-
Journal of Pharmaceutical and... Sep 2024Therapeutic drug monitoring of pegylated L-asparaginase (ASNase) ensures the drug effectiveness in childhood acute lymphoblastic leukaemia (ALL) patients. The biological...
Improved HPLC method with automated pre-column sample derivatisation for serum pegylated L-asparaginase activity measurement in paediatric acute lymphoblastic leukaemia patients.
Therapeutic drug monitoring of pegylated L-asparaginase (ASNase) ensures the drug effectiveness in childhood acute lymphoblastic leukaemia (ALL) patients. The biological drug property with variable immunogenic host clearance, and the prescription of its generic formulation urge the need for a reliable assay to ensure an optimal treatment and improve outcome. This study aimed to optimise an existing isocratic reversed-phase high performance liquid chromatography (RP-HPLC) method with an automated pre-column sample derivatisation and injection program, and a computational algorithm for measuring serum pegylated ASNase activity in children with ALL. Nath et al.'s method in 2009 was adopted and modified using a pegylated ASNase. A set of Microsoft Excel macros was developed for the serum drug activity computation. An Agilent InfinityLab LC Series 1260 Infinity II Quaternary System with fluorescence detection was employed with an Agilent Poroshell 120 EC-C18 4.6×100 mm, 2.7 µm analytical column. System flow rate was optimised to 2.0 mL/min with 40×10/bar pump compressibility. The O-phthaldialdehyde (OPA) solution composition was optimised to 1 % o-phthaldialdehyde, 0.8 % 2-mercaptoethanol, 7.13 % methanol, and 1.81 % sodium tetraborate. The pre-column derivatisation program mixed 0.1 µL sample with 25 µL OPA solution before the automated injection. Method validation was according to the ICH guidelines. Total analysis time was 15 min, with L-aspartic acid eluted at 0.96 min and internal standard at 4.7 min. The calibration curves showed excellent linearity (R ≥0.9999). Interday precision for the drug activity at 0.1 IU/mL, 0.5 IU/mL, and 1 IU/mL were 4.15 %, 3.05 %, and 3.09 % (n = 6). Mean %error for the drug activity at 0.1 IU/mL, 0.5 IU/mL, and 1 IU/mL were 0.90±4.41 %, -1.37±3.04 %, and -3.03±3.02 % (n = 6). Limit of quantitation was 0.03 IU/mL. Majority of the patients' serum drug activity fell within the assay calibration range. Our improved method is automated, having shorter analysis time with a well-maintained separation resolution that enables a high-throughput analysis for application.
Topics: Asparaginase; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Humans; Chromatography, High Pressure Liquid; Child; Polyethylene Glycols; Drug Monitoring; Antineoplastic Agents; Reproducibility of Results; Chromatography, Reverse-Phase; Calibration
PubMed: 38843612
DOI: 10.1016/j.jpba.2024.116243 -
Annals of Allergy, Asthma & Immunology... May 2024
PubMed: 38762055
DOI: 10.1016/j.anai.2024.05.009 -
Annals of Hematology May 2024
PubMed: 38733396
DOI: 10.1007/s00277-024-05789-7 -
Journal of Oncology Pharmacy Practice :... Apr 2024Pegaspargase (PEG) is a key component of standard regimens for acute lymphoblastic leukemia/lymphoma (ALL) and extranodal natural killer/T-cell lymphoma (NKTCL)....
INTRODUCTION
Pegaspargase (PEG) is a key component of standard regimens for acute lymphoblastic leukemia/lymphoma (ALL) and extranodal natural killer/T-cell lymphoma (NKTCL). Emerging evidence suggests an opportunity to decrease incidence of PEG-associated toxicities with dose capping, but evidence is limited. This study aims to evaluate whether a significant difference in PEG-associated toxicities related to dosing strategy exists and to identify patient-specific or regimen-specific factors for PEG-related toxicity.
METHODS
A retrospective analysis of PEG-associated toxicities was completed in adult patients with ALL or NKTCL who received PEG within Cancer and Leukemia Group B (CALGB) 10403 or modified dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (mSMILE) regimens at the UW Medical Center/Fred Hutchinson Cancer Center. PEG-associated toxicities that occurred through 8 weeks after PEG doses were noted.
