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Pharmacogenomics Nov 2021To evaluate the associations between human leukocyte antigen ( variants and the rs6021191 variant in nuclear factor of activated T cells 2 () with PEG-asparaginase...
To evaluate the associations between human leukocyte antigen ( variants and the rs6021191 variant in nuclear factor of activated T cells 2 () with PEG-asparaginase hypersensitivity in children with acute lymphoblastic leukemia (ALL) treated according to the Chinese Children Leukemia Group (CCLG) ALL 2018 protocol. genotyping was performed using a PCR sequence-based typing (SBT) method. rs6021191 was genotyped applying TaqMan Genotyping Assay. T-ALL and higher risk groups were at higher risk for PEG-asparaginase hypersensitivity. No association was found between rs6021191 and PEG-asparaginase hypersensitivity. *16:02 variant was associated with PEG-asparaginase allergy both in univariate and multivariate logistic regression analysis. Our results confirm that variations in might influence the development of asparaginase hypersensitivity.
Topics: Adolescent; Asparaginase; Child; Child, Preschool; Drug Hypersensitivity; Female; Genotype; HLA-DRB1 Chains; Humans; Infant; Male; NFATC Transcription Factors; Polyethylene Glycols; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 34747637
DOI: 10.2217/pgs-2021-0107 -
The Journal of Allergy and Clinical... Jan 2022
Topics: Asparaginase; COVID-19; COVID-19 Vaccines; Humans; Hypersensitivity, Immediate; Polyethylene Glycols; RNA, Messenger; SARS-CoV-2
PubMed: 34678498
DOI: 10.1016/j.jaip.2021.09.051 -
World Journal of Clinical Cases Sep 2021Chronic active Epstein-Barr virus infection (EBV) is a systemic EBV-positive lymphoproliferative disease, which may lead to fatal illness. There is currently no standard...
BACKGROUND
Chronic active Epstein-Barr virus infection (EBV) is a systemic EBV-positive lymphoproliferative disease, which may lead to fatal illness. There is currently no standard treatment regimen for chronic active EBV (CAEBV), and hematopoietic stem cell transplantation is the only effective treatment. We here report a CAEBV patient treated with PEG-aspargase, who achieved negative EBV-DNA.
CASE SUMMARY
A 33-year-old female Chinese patient who had fever for approximately 3 mo was admitted to our hospital in December 2017. EBV-DNA was positive with a high copy number. She was diagnosed with chronic active EB virus infection. PEG-aspargase was administered at a dose of 1500 U/m at a 14-d interval, resulting in eradication of EBV for more than 6 mo. The effect of PEG-aspargase in this patient was excellent.
CONCLUSION
A chemotherapy regimen containing PEG-aspargase for CAEBV may be further considered.
PubMed: 34621836
DOI: 10.12998/wjcc.v9.i26.7845 -
Blood Advances Jan 2022Adolescent and young adult patients with acute lymphoblastic leukemia (ALL) have superior outcomes when treated on pediatric regimens. Pediatric ALL regimens rely...
Adolescent and young adult patients with acute lymphoblastic leukemia (ALL) have superior outcomes when treated on pediatric regimens. Pediatric ALL regimens rely heavily on corticosteroids and asparaginase and are known to increase the risk of osteonecrosis (ON) and fractures in children, particularly adolescents. Orthopedic toxicity among young adults treated on pediatric-inspired regimens is not well described. Here, we report the symptomatic orthopedic toxicities of patients aged 15 to 50 years treated on sequential Dana-Farber Cancer Institute ALL Consortium protocols. Among 367 patients with a median age of 23 years (range, 15-50 years; 68% aged <30 years), 60 patients were diagnosed with ON (5-year cumulative incidence, 17%; 95% confidence interval [CI], 13-22), and 40 patients experienced fracture (5-year cumulative incidence, 12%; 95% CI, 8-15). Patients aged <30 years were significantly more likely to be diagnosed with ON (5-year cumulative incidence, 21% vs 8%; P = .004). Patients treated more recently on pegaspargase-based protocols were significantly more likely to be diagnosed with ON compared with those treated on earlier trials with native Escherichia coli asparaginase (5-year cumulative incidence, 24% vs 5%; P < .001). Of the 54 ON events for which adequate information was available, surgery was performed in 25 (46%). Patients with ON had superior overall survival (OS) compared with those without (multivariable OS hazard ratio, 0.15; 95% CI, 0.05-0.46; P = .001; ON included as a time-varying exposure). Increased rates of orthopedic toxicity in late-generation protocols may be driven by the pharmacokinetic drug interaction between pegaspargase and dexamethasone, leading to higher dexamethasone exposure.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Disease-Free Survival; Humans; Incidence; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proportional Hazards Models; Young Adult
PubMed: 34610104
DOI: 10.1182/bloodadvances.2021005278 -
Applied Biochemistry and Biotechnology Feb 2022PEGylation is a reductive alkylation of a protein N-terminal/α-amine of protein with mPEG chain by reducing agent. To obtain quantitative and site-specific PEGylation,...
