-
Cancer Medicine Dec 2023The clinicopathologic characteristics and prognosis of nasal and nonnasal extranodal natural killer T-cell lymphoma (ENKTL) are considered to be different. However, the...
BACKGROUND
The clinicopathologic characteristics and prognosis of nasal and nonnasal extranodal natural killer T-cell lymphoma (ENKTL) are considered to be different. However, the underlying features responsible for these differences are not well clarified especially in the era of asparaginase therapy.
METHODS
In total, 1007 newly diagnosed ENKTL patients from 11 medical centers were included in this study. Clinicopathologic characteristics and survival data were collected. The chi-squared test and Kruskal-Wallis test were utilized for the comparison of different groups. Univariable and multivariable Cox proportional hazards models were used to screen prognostic factors.
RESULTS
Overall, 869 (86.3%) patients were nasal forms. Compared to patients with nasal ENKTL, nonnasal patients were at more advanced stages and had poor performance status, bone marrow involvement, elevated serum lactate dehydrogenase (LDH), and CD56-negative status (p < 0.05). The 5-year overall survival (OS) for nasal and nonnasal patients were 65.6% and 45.0%, respectively. The OS of nasal forms patients were superior to nonnasal patients, especially in Eastern Cooperative Oncology Group performance status (ECOG PS) (≥2), advanced stage, KPI (HIR/HR), IPI (HIR/HR), PINK (HR), and high EBV DNA load groups. In patients treated with pegaspargase/L-asparaginase-based regimens, the OS of nasal patients was better than that of nonnasal patients. After adjusting the covariates of age, stage, ECOG PS score, LDH, B symptoms, and BM involvement, results showed that the nonnasal site was associated with poor survival of ENKTL.
CONCLUSIONS
The clinicopathologic characteristics and prognosis of nasal and nonnasal ENKTL patients are different. Nasal forms patients had superior OS than nonnasal patients, especially in the era of asparaginase.
Topics: Humans; Asparaginase; Lymphoma, Extranodal NK-T-Cell; Neoplasm Staging; Prognosis; Retrospective Studies
PubMed: 37902266
DOI: 10.1002/cam4.6674 -
Pediatric Blood & Cancer Jul 2022Chemotherapy regimens containing glucocorticoids and pegaspargase are associated with hyperglycemia; however, the pattern and underlying risk factors are not well...
BACKGROUND
Chemotherapy regimens containing glucocorticoids and pegaspargase are associated with hyperglycemia; however, the pattern and underlying risk factors are not well characterized. We determined the pattern of hyperglycemia and associated factors in children with acute lymphoblastic leukemia (ALL) receiving glucocorticoids and pegaspargase during induction.
METHODS
Retrospective analysis of patients treated between 2010 and 2020 at a single institution. Pretreatment data, glucose values, and insulin regimens were abstracted from the record. Hyperglycemia was defined as two or more random glucose measurements ≥200 mg/dl. Analyses of demographic and clinical factors were conducted with logistic regression.
RESULTS
Two hundred thirteen patients, median age 6 years (range 1.0-18.9 years), 47% female, were included. The prevalence of hyperglycemia was 23% (n = 48). Mean glucose levels peaked 3 days following administration of pegaspargase. In multivariable analysis, age ≥10 years (odds ratio [OR] 6.2, 95% confidence interval [CI]: 2.9-13.4), female sex (OR 2.7, 95% CI: 1.2-6.2), and family history of diabetes (OR 3.2, 95% CI: 1.4-7.3) were predictive of hyperglycemia. Age ≥10 years (OR 19.4, 95% CI: 5.5-68.4), family history of diabetes (OR 8.2, 95% CI: 2.7-25.3), and higher body mass index (BMI) (OR 1.8, 95% CI: 1.1-2.9) were associated with insulin treatment.
CONCLUSIONS
Onset of hyperglycemia in children receiving induction chemotherapy for ALL is temporally linked to administration of pegaspargase. Older age, female sex, and family history of diabetes are predictive of hyperglycemia during induction; older age, family history of diabetes, and higher BMI are associated with insulin treatment. Frequent glucose monitoring is indicated during induction therapy for ALL.
Topics: Adolescent; Asparaginase; Blood Glucose; Blood Glucose Self-Monitoring; Child; Child, Preschool; Diabetes Mellitus; Female; Glucocorticoids; Humans; Hyperglycemia; Induction Chemotherapy; Infant; Insulin; Male; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies
PubMed: 34931744
DOI: 10.1002/pbc.29505 -
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 -
Oncotarget Jun 2016Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive neoplasm with a poor outcome. Novel L-asparaginase-based treatment regimens, such as GELOX...
Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive neoplasm with a poor outcome. Novel L-asparaginase-based treatment regimens, such as GELOX (gemcitabine, oxaliplatin, and L-asparaginase) and P-gemox (gemcitabine, oxaliplatin, and pegaspargase), have shown promising results against stage IE/IIE ENKTL. To define the general applicability of P-gemox, in a retrospective analysis we examined the efficacy and safety of P-gemox in a cohort of 117 patients with newly diagnosed or relapsed/refractory ENKTL. Treatment included 2 to 8 cycles of P-gemox: intravenous gemcitabine (1250 mg/m2) and oxaliplatin (85 mg/m2) and intramuscular pegaspargase (2500 IU/ m2) on day 1 and repeated every 2 weeks, or intravenous gemcitabine (1000 mg/m2) on days 1 and 8 and intravenous oxaliplatin (130 mg/m2) and intramuscular pegaspargase (2500 IU/m2) on day 1 and repeated every 3 weeks. Upon completion of treatment, the overall response rate was 88.8%, and responses were similar for newly diagnosed and relapsed/refractory patients. After a median follow-up of 17 months, the 3-year overall and progression-free survival rates were 72.7% and 57.8%, respectively. Multivariate analysis showed that CR after treatment was the most significant factor affecting survival. P-gemox thus appears to be an effective and well-tolerated treatment for patients with ENKTL.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Deoxycytidine; Disease-Free Survival; Female; Humans; Lymphoma, Extranodal NK-T-Cell; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Polyethylene Glycols; Retrospective Studies; Treatment Outcome; Young Adult; Gemcitabine
PubMed: 27072578
DOI: 10.18632/oncotarget.8643 -
Leukemia Research Mar 2018Pediatric acute lymphoblastic leukemia (ALL) regimens, including higher cumulative asparaginase doses, have been investigated in adult ALL to improve outcomes....
Pegaspargase-related high-grade hepatotoxicity in a pediatric-inspired adult acute lymphoblastic leukemia regimen does not predict recurrent hepatotoxicity with subsequent doses.
Pediatric acute lymphoblastic leukemia (ALL) regimens, including higher cumulative asparaginase doses, have been investigated in adult ALL to improve outcomes. Preliminary results are promising, but hepatotoxicity rates with long-acting pegaspargase are greater in adults than children. However, adult pegaspargase-related hepatotoxicity is not as clearly defined despite being the commonest adult toxicity. We studied the frequency and characteristics of high-grade pegaspargase-related hepatotoxicity in newly diagnosed adults on a pediatric-inspired regimen that included six planned pegaspargase doses, 2000 IU/m/dose intravenously, with doses given at least four weeks apart and not discontinued or dose-reduced for previous hepatotoxicity. Pegaspargase-related toxicity was monitored weekly after 185 delivered doses and reported by NCI CTCAE v3.0. Fifty-one patients, aged 18-57, received 192 pegaspargase doses (3.8 doses/patient). High-grade hyperbilirubinemia occurred in 16 (31.4%) patients and 23 (12.4%) doses; high-grade transaminitis occurred in 33 (64.7%) patients and 62 (33.5%) doses. Of 11 patients with high-grade hyperbilirubinemia who received at least one subsequent pegaspargase dose, six (54.5%) experienced recurrent toxicity; of 24 patients with high-grade transaminitis who received at least one subsequent pegaspargase dose, 15 (62.5%) developed recurrent toxicity. Pegaspargase at this dose and interval is associated with high hepatotoxicity rates, but patients can be rechallenged despite earlier pegaspargase-related hepatotoxicity.
Topics: Adolescent; Adult; Asparaginase; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence
PubMed: 29407583
DOI: 10.1016/j.leukres.2017.12.013 -
Journal of Clinical Oncology : Official... Aug 2019Pegaspargase (PEG-ASP) has largely replaced native asparaginase (L-ASP) in the treatment of acute lymphoblastic leukemia because of its longer half-life and lower...
PURPOSE
Pegaspargase (PEG-ASP) has largely replaced native asparaginase (L-ASP) in the treatment of acute lymphoblastic leukemia because of its longer half-life and lower immunogenicity. Risk factors for allergic reactions to PEG-ASP remain unclear. Here, we identify risk factors for reactions in a front-line acute lymphoblastic leukemia trial and assess the usefulness of serum antibodies for diagnosing allergy and predicting rechallenge outcome.
