The impact of prophylactic fresh-frozen plasma and cryoprecipitate on the incidence of central nervous system thrombosis and hemorrhage in children with acute lymphoblastic leukemia receiving asparaginase

Blood ◽  
2009 ◽  
Vol 114 (25) ◽  
pp. 5146-5151 ◽  
Author(s):  
Lesleigh S. Abbott ◽  
Mariana Deevska ◽  
Conrad V. Fernandez ◽  
David Dix ◽  
Victoria E. Price ◽  
...  

Abstract Asparaginase (ASP) therapy is associated with depletion of antithrombin (AT) and fibrinogen (FG). Potential toxicities include central nervous system thrombosis (CNST) and hemorrhage. Historical practice at the Izaak Walton Killam Health Centre (IWK) involves measuring AT and FG levels after ASP administration and transfusing fresh-frozen plasma (FFP) or cryoprecipitate (CRY) to prevent thrombotic and hemorrhagic complications. To determine whether this reduced these complications in children with acute lymphoblastic leukemia (ALL), incidence, outcome, and clinical characteristics of ASP-related CNST in ALL patients at IWK were compared with a similar cohort from BC Children's Hospital (BCCH), where prophylaxis was not performed. Costs associated with preventative versus expectant management were estimated. From 1990 to 2005, 240 patients were treated at IWK and 479 at BCCH. Seven BCCH patients developed venous CNST (1.5%), compared with none at IWK. CNST occurred exclusively during induction. Six patients received anticoagulation and continued ASP. All 7 patients remain in remission. National Cancer Institute high-risk ALL predicted CNST risk (P = .02), whereas sex, age, race, and body mass index did not. Neither FFP nor CRY protected against CNST, suggesting prophylaxis is unwarranted for unselected ALL patients. However, prophylactic replacement for HR patients in induction may be cost-effective.

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3345-3345
Author(s):  
Mandy N Lauw ◽  
Bronno Van der Holt ◽  
Saskia Middeldorp ◽  
Joost CM Meijers ◽  
Bart J Biemond

Abstract Abstract 3345 Background: Acute lymphoblastic leukemia (ALL) is frequently complicated by venous thromboembolism (VTE). The reported incidence varies from 2% to 37%, with the highest risk arising in the first weeks after treatment initiation. VTE leads to morbidity, mortality and premature termination of therapy. Prevention of VTE in ALL is complicated, as thrombotic and bleeding factors need to be balanced. The efficacy of prophylactic antithrombotic measures is not clear yet, and standardized guidelines are lacking. We assessed the effect of various prevention protocols on the VTE risk in adults treated for ALL. Methods: Between April 1999 and November 2005, 240 consecutive patients aged 16–59 years with newly diagnosed ALL were treated with the same anti-leukemic protocol in a Dutch-Belgian multicenter study, which included L-asparaginase in cycle 1 (5000 U/m2/day, day 15–28). All VTE events during treatment were prospectively recorded. VTE prophylaxis was applied only in cycle 1 during asparaginase administration, and varied between different centers: no prophylaxis, fresh frozen plasma (FFP), or antithrombin (AT) concentrate. A centers' prevention protocol was used as a proxy for all patients treated in that center. AT plasma levels were assessed of patients with VTE and 22 controls without VTE. We determined VTE incidence in cycle 1, the impact of the various prophylactic measures, and VTE incidence during the total treatment period for ALL. Secondly, we assessed the clinical relevance of VTE on ALL outcome. Results: 25 of 240 patients (10.4%; 95% CI 6.6–14.3) experienced objectively diagnosed, symptomatic VTE in cycle 1 (10 cerebral thromboses of which 8 in the sagittal sinus, 11 upper limb vein thromboses (10 central venous catheter (CVC)-related), 3 deep vein thromboses of the leg, 1 pulmonary embolism). VTE incidence in patients receiving FFP prophylaxis was reduced by 70% as compared to patients without prophylactic measures (7.2% vs. 23.9%; RR 0.3; 95% CI 0.1–0.6; Table 1). Age, sex, ALL-type and CVC-placement did not differ significantly between patients with and without FFP prophylaxis. The effect of prophylactic AT concentrate could not be properly assessed as it was only rarely given in two centers. Mean AT plasma levels did not differ significantly between VTE patients with or without FFP, neither between patients with VTE and controls without VTE (Figure 1). During the total treatment period, VTE occurred in 36 of 240 patients (15.0%; 95% CI 10.5–19.5). Patients with VTE in cycle 1 were less likely to obtain complete remission after cycle 1 (HR 0.5; 95% CI 0.3–0.9), but did not have a significantly decreased overall survival (HR 1.5; 95% CI 0.9–2.6). Conclusions: FFP significantly reduced VTE incidence by 70% during ALL treatment, without reversing the AT deficiency induced by asparaginase. Our observation is in contrast with two previous studies on the effect of FFP on VTE in ALL. The mechanisms by which FFP accomplishes this antithrombotic effect are not clear yet and require further investigation. Since this was a retrospective, observational study, the effect of prophylactic FFP on VTE risk in adults treated for ALL should be confirmed by a randomized controlled trial. Disclosures: No relevant conflicts of interest to declare.


