Markers of hypercoagulability in children with newly diagnosed acute lymphoblastic leukemia.

BACKGROUND: Venous thromboembolism (VTE) is a known complication for children with acute lymphoblastic leukemia (ALL). The aim of this study was to identify laboratory biomarkers that predict which children with ALL are at risk for VTE during induction chemotherapy. MATERIALS AND METHODS: Newly diagnosed ALL patients admitted to Children's Hospital Los Angeles with a central venous catheter (CVC) were eligible to participate. Participants' blood samples (complete blood count [CBC], quantitative D-dimer, prothrombin fragment 1.2 [PTF 1.2], and thrombin-antithrombin complexes [TAT]) were collected at day 0 (baseline/prior to induction), day 7 (±2 days), day 14 (±2 days), day 21 (±2 days), and day 28 (±2 days) of induction chemotherapy or until participants presented with a symptomatic VTE. RESULTS: Seventy-five participants aged 1-21 years were enrolled and included in the final analysis. Twenty-six (35%) of the 75 participants were diagnosed with a CVC-associated VTE (22 asymptomatic and four symptomatic). There was a statistically significant difference between VTE and non-VTE participants for D-dimer (odds ratio [OR] 1.61, 95% confidence interval [CI]: 1.59-1.64), TAT (OR 1.34, 95% CI: 1.32-1.38), and PTF 1.2 (OR 1.31, 95% CI: 1.25-1.37) at all time points. Participants >10 years had a significantly higher risk of developing a VTE compared to participants <4 years (p = .007). CONCLUSION: Older children with ALL as well as those with an elevated TAT, PTF 1.2, or D-dimer showed an increased risk of VTE, which may hold potential for predicting VTE in future studies.

Allergic reactions and antiasparaginase antibodies in children with high-risk acute lymphoblastic leukemia: A children's oncology group report.

BACKGROUND: The objectives of this study were to assess the incidence of clinical allergy and end-induction antiasparaginase (anti-ASNase) antibodies in children with high-risk acute lymphoblastic leukemia treated with pegylated (PEG) Escherichia coli ASNase and to determine whether they carry any prognostic significance. METHODS: Of 2057 eligible patients, 1155 were allocated to augmented arms in which PEG ASNase replaced native ASNase postinduction. Erwinia chrysanthemi (Erwinia) ASNase could be used to replace native ASNase after allergy, if available. Allergy and survival data were complete for 990 patients. End-induction antibody titers were available for 600 patients. RESULTS: During the consolidation phase, 289 of 990 patients (29.2%) had an allergic reaction. There were fewer allergic reactions to Erwinia ASNase than to native ASNase (odds ratio, 4.33; P < .0001) or PEG ASNase (odds ratio, 3.08; P < .0001) only during phase 1 of interim maintenance. There was no significant difference in 5-year event-free survival (EFS) between patients who received PEG ASNase throughout the entire study postinduction versus those who developed an allergic reaction to PEG ASNase during consolidation phase and subsequently received Erwinia ASNase (80.8% ± 2.8% and 81.6% ± 3.8%, respectively; P = .66). Patients who had positive antibody titers postinduction were more likely to have an allergic reaction to PEG ASNase (odds ratio, 2.4; P < .001). The 5-year EFS rate between patients who had negative versus positive antibody titers (80% ± 2.6% and 77.7% ± 4.3%, respectively; P = .68) and between patients who did not receive any ASNase postconsolidation and those who received PEG ASNase throughout the study (P = .22) were significantly different. CONCLUSIONS: The current results demonstrate differences in the incidence rates of toxicity between ASNase preparations but not in EFS. The presence of anti-ASNase antibodies did not affect EFS.

Corrigendum to 'Efficacy of emicizumab is maintained throughout dosing intervals for bleed prophylaxis' [Research and Practice in Thrombosis and Haemostasis, Volume 7, Issue 2, February 2023, 100077].

[This corrects the article DOI: 10.1016/j.rpth.2023.100077.].

Efficacy of emicizumab is maintained throughout dosing intervals for bleed prophylaxis.