RESULTS
Twenty-eight patients received dose-capped PEG, and 29 received noncapped PEG. Fewer all-grade and grade 3/4 toxicities were observed in the dose-capped cohort. Grade 3/4 toxicities observed were hepatotoxicity, hyperglycemia, hypersensitivity, and hypertriglyceridemia. In addition, fewer grade 3/4 pancreatitis and thrombosis events occurred in the dose-capped cohort. Hypertriglyceridemia and hepatotoxicity were associated with the highest cumulative incidence proportions among all toxicities.
CONCLUSION
Dose capping of PEG was associated with a similar or later median onset for most toxicities, a less heterogeneic toxicity profile, and a lower recurrence of most toxicities upon PEG rechallenge compared to the non-dose-capped cohort. Standardizing PEG dose capping in the CALGB 10403 and mSMILE regimens may translate to improved tolerance compared to a historical standard of no dose capping PEG.
PubMed: 38613330
DOI: 10.1177/10781552241246104 -
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Feb 2024To assess the efficacy, safety, and related prognostic factors associated with the P-GemDOx regimen as a first-line treatment for patients with early-stage extranodal...
To assess the efficacy, safety, and related prognostic factors associated with the P-GemDOx regimen as a first-line treatment for patients with early-stage extranodal natural killer (NK) /T cell lymphoma (ENKTL) . A retrospective analysis was performed on sixty early-stage ENKTL patients treated with the P-GemDOx regimen who were admitted to the First Affiliated Hospital of Nanjing Medical University between August 2015 and May 2021. The Chi-square test or Fisher's exact test was used to compare group differences, and the Log-rank test was used to compare the differences in survival. Survival outcomes and prognostic factors were examined. After completing 4 to 6 cycles of P-GemDOx chemotherapy, the overall response rate (ORR) was 88.3%, with forty-six patients (76.7% ) achieving complete response (CR). The 4-year progression-free survival (PFS) and overall survival (OS) rates were (66.3±7.1) % and (79.5±6.0) %, respectively. According to the PINK/PINK-E model, there was no significant difference in survival outcomes among risk groups. 23.3% of patients experienced progression of disease within 24 months (POD<24). OS estimates differed significantly (<0.001) between the POD<24 group (=14) and the POD≥24 group (=46). Analysis showed that SUVmax > 12.8 at diagnosis, non-single nasal cavity infiltration, and response less than CR after 4-6 cycles all had a significant association with POD24. We used these data as the basis for predicting POD<24 international prognostic index (POD24-IPI). Patients were stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high risk (two or three risk factors). These groups were associated with 4-year OS rate of 100%, (85.6±9.7) %, and (65.0±10.2) %, respectively (=0.014). The P-GemDOx regimen was well tolerated, with hematological toxicity being the main side effect. This study demonstrated that the P-GemDOx regimen is effective and safe in the first-line treatment of early-stage ENKTL, and POD24-IPI is a promising prognostic model.
Topics: Humans; Lymphoma, Extranodal NK-T-Cell; Retrospective Studies; Neoplasm Staging; Prognosis; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38604793
DOI: 10.3760/cma.j.cn121090-20230726-00029 -
Toxicology and Applied Pharmacology Apr 2024Asparaginase-associated pancreatitis (AAP) is a severe and potentially life-threatening drug-induced pancreas targeted toxicity in the combined chemotherapy of acute...
Asparaginase-associated pancreatitis (AAP) is a severe and potentially life-threatening drug-induced pancreas targeted toxicity in the combined chemotherapy of acute lymphoblastic leukemia among children and adolescents. The toxicological mechanism of AAP is not yet clear, and there are no effective preventive and treatment measures available clinically. Fibroblast growth factor 21 (FGF21) is a secretory hormone that regulates lipid, glucose, and energy metabolism balance. Acinar tissue is the main source of pancreatic FGF21 protein and plays an important role in maintaining pancreatic metabolic balance. In this study, we found that the decrease of FGF21 in pancreas is closely related to AAP. Pegaspargase (1 IU/g) induces widespread edema and inflammatory infiltration in the pancreas of rats/mice. The specific expression of FGF21 in the acinar tissue of AAP rats was significantly downregulated. Asparaginase caused dysregulation of the ATF4/ATF3/FGF21 axis in acinar tissue or cells, and thus mediated the decrease of FGF21. It greatly activated ATF3 in the acinar, which competed with ATF4 for the Fgf21 promoter, thereby inhibiting the expression of FGF21. Pharmacological replacement of FGF21 (1 mg/kg) or PERK inhibitors (GSK2656157, 25 mg/kg) can significantly mitigate the pancreatic tissue damage and reduce markers of inflammation associated with AAP, representing potential strategies for the prevention and treatment of AAP.