PATIENTS AND METHODS
PEG-ASP was administered to 598 patients in St Jude's Total XVI study. Results were compared with Total XV study (ClinicalTrials.gov identifiers: NCT00549848 and NCT00137111), which used native L-ASP. Serum samples (n = 5,369) were analyzed for anti-PEG-ASP immunoglobulin G by enzyme-linked immunosorbent assay. Positive samples were tested for anti-polyethylene glycol (PEG) and anti-L-ASP. We analyzed potential risk factors for reactions and associations between antibodies and reactions, rechallenge outcomes, and PEG-ASP pharmacokinetics.
RESULTS
Grade 2 to 4 reactions were less common in the Total XVI study with PEG-ASP (81 [13.5%] of 598) than in the Total XV study with L-ASP (169 [41.2%] of 410; = 1.4 × 10). For Total XVI, anti-PEG, not anti-L-ASP, was the predominant component of anti-PEG-ASP antibodies (96%). In a multivariable analysis, more intrathecal therapy (IT) predicted fewer reactions ( = 2.4 × 10), which is consistent with an immunosuppressant contribution of IT. Anti-PEG-ASP was associated with accelerated drug clearance ( = 5.0 × 10). Failure of rechallenge after initial reactions was associated with anti-PEG-ASP ( = .0078) and was predicted by the occurrence of angioedema with first reaction ( = .01).
CONCLUSION
Less IT therapy was the only independent clinical risk factor for reactions to PEG-ASP. PEG, and not L-ASP, is the major antigen that causes allergic reactions. Anti-PEG-ASP has utility in predicting and confirming clinical reactions to PEG-ASP as well as in identifying patients who are most likely to experience failure with rechallenge.
Topics: Antibodies; Antineoplastic Agents; Asparaginase; Female; Humans; Hypersensitivity; Male; Polyethylene Glycols; Risk Factors
PubMed: 31188727
DOI: 10.1200/JCO.18.02439 -
Archives of Endocrinology and Metabolism Apr 2016Asparaginase (ASP) is an effective chemotherapy agent extensively used in children with acute lymphocytic leukemia (ALL). There has been a recent interest in using ASP... (Review)
Review
Asparaginase (ASP) is an effective chemotherapy agent extensively used in children with acute lymphocytic leukemia (ALL). There has been a recent interest in using ASP in adults with ALL, particularly the less toxic pegylated (PEG) formulation. Hypertriglyceridemia (HTG) is a rare complication of PEG-ASP therapy. We report two cases of obese patients who developed severe HTG after receiving PEG for ALL. Both patients were incidentally found to have severe HTG (TG of 4,330 and 4,420 mg/dL). In both patients, there was no personal or family history of dyslipidemia or hypothyroidism. There was no evidence of pancreatitis or skin manifestations of HTG. Both patients were treated with PEG cessation, low-fat diet and pharmacotherapy. Both patients were re-challenged with PEG, with subsequent increase in TG but no associated complications. TG returned to baseline after discontinuing PEG and while on therapy for HTG. A literature review of PEG-induced HTG in adults demonstrated similar results: asymptomatic presentation despite very severe HTG. HTG is a rare but clinically important adverse effect of PEG. Underlying obesity and/or diabetes may represent risk factors. Clinicians should monitor TG levels during PEG therapy to avoid TG-induced pancreatitis.
Topics: Adult; Antineoplastic Agents; Asparaginase; Diabetes Complications; Disease Progression; Female; Humans; Hypertriglyceridemia; Male; Obesity; Polyethylene Glycols; Risk Factors; Triglycerides
PubMed: 26331232
DOI: 10.1590/2359-3997000000068 -
Journal of Clinical Gastroenterology 2017To evaluate potential risk factors for the development of asparaginase-associated pancreatitis (AAP), we performed a systematic review of the current literature from... (Review)
Review
GOALS
To evaluate potential risk factors for the development of asparaginase-associated pancreatitis (AAP), we performed a systematic review of the current literature from January 1946 through May 2015.
BACKGROUND
Asparaginase, a primary treatment for the most common childhood cancer, acute lymphoblastic leukemia (ALL), is a well-described cause of pancreatitis. Further, pancreatitis is among the most burdensome and common complications of asparaginase treatment and represents a major reason for early-drug termination and inferior outcomes. The literature lacks clarity about the risk factors for AAP, and this knowledge gap has hampered the ability to reliably predict which patients are likely to develop AAP.
STUDY
In an expansive screen, 1842 citations were funneled into a review of 59 full articles, of which 10 were deemed eligible based on predetermined inclusion criteria.