Background: Across the HAVEN clinical trial program, the efficacy of emicizumab has been demonstrated in children, adolescents, and adults with hemophilia A, with or without factor VIII inhibitors. After the 4-week loading dose period, emicizumab concentrations are expected to remain at levels that provide bleed protection throughout the entire dosing interval, regardless of the chosen maintenance dosing regimen, ie, weekly, every 2 weeks, or every 4 weeks. Objectives: The objective of this study was to examine the timing of treated bleeds within the dosing intervals for emicizumab administered during the HAVEN 1 to 4 studies. Methods: In this post hoc analysis, we pooled data from all the participants of the HAVEN 1 to 4 studies and analyzed the timing of treated bleeds in relation to the emicizumab dose. Results: A total of 392 participants were included in this analysis, with a median (range) age of 28.0 years (1.1-77.0 years). Target joints were identified in 237 of 392 (60.5%) participants before the study entry. Overall, 211 of 392 (53.8%) participants experienced 907 treated bleeding events. The total mean (SD) annualized bleeding rate across the 4 studies was 1.6 (5.9). There was no evidence that bleeding events clustered on any 1 particular day in any dosing schedule from HAVEN 1 to 4 (P > .05 for all 3 treatment regimens). Conclusion: Data from the HAVEN 1 to 4 trials show consistent bleed prevention within the dosing interval, regardless of the dosing regimen chosen. These findings provide further evidence of the sustained efficacy of emicizumab across all approved dosing regimens to reduce bleeding in people with hemophilia A.

Surgical outcomes in people with hemophilia A taking emicizumab prophylaxis: experience from the HAVEN 1-4 studies.

Many people with hemophilia A (PwHA) undergo surgery in their lifetime, often because of complications of their disease. Emicizumab is the first bispecific monoclonal antibody prophylactic therapy for PwHA, and its efficacy and safety have been previously demonstrated; however, there is a need to build an evidence base on the management of PwHA on emicizumab undergoing surgery. Data from the HAVEN 1-4 phase 3 clinical trials were pooled to provide a summary of all minor and major surgeries in PwHA with or without factor VIII (FVIII) inhibitors who were receiving emicizumab prophylaxis. Overall, 233 surgeries were carried out during the HAVEN 1-4 trials: 215 minor surgeries (including minor dental and joint procedures, central venous access device placement or removal, and endoscopies) in 115 PwHA (64 with FVIII inhibitors) and 18 major surgeries (including arthroplasty and synovectomy) in 18 PwHA (10 with FVIII inhibitors). Perioperative hemostatic support was at the discretion of the treating physician. Overall, the median (interquartile range [IQR]) age was 33.5 (13.0-49.0) years and the median (IQR) emicizumab exposure time before surgery was 278.0 (177.0-431.0) days. Among the 215 minor surgeries, 141 (65.6%) were managed without additional prophylactic factor concentrate, and of those, 121 (85.8%) were not associated with a postoperative bleed. The majority (15 of 18 [83.3%]) of major surgeries were managed with additional prophylactic factor concentrate. Twelve (80.0%) of these 15 surgeries were associated with no intraoperative or postoperative bleeds. The data demonstrate that minor and major surgeries can be performed safely in PwHA receiving emicizumab prophylaxis. These trials are registered at www.clinicaltrials.gov as #NCT02622321, #NCT02795767, #NCT02847637, and #NCT03020160.

Establishment of a framework for assessing mortality in persons with congenital hemophilia A and its application to an adverse event reporting database.

BACKGROUND: Despite recent therapeutic advances, life expectancy in persons with congenital hemophilia A (PwcHA) remains below that of the non-HA population. As new therapies are introduced, a uniform approach to the assessment of mortality is required for comprehensive evaluation of risk-benefit profiles, timely identification of emerging safety signals, and comparisons between treatments. OBJECTIVES: Develop and test a framework for consistent reporting and analysis of mortality across past, current, and future therapies. PATIENTS/METHODS: We identified known causes of mortality in PwcHA through literature review, analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, and expert insights. Leading causes of death in general populations are those recognized by the Centers for Disease Control and Prevention and the World Health Organization. We developed an algorithm for assessing fatalities in PwcHA and used this to categorize FAERS data as a proof of concept. RESULTS: PwcHA share mortality causes with the non-HA population including cardiovascular disease, malignancy, infections, pulmonary disease, dementias, and trauma/suicide. Causes associated with HA include hemorrhage, thrombosis, human immunodeficiency virus, hepatitis C virus, and liver dysfunction. We propose an algorithm employing these classes to categorize fatalities and use it to classify FAERS fatality data between 01/01/2000 and 03/31/2020; the most common causes were hemorrhage (22.2%) and thrombosis (10.4%). CONCLUSIONS: A conceptual framework for examining mortality in PwcHA receiving any hemophilia therapy is proposed to analyze and interpret fatalities, enabling consistent and objective assessment. Application of the framework using FAERS data suggests a generally consistent pattern of reported mortality across HA treatments, supporting the utility of this unified approach.

Outcome for children treated for relapsed or refractory acute myelogenous leukemia (rAML): a Therapeutic Advances in Childhood Leukemia (TACL) Consortium study.