PEGylation is a reductive alkylation of a protein N-terminal/α-amine of protein with mPEG chain by reducing agent. To obtain quantitative and site-specific PEGylation, sodium cyanoborohydride is commonly used as a reducing agent. The reduction process of sodium cyanoborohydride produces highly poisonous hydrogen cyanide, which may render the final product toxic. Herein, we have studied various reducing agents such as dimethylamine borane, triethylamine borane, trimethylamine borane, pyridine borane, morpholine borane, 2-picoline borane, and 5-ethyl-2-methyl-pyridine borane were tested as alternatives to sodium cyanoborohydride for the PEGylation of L-asparaginase. The characterization of reacted pegaspargase was carried out by SDS-PAGE, Western blotting, SEC-HPLC, RP-HPLC, SEC-MALS, CD, enzyme activity, and cell proliferation assays using with lymphoblast cells and MTS/PMS as substrate. Pyridine borane was determined to be the best acceptable reducing agent for PEGylation in terms of purity and activity. As a result, instead of sodium cyanoborohydride, pyridine borane can be employed.
Topics: Borohydrides
PubMed: 34550501
DOI: 10.1007/s12010-021-03657-y -
European Journal of Cancer (Oxford,... Nov 2021This review focuses on asparaginase, a key component of childhood acute lymphoblastic leukaemia (ALL) treatment since the 1970s. This review evaluates how much...
This review focuses on asparaginase, a key component of childhood acute lymphoblastic leukaemia (ALL) treatment since the 1970s. This review evaluates how much asparaginase is needed for optimal outcome in childhood ALL. We provide an overview of asparaginase dose intensity, i.e. duration of total cumulative exposure in weeks and level of exposure reflected by dose and/or asparaginase activity level, and the corresponding outcome. We systematically searched papers published between January 1990 and March 2021 in the PubMed and MEDLINE databases and included 20 papers. The level and duration of exposure were based on the pharmacokinetic profile of the drug and the assumption that trough asparaginase activity levels of ≥100 IU/L should be achieved for complete l-asparagine depletion. The statistical meta-analysis of outcomes was not performed because different outcome measures were used. The level of exposure was not associated with the outcome as long as therapeutic asparaginase activity levels of ≥100 IU/L were reached. Conflicting results were found in the randomised controlled trials, but all truncation studies showed that the duration of exposure (expressed as weeks of l-asparagine depletion) does affect the outcome; however, no clear cutoff for optimal exposure duration was determined. Optimal exposure duration will also depend on immunophenotype, (cyto)genetic subgroups, risk group stratification and backbone therapy.
Topics: Antineoplastic Agents; Asparaginase; Child; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Neoplasm Recurrence, Local; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Progression-Free Survival; Randomized Controlled Trials as Topic; Time Factors
PubMed: 34536947
DOI: 10.1016/j.ejca.2021.08.025 -
Clinical Journal of Oncology Nursing Oct 2021Pegaspargase, a chemotherapy drug known to improve survival outcomes in acute lymphoblastic leukemia, is associated with a risk for hypersensitivity reactions. At a...
Pegaspargase, a chemotherapy drug known to improve survival outcomes in acute lymphoblastic leukemia, is associated with a risk for hypersensitivity reactions. At a children's hospital in the midwestern United States, two patients developed unusual reactions consisting of disseminated urticaria about two weeks after their second dose of pegaspargase. Both patients then proceeded to have severe anaphylaxis with the third dose of pegaspargase. These cases highlight the importance of advanced practice nurses being alert for the occurrence of unusual and delayed reactions to chemotherapy administration.
Topics: Anaphylaxis; Asparaginase; Child; Drug Hypersensitivity; Humans; Polyethylene Glycols; Urticaria
PubMed: 34533506
DOI: 10.1188/21.CJON.511-513 -
Cancer Medicine Nov 2021Pegaspargase (PEG-ASP) is an integral component of therapy for acute lymphoblastic leukemia (ALL) but is associated with hepatotoxicity that may delay or limit future...
BACKGROUND
Pegaspargase (PEG-ASP) is an integral component of therapy for acute lymphoblastic leukemia (ALL) but is associated with hepatotoxicity that may delay or limit future therapy. Obese and adolescent and young adult (AYA) patients are at high risk. Levocarnitine has been described as potentially beneficial for the treatment or prevention of PEG-ASP-associated hepatotoxicity.
METHODS
We collected data for patients age ≥10 years who received levocarnitine during induction therapy for ALL, compared to a similar patient cohort who did not receive levocarnitine. The primary endpoint was conjugated bilirubin (c.bili) >3 mg/dl. Secondary endpoints were transaminases >10× the upper limit of normal and any Grade ≥3 hepatotoxicity.
