scholarly journals Drug Monitoring of Asparaginase Activity to Detect Silent Inactivation in Pediatric Acute Lymphoblastic Leukemia Patients Receiving Peg-Asparaginase

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3968-3968 ◽  
Author(s):  
Van Thu Huynh ◽  
Alexa Love ◽  
Mary English ◽  
Carol Hwang Lin
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Prospective Study ◽  
Lymphoblastic Leukemia ◽  
Lymphoblastic Lymphoma ◽  
Therapeutic Drug ◽  
Allergic Reactions ◽  
Newly Diagnosed ◽  
Drug Levels ◽  
Pediatric All ◽  
Asparaginase Activity

Abstract Background Asparaginase is a key component of pediatric therapy for Acute lymphoblastic leukemia (ALL). Two formulations available in the USA are pegylated E. coli asparaginase (PEG) and Erwinia chrysanthemi asparaginase (Erwinaze). Hypersensitivity reactions have been observed in ~ 20% of patients receiving PEG. Patients with overt symptoms of hypersensitivity are typically switched to Erwinaze. In cases of hypersensitivity, anti-asparaginase antibodies may be present that neutralize circulating asparaginase and in some cases may present without clinical signs, a phenomenon known as silent inactivation. Few studies have prospectively evaluated the incidence of silent inactivation in pediatric ALL patients. In this prospective study, we performed therapeutic drug monitoring of asparaginase levels on newly diagnosed pediatric ALL patients to determine the incidence of silent inactivation and to switch patients to Erwinaze, if silent inactivation was detected. Methods A prospective study was conducted at CHOC Children's Hospital on patients with newly diagnosed ALL or lymphoblastic lymphoma between 2016 to 2018. Patients designated as high or very high risk B-ALL post induction, T-ALL and B/T lymphoblastic lymphoma were enrolled. Patients received therapy on or according to a COG protocol with PEG (2500 IU/m2) administered via 2-hour i.v. infusion without antihistamine or steroid premedication. Asparaginase activity was measured days 7 and 14 after each of the two PEG doses during Consolidation. Serum asparaginase level of >0.1 IU/ml and >0.02 IU/ml was considered therapeutic at 7 or 14 days post PEG, respectively. Silent inactivation was defined as serum asparaginase levels below these values without signs of overt allergy. Any patient found to have silent inactivation was immediately switched to Erwinaze. Patient characteristics, common adverse events associated with asparaginase and serum asparaginase levels were analyzed. Descriptive statistics and Pearson's coefficient was used for analysis. Results Thirty-nine patients were enrolled with a mean age of 9.8 years (range, 1-23) with the majority being B-ALL (87.2%) of which 3 were Ph-like (Table 1). Twelve patients (30.7%) had overt hypersensitivity and one patient (2.6%) had silent inactivation. One patient had overt hypersensitivity after completion of the PEG infusion with a measured asparaginase level 7 days post that was therapeutic. One-hundred fifteen drug levels were collected, for an average of 2.9 levels per patient (maximum 4 levels). There was a difference in mean asparaginase activity in patients without hypersensitivity compared to those with hypersensitivity (1.110 IU/mL versus 0.737 IU/mL, respectively, p=.0095). There were no significant differences in asparaginase levels based on age, gender or BSA. The highest asparaginase level observed was 7 days post the 2nd dose of asparaginase in Consolidation. Overall, the incidence of patients with CTCAE grade ≥2 transaminitis was 51.3% (n=20), hyperglycemia 2.6 % (n=1), hyperbilirubinemia 5.1% (n=2), and thrombosis 2.6% (n=1). Pancreatitis of any grade was not observed in this cohort. Discussion We detected silent inactivation in a single patient who had an asparaginase level of 0.01 seven days after the first dose of PEG and showed no signs of overt allergic reaction. This patient was switched to Erwinaze and an asparaginase level drawn 48 hours post Erwinaze was therapeutic at 0.719. Another patient developed a hypersensitivity reaction 12-hours after PEG and had a serum asparaginase level of 1.29 7-days post PEG. This suggests that not all anti-asparaginase antibodies are neutralizing since this patient continued to demonstrate therapeutic drug levels. The incidence of allergic reactions to PEG at our institution appears higher than reported in prior studies. Our data shows a statistically significant difference between serum asparaginase levels in patients with and without hypersensitivity. Our study also shows that silent inactivation exists in a very small proportion of patients. Additionally, patients who develop late allergic reactions to PEG may still have therapeutic asparaginase levels. Thus, monitoring of asparaginase levels may be warranted to detect silent inactivation and to monitor asparaginase levels in patients who develop delayed hypersensitivity. A larger prospective study is needed to confirm these results. Disclosures No relevant conflicts of interest to declare.

