate nutrition in childhood cancer and the role of n-3 PUFAs and critically interpret findings. Possible effects of supplementation on the nutritional status and benefits during chemotherapy are discussed as well as strategies for primary and secondary prevention. CONCLUSION: We here describe the obvious benefits of omega-3 supplementation in childhood cancer. Further large scale clinical trials are required to verify potential anti-cancer effects of n-3 fatty acids.

Long-Term Outcome and Role of Biology within Risk-Adapted Treatment Strategies: The Austrian Neuroblastoma Trial A-NB94.

We evaluated long-term outcome and genomic profiles in the Austrian Neuroblastoma Trial A-NB94 which applied a risk-adapted strategy of treatment (RAST) using stage, age and MYCN amplification (MNA) status for stratification. RAST ranged from surgery only to intensity-adjusted chemotherapy, single or multiple courses of high-dose chemotherapy (HDT) followed by autologous stem cell rescue depending on response to induction chemotherapy, and irradiation to the primary tumor site. Segmental chromosomal alterations (SCAs) were investigated retrospectively using multi- and pan-genomic techniques. The A-NB94 trial enrolled 163 patients. Patients with localized disease had an excellent ten-year (10y) event free survival (EFS) and overall survival (OS) of 99 ± 1% and 93 ± 2% whilst it was 80 ± 13% and 90 ± 9% for infants with stage 4S and for infants with stage 4 non-MNA disease both 83 ± 15%. Stage 4 patients either >12 months or ≤12 months but with MNA had a 10y-EFS and OS of 45 ± 8% and 47 ± 8%, respectively. SCAs were present in increasing frequencies according to stage and age: in 29% of localized tumors but in 92% of stage 4 tumors (p < 0.001), and in 39% of patients ≤ 12 months but in 63% of patients > 12 months (p < 0.001). RAST successfully reduced chemotherapy exposure in low- and intermediate-risk patients with excellent long-term results while the outcome of high-risk disease met contemporary trials.

Extracorporeal membrane oxygenation as a rescue therapy for leukaemic children with pulmonary failure.

In patients with leukaemia, acute respiratory distress syndrome (ARDS) secondary to intensified chemotherapy-induced immunosuppression is a devastating disorder resulting in high morbidity and mortality. Compared to standard indications for extracorporeal membrane oxygenation (ECMO), cytopenia further increases the risks of infection and bleeding. We describe the use of ECMO in four children with ARDS and leukaemia. Two patients (50%) survived, pulmonary function recovered and they are in prolonged first remission. The two other patients died from ARDS and pulmonary leukaemic infiltration. Although ECMO support is a high-risk setup for nosocomial infection we observed no additional septic episodes. All patients had a highly increased demand for packed platelet and red blood cell transfusions. This increased demand and unmanageable chronic bleeding into both lungs in one patient were probably caused by a combination of coagulopathy from the primary illness, the use of anticoagulants, chemotherapy-induced cytopenia, and a reduced survival rate of platelets and red cells due to permanent contact to foreign surface. We concluded that ECMO is a supportive tool to reduce the incidence of early death, treatment-related mortality and, ultimately, to improve overall survival in childhood leukaemia.

Expression, regulation and function of phosphofructo-kinase/fructose-biphosphatases (PFKFBs) in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia cells.

BACKGROUND: Glucocorticoids (GCs) cause apoptosis and cell cycle arrest in lymphoid cells and constitute a central component in the therapy of lymphoid malignancies, most notably childhood acute lymphoblastic leukemia (ALL). PFKFB2 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-2), a kinase controlling glucose metabolism, was identified by us previously as a GC response gene in expression profiling analyses performed in children with ALL during initial systemic GC mono-therapy. Since deregulation of glucose metabolism has been implicated in apoptosis induction, this gene and its relatives, PFKFB1, 3, and 4, were further analyzed. METHODS: Gene expression analyses of isolated lymphoblasts were performed on Affymetrix HGU133 Plus 2.0 microarrays. GCRMA normalized microarray data were analyzed using R-Bioconductor packages version 2.5. Functional gene analyses of PFKFB2-15A and -15B isoforms were performed by conditional gene over-expression experiments in the GC-sensitive T-ALL model CCRF-CEM. RESULTS: Expression analyses in additional ALL children, non-leukemic individuals and leukemic cell lines confirmed frequent PFKFB2 induction by GC in most systems sensitive to GC-induced apoptosis, particularly T-ALL cells. The 3 other family members, in contrast, were either absent or only weakly expressed (PFKFB1 and 4) or not induced by GC (PFKFB3). Conditional PFKFB2 over-expression in the CCRF-CEM T-ALL in vitro model revealed that its 2 splice variants (PFKFB2-15A and PFKFB2-15B) had no detectable effect on cell survival. Moreover, neither PFKFB2 splice variant significantly affected sensitivity to, or kinetics of, GC-induced apoptosis. CONCLUSIONS: Our data suggest that, at least in the model system investigated, PFKFB2 is not an essential upstream regulator of the anti-leukemic effects of GC.