1992 ◽  
Vol 41 (4) ◽  
pp. 295-296 ◽  
Author(s):  
Hideshi Ishii ◽  
Hakumei Oh ◽  
Nobuko Ishizuka ◽  
Yasuhiro Matsuura ◽  
Hirotoshi Nakamura ◽  
...  

TH Open ◽  
2019 ◽  
Vol 03 (02) ◽  
pp. e109-e116
Author(s):  
Irene Klaassen ◽  
Charlotte Zuurbier ◽  
Barbara Hutten ◽  
Cor van den Bos ◽  
A. Schouten ◽  
...  

Background Venous thromboembolism (VTE) is an important complication for treatment of acute lymphoblastic leukemia (ALL) in children. Especially, ALL treatment, with therapeutics such as asparaginase and steroids, increases the thrombotic risk by reduction in procoagulant and anticoagulant proteins. Replacement of deficient natural anticoagulants by administration of fresh frozen plasma (FFP) may have a preventive effect on the occurrence of VTE. Methods We retrospectively analyzed all consecutive children (≤18 years) with ALL, treated on the Dutch Childhood Oncology Group (DCOG) ALL-9 and ALL-10 protocols at the Emma Children's Hospital Academic Medical Center between February 1997 and January 2012, to study the effect of FFP on VTE incidence, antithrombin and fibrinogen plasma levels, and VTE risk factors. Results In total, 18/205 patients developed VTE (8.8%; 95% confidence interval [CI]: 4.9–12.7%). In all patients, VTE occurred after asparaginase administration. In total, 82/205 patients (40%) received FFP. FFP supplementation did not prevent VTE or alter plasma levels of antithrombin or fibrinogen. In the multivariate analysis, VTE occurred significantly more frequently in children ≥12 years (odds ratio [OR]: 3.89; 95% CI: 1.29–11.73) and treated according to the ALL-10 protocol (OR: 3.71; 95% CI: 1.13–12.17). Conclusion FFP supplementation does not seem to be beneficial in the prevention of VTE in pediatric ALL patients. In addition, age ≥12 years and treatment according to the DCOG ALL-10 protocol with intensive and prolonged administration of asparaginase in combination with prednisone are risk factors. There is a need for effective preventive strategies in ALL patients at high risk for VTE.


2008 ◽  
Vol 30 (9) ◽  
pp. 643-650 ◽  
Author(s):  
Maria Teresa Amparo Buendia H ◽  
Juan Manuel Lozano ◽  
Gloria Elena Suarez ◽  
Carlos Saavedra A ◽  
Gonzalo Guevara

Blood ◽  
2012 ◽  
Vol 119 (7) ◽  
pp. 1658-1664 ◽  
Author(s):  
Jitesh D. Kawedia ◽  
Chengcheng Liu ◽  
Deqing Pei ◽  
Cheng Cheng ◽  
Christian A. Fernandez ◽  
...  