Improving pneumococcal vaccination rates in pediatric acute lymphoblastic leukemia/lymphoblastic lymphoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18666-e18666
Author(s):  
Simone Chang ◽  
Alexandra Cheerva ◽  
Michael Angelo Huang ◽  
Kerry McGowan ◽  
Esther E Knapp ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Hematologic Malignancy ◽  
Lymphoblastic Leukemia ◽  
Pneumococcal Vaccination ◽  
Vaccination Rate ◽  
Lymphoblastic Lymphoma ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Vaccination Rates ◽  
Targeted Interventions ◽  
Pediatric All

e18666 Background: Pediatric Acute Lymphoblastic Leukemia/ Lymphoblastic Lymphoma (ALL/LLy) is the most common pediatric cancer. Invasive pneumococcal disease (IPD) is prevalent in this population and the Centers for Disease Control and Prevention recommends pneumococcal vaccination to decrease morbidity and mortality. Despite these recommendations, vaccination rates remain low and the incidence of IPD among children with hematologic malignancy is significantly higher compared to the average pediatric population. An interventional study was designed to improve the vaccination rate and reduce the incidence of IPD in our institution. Methods: A plan-do-study-act (PDSA) model of quality improvement (QI) was used. Chart review at our institute was done for the 6-month period of January 2020 - June 2020 and baseline rates for pneumococcal polysaccharide (PPSV23) vaccination were calculated. Patients were included if they were ≥ 2 years old, diagnosed with ALL/LLy, and undergoing maintenance. A multidisciplinary team performed the root cause analysis. Immunization records were obtained and reviewed and targeted interventions were implemented. The interventions used are outlined in Table. The percentage of pediatric ALL/LLy patients per month in maintenance who received age-appropriate pneumococcal vaccinations was monitored before and after the interventions. Results: Analysis of the 6-month retrospective cohort (n=36) showed a baseline vaccination rate of 5.5%. During the subsequent 6-month phase with interventions, 40 patients were prospectively enrolled. Demographics showed a mean age of 10.2 years (range, 2-21) and a predominantly male (66.7%) cohort. B-cell ALL/LLy comprised the majority (78.9%); the rest included T-cell ALL/LLy and mixed phenotype acute leukemia. As seen in Table, the percentage receiving at least 1 pneumococcal vaccine increased from 5.5% to 84.8% over the first 3 months, this plateaued around 81%. Completion of the series mirrored this and increased to 74.2%. Pre-visit planning and cues proved to be the most helpful interventions. Conclusions: Use of a PDSA model successfully improved pneumococcal vaccination rates in the pediatric ALL/LLy population. We suggest these results can be achieved with planning and implementation of the outlined interventions. [Table: see text]

Thromboelastography to Detect Hypercoagulability in Patients with Newly Diagnosed Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1118-1118 ◽  
Author(s):  
Richard Har Ko ◽  
Richard Sposto ◽  
Fariba Goodarzian ◽  
Roxana Carmona ◽  
Siobhan Vasquez ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Central Venous Catheter ◽  
Prospective Study ◽  
Thrombin Generation ◽  
Lymphoblastic Leukemia ◽  
Venous Catheter ◽  
Newly Diagnosed ◽  
Older Children ◽  
Central Venous ◽  
Patient Demographics

