ABSTRACT
L-Asparaginase (L-Asp) is often used to induce remission in feline large-cell gastrointestinal lymphoma (LCGIL). However, no study has evaluated the efficacy and adverse events following the initial use of this drug as a first-line treatment in feline LCGIL. We retrospectively reviewed medical records of cats with LCGIL treated with L-Asp to induce remission. This study included 43 cats. The response rate (RR) after the first administration of L-Asp was 37.2% (Complete remission: 7.0%, partial remission: 30.2%). RR was significantly higher in cases with primary gastric lesions (64.3%) than in those with primary intestinal lesions (24.1%) (P=0.018), and it was also higher in cases without anemia (57.1%) than those with anemia (15.0%) (P=0.009). The most common adverse event was hyperammonemia, which occurred in 10 of 12 cases where we could compare plasma ammonia concentrations before and after the first dose of L-Asp. Plasma phosphate concentrations were also significantly increased (P<0.001) within 24 hr after the first dose. Decreased appetite, vomiting, and diarrhea were also observed in five, three, and seven cases, respectively, and Grade 3 or higher gastrointestinal signs were observed as adverse events in three cases. The median overall survival of all cats was 150 days (range, 5-1,065 days), and the median progression-free survival was 104 days (range, 2-978 days). In conclusion, L-Asp was effective to induce remission, and severe adverse events were uncommon in feline LCGIL.
Subject(s)
Antineoplastic Agents , Asparaginase , Cat Diseases , Gastrointestinal Neoplasms , Cats , Animals , Asparaginase/adverse effects , Asparaginase/administration & dosage , Asparaginase/therapeutic use , Cat Diseases/drug therapy , Cat Diseases/chemically induced , Male , Female , Retrospective Studies , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Neoplasms/veterinary , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/administration & dosage , Treatment Outcome , Lymphoma/drug therapy , Lymphoma/veterinary , Remission InductionABSTRACT
Studies on asparaginase enzyme activity (AEA) monitoring in Chinese patients receiving PEG-asparaginase remain limited. We monitored AEA in paediatric patients diagnosed with acute lymphoblastic leukaemia (ALL) and treated according to the Chinese Children's Cancer Group study protocols, CCCG-ALL-2015/CCCG-ALL-2020 protocols. We measured the AEA at days 7 ± 1 and 14 ± 1 and analysed their association with patient characteristics and PEG-asparaginase-related adverse effects (AEs). We measured 2147 samples from 329 patients. Mean AEA levels (interquartile range) were 931 iu/L (654-1174 iu/L) at day 7 ± 1 and 664 iu/L (463-860 iu/L) at day 14 ± 1. The AEA levels were higher in younger children and increased with the cumulative dose numbers. PEG-asparaginase inactivation rate was 19.1%, and the silent inactivation (SI) rate was 12.5%. Nine patients were identified with allergic-like reactions. Hypofibrinogenaemia, hypertriglyceridaemia, pancreatitis and thrombosis were associated with older age, whereas hypoglycaemia was associated with younger age. The risk of hypertriglyceridaemia and hypoglycaemia increased with cumulative dose numbers of PEG-asparaginase. Except for hypofibrinogenaemia, elevated AEA levels did not increase the risk of PEG-asparaginase-related AEs. Drug monitoring can be utilized as guidance for treatment decision-making. Individualizing asparaginase doses do not reduce toxicities. The treatment target of PEG-asparaginase remains to achieve sustained and adequate activity.