RESULTS
Fifty-two patients received levocarnitine for prophylaxis (n = 29) or rescue (n = 32) of hepatotoxicity. Compared to 109 patients without levocarnitine, more patients receiving levocarnitine were obese and/or older and had significantly higher values for some hepatotoxicity markers at diagnosis and after PEG-ASP. Levocarnitine regimens varied widely; no adverse effects of levocarnitine were identified. Obesity and AYA status were associated with an increased risk of conjugated hyperbilirubinemia and severe transaminitis. Multivariable analysis identified a protective effect of levocarnitine on the development of c.bili >3 mg/dl (OR 0.12, p = 0.029). There was no difference between groups in CTCAE Grade ≥3 hepatotoxicity. C.bili >3 mg/dl during induction was associated with lower event-free survival.
CONCLUSIONS
This real-world data on levocarnitine supplementation during ALL induction highlights the risk of PEG-ASP-associated hepatotoxicity in obese and AYA patients, and hepatotoxicity's potential impact on survival. Levocarnitine supplementation may be protective, but prospective studies are needed to confirm these findings.
Topics: Adolescent; Adult; Antineoplastic Agents; Asparaginase; Carnitine; Chemical and Drug Induced Liver Injury; Child; Female; Humans; Induction Chemotherapy; Male; Pediatric Obesity; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survival Analysis; Young Adult
PubMed: 34528411
DOI: 10.1002/cam4.4281 -
American Journal of Hematology Nov 2021Extranodal natural killer/T-cell lymphoma, nasal-type (ENKTL) is a distinct subtype of non-Hodgkin lymphoma and most of the patients presented localized disease....
Extranodal natural killer/T-cell lymphoma, nasal-type (ENKTL) is a distinct subtype of non-Hodgkin lymphoma and most of the patients presented localized disease. Combined modality therapy (CMT), namely chemotherapy combined with radiotherapy, has been recommended for patients with early-stage ENKTL. However, the optimal CMT has not been fully clarified. This study reports the efficacy and toxicity of sequential P-GEMOX (pegaspargase, gemcitabine and oxaliplatin) and radiotherapy in a large Chinese cohort comprising of 202 patients diagnosed with early-stage ENKTL from six medical centers. The observed best overall response rate was 96.0% and 168 (83.2%) patients achieved complete remission. With a median follow-up of 44.1 months, the 3-year progression-free survival (PFS) and overall survival (OS) were 74.6% and 85.2%, respectively. Multivariate analysis suggested that extensive primary tumor (PFS, hazard ratio [HR] 3.660, 95% CI 1.820-7.359, p < 0.001; OS, HR 3.825, 95% CI 1.442-10.148, p = 0.007) and Eastern Cooperative Oncology Group performance status ≥ 2 (PFS, 3.042, 95% CI 1.468-6.306, p = 0.003; OS, HR 3.983, 95% CI 1.678-9.457, p = 0.02) were independent prognostic factors for survival outcomes. Among the established prognostic models for ENKTL, the nomogram-revised risk index model had optimal prognostic risk stratification ability (PFS, p < 0.001; OS, p < 0.001) and relatively balanced population distribution. The adverse events of this CMT were well-tolerated and manageable. In conclusion, sequential P-GEMOX and radiotherapy showed favorable efficacy with acceptable toxicity, and could be an effective treatment option for early-stage ENKTL patients.
Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Deoxycytidine; Female; Humans; Lymphoma, Extranodal NK-T-Cell; Male; Middle Aged; Organoplatinum Compounds; Polyethylene Glycols; Prognosis; Survival Analysis; Treatment Outcome; Young Adult
PubMed: 34449095
DOI: 10.1002/ajh.26335 -
Pediatric Blood & Cancer Nov 2021Vaccinationis a critical tool in the prevention of COVID-19 infection for individuals and for communities. The mRNA vaccines contain polyethylene glycol (PEG) as a...
Safety of administration of BNT162b2 mRNA (Pfizer-BioNTech) COVID-19 vaccine in youths and young adults with a history of acute lymphoblastic leukemia and allergy to PEG-asparaginase.
Vaccinationis a critical tool in the prevention of COVID-19 infection for individuals and for communities. The mRNA vaccines contain polyethylene glycol (PEG) as a stabilizer. Currently, in North America, only the BNT162b2 (Pfizer-BioNTech) mRNA vaccine is approved for individuals aged 12-17. Most patients treated with contemporary regimens for acute lymphoblastic leukemia receive PEG-asparaginase (PEG-ASNase) and 10%-30% will develop allergic reactions. Optimizing access and safety for vaccine administration for these patients is critical. This report describes a process developed to support COVID vaccination in a cohort of adolescents and young adults with a history of PEG-ASNase allergy.
Topics: Adolescent; Adult; Antineoplastic Agents; Asparaginase; BNT162 Vaccine; COVID-19; COVID-19 Vaccines; Child; Drug Hypersensitivity; Humans; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Young Adult
PubMed: 34398511
DOI: 10.1002/pbc.29295