Abstract Background: Patients with newly diagnosed acute lymphoblastic leukemia (ALL) are known to be hypercoagulable due to their disease and from side effects of chemotherapy. Studies have shown rates of venous thromboembolism (VTE) between 5-70% in patients with ALL (depending on various definitions and modalities of investigation) (Caruso et al, 2006, Mitchell et al, 2003). Established methods to monitor hypercoagulability or predict VTE do not exist. We have previously described methods using thromboelastography (TEG) to detect hypercoagulability (Ko et al., 2013). We believe that a global assay of hemostasis such as TEG holds promise to monitor hypercoagulability in patients with newly diagnosed ALL. Methods: This was a prospective study of newly diagnosed ALL patients between 1-21 years in whom a central venous catheter (either a peripherally inserted central catheter [PICC] or a subcutaneously implanted port) was placed at diagnosis. Patients were enrolled at Children's Hospital Los Angeles from September 2012 until July 2015. None of the patients had a known past medical or family history of thrombosis or bleeding or clotting disorders and none were taking any medications (other than induction chemotherapy) that could affect coagulation (e.g. NSAIDs). Patients had complete blood counts (CBC), TEG, and markers of thrombin generation (quantitative D-dimers, thrombin:antithrombin complexes, and prothrombin fragment 1.2) performed before initiation of treatment and then once weekly during induction until they either presented with a symptomatic VTE or completed Induction therapy. All patients had a Doppler ultrasound of the extremity in which their central venous catheter was placed at the end of induction or at presentation with symptoms suggesting thrombosis. Results: Eighty patients have been enrolled (see Table 1 for demographics) with 72 being fully evaluable currently. Three (4.3%) patients developed symptomatic VTE and 7 (15%) patients had an asymptomatic VTE for an overall incidence of VTE of 21.7%. We demonstrate that R time gradually increases over time from baseline during induction therapy. Additionally, maximum amplitude (MA) is initially diminished, but then increases with time. There were no statistically significant differences in VTE incidence between males and females, different age groups (though there was a trend towards increased incidence for older children), or CVC type (none of the patients with an implanted port had a VTE). Interestingly, MA did not seem to be associated with platelet count. Conclusion: Patients in this prospective study of patients with newly diagnosed ALL during induction at a single institution show rates of thrombosis in patients with ALL similar to that in the literature. Furthermore, TEG results demonstrated a shortening of the clotting time (R) and an increase in the clot rigidity (MA) during induction. Though not statistically significant, older children and patients with HR-ALL were more likely to have a VTE. Additional analyses will be performed to investigate the ability of the TEG, as well as the CBC and markers of thrombin generation, in predicting the development of VTE in these patients. Table 1. Patient Demographics Patient Demographics Gender Female 33 (46%) Male 38 (54%) Age < 5 years 28 (39%) 9-12 years 26 (37%) 10+ years 17 (24%) Patient VTE classification Symptomatic VTE 3 (4%) Asymptomatic VTE 12 (17%) No VTE 56 (79%) Demographics by CVC Type Type of CVC PICC Port-a-Cath Total Gender Female 35 (45%) 3 (100%) 38 (48%) Male 42 (55%) 0 (0%) 42 (53%) Age < 5 years 29 (38%) 2 (67%) 31 (39%) 9-12 years 30 (39%) 0 (0%) 30 (38%) 10+ years 18 (23%) 1 (33%) 19 (24%) Type of ALL SR-ALL 54 (70%) 0 (0%) 54 (68%) HR-ALL 23 (30%) 2 (67%) 25 (31%) T-ALL 0 (0%) 1 (33%) 1 (1%) Patient VTE classification Symptomatic VTE 3 (4%) 0 (0%) 3 (4%) Asymptomatic VTE 12 (17%) 0 (0%) 12 (17%) No VTE 54 (78%) 2 (100%) 56 (79%) Patient VTE classification Demographics by VTE Symptomatic VTE Asymptomatic VTE No VTE Total Gender Female 1 (33%) 7 (58%) 25 (45%) 33 (46%) Male 2 (67%) 5 (42%) 31 (55%) 38 (54%) Age categories < 5 years 1 (33%) 4 (33%) 23 (41%) 28 (39%) 9-12 years 0 (0%) 3 (25%) 23 (41%) 26 (37%) 10+ years 2 (67%) 5 (42%) 10 (18%) 17 (24%) Type of ALL SR-ALL 1 (33%) 7 (58%) 39 (70%) 47 (66%) HR-ALL 2 (67%) 5 (42%) 16 (29%) 23 (32%) T-ALL 0 (0%) 0 (0%) 1 (2%) 1 (1%) Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Ko: Alexion: Honoraria; NovoNordisk: Consultancy. Young:Bayer: Consultancy; Kedrion: Consultancy; Novo Nordisk: Consultancy, Honoraria; Baxter: Consultancy; Biogen Idec: Consultancy, Honoraria.