Subject(s)
Asparaginase , Polyethylene Glycols , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Male , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Asparaginase/administration & dosage , Asparaginase/adverse effects , China , East Asian People , Pancreatitis/chemically induced , Polyethylene Glycols/adverse effects , Polyethylene Glycols/administration & dosage , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapySubject(s)
Asparaginase , Plasmapheresis , Polyethylene Glycols , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Asparaginase/adverse effects , Asparaginase/therapeutic use , Polyethylene Glycols/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Male , Chemical and Drug Induced Liver Injury/etiology , Female , AdultSubject(s)
Asparaginase , Desensitization, Immunologic , Drug Hypersensitivity , Polyethylene Glycols , Adult , Female , Humans , Male , Middle Aged , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Asparaginase/therapeutic use , Asparaginase/adverse effects , Desensitization, Immunologic/methods , Drug Hypersensitivity/diagnosis , Polyethylene Glycols/therapeutic useABSTRACT
Background: Asparaginase (ASNase) is a crucial part of acute leukemia treatment, but immune responses to the agent can reduce its effectiveness and increase the risk of relapse. Currently, no reliable and validated biomarker predicts ASNase-induced hypersensitivity reactions during therapy. We aimed to identify predictive biomarkers and determine immune cells responsible for anaphylaxis using a murine model of ASNase hypersensitivity. Methods: Our preclinical study uses a murine model to investigate predictive biomarkers of ASNase anaphylaxis, including anti-ASNase antibody responses, immune complex (IC) levels, ASNase-specific binding to leukocytes or basophils, and basophil activation. Results: Our results indicate that mice immunized to ASNase exhibited dynamic IgM, IgG, and IgE antibody responses. The severity of ASNase-induced anaphylaxis was found to be correlated with levels of IgG and IgE, but not IgM. Basophils from immunized mice were able to recognize and activate in response to ASNase ex vivo, and the extent of recognition and activation also correlated with the severity of anaphylaxis observed. Using a multivariable model that included all biomarkers significantly associated with anaphylaxis, independent predictors of ASNase-induced hypersensitivity reactions were found to be ASNase IC levels and ASNase-specific binding to leukocytes or basophils. Consistent with our multivariable analysis, we found that basophil depletion significantly protected mice from ASNase-induced hypersensitivity reactions, supporting that basophils are essential and can be used as a predictive marker of ASNase-induced anaphylaxis. Conclusions: Our study demonstrates the need for using tools that can detect both IC- and IgE-mediated hypersensitivity reactions to mitigate the risk of ASNase-induced hypersensitivity reactions during treatment.
Subject(s)
Anaphylaxis , Asparaginase , Basophils , Drug Hypersensitivity , Immunoglobulin E , Animals , Asparaginase/adverse effects , Asparaginase/immunology , Basophils/immunology , Basophils/metabolism , Mice , Drug Hypersensitivity/immunology , Drug Hypersensitivity/diagnosis , Anaphylaxis/immunology , Anaphylaxis/chemically induced , Immunoglobulin E/immunology , Immunoglobulin E/blood , Female , Disease Models, Animal , Biomarkers , Immunoglobulin G/immunology , Immunoglobulin G/blood , Antineoplastic Agents/adverse effectsABSTRACT
Asparaginase is essential in the initial management of acute lymphoblastic leukemia (ALL) but frequently leads to venous thromboembolism (VTE). Using anticoagulants for primary VTE prevention has been studied with no consensus. We conducted a systematic literature search in PubMed, Scopus, and Web of science and performed random-effect meta-analysis using Mantel-Haenszel method in RevMan 5.4 to analyze primary pharmacological thromboprophylaxis during asparaginase treatment in early-phase (induction, consolidation, or intensification phase) therapy in patients with ALL with all ages and followed with subgroup analysis by age. Meta-analysis of 13 articles describing the effect of antithrombin supplementation in 1375 patients showed that antithrombin prophylaxis decreases the risk of VTE by 43% (RR, 0.57; 95% CI, 0.38 - 0.83; p=0.004), with mild heterogeneity (I2=35%, p=0.10) and moderate certainty by GRADE. 8 articles included for meta-analysis of low-molecular weight heparin (LMWH) treatment in 612 patients showed that it decreased the risk of VTE by nearly 40% (RR, 0.61; 95% CI, 0.45 - 0.81; p=0.00081), with minimal heterogeneity (I2=14%, p=0.31) but low certainty. Subgroup analysis showed that only prophylaxis with antithrombin supplementation significantly decreased the VTE rate in adult patients with moderate certainty. In pediatric patients, one nonrandomized prospective study showed that LMWH combined with antithrombin has a better thromboprophylaxis effect than antithrombin alone. In the PREVAPIX-ALL trial, prophylaxis with direct factor Xa inhibitor Apixaban did not benefit children younger than 18 years except for cases of obesity. We concluded that thromboprophylaxis with antithrombin is effective in ALL patients older than 18 years during the early phase of therapy, and LMWH combined with antithrombin supplementation might be effective for pediatric patients with ALL. Apixaban is effective in pediatric ALL patients with obesity and needs further study in other high-risk patients.
