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The Journal of Allergy and Clinical... Feb 2022
Topics: Asparaginase; COVID-19; COVID-19 Vaccines; Humans; Hypersensitivity; Polyethylene Glycols; SARS-CoV-2
PubMed: 34883262
DOI: 10.1016/j.jaip.2021.11.025 -
European Journal of Drug Metabolism and... Mar 2022Besides allergic reactions, antibodies against polyethylene glycol (PEG) have been associated with reduced PEG-asparaginase (PEG-ASNase) activity. Population... (Clinical Trial)
Clinical Trial
Impact of Antibodies Against Polyethylene Glycol on the Pharmacokinetics of PEGylated Asparaginase in Children with Acute Lymphoblastic Leukaemia: A Population Pharmacokinetic Approach.
BACKGROUND AND OBJECTIVES
Besides allergic reactions, antibodies against polyethylene glycol (PEG) have been associated with reduced PEG-asparaginase (PEG-ASNase) activity. Population pharmacokinetics (popPK) allow for an in-depth investigation of the influence of anti-PEG antibodies on PEG-ASNase pharmacokinetics.
METHODS
PEG-ASNase activity (6261 samples) and anti-PEG antibodies (2082/6412 samples prior to/post administration) in 1444 children with acute lymphoblastic leukaemia treated in the AIEOP-BFM ALL 2009 trial were evaluated. Patients received two doses of PEG-ASNase during induction (2500 U/m, intravenous, biweekly) and a third dose during reinduction treatment. Anti-PEG IgG and IgM measured prior to and post administration were explored for their influence on the initial clearance of PEG-ASNase using a previously established popPK model. Categorical and continuous antibody data, including each isotype individually as well as in combination, were assessed.
RESULTS
High pre-existing levels of anti-PEG antibodies increase the initial drug clearance. Analysed separately, both anti-PEG IgG and IgM were significant covariates; the stronger effect was observed for anti-PEG IgM. Hockey stick models best described the data. For anti-PEG IgM, each additional log unit above the estimated cut point was related to a 41.4% increase in initial clearance after the first dose in induction. Antibody levels below the cut point were not associated with an effect on clearance. The combination of both isotypes did not provide additional information compared to anti-PEG IgM alone. Antibody levels post administration were not associated with an effect on clearance.
CONCLUSION
Pre-existing antibodies against PEG-ASNase significantly increased the initial clearance in a subgroup of patients showing high antibody levels. (Trial registration: EU clinical trials register; EudraCT No: 2007-004270-43; first registered 23 October 2009.).
Topics: Antineoplastic Agents; Asparaginase; Child; Humans; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 34878584
DOI: 10.1007/s13318-021-00741-w -
Annals of Palliative Medicine Nov 2021Extranodal natural killer (NK)/T-cell lymphoma-nasal type (ENKTL-NT) is a rare, aggressive subtype of non-Hodgkin's lymphoma associated with Epstein-Barr virus (EBV)... (Review)
Review
Extranodal natural killer (NK)/T-cell lymphoma-nasal type (ENKTL-NT) is a rare, aggressive subtype of non-Hodgkin's lymphoma associated with Epstein-Barr virus (EBV) infection and has a poor prognosis. ENKTL-NT primarily involves the nasal cavity, and the colon as the primary site has rarely been reported. Its lack of a characteristic clinical presentation makes early diagnosis difficult to diagnose early, and misdiagnosis is common without the use of immunohistochemistry of specimens. To further understand this rare solid tumor, we report a case in a 51-year-old male patient admitted to hospital with abdominal pain as the primary symptom. A provisional diagnosis of gastrointestinal perforation was made on the basis of enhanced computed tomography of the abdomen, and emergency surgery was performed. However, 58 days after discharge, he suffered a second colonic perforation, underwent emergency surgery and was diagnosed with primary colonic ENKTL-NT based on the immunohistochemical results of the surgical specimen. He was transferred to the oncology department for chemotherapy after recovery from surgery, with gemcitabine, oxaliplatin, and pegaspargase as the chemotherapy regimen. To date, he has completed 11 courses of chemotherapy, and is now in a significantly improved general condition with no signs of tumor recurrence. We also reviewed and compared the literature related to primary colonic ENKTL-NT.
Topics: Colon; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Killer Cells, Natural; Lymphoma, Extranodal NK-T-Cell; Male; Middle Aged
PubMed: 34872326
DOI: 10.21037/apm-21-3178 -
European Journal of Cancer (Oxford,... Mar 2022Cancer in neonates and infants is a rare but challenging entity. Treatment is complicated by marked physiological changes during the first year of life, excess rates of... (Review)
Review
Cancer in neonates and infants is a rare but challenging entity. Treatment is complicated by marked physiological changes during the first year of life, excess rates of toxicity, mortality, and late effects. Dose optimisation of chemotherapeutics may be an important step to improving outcomes. Body size-based dosing is used for most anticancer drugs used in infants. However, dose regimens are generally not evidence based, and dosing strategies are frequently inconsistent between tumour types and treatment protocols. In this review, we collate available pharmacological evidence supporting dosing regimens in infants for a wide range of cytotoxic drugs. A systematic review was conducted, and available data ranked by a level of evidence (1-5) and a grade of recommendation (A-D) provided on a consensus basis, with recommended dosing approaches indicated as appropriate. For 9 of 29 drugs (busulfan, carboplatin, cyclophosphamide, daunorubicin, etoposide, fludarabine, isotretinoin, melphalan and vincristine), grade A was scored, indicating sufficient pharmacological evidence to recommend a dosing algorithm for infants. For busulfan and carboplatin, sufficient data were available to recommend therapeutic drug monitoring in infants. For eight drugs (actinomycin D, blinatumomab, dinutuximab, doxorubicin, mercaptopurine, pegaspargase, thioguanine and topotecan), some pharmacological evidence was available to guide dosing (graded as B). For the remaining drugs, including commonly used agents such as cisplatin, cytarabine, ifosfamide, and methotrexate, pharmacological evidence for dosing in infants was limited or non-existent: grades C and D were scored for 10 and 2 drugs, respectively. The review provides clinically relevant evidence-based dosing guidance for cytotoxic drugs in neonates and infants.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Carboplatin; Etoposide; Humans; Infant; Infant, Newborn
PubMed: 34865945
DOI: 10.1016/j.ejca.2021.11.001 -
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 -
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