Nilotinib Combined with Multi-Agents Chemotherapy for Adult Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Results of a Prospective Study from a Single Center

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1301-1301
Author(s):  
Bingcheng Liu ◽  
Ying Wang ◽  
Chunlin Zhou ◽  
Hui Wei ◽  
Dong Lin ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Maintenance Therapy ◽  
Prospective Study ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
Induction Cycle

Abstract Background: Imatinib combined with conventional chemotherapy has significantly improved the prognosis of adults with Philadelphia-positive acute lymphoblastic leukemia ( Ph+ ALL ). Nilotinib, the second generation TKIs is approximately 30 fold more potent than imatinib and is active in vitro against multiple BCR/ABL mutations. Here, we report the efficacy and safety of nilotinib combined with multiple reagents chemotherapy in newly diagnosed patients with Ph+ ALL. Methods: Newly diagnosed Ph+ ALL patients aged 15 to 59 and with adequate organ function were recruited. The 4weeks induction cycle consist of vincristine, daunorubicin, cyclophosphamide and prednisone. After achieving hematological complete remission (HCR), patients received 2 years of consolidation and maintenance therapy. Consolidation therapy was including 7 courses of multiple drug chemotherapy or allogeneic/autologous hematopoietic cell transplantation (allo/auto HCT). Nilotinib was the only drug for maintenance therapy. Nilotinib 400mg was given orally twice daily along with combination chemotherapy starting from day 15 of induction until the initiation of conditioning for transplantation, hematological relapse or continuing for 2 years since achievement of hematological complete remission (HCR).Central nervous system (CNS) prophylaxis was performed by intrathecally administering triple agents. The data cut-off day was June 1st 2015. HCR and molecular complete remission (MCR), overall survival(OS), hematologic relapse free survival (HRFS), toxicity, nilotinib concentration in serum and cerebrospinal fluid(CSF) were evaluated. MCR was defined as Bcr-Abl fusion gene becomes negative in bone marrow using quantitative RT-PCR. Results: A total of 30 patients (19 males and 11 females) were enrolled from September 2011 to November 2013. The median age was 40 (range 21-57) years old. The type of BCR breakpoint was minor in 24 patients, major in 2 patients and both in 4 patients. All the 30 patients (100%) and 8 patients (26.7%) achieved HCR and MCR respectively after the induction cycle. Cumulative MCR rate was 80%. 17 patients underwent HCT, 14 patients with alloHCT and 2 patients with autoHCT in first HCR, 1 patient received alloHCT after relapse. 9 patients died from leukemia relapse and 4 patients died post-alloHCT without relapse. The median HRFS and OS were 20.7 and 34 months respectively. The 4 year HRFS rate was 41% and the 4 year OS rate was 48%. The molecular response after induction has no impact on HRFS and OS. Patients achieving MCR had better HRFS (32 vs 8.9 months, p=0.006) but not OS(33.3vs 17.2months, p=0.068) than those patient without MCR. During induction, 23 patients experienced infectious fever including 2 patients with septicemia and 6 patients with pneumonia needing antifungal therapy. Intestinal obstruction occurred in 7 patients during induction and relived by interrupting nilotinib treatment. The incidence of non-hematologic adverse events (AE) over grade 3 during the study was 23% jaundice, 10% rash, 6.7% arthralgia and bone pain, 6.7%headache, 3.3% ALT elevation. No QTc prolongation over 500ms happened. Grade 2 tachycardia and premature ventricular contraction occurred in 2 patients and 1 patient respectively. During the high-dose methotrexate treatment cycle, delaying of methotrexate metabolism happened in 20 patients (66.7%), increasing creatine occurred in 8 patients (26.7%, grade 3 in 3 patients), 1 patient received haemodialysis. Nilotinib serum level reached to stable concentration after 15 days of administration. Only traces of nilotinib was detected in CSF. Conclusion: In this prospective study, combination of nilotinib and cytotoxic drug was shown to be effective and tolerable for adult Ph+ALL. Nilotinib could not penetrate the blood brain barrier. (ChiCTR-ONC-12002469) Disclosures Off Label Use: nilotinib,the 2nd generation TKI, was approved for CML. Wang:Novarits and Bristol-Mayers squibb. G.S.: Consultancy.