Topics: Animals; Fibroblast Growth Factors; Asparaginase; Pancreatitis; Male; Rats; Pancreas; Mice; Rats, Sprague-Dawley; Polyethylene Glycols; Antineoplastic Agents; Activating Transcription Factor 4; Mice, Inbred C57BL; eIF-2 Kinase
PubMed: 38582373
DOI: 10.1016/j.taap.2024.116920 -
The Lancet. Haematology May 2024Programmed cell death protein 1 (PD-1) inhibitor sintilimab is effective in relapsed and refractory extranodal natural killer/T cell lymphoma (ENKTL), nasal type. We...
First-line sintilimab with pegaspargase, gemcitabine, and oxaliplatin in advanced extranodal natural killer/T cell lymphoma (SPIRIT): a multicentre, single-arm, phase 2 trial.
BACKGROUND
Programmed cell death protein 1 (PD-1) inhibitor sintilimab is effective in relapsed and refractory extranodal natural killer/T cell lymphoma (ENKTL), nasal type. We aimed to assess the safety and activity of sintilimab plus P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) in the first-line setting for advanced ENKTL.
METHODS
The multicentre, single-arm, phase 2 trial was done at three medical centres in China. Patients aged 18-75 years with treatment-naive pathologically confirmed advanced ENKTL and an with Eastern Cooperative Oncology Group performance status score of 0-2 were eligible. Patients received intravenous sintilimab (200 mg on day 1), intramuscular pegaspargase (2000 U/m on day 1), intravenous gemcitabine (1 g/m on days 1 and 8), and intravenous oxaliplatin (130 mg/m on day 1) every 3 weeks for six cycles, followed by intravenous sintilimab (200 mg) every 3 weeks for up to 2 years or until disease progression or unacceptable toxicities. The primary endpoint was the complete response rate in the intention-to-treat population. The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), disease-free survival (DFS), and overall survival. This trial is registered with ClinicalTrials.gov, NCT04127227. Enrolment has been completed, and follow-up is ongoing.
FINDINGS
Between Nov 29, 2019, and Sept 7, 2022, 34 eligible patients were enrolled (median age 39 years [IQR 32-55]; 25 [74%] of 34 patients were male; nine [26%] were female; and all were of Asian ethnicity). At the data cutoff (July 20, 2023), the median follow-up was 21 months (IQR 13-32). The complete response rate was 85% (29 of 34 patients, 95% CI 70-94). Five patients (15%; 95% CI 7-30) attained partial response and the ORR was 100% (34 of 34 patients). 24-month PFS was 64% (95% CI 48-86), 24-month DFS was 72% (54-95), and 36-month overall survival was 76% (52-100). The most common grade 3 or 4 treatment-related adverse events were neutropenia (17 [50%] of 34 patients), anaemia (10 [29%] patients), and hypertriglyceridemia (10 [29%] patients). Hypothyroidism was the most frequent immune-related adverse event (18 [53%]), including grade 3 hypothyroidism in one (3%) patient that caused treatment termination. No severe adverse events occurred. There were three deaths: one due to haemophagocytic syndrome, one due to disease progression, and one due to unknown cause, which were not considered to be treatment related.
INTERPRETATION
Combination of sintilimab with P-GEMOX seems to be an active and safe first-line regimen for patients with advanced ENKTL.
FUNDING
National Key Research and Development Program and National Natural Science Foundation of China, Guangzhou Science and Technology Program and the Clinical Oncology Foundation of Chinese Society of Clinical Oncology.
Topics: Humans; Middle Aged; Asparaginase; Male; Lymphoma, Extranodal NK-T-Cell; Female; Deoxycytidine; Gemcitabine; Polyethylene Glycols; Adult; Antineoplastic Combined Chemotherapy Protocols; Oxaliplatin; Aged; Antibodies, Monoclonal, Humanized; Young Adult; Adolescent
PubMed: 38554717
DOI: 10.1016/S2352-3026(24)00066-8 -
Pediatric Hematology and Oncology Mar 2024Due to an evidence gap, the emetogenicity of intravenous (IV) pegaspargase was unable to be included in the clinical practice guideline classifying chemotherapy...