Subject(s)
Asparaginase , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Venous Thromboembolism , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Asparaginase/adverse effects , Asparaginase/administration & dosage , Asparaginase/therapeutic use , Venous Thromboembolism/prevention & control , Venous Thromboembolism/etiology , Anticoagulants/therapeutic use , Anticoagulants/administration & dosage , Heparin, Low-Molecular-Weight/therapeutic use , Heparin, Low-Molecular-Weight/administration & dosage , Antithrombins/administration & dosage , Antithrombins/therapeutic use , Antithrombins/adverse effectsABSTRACT
This retrospective report presents the outcomes and adverse events (AEs) observed in 73 patients aged 60 years or older diagnosed with Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia (Ph-negative ALL) treated with a pediatric-inspired protocol incorporating either Pegylated (PEG-ASP) or Native Asparaginase (EC-ASP). Notably, 61% of patients experienced AEs of Grade III-IV severity. The most prevalent AEs included thrombosis (35.6%), febrile neutropenia (38.4%), and transaminitis (34.2%). AEs did not translate into significant differences concerning overall survival, leukemia-free survival, or early mortality. Furthermore, we observed a reduction in early mortality rates (11% vs. 20%) and an increase in median overall survival (54 vs. 48 months) compared to our previous data. These findings suggest that the utilization of a pediatric-inspired chemotherapy protocol, with ASP, is an effective and well-tolerated therapeutic option for older patients with Ph-negative ALL. However, it emphasizes the importance of diligent monitoring and close follow-up throughout treatment.
Subject(s)
Asparaginase , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Aged , Asparaginase/adverse effects , Retrospective Studies , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Polyethylene Glycols/adverse effectsABSTRACT
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/m2 on day 1), intravenous gemcitabine (1 g/m2 on days 1 and 8), and intravenous oxaliplatin (130 mg/m2 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.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Asparaginase , Deoxycytidine , Gemcitabine , Lymphoma, Extranodal NK-T-Cell , Oxaliplatin , Polyethylene Glycols , Humans , Middle Aged , Asparaginase/therapeutic use , Asparaginase/adverse effects , Asparaginase/administration & dosage , Male , Lymphoma, Extranodal NK-T-Cell/drug therapy , Lymphoma, Extranodal NK-T-Cell/mortality , Female , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Polyethylene Glycols/therapeutic use , Polyethylene Glycols/adverse effects , Polyethylene Glycols/administration & dosage , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Oxaliplatin/therapeutic use , Oxaliplatin/administration & dosage , Oxaliplatin/adverse effects , Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/administration & dosage , Young Adult , AdolescentABSTRACT
BACKGROUND: Medications used to treat acute lymphoblastic leukemia (ALL), such as L-asparaginase, can cause blood lipid disturbances. These can also be associated with polymorphisms of the lipoprotein lipase (LpL) and apolipoprotein E (APOE) genes. PROCEDURE: We aimed to investigate the association between lipid profile, certain LpL and APOE gene polymorphisms (rs268, rs328, rs1801177 and rs7412, rs429358 respectively) as well as the risk subgroup in 30 pediatric patients being treated for ALL, compared with 30 pediatric ALL survivors and 30 healthy controls. RESULTS: The only APOE gene polymorphism with significant allelic and genotypic heterogeneity was rs429358. Further analysis of this polymorphism showed that genotype (CC, CT, or TT) was significantly associated with (1) changes in the lipid profile at the end of consolidation (total cholesterol, LDL, apo-B100, and lipoprotein a) and during re-induction (total cholesterol and apo-B100), and (2) classification in the high risk-ALL subgroup (for CC genotype/C allele presence). CONCLUSIONS: Lipid abnormalities in children being treated for ALL may be associated with the APOE genotype, which is also possibly associated with risk stratification. Further research is needed to confirm the potential prognostic value of these findings.
Subject(s)
Apolipoproteins E , Lipids , Lipoprotein Lipase , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Apolipoproteins E/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood , Child , Male , Female , Lipoprotein Lipase/genetics , Child, Preschool , Lipids/blood , Adolescent , Polymorphism, Single Nucleotide , Genotype , Alleles , Asparaginase/administration & dosage , Asparaginase/therapeutic use , Asparaginase/adverse effects , Polymorphism, GeneticABSTRACT
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.