The Level of Histone Deacetylase 7 in Pediatric ALL and Its Effect on Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5099-5099
Author(s):  
Bei Hou ◽  
Huyong Zheng
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Histone Deacetylase ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Intermediate Risk ◽  
Newly Diagnosed ◽  
Altered Expression ◽  
Expression Levels ◽  
Pediatric All

Abstract Background Leukemia is the most common pediatric malignancy and a major cause of mortality and morbidity in children. Nearly 15,000 children are newly diagnosed with leukemia in China each year and among them, acute lymphoblastic leukemia (ALL) accounts for more than 75%. Altered expression of histone deacetylases (HDACs) is a common feature in several human malignancies and may represent an interesting target for cancer treatment . With increasing focus on precision medicine, HDACs have emerged as promising therapeutic target in pediatric ALL. Methods We detect the histone deacetylase 7(HDAC7) expression in the bone marrow samples of 254 children with newly diagnosed acute lymphoblastic leukemia (ALL) at Hematology Oncology Center of Beijing Children`s Hospital from January 2010 to the end of 2012 via qRT-PCR using the TaqMan gene expression probes. 3 patients that have been completely remission for 3 years are used as normal control. We find out that the expression levels of HDAC7 are associated with the unfavorable events (such as induction failure, relapse and/or death due to any cause ) occurence rates and 5-EFS. Results Here we find that the HDAC7 expression levels are associated with the unfavorable events occurence rates and 5-EFS. We find that in the intermediate risk group of 157 patients, the patients who have lower level of HDAC7 expression have higher unfavorable event occurence rates than the higher expression of HDAC7 group (p=0.001). The group of higher HDAC7 expression have higher 5-EFS than the lower group in both the intermediate risk group(p=0.001) and the T-ALL group(n=18). Conclusion We conclude that HDAC7 has a potent anti-oncogenic effect on specific pediatric B-cell leukemia, indicating that its deregulation may contribute to the pathogenesis of the disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals A prospective study on drug monitoring of PEGasparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia

Blood ◽  
2014 ◽  
Vol 123 (13) ◽  
pp. 2026-2033 ◽  
Author(s):  
Wing H. Tong ◽  
Rob Pieters ◽  
Gertjan J. L. Kaspers ◽  
D. Maroeska W. M. te Loo ◽  
Marc B. Bierings ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Prospective Study ◽  
Lymphoblastic Leukemia ◽  
Activity Levels ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
E Coli ◽  
Key Points ◽  
Asparaginase Activity ◽  
Erwinia Asparaginase ◽  
A Prospective Study

Key Points Use of native E coli asparaginase in induction leads to high hypersensitivity rates to PEGasparaginase in intensification. Switching to Erwinia asparaginase leads to effective asparaginase activity levels in most patients who experienced an allergy to PEGasparaginase.

scholarly journals Retrospective cohort study monitoring PEG-asparaginase activity in acute lymphoblastic leukemia patients with and without premedication

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1007
Author(s):  
Michael Losasso ◽  
Bruce Bostrom ◽  
Yoav Messinger
Keyword(s):  
Cohort Study ◽  
Acute Lymphoblastic Leukemia ◽  
Retrospective Cohort Study ◽  
Neutralizing Antibodies ◽  
Retrospective Cohort ◽  
Lymphoblastic Leukemia ◽  
Allergic Reactions ◽  
Number Of Patients ◽  
Before And After ◽  
Asparaginase Activity

Background: PEG-L-asparaginase (pegaspargase) is a critical component of therapy for children and adults with acute lymphoblastic leukemia (ALL). Allergic reactions, which may occur in up to one third of patients, are the major cause for discontinuation. One study reported lower rates of allergic reactions with premedication. Besides allergy, an unknown number of patients develop silent neutralizing antibodies not associated with allergic reactions. The purpose of this retrospective cohort study was to determine the incidence of silent inactivation of pegasparaginase and compare incidence of allergic reactions with and without premedication. Methods: Using a commercial assay, asparaginase activity was monitored following pegaspargase (2500 units/m2) in newly diagnosed children and young adults with B- and T-cell ALL from February 2013 to May 2017. The incidence of allergic reactions before and after initiation of premedication in May 2015 was compared. Results: One patient out of 59 (1.7%) had silent inactivation after the second dose. No patient had silent inactivation after the first pegaspargase dose and no standard risk B-cell ALL patients, who received only two pegaspargase doses in combination with oral dexamethasone, had silent inactivation. The incidence of grade 3 or 4 allergic reactions was 3.7% per dose with premedication (methylprednisolone, acetaminophen and diphenhydramine) versus 5.2% without.  The incidence per patient with premedication given for most of the doses was 8.3% versus 17% without. These values are not statistically significant. Premedication did not affect pegaspargase activity. Conclusions: Due to the low incidence of silent inactivation with intravenous pegaspargase and the unlikely event patients receiving only two doses of pegasparaginase would receive erwinase for this possible transient silent inactivation, we recommend routine monitoring of pegaspargase activity only in patients scheduled to receive more than two doses.