Due to an evidence gap, the emetogenicity of intravenous (IV) pegaspargase was unable to be included in the clinical practice guideline classifying chemotherapy emetogenicity in pediatric patients. This single-center, retrospective chart review describes the proportion of pediatric patients who did not vomit during the acute phase (complete response; CR) after receiving IV pegaspargase and provides an emetogenicity classification using a preexisting framework. Of 44 patients who received IV pegaspargase between 2011 and 2020, 13 received a serotonin receptor antagonist plus dexamethasone or palonosetron alone and all experienced a CR. We, therefore, recommend classifying IV pegaspargase as moderately emetogenic.
PubMed: 38454568
DOI: 10.1080/08880018.2024.2311886 -
Signal Transduction and Targeted Therapy Mar 2024Natural killer T cell lymphoma (NKTCL) is highly aggressive, with advanced stage patients poorly responding to intensive chemotherapy. To explore effective and safe...
Natural killer T cell lymphoma (NKTCL) is highly aggressive, with advanced stage patients poorly responding to intensive chemotherapy. To explore effective and safe treatment for newly diagnosed advanced stage NKTCL, we conducted a phase II study of anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab (NCT04096690). Twenty-two patients with a median age of 51 years (range, 24-74) were enrolled and treated with induction treatment of pegaspargase 2500 IU/m intramuscularly on day 1 and sintilimab 200 mg intravenously on day 2 for 6 cycles of 21 days, followed by maintenance treatment of sintilimab 200 mg for 28 cycles of 21 days. The complete response and overall response rate after induction treatment were 59% (95%CI, 43-79%) and 68% (95%CI, 47-84%), respectively. With a median follow-up of 30 months, the 2 year progression-free and overall survival rates were 68% (95%CI, 45-83%) and 86% (95%CI, 63-95%), respectively. The most frequently grade 3/4 adverse events were neutropenia (32%, n = 7) and hypofibrinogenemia (18%, n = 4), which were manageable and led to no discontinuation of treatment. Tumor proportion score of PD-L1, peripheral blood high-density lipoprotein cholesterol, and apolipoprotein A-I correlated with good response, while PD-1 on tumor infiltrating lymphocytes and peripheral Treg cells with poor response to pegaspargase plus sintilimab treatment. In conclusion, the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed, advanced stage NKTCL. Dysregulated lipid profile and immunosuppressive signature contributed to treatment resistance, providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.
Topics: Humans; Antibodies, Monoclonal, Humanized; Asparaginase; Lymphoma; Natural Killer T-Cells; Polyethylene Glycols; Programmed Cell Death 1 Receptor; Adult; Middle Aged; Aged; Young Adult
PubMed: 38448403
DOI: 10.1038/s41392-024-01782-8 -
Journal of Pediatric Hematology/oncology Mar 2024Asparaginases are a mainstay treatment for pediatric acute lymphoblastic leukemia (ALL). Recent reports identified hypoglycemia associated with asparaginases. Other...
BACKGROUND
Asparaginases are a mainstay treatment for pediatric acute lymphoblastic leukemia (ALL). Recent reports identified hypoglycemia associated with asparaginases. Other reports describe hypoglycemia associated with 6-mercaptopurine (6-MP), another fundamental ALL therapy. Little is known about the risk of hypoglycemia associated with ALL therapy, an adverse event that puts children at risk of decreased level of consciousness, seizures, and possibly negative neurocognitive sequelae.
METHODS
We performed a retrospective chart review of 6 children with hypoglycemia during ALL treatment in our institution from May 2016 to August 2019. Timing and duration of hypoglycemia relative to polyethylene glycol (PEG)-asparaginase, 6-MP, and corticosteroids were determined. Laboratory values of the critical sample were collected.
RESULTS
The median age was 2.75 (interquartile range: 1.88 to 3.63) years. Three patients had trisomy 21. The onset of hypoglycemia was 5 to 19 days after the most recent PEG-asparaginase administration or 6 to 7 months after initiating daily 6-MP. Sixteen hypoglycemic events were documented, and 9/16 had a critical sample drawn. Six events were hypoketotic, associated with PEG-asparaginase. Three were ketotic, associated with 6-MP. Two patients required treatment with diazoxide and cornstarch.
CONCLUSIONS
Hypoglycemia associated with PEG-asparaginase occurred later and lasted longer than previous reports with l-asparaginase, with the likely mechanism being hyperinsulinism. 6-MP was associated with ketotic hypoglycemia.
Topics: Humans; Child; Child, Preschool; Asparaginase; Mercaptopurine; Retrospective Studies; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Polyethylene Glycols; Hypoglycemia
PubMed: 38411659
DOI: 10.1097/MPH.0000000000002818