Subject(s)
Asparaginase , Polyethylene Glycols , Vomiting , Humans , Retrospective Studies , Child , Adolescent , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/adverse effects , Polyethylene Glycols/therapeutic use , Male , Female , Asparaginase/administration & dosage , Asparaginase/adverse effects , Vomiting/chemically induced , Child, Preschool , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Dexamethasone/therapeutic use , Administration, Intravenous , Antiemetics/administration & dosage , Antiemetics/therapeutic use , InfantABSTRACT
Silent inactivation of L-asparaginase (L-Asp) represents rapid clearance of L-Asp by anti-L-Asp IgG antibodies without clinical symptoms. Measurement of L-Asp activity is the gold standard for diagnosis of silent inactivation, but this test is not commercially available in Japan as of 2023. We evaluated ex vivo and in vivo ammonia production in relation to L-Asp activity. Blood samples from ten adult patients treated with L-Asp were collected to measure ammonia levels and L-Asp activity before the first dose and 24 h after the last dose of L-Asp, during each cycle of treatment. Plasma ammonia levels were analyzed immediately and 1 h after incubation at room temperature, and ex vivo ammonia production was defined as the increase in ammonia concentration. Ex vivo ammonia production correlated with L-Asp activity (R2 = 0.741), and ammonia levels measured immediately after blood collection were moderately correlated with L-Asp activity (R2 = 0.709). One patient with extranodal NK/T-cell lymphoma showed an increase in ammonia levels during the first cycle, but no increase in ammonia levels or L-Asp activity after L-Asp administration during the second cycle. Both ex vivo and in vivo ammonia production and surrogate markers are used for L-Asp biological activity.
Subject(s)
Asparaginase , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Adult , Humans , Asparaginase/adverse effects , Ammonia/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Antibodies , BiomarkersABSTRACT
BACKGROUND: L-Asparaginase is a crucial component of acute lymphoblastic leukemia (ALL) treatment. However, hypersensitivity is a common adverse event. This study aimed to identify risk factors for L-asparaginase hypersensitivity in childhood ALL. METHODS: Children treated for ALL at Chiang Mai University Hospital, Thailand, between 2005 and 2020 were included. Demographic data, clinical characteristics, and factors related to L-asparaginase were retrospectively reviewed. RESULTS: L-Asparaginase hypersensitivity was observed in 24 of 216 children with ALL (11.1%). All patients received native L-asparaginase intramuscularly, and events occurred exclusively during the post-induction phase without concurrent corticosteroid use. Univariable analysis showed that relapsed ALL, higher accumulated doses, increased exposure days, and longer interval between drug administrations were potential risk factors. In multivariable logistic regression analysis, interruption of L-asparaginase administration for ≥ 52 weeks and exposure duration of ≥ 15 days were independent risk factors, with adjusted odds ratio of 16.481 (95% CI 3.248-83.617, p = 0.001) and 4.919 (95% CI 1.138-21.263, p = 0.033), respectively. CONCLUSIONS: Children with ALL who require re-exposure to L-asparaginase after 52-week interruption or who have received L-asparaginase for ≥ 15 exposure days are at risk of developing L-asparaginase hypersensitivity. Further management strategies in this setting should be evaluated.
Subject(s)
Antineoplastic Agents , Drug Hypersensitivity , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Humans , Asparaginase/adverse effects , Retrospective Studies , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Risk Factors , Drug Hypersensitivity/epidemiology , Drug Hypersensitivity/etiology , Drug Hypersensitivity/drug therapy , Antineoplastic Agents/therapeutic use , Polyethylene GlycolsSubject(s)
Antineoplastic Agents , Dickeya chrysanthemi , Erwinia , Leukemia, Myeloid, Acute , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Humans , Asparaginase/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Leukemia, Myeloid, Acute/drug therapy , Antineoplastic Agents/therapeutic useABSTRACT
OBJECTIVES: Asparaginase-associated pancreatitis (AAP) occurs in up to 18% of patients treated for acute lymphoblastic leukemia (ALL); however, long-term sequelae are largely unexplored. We aimed to explore pancreatic sequelae among ALL survivors with and without AAP. METHODS: We investigated pancreatic sequelae in a national cohort of ALL survivors, aged 1-45 years at ALL diagnosis treated according to the NOPHO-ALL2008 protocol and included sex- and age-matched community controls. RESULTS: We included 368 survivors (median follow-up 6.9 years), including 47 survivors with AAP and 369 controls. The p-lipase and p-pancreas-type amylase levels were lower in AAP survivors compared with both non-AAP survivors (Medians: 23 U/L [IQR 14-32] and 18 U/L [IQR 10-25] versus 29 [IQR 24-35] and 22 [17-28], p < .001 and p = .002) and community controls (28 U/L [IQR 22-33] and 21 U/L [IQR 17-26], both p < .006). Fecal-elastase was more frequently reduced in AAP survivors compared with non-AAP survivors (7/31 vs. 4/144, p = .001). Persisting pancreatic sequelae were found in 15/47 of AAP survivors and 20/323 of non-AAP survivors (p < .001), including diabetes mellitus in 2/39 of AAP survivors and 2/273 of non-AAP survivors. CONCLUSIONS: ALL survivors with AAP are at increased risk of persisting pancreatic dysfunction and require special attention during follow-up.