scholarly journals Retrospective cohort study monitoring PEG-asparaginase activity in acute lymphoblastic leukemia patients with and without premedication

F1000Research ◽  
2020 ◽  
Vol 8 ◽  
pp. 1007
Author(s):  
Michael Losasso ◽  
Bruce Bostrom ◽  
Yoav Messinger
Keyword(s):  
Cohort Study ◽  
Acute Lymphoblastic Leukemia ◽  
Retrospective Cohort Study ◽  
Neutralizing Antibodies ◽  
Retrospective Cohort ◽  
Lymphoblastic Leukemia ◽  
Allergic Reactions ◽  
Number Of Patients ◽  
Before And After ◽  
Asparaginase Activity

Background: PEG-L-asparaginase (pegaspargase) is a critical component of therapy for children and adults with acute lymphoblastic leukemia (ALL). Allergic reactions, which may occur in up to one third of patients, are the major cause for discontinuation. One study reported lower rates of allergic reactions with premedication. Besides allergy, an unknown number of patients develop silent neutralizing antibodies not associated with allergic reactions. The purpose of this retrospective cohort study was to determine the incidence of silent inactivation of pegasparaginase and compare incidence of allergic reactions with and without premedication. Methods: Using a commercial assay, asparaginase activity was monitored following pegaspargase (2500 units/m ) in newly diagnosed children and young adults with B- and T-cell ALL from February 2013 to May 2017. The incidence of allergic reactions before and after initiation of premedication in May 2015 was compared. Results: One patient out of 59 (1.7%) had silent inactivation after the second dose. No patient had silent inactivation after the first pegaspargase dose and no standard risk B-cell ALL patients, who received only two pegaspargase doses in combination with oral dexamethasone, had silent inactivation. The incidence of grade 3 or 4 allergic reactions was 3.7% per dose with premedication (methylprednisolone, acetaminophen and diphenhydramine) versus 5.2% without. The incidence per patient with premedication given for most of the doses was 8.3% versus 17% without. These values are not statistically significant. Premedication did not affect pegaspargase activity. Conclusions: Due to the low incidence of silent inactivation with intravenous pegaspargase and the unlikely event patients receiving only two doses of pegasparaginase would receive erwinase for this possible transient silent inactivation, we recommend routine monitoring of pegaspargase activity only in patients scheduled to receive more than two doses.

A Prospective Study On Drug Monitoring Of Pegasparaginase and Erwinia Asparaginase and Asparaginase Antibodies In Pediatric Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2634-2634 ◽  
Author(s):  
Wing H. Tong ◽  
Rob Pieters ◽  
Gertjan Kaspers ◽  
Maroeska D.W.M. te Loo ◽  
Marc Bierings ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Drug Monitoring ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Activity Level ◽  
Therapeutic Drug ◽  
Activity Levels ◽  
Asparaginase Activity ◽  
Erwinia Asparaginase ◽  
Pre Treatment