Long-term outcome of initially homogenously treated and relapsed childhood acute lymphoblastic leukaemia in Austria--a population-based report of the Austrian Berlin-Frankfurt-Münster (BFM) Study Group.

Relapsed acute lymphoblastic leukaemia (ALL) is the most common cause for a fatal outcome in paediatric oncology. Although initial ALL cure rates have improved up to 80%, the prognosis of recurrent ALL remains dismal with event-free-survival (EFS) rates about 35%. In order to analyse a population-based cohort with uniform treatment of initial disease, we examined the outcome of children suffering from relapsed ALL in Austria for the past 20 years and the validity of the currently used prognostic factors (e.g. time to and site of relapse, immunophenotype). Furthermore, we compared survival rates after chemotherapy alone with those after allogeneic stem cell transplantation (SCT). All 896 patients who suffered from ALL in Austria between 1981 and 1999 were registered in a prospectively designed database and treated according to trials ALL-Berlin-Frankfurt-Münster (BFM)-Austria (A) 81, ALL-A 84 and ALL-BFM-A 86, 90 and 95. Of these, 203 (23%) suffered from recurrent disease. One-hundred-and-seventy-two patients (85%) achieved second complete remission. The probability of 10-year EFS for the total group was 34 +/- 3%. Clinical prognostic markers that independently influenced survival were time to relapse, site of relapse and the immunophenotype. Additionally, a Cox regression model demonstrated that allogeneic SCT after first relapse was associated with a superior EFS compared with chemo/radiotherapy only (hazard ratio = 0.254; P = 0.0017).

Comparison of low-molecular-weight heparin and antithrombin versus antithrombin alone for the prevention of symptomatic venous thromboembolism in children with acute lymphoblastic leukemia.

BACKGROUND: Children with acute lymphoblastic leukemia (ALL) have a substantial risk for thromboembolism (TE) that is related to L-asparaginase-induced antithrombin (AT) deficiency and placement of central venous lines. Recent in vitro studies showed that the anticoagulant effects of low-molecular-weight heparin were profoundly affected by endogenous AT levels in children undergoing ALL therapy. METHODS: A total of 112 consecutively recruited children with newly diagnosed ALL treated according to BFM 95/2000 protocols were enrolled in this trial. This prospective cohort study was carried out to determine the influence of combined low molecular weight heparin-prophylaxis (enoxaparin 1 mg/kg/ per day) and AT supplementation versus AT alone (noncontemporaneous control group) on the incidence of symptomatic TE during a follow-up of 240 days. RESULTS: To maintain AT plasma levels above 50%, nearly 60% of all children needed at least one, most children two or three AT supplementations during induction therapy. 12.7% of the children that did receive only AT-prophylaxis (n = 71) (95% CI = 6.0-22.7) developed objectively confirmed symptomatic TE, as compared with no TE in children after combined prophylaxis (n = 41) (95% CI = 0.0-8.6, P < 0.05). Thromboses were located in the sinovenous system in the brain (n = 3), the lower deep veins (n = 3), the upper deep veins (n = 2) and in an upper deep vein combined with pulmonary embolism (n = 1). CONCLUSION: Prophylaxis with enoxaparin was safe and effective in preventing TE. Although our data are encouraging, the in vivo efficacy of combined enoxaparin and AT prophylaxis to prevent symptomatic venous TE in children with ALL should be evaluated in a prospective randomized clinical trial.