BACKGROUND: Current event-free survival (EFS) rates for children with newly diagnosed acute myeloid leukemia (AML) approach 50-60%. We hypothesize that further improvements in survival are unlikely to be achieved with traditional approaches such as dose intensive chemotherapy or hematopoietic stem cell transplants, since these therapies have been rigorously explored in clinical trials. This report highlights efforts to assess the response rates and survival outcomes after first or greater relapse in children with AML. PROCEDURE: We performed a retrospective cohort review of pediatric patients with relapsed and refractory AML (rAML) previously treated at TACL institutions between the years of 1995 and 2004. Data regarding disease characteristics at diagnosis and relapse, treatment response, and survival was collected on 99 patients and 164 medullary relapses or treatment failures. RESULTS: The complete response (CR) rate following the second therapeutic attempt was 56 +/- 5%. CR rates following a third treatment attempt was 25 +/- 8% while 17 +/- 7% achieved CR following the fourth through sixth treatments. The 5-year disease-free survival in patients achieving CR following a second therapeutic attempt was 43 +/- 7%. The 5-year EFS and overall survival (OS) rates for all patients receiving a second treatment attempt was 24 +/- 5% and 29 +/- 5%, respectively. CONCLUSIONS: This CR rate following a second therapeutic attempt and OS rate in patients with rAML is consistent with the literature. There are limited published data of CR rates for subsequent relapses. Our data can serve as a historical benchmark to compare outcomes of future therapeutic trials in rAML against traditional chemotherapy regimens.

Obesity and risk for venous thromboembolism from contemporary therapy for pediatric acute lymphoblastic leukemia.

INTRODUCTION: Acute lymphoblastic leukemia (ALL) therapy confers risk for venous thromboembolism (VTE) and associated acute and long-term morbidity. Obesity increases VTE risk in the general population but its impact on ALL therapy-associated VTE is unknown. METHODS: In a retrospective cohort of children treated for ALL between 2008 and 2016 (n = 294), we analyzed obesity at diagnosis (body mass index [BMI] ≥95%) and subsequent development of VTE. A subset participated in two concurrent prospective ALL trials studying body composition via dual-energy X-ray absorptiometry (DXA) (n = 35) and hypercoagulability via thromboelastography (TEG) (n = 46). Secondary analyses explored whether precise measurement of body fat and/or global hemostasis ex vivo by TEG could further delineate VTE risk in the obese. RESULTS: Overall, we found 27/294 (9.2%) patients developed symptomatic VTE during therapy, 19/27 (70%) occurred during Induction. Study-defined "serious" VTE developed in 4/294 (1.4%) of patients. Obesity but not overweight was strongly predictive of symptomatic VTE (obesity odds ratio = 3.8, 95% confidence interval 1.5-9.6, p = 0.008). In the DXA subset, only 2/35 patients developed symptomatic VTE. However, within those prospectively screened during Induction, 30% (14/46) developed VTE; eight (17%) of these were asymptomatic and found only via screening. CONCLUSIONS: In this pediatric ALL cohort, obesity conferred more than a three-fold increased risk for symptomatic VTE. In a subgroup of patients who underwent active screening, up to a third were noted to have VTE (symptomatic and asymptomatic). TEG did not predict VTE. Additional studies are necessary to validate these findings and to further refine a risk-stratified approach to thrombo-prevention during ALL therapy.

Venous Thromboembolism in Children with Cancer and Blood Disorders.

Venous thromboembolism (VTE) in children is multifactorial and most often related to a combination of inherited and acquired thrombophilias. Children with cancer and blood disorders are often at risk for VTE due to disease-related factors such as inflammation and abnormal blood flow and treatment-related factors such as central venous catheters and surgery. We will review risk factors for VTE in children with leukemia, lymphoma, and solid tumors. We will also review risk factors for VTE in children with blood disorders with specific focus on sickle cell anemia and hemophilia. We will present the available evidence and clinical guidelines for prevention and treatment of VTE in these populations.

The bleeding newborn: A review of presentation, diagnosis, and management.

The neonatal hemostatic system is continuously developing with rapidly changing concentrations of many coagulation proteins. Thus, determining the etiology of bleeding in a newborn has additional challenges beyond those seen in older children or adults. Bleeding can be seen in both well and sick newborns due to congenital causes, such as hemophilia or von Willebrand disease, and acquired causes, such as liver failure or disseminated intravascular coagulation. Traditional coagulation testing should be interpreted with caution and with the help of a hematologist, if possible, due to the greatly different normal ranges between neonates as compared with older children and adults. However, despite these challenges, both clinical and laboratory clues can guide physicians appropriately to diagnose and treat the bleeding newborn.