Abstract Purpose A prospective drug monitoring study was performed to analyse the efficacy of very prolonged use of PEGasparaginase and Erwiniaasparaginase by assessing asparaginase activity, asparagine, glutamine levels and asparaginase antibodies in children with newly diagnosed acute lymphoblastic leukemia (ALL). Patients and Methods Children received 15 PEGasparaginase infusions (2,500 IU/m2 every other week) according to the Dutch Childhood Oncology Group (DCOG)-ALL-10 medium risk intensification protocol after having received native E.coli asparaginase (5,000 IU/m2 every 3 days, 8 doses in total) in the induction course. In case of an allergy to or silent inactivation of PEGasparaginase, Erwinia asparaginase (20,000 IU/m22x-3x per week) was given. All asparaginase preparations were administered intravenously in one hour. Serum asparaginase activity, asparagine, glutamine levels and asparaginase antibodies were measured. Results 89 patients were enrolled in two centers to monitor the PEGasparaginase courses. 62/89 (70%) patients without clinical allergy to and without silent inactivation of PEGasparaginase had serum mean trough activity levels of 899 U/L which were much higher than requested. 20/89 (22%) of the patients showed an allergy and 7/89 (8%) silent inactivation in intensification. All 20 allergic patients (grade 1-4 Common Terminology Criteria Adverse Events) showed PEGasparaginase activity levels of zero. This was not due to the fact that the PEGasparaginase infusion was stopped, as 18 patients showed their allergic reactions at the second dose whereas the serum asparaginase activity level after the first full dose already appeared to be zero in all 18 cases. Moreover, in 4 patients with grade 1 allergy, the second full PEGasparaginase dose was given with pre-treatment of clemastine and hydrocortisone, also resulting in unmeasurable serum activity levels of PEGasparaginase. 59 children from 7 centers with allergy to or silent inactivation of PEGasparaginase who were switched to Erwinia asparaginase were enrolled to monitor the Erwiniaasparaginase courses. Only 2/59 (3%) of the patients developed an allergy to Erwinia asparaginase. No patients with silent inactivation of Erwinia asparaginase were seen. Of the non-allergic Erwinia asparaginase patients, 55/57 (96%) had at least one serum Erwinia asparaginase trough activity level ≥ 100 U/L and 57/57 (100%) ≥ 50 U/L. In 65% and 85% of all samples had serum trough activity levels ≥ 100 U/L and ≥ 50 U/L, respectively. In 33% of patients, the administration frequency could be reduced from 3 times to 2 times per week based upon serum Erwinia asparaginase activity levels ≥ 100 U/L at 72 hours. Serum asparagine level was strongly depleted, but not always completely depleted in Erwinia asparaginase treated patients in contrast to PEGasparaginase. Serum glutamine level was slightly lowered by Erwiniaasparaginase, but no glutamine depletion was observed with both compounds. The presence of serum asparaginase antibodies is related to allergy to and silent inactivation of asparaginase, but predicting asparaginase allergy or silent inactivation is clinically not applicable because of the low specificity, 64% (95%-CI: 43%-82%). Conclusion The use of native E.coli asparaginase in induction leads to 22% allergy and 8% silent inactivation rates of PEGasparaginase in intensification. Therefore, PEGasparaginase should be used upfront already in the induction course instead of native E.coli asparaginase. The dose of PEGasparaginase of 2,500 IU/m2 can be lowered. Switching to Erwinia asparaginase in case of allergy to or silent inactivation of PEGasparaginase leads to effective asparaginase activity levels in the majority of patients. Measuring serum asparaginase activity levels to monitor efficacy of asparaginase is preferred over serum asparagine levels and serum asparaginase antibodies. Therapeutic drug monitoring has now been implemented to individualize PEGasparaginase and Erwinia asparaginase dose and to detect silent inactivation in the current DCOG-ALL-11 protocol. Disclosures: No relevant conflicts of interest to declare.

A randomized comparison of nativeEscherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study

Blood ◽  
2002 ◽  
Vol 99 (6) ◽  
pp. 1986-1994 ◽  
Author(s):  
Vassilios I. Avramis ◽  
Susan Sencer ◽  
Antonia P. Periclou ◽  
Harland Sather ◽  
Bruce C. Bostrom ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Titer ◽  
Lymphoblastic Leukemia ◽  
Newly Diagnosed ◽  
Nonlinear Mixed Effects Model ◽  
Enzyme Preparations ◽  
Cancer Group ◽  
Asparaginase Activity ◽  
Rapid Clearance ◽  
Standard Risk

Abstract For this study, 118 children with standard-risk acute lymphoblastic leukemia (ALL) were given randomized assignments to receive native or pegylated Escherichia coli asparaginase as part of induction and 2 delayed intensification phases. Patients treated with pegaspargase had more rapid clearance of lymphoblasts from day 7 and day 14 bone marrow aspirates and more prolonged asparaginase activity than those treated with native asparaginase. In the first delayed intensification phase, 26% of native asparaginase patients had high-titer antibodies, whereas 2% of pegaspargase patients had those levels. High-titer antibodies were associated with low asparaginase activity in the native arm, but not in the pegaspargase arm. Adverse events, infections, and hospitalization were similar between arms. Event-free survival at 3 years was 82%. A population pharmacodynamic model using the nonlinear mixed effects model (NONMEM) program was developed that closely fit the measured enzyme activity and asparagine concentrations. Half-lives of asparaginase were 5.5 days and 26 hours for pegaspargase and native asparaginase, respectively. There was correlation between asparaginase enzymatic activity and depletion of asparagine or glutamine in serum. In cerebrospinal fluid asparagine, depletion was similar with both enzyme preparations. Intensive pegaspargase for newly diagnosed ALL should be tested further in a larger population.

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