RESULTS
Of the 10 identified studies, only 2 studies showed that children above 10 years of age had a >2-fold risk of AAP compared with younger children. Patients placed in high-risk ALL categories had a greater incidence of pancreatitis in 2 studies. In addition, use of pegylated asparaginase resulted in a higher incidence of AAP in 1 study.
CONCLUSIONS
In this systematic review, older age, asparaginase formulation, higher ALL risk stratification, and higher asparaginase dosing appear to play a limited role in the development of AAP. Further studies are needed to probe the underlying mechanisms contributing to the development of pancreatitis in patients receiving asparaginase.
Topics: Age Factors; Antineoplastic Agents; Asparaginase; Child; Dose-Response Relationship, Drug; Humans; Pancreatitis; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors
PubMed: 28375864
DOI: 10.1097/MCG.0000000000000827 -
Journal of Feline Medicine and Surgery Sep 2023The present study aimed to investigate pegylated-l-asparaginase monotherapy for feline large cell lymphoma as a potential alternative to palliative corticosteroids...
OBJECTIVES
The present study aimed to investigate pegylated-l-asparaginase monotherapy for feline large cell lymphoma as a potential alternative to palliative corticosteroids treatment in animals whose owners declined cytotoxic chemotherapy.
METHODS
A retrospective, descriptive case series of cats treated initially with pegylated-l-asparaginase as a sole therapy for feline large cell lymphoma is reported. The treatment protocol consisted of 12 intramuscular injections of pegylated-l-asparaginase with increasing intervals. If cats were unresponsive to pegylated-l-asparaginase monotherapy, a second-line treatment was initiated. Signalment, origin of lymphoma, staging, treatment, possible adverse events and follow-up data were extracted from the medical records. Responses and survival data were analysed.
RESULTS
Eighty-two cats with lymphoma of five different anatomic types were included: alimentary, abdominal extra-alimentary, peripheral nodal, nasal/nasopharyngeal and other (mediastinal, renal [solitary] and miscellaneous combined in one group for analytical purposes). The response rate was 74.1% (95% confidence interval = 63.4-83.5) with 38.3% (95% confidence interval = 27.8-48.8) in complete remission. The median disease-free period and calculated overall survival time were 70 days (12-1702+) and 79 days (1-1715+), respectively. The response rate was significantly correlated with the origin of the lymphoma and the combined group had a significantly lower response rate ( = 0.035). Twenty-four cats were also treated with corticosteroids. There was no significant difference in outcomes between the group treated with or without corticosteroids. Adverse events were present in a small number of cats (14/82). The majority of these adverse events were mild to moderate in 5/14 cats; however, the adverse events were severe enough to cause discontinuation of therapy.
CONCLUSIONS AND RELEVANCE
Based on the response rate and median disease-free period, treatment with pegylated-l-asparaginase is inferior when compared with historical chemotherapy protocols. However, some cats demonstrated an exceptional long disease-free period. Therefore, pegylated-l-asparaginase could be offered as an alternative to corticosteroid therapy alone. Further studies are needed to evaluate the additional benefit over palliative corticosteroid monotherapy.
Topics: Cats; Animals; Retrospective Studies; Polyethylene Glycols; Asparaginase; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37713175
DOI: 10.1177/1098612X231193536 -
Leukemia & Lymphoma Dec 2021Treatment of pediatric acute lymphoblastic leukemia (ALL) with pegaspargase exploits ALL cells dependency on asparagine. Pegaspargase depletes asparagine,...
Treatment of pediatric acute lymphoblastic leukemia (ALL) with pegaspargase exploits ALL cells dependency on asparagine. Pegaspargase depletes asparagine, consequentially affecting aspartate, glutamine and glutamate. The gut as a confounding source of these amino acids (AAs) and the role of gut microbiome metabolism of AAs has not been examined. We examined asparagine, aspartate, glutamine and glutamate in stool samples from patients over pegaspargase treatment. Microbial gene-products, which interact with these AAs were identified. Stool asparagine declined significantly, and 31 microbial genes changed over treatment. Changes were complex, and included genes involved in AA metabolism, nutrient sensing, and pathways increased in cancers. While we identified changes in a gene () with limited asparaginase activity, it lacked significance after correction leaving open other mechanisms for asparagine decline, possibly including loss from gut to blood. Understanding pathways that change AA availability, including by microbes in the gut, could be useful in optimizing pegaspargase therapy.
Topics: Antineoplastic Agents; Asparaginase; Asparagine; Aspartic Acid; Child; Genes, Bacterial; Glutamic Acid; Glutamine; Humans; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 34279176
DOI: 10.1080/10428194.2021.1953006