Subject(s)
Asparaginase , Pancreatitis , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Pancreatitis/diagnosis , Pancreatitis/chemically induced , Pancreatitis/etiology , Pancreatitis/epidemiology , Male , Female , Asparaginase/adverse effects , Asparaginase/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Adult , Adolescent , Middle Aged , Young Adult , Child , Child, Preschool , Infant , Case-Control Studies , Antineoplastic Agents/adverse effects , Pancreas/pathology , Pancreas/drug effects , Cancer Survivors , Follow-Up Studies , SurvivorsABSTRACT
PURPOSE: The primary objective of this randomized study was to determine whether a continuous dosing schedule (without the asparaginase-free interval) would result in less hypersensitivity reactions to PEGasparaginase (PEGasp) compared with the standard noncontinuous dosing schedule. METHODS: Eight hundred eighteen patients (age 1-18 years) with ALL were enrolled in the Dutch Childhood Oncology Group-ALL11 protocol and received PEGasp. Three hundred twelve patients stratified in the medium-risk arm were randomly assigned to receive 14 individualized PEGasp doses once every two weeks in either a noncontinuous or continuous schedule after the first three doses in induction (EudraCT: 2012-000067-25). Hypersensitivity reactions were defined as allergies, allergic-like reactions, and silent inactivation. Secondary end points were other asparaginase-related toxicities, asparaginase activity and antibody levels, and outcome. RESULTS: During induction, 27 of 818 patients (3.3%) experienced hypersensitivity reactions. After random assignment, 4 of 155 (2.6%) in the continuous treatment arm versus 17 of 157 (10.8%) patients in the noncontinuous treatment arm had hypersensitivity reactions (P < .01), of which two (1.3%) versus 13 (8.3%) were inactivating reactions (P < .01). The occurrence of inactivating hypersensitivity reactions was seven times lower in the continuous arm (odds ratio, 0.15 [0.032-0.653]). In addition, antibody levels were significantly lower in the continuous arm (P < .01). With exception of a lower incidence of increased amylase in the continuous arm, there were no significant differences in total number of asparaginase-associated toxicities between arms. However, the timing of the toxicities was associated with the timing of the asparaginase administrations. No difference in 5-year cumulative incidence of relapse, death, or disease-free survival was found between both treatment arms. CONCLUSION: A continuous dosing schedule of PEGasp is an effective approach to prevent antibody formation and inactivating hypersensitivity reactions. The continuous PEGasp schedule did not increase toxicity and did not affect the efficacy of the therapy.
Subject(s)
Asparaginase , Drug Hypersensitivity , Polyethylene Glycols , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Asparaginase/administration & dosage , Asparaginase/adverse effects , Child , Child, Preschool , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/adverse effects , Female , Male , Adolescent , Drug Hypersensitivity/etiology , Infant , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Drug Administration Schedule , Netherlands , Antineoplastic Agents/adverse effects , Antineoplastic Agents/administration & dosageABSTRACT
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.