Abstract We have previously hypothesized that higher systemic exposure to asparaginase may cause increased exposure to dexamethasone, both critical chemotherapeutic agents for acute lymphoblastic leukemia. Whether interpatient pharmaco-kinetic differences in dexamethasone contribute to relapse risk has never been studied. The impact of plasma clearance of dexamethasone and anti–asparaginase antibody levels on risk of relapse was assessed in 410 children who were treated on a front-line clinical trial for acute lymphoblastic leukemia and were evaluable for all pharmacologic measures, using multivariate analyses, adjusting for standard clinical and biologic prognostic factors. Dexamethasone clearance (mean ± SD) was higher (P = 3 × 10−8) in patients whose sera was positive (17.7 ± 18.6 L/h per m2) versus nega-tive (10.6 ± 5.99 L/h per m2) for anti–asparaginase antibodies. In multivariate analyses, higher dexamethasone clearance was associated with a higher risk of any relapse (P = .01) and of central nervous system relapse (P = .014). Central nervous system relapse was also more common in patients with anti–asparaginase antibodies (P = .019). In conclusion, systemic clearance of dexamethasone is higher in patients with anti–asparaginase antibodies. Lower exposure to both drugs was associated with an increased risk of relapse.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4871-4871
Author(s):  
Christian Omar Ramos Peñafiel ◽  
Humberto Baldemar Castellanos Sinco ◽  
Efreen Montaño Figueroa ◽  
María Guadalupe Leon Gonzalez ◽  
Etta Rozen Fuller ◽  
...  

Abstract Introduction Acute lymphoblastic leukemia is a lymphoproliferative malignancy characterized by an uncontrolled growth of lymphoid progenitors of B or T lineage, who evade apoptosis and displace normal hematopoiesis. Based on the pediatric pre-induction steroid, the protocol assessed the impact ALL0288 GIMEMA 7 days pre-induction with steroids, complete remissions (CR). Similar to this study, our institutional protocol also considers the pre-induction with steroids, but unlike the Italian protocol fewer cases steroid responders and a lower rate of complete remissions were recorded. A 36 month follow-up overall survival was 32% The main objective of this study was to evaluate the results at 5 years of follow institutional protocol based on a pre-treatment with steroids HGMLAL07. Patients. We included patients diagnosed with acute lymphoblastic leukemia under morphological criteria French-American-British (FAB) and corroborated by flow cytometry. The criteria for complete remission was seen at 4 weeks of treatment (<5% blasts in bone marrow with normal number of leukocytes and platelets). Prophylaxis central nervous system was carried out by weekly and then monthly lumbar punctures to the maintenance stage. If express the BCR-ABL oncogene was added to treatment Imatinib 400mg PO every 24 hours you first 14 days of each cycle. Materials and methods. Study design. Retrospective cohort study of adult patients treated with institutional protocol HGMLAL07 carriers de novo acute lymphoid leukemia in the period from 2007 to 2015 in the Department of Hematology, General Hospital of Mexico. We excluded patients treated with another induction therapy and those of mixed lineage leukemia. General treatment. It was considered relapse if they had at any time monitoring the presence of more than 10% blasts in bone marrow or isolation in the cerebrospinal fluid. If u have HLA-matched donor, he referred to the area of stem cell transplantation. Statistic analysis. SPSS statistical software version 20.0 was used. Chi-Square test considered significant at p <0.05 (95% CI) was used to test hypothesis testing. Survival analysis was performed using the Kaplan-Meyer test for comparing groups for overall survival and disease-free survival test was used log-rank2. The COX regression model was used for the risk function between different risk variables Results. Of the 262 patients with LLA de novo, 255 patients met the inclusion criteria and were treated with institutional protocol HGMLAL07, 52.9% were male gender (n = 135) and 47.1% (n = 120) Gender female. The mean age was 31 years (range 16- 80 years), the average for older female compared with male (34 versus 29years, p = 0.001, 95% CI). The average of leukocytes at diagnosis was 56.1 x 10 (9) / L. Phenotypically, most were classified leukemia B-cell (95.3%, n = 243) and the remaining T lineage (4.7%, n = 12). Only 3.1% of cases expressed the oncogene BCRABL1 (n = 8). Finally concluding that 62.7% of cases were classified as high risk (n = 160) and 37.3% (n = 95) and normal risk. Response to induction therapy. Of the 255 patients who started the protocol remission induction in 1.6% of confirmed with CNS infiltration diagnosis (n = 4). The complete remission rate was around 82.7% (n = 211), registering an induction mortality 3.9% (n = 10). A total of 34 patients were considered refractory leukemia (n = 34), requiring a second line treatment. Among the variables that showed the impact of the failure to initial treatment (refractory or death) were the type of risk at diagnosis (p = 0.020) and white blood cell count> 30 x 10 (9) / L (p = 0.001). Mean neutrophil recovery was 28 days and the platelet recovery was at 32 days. The main cause of death was infectious processes, followed by central nervous system bleeding. Postremisión treatment and outcome Of the total patients, 51% (n = 130) presented relapse, the main site bone marrow, followed by infiltration of the central nervous system Prognostic factors that impacted on survival The median overall survival (OS) was 1053 days, with survival at 5 years of follow-up of 29%, overall survival at 5 years was influenced by the type of risk (p = 0.020, 95% CI). None of the risk factors impact on survival at one year. The disease-free survival was 11% at 5 years of follow-up, within the variables that impacted on the SLE, a leukocyte count> 30 (9) / L and age> 35 years directly impacted prognosis (p = 0.006 and p = 0.030, 95% CI respectively). Disclosures No relevant conflicts of interest to declare.


Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2333
Author(s):  
Judit C. Sági ◽  
András Gézsi ◽  
Bálint Egyed ◽  
Zsuzsanna Jakab ◽  
Noémi Benedek ◽  
...  

Despite improving cure rates in childhood acute lymphoblastic leukemia (ALL), therapeutic side effects and relapse are ongoing challenges. These can also affect the central nervous system (CNS). Our aim was to identify germline gene polymorphisms that influence the risk of CNS events. Sixty single nucleotide polymorphisms (SNPs) in 20 genes were genotyped in a Hungarian non-matched ALL cohort of 36 cases with chemotherapy related acute toxic encephalopathy (ATE) and 544 controls. Five significant SNPs were further analyzed in an extended Austrian-Czech-NOPHO cohort (n = 107 cases, n = 211 controls) but none of the associations could be validated. Overall populations including all nations’ matched cohorts for ATE (n = 426) with seizure subgroup (n = 133) and posterior reversible encephalopathy syndrome (PRES, n = 251) were analyzed, as well. We found that patients with ABCB1 rs1045642, rs1128503 or rs2032582 TT genotypes were more prone to have seizures but those with rs1045642 TT developed PRES less frequently. The same SNPs were also examined in relation to ALL relapse on a case-control matched cohort of 320 patients from all groups. Those with rs1128503 CC or rs2032582 GG genotypes showed higher incidence of CNS relapse. Our results suggest that blood-brain-barrier drug transporter gene-polymorphisms might have an inverse association with seizures and CNS relapse.


2021 ◽  
Vol 47 (01) ◽  
pp. 074-083
Author(s):  
Kathryn W. Chang ◽  
Steve Owen ◽  
Michaela Gaspar ◽  
Mike Laffan ◽  
Deepa R. J. Arachchillage

AbstractThis study aimed to determine the impact of major hemorrhage (MH) protocol (MHP) activation on blood administration and patient outcome at a UK major cardiothoracic center. MH was defined in patients (> 16 years) as those who received > 5 units of red blood cells (RBCs) in < 4 hours, or > 10 units in 24 hours. Data were collected retrospectively from patient electronic records and hospital transfusion databases recording issue of blood products from January 2016 to December 2018. Of 134 patients with MH, 24 had activated MHP and 110 did not have activated MHP. Groups were similar for age, sex, baseline hemoglobin, platelet count, coagulation screen, and renal function with no difference in the baseline clinical characteristics. The total number of red cell units (median and [IQR]) transfused was no different in the patients with activated (7.5 [5–11.75]) versus nonactivated (9 [6–12]) MHP (p = 0.35). Patients in the nonactivated MHP group received significantly higher number of platelet units (median: 3 vs. 2, p = 0.014), plasma (median: 4.5 vs. 1.5, p = 0.0007), and cryoprecipitate (median: 2 vs. 1, p = 0.008). However, activation of MHP was associated with higher mortality at 24 hours compared with patients with nonactivation of MHP (33.3 vs. 10.9%, p = 0.005) and 30 days (58.3 vs. 30.9%, p = 0.01). The total RBC and platelet (but not fresh frozen plasma [FFP]) units received were higher in deceased patients than in survivors. Increased mortality was associated with a higher RBC:FFP ratio. Only 26% of patients received tranexamic acid and these patients had higher mortality at 30 days but not at 24 hours. Deceased patients at 30 days had higher levels of fibrinogen than those who survived (median: 2.4 vs. 1.8, p = 0.01). Patients with activated MHP had significantly higher mortality at both 24 hours and 30 days despite lack of difference in the baseline characteristics of the patients with activated MHP versus nonactivated MHP groups. The increased mortality associated with a higher RBC:FFP ratio suggests dilutional coagulopathy may contribute to mortality, but higher fibrinogen at baseline was not protective.


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