FondaKIDS II: long-term follow-up data of children receiving fondaparinux for treatment of venous thromboembolic events.

BACKGROUND: The incidence of venous thrombotic events (VTE) and use of anticoagulants in children have both risen over time. It is imperative that safety and efficacy studies of newer anticoagulants include children. OBJECTIVES: The purpose of this study was to investigate the long-term safety, dosing, and efficacy of fondaparinux in children. PATIENTS/METHODS: The study included children 1-18 years old treated with fondaparinux at Children's Hospital Los Angeles. Descriptive statistics were used to present our findings. RESULTS: Data from 35 patients were collected and analyzed. Fourteen of 22 evaluable patients (63.6%) had complete resolution of their thrombus, 6/22 (27.3%) had partial resolution, and 2/22 (9.1%) had no change. Ten patients needed a total of 16 dose adjustments over a median 152 days treatment duration to achieve therapeutic levels. Two patients (9.1%) had VTE recurrence. There were 3 major (intracranial hemorrhage- prior to initiation of fondaparinux, pulmonary hemorrhage, and subretinal hemorrhage) and 6 minor (2 with blood in stool, 1 with injection site, 1 CVC site, 1 tracheostomy bleed, 1 epistaxis) bleeding events. CONCLUSIONS: In this long-term follow-up study on children treated with fondaparinux for VTE, 90.9% of patients had either complete or partial resolution while the recurrence rate was in line with previous studies. There were 9 bleeding events (3 major and 6 minor), though only 1 event required the discontinuation of fondaparinux. Given the advantages of fondaparinux over other anticoagulants, this study suggests that fondaparinux could be considered a safe and effective alternative for the management of VTE in children.

A novel approach for detecting hypercoagulability utilizing thromboelastography.

INTRODUCTION: The thromboelastograph is a point-of-care, global hemostasis assay that measures the dynamics of clot formation, including physical properties, over time and is licensed for use in monitoring coagulation during complex surgical procedures. It has more recently been used as a research tool to investigate various bleeding and clotting disorders. Although attempts have been made to use thromboelastography to detect hypercoagulable states, thus far a consistent, reliable approach has not been discovered. The objective of this study was to develop a novel approach utilizing thromboelastography that is sensitive for detecting hypercoagulability. MATERIALS AND METHODS: Healthy, adult volunteers provided blood samples that were subjected to pre-analytic modifications from standard thromboelastography methods with the goal of prolonging clot initiation and propagation times. The methods which resulted in the desired changes in a consistent and reliable manner utilized corn trypsin inhibitor, a contact pathway inhibitor, on unactivated blood samples. To demonstrate that these methods are sensitive to detecting hypercoagulability, increasing concentrations of recombinant human thrombin were added as a surrogate for hypercoagulability. RESULTS: Our methods were able to consistently and statistically significantly change the baseline TEG parameters of R time, K time, and angle in the desired fashion. Additionally, these methods were able to detect increasing concentrations of thrombin. CONCLUSIONS: We describe a novel approach in which thromboelastography is highly sensitive to detecting increasing concentrations of thrombin in vitro. Further studies are underway to determine if these methods will be sensitive for detecting hypercoagulable states in vivo.

Outcome of patients treated for relapsed or refractory acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium study.

PURPOSE: Despite improvements in treatment, approximately 20% of patients with acute lymphoblastic leukemia (ALL) experience relapse and do poorly. The Therapeutic Advances in Childhood Leukemia (TACL) Consortium was assembled to assess novel drugs for children with resistant leukemia. We hypothesize that novel agents and combinations that fail to improve baseline complete remission rates in comparable populations are unlikely to contribute to better outcomes and should be abandoned. We sought to define response rates and disease-free survival (DFS) rates in patients treated at TACL institutions, which could serve as a comparator for future studies. PATIENTS AND METHODS: We performed a retrospective cohort review of patients with relapsed and refractory ALL previously treated at TACL institutions between the years of 1995 and 2004. Data regarding initial and relapsed disease characteristics, disease response, and survival were collected and compared with those of published reports. RESULTS: Complete remission (CR) rates (mean +/- SE) were 83% +/- 4% for early first marrow relapse, 93% +/- 3% for late first marrow relapse, 44% +/- 5% for second marrow relapse, and 27% +/- 6% for third marrow relapse. Five-year DFS rates in CR2 and CR3 were 27% +/- 4% and 15% +/- 7% respectively. CONCLUSION: We generally confirm a 40% CR rate for second and subsequent relapse, but our remission rate for early first relapse seems better than that reported in the literature (83% v approximately 70%). Our data may allow useful modeling of an expected remission rate for any population of patients who experience relapse.