Subject(s)
Hypoglycemia , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Child , Child, Preschool , Asparaginase/adverse effects , Mercaptopurine/adverse effects , Retrospective Studies , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Polyethylene Glycols/adverse effects , Hypoglycemia/chemically inducedABSTRACT
BACKGROUND: Pegaspargase is a therapeutic enzyme that is utilized in treatment regimens targeting pediatric acute lymphoblastic leukemia. However, many patients experience hypersensitivity reactions, requiring discontinuation of the therapy. Historically, this necessitated switching to an alternative form of the drug, most commonly asparaginase Erwinia chrysanthemi; however, in recent years this was difficult due to drug shortages and eventually commercial discontinuation. We report here our experience performing pegaspargase desensitizations in patients with prior hypersensitivity reactions. PROCEDURE: Patients with a clinical hypersensitivity reaction to pegaspargase were identified. When due for their next dose, patients were admitted to the pediatric intensive care unit, bone marrow transplant unit, or oncology unit, and underwent desensitization utilizing a rigorous premedication and multistep dilution-based protocol. Serum asparaginase activity levels were drawn after desensitization to assess for therapeutic levels of enzyme activity. RESULTS: We identified 11 patients who underwent a total of 33 desensitizations to pegaspargase and calaspargase pegol-mknl. No patients experienced clinically significant hypersensitivity reactions necessitating stopping the infusion, nor administration of rescue medications. All serum asparaginase activity levels collected demonstrated enzyme activity levels above predefined therapeutic thresholds. Cost analysis revealed substantial savings when patients received asparaginase desensitization over the now commercially available asparaginase E. chrysanthemi (recombinant) rywn. CONCLUSIONS: Performing desensitization to pegaspargase in the pediatric acute lymphoblastic leukemia population is feasible, safe, and effective. It is financially advantageous over available alternative approaches, and requires fewer injections and presentations to care.
Subject(s)
Antineoplastic Agents , Drug Hypersensitivity , Erwinia , Hypersensitivity , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Humans , Asparaginase/adverse effects , Antineoplastic Agents/therapeutic use , Drug Hypersensitivity/etiology , Drug Hypersensitivity/drug therapy , Polyethylene Glycols/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapyABSTRACT
OBJECTIVES: Hyperglycemia is a known side effect of anticancer chemotherapeutic drugs. This entity known as drug-induced diabetes mellitus usually does not present with the development of diabetic ketoacidosis (DKA). We hereby report a case of drug induced diabetes mellitus in a child with acute leukemia presenting with DKA. CASE PRESENTATION: We report a case of a teenage boy diagnosed with B cell acute lymphoblastic leukemia and was started on induction phase chemotherapy as per the Indian Collaborative Childhood Leukemia group (ICICLe) acute lymphoblastic leukemia-14 protocol. On day 12 of the induction phase, he developed hyperglycemia and presented to us with severe diabetic ketoacidosis (DKA). Serum anti glutamic acid decarboxylase 65 antibody levels were negative with low serum C peptide levels. Initially, the possibility of drug-induced acute pancreatitis was kept which was ruled out. Keeping the possibility of drug-induced hyperglycemia, the child was started on subcutaneous regular insulin which was titrated as per sugar records. Continuation of remaining chemotherapy was done by PEGylated L-asparaginase with titration of insulin as per home-based sugar records. Insulin requirement increased from 0.3â¯unit/kg/day to a maximum of 1â¯unit/kg/day during consolidation phase 1 with PEGylated L-asparaginase suggesting drug-induced hyperglycemia but subsequently insulin requirement decreased and insulin was stopped. CONCLUSIONS: Drug induced diabetes mellitus can present as DKA during induction phase of acute lymphoblastic leukemia (ALL) chemotherapy. A high index of suspicion and close monitoring are required. The insulin requirements in these patients can be very fluctuant and may become nil during the course of treatment.
Subject(s)
Antineoplastic Agents , Diabetes Mellitus , Diabetic Ketoacidosis , Hyperglycemia , Pancreatitis , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Adolescent , Humans , Male , Acute Disease , Antineoplastic Agents/adverse effects , Asparaginase/adverse effects , Diabetes Mellitus/drug therapy , Diabetic Ketoacidosis/diagnosis , Hyperglycemia/chemically induced , Insulin/therapeutic use , Pancreatitis/chemically induced , Pancreatitis/complications , Pancreatitis/drug therapy , Polyethylene Glycols/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Sugars/adverse effectsABSTRACT
Polyethylene glycol-asparaginase (PEGAsp) is an established component of acute leukemia therapy. Hypersensitivity reactions to PEGAsp occur in 10% to 15% of patients, with polyethylene glycol suggested as the antigenic culprit. As coronavirus disease 2019 (COVID-19) mRNA vaccines contain polyethylene glycol, the safety of administration of these vaccines to patients with prior PEGAsp hypersensitivity has been questioned. Between December 21, 2020 and March 3, 2022, 66 patients with acute leukemia and PEGAsp allergy received COVID-19 vaccination. No patients (0/66 0%, 95% CI: 0%-5.4%) experienced an allergic reaction to the vaccine. COVID-19 mRNA vaccination appears to be safe in pediatric and young adult patients with acute lymphoblastic leukemia with PEGAsp allergy.