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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 -
Blood Apr 2007In contrast to that in children, pharmacokinetic, pharmacodynamic, and safety information on pegaspargase in adults is very limited. We administered a single intravenous... (Clinical Trial)
Clinical Trial
In contrast to that in children, pharmacokinetic, pharmacodynamic, and safety information on pegaspargase in adults is very limited. We administered a single intravenous dose of pegaspargase (2000 IU/m2) as part of a standard frontline induction regimen to 25 adults with newly diagnosed acute lymphoblastic leukemia (ALL), and obtained serum samples on several time points. The population mean peak serum concentration of asparaginase enzymatic activity was 1 IU/mL, the elimination half-life was 7 days, and the volume of distribution was 2.43 L/m2. After the single dose, asparagine deamination was complete in all patients after 2 hours, and in 100%, 81%, and 44% on days 14, 21, and 28, respectively. A pharmocodynamic correlation model showed minimal enzymatic activity of 0.2 IU/mL for optimal asparagine depletion. The kinetic posthoc analyses demonstrated enzymatic activity for 3 weeks or more. One patient developed neutralizing antiasparaginase antibodies on day 22 after administration. Pegaspargase was well tolerated, with few grade 3/4 side effects. No allergic reactions or pancreatitis were observed. In adults aged 55 years or younger, pegaspargase produces a long duration of asparagine depletion and can be given intravenously, with a safety profile that is similar to equivalent multiple doses of intramuscular Escherichia coli asparaginase.
Topics: Adolescent; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Clinical Protocols; Daunorubicin; Disease-Free Survival; Female; Humans; Male; Middle Aged; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Safety; Survival Rate; Vincristine
PubMed: 17132721
DOI: 10.1182/blood-2006-07-035006 -
Frontiers in Oncology 2020The prognosis of patients with relapsed/refractory NK/T-cell lymphoma (NKTCL) is dismal. Immunotherapy has showed encouraging anti-tumor activity in patients with...
The prognosis of patients with relapsed/refractory NK/T-cell lymphoma (NKTCL) is dismal. Immunotherapy has showed encouraging anti-tumor activity in patients with asparaginase-resistant NKTCL; however, only a portion of patients benefit and the median response duration is rather short. Treatment strategies have not been identified for immunotherapy-resistant NKTCL. We describe a patient with primary cutaneous NKTCL experienced disease progression after pegaspargase-based chemotherapy and PD-1 inhibitor (sintilimab)-based immunotherapy. Following a combined treatment of sintilimab and the HDAC inhibitor chidamide, the patient achieved a durable complete molecular response with mild toxicity. This case indicates that the combination of PD-1 inhibitor and HDAC inhibitor might be a treatment choice for immunotherapy-resistant NKTCL.
PubMed: 33363038
DOI: 10.3389/fonc.2020.608304 -
OncoTargets and Therapy 2017Adults with acute lymphoblastic leukemia (ALL) are known to have inferior outcomes compared to the pediatric population. Although the reasons for this are likely... (Review)
Review
Adults with acute lymphoblastic leukemia (ALL) are known to have inferior outcomes compared to the pediatric population. Although the reasons for this are likely manyfold, the agents utilized and the increased intensity of pediatric treatments compared to adult treatments are likely significant contributing factors. Asparaginase, an enzyme that converts asparagine to aspartic acid, forms the backbone of almost all pediatric regimens and works by depleting extracellular asparagine, which ALL cells are unable to synthesize. Asparaginase toxicities, which include hypersensitivity reactions, pancreatitis, liver dysfunction, and thrombosis, have hindered its widespread use in the adult population. Here, we review the toxicity and efficacy of asparaginase in adult patients with ALL. With the proper precautions, it is a safe and effective agent in the treatment of younger adults with ALL with response rates in the frontline setting ranging from 78% to 96%, compared to most trials showing a 4-year overall survival of 50% or better. The age cutoff for consideration of treatment with pediatric-inspired regimens is not clear, but recent studies show promise particularly in the adolescent and young adult population. New formulations of asparaginase are actively in development, including erythrocyte-encapsulated asparaginase, which is designed to minimize the toxicity and improve the delivery of the drug.
PubMed: 28331334
DOI: 10.2147/OTT.S106810 -
Children (Basel, Switzerland) Jul 2023Asparaginase is a key component of chemotherapy protocols for the treatment of lymphoblastic malignancies among children. Adequate asparagine depletion is an important...
BACKGROUND
Asparaginase is a key component of chemotherapy protocols for the treatment of lymphoblastic malignancies among children. Adequate asparagine depletion is an important factor to achieve optimal therapeutic outcomes.
METHODS
Over a 3.5 year period, 106 patients were monitored for asparaginase activity (329 samples) in a single center of the Hungarian Pediatric Oncology-Hematology Group. In Hungary, three asparaginase products are available: native E. coli ASNase (Kidrolase), a pegylated form of this enzyme (Pegaspargase) and another native product from Erwinia chrysanthemi (Erwinase). A retrospective data analysis was performed.
RESULTS
In 81% (268/329) of our patients, AEA levels were in the optimal therapeutic range of over 100 IU/L. Of 106 patients, 13 (12%) were diagnosed with 'silent inactivation'.
CONCLUSIONS
Monitoring of AEA can help to identify patients with 'silent inactivation' and their asparaginase therapy can thus be optimized.
PubMed: 37508657
DOI: 10.3390/children10071160 -
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Jun 2020This study aimed to explore the clinical characteristics, survival rate, and prognostic factors of advanced-stage extranodal nasal type NK/T cell lymphoma (ENKTL)...
This study aimed to explore the clinical characteristics, survival rate, and prognostic factors of advanced-stage extranodal nasal type NK/T cell lymphoma (ENKTL) patients. The clinical data of 51 advanced-stage ENKTL patients in Peking Union Medical College Hospital from January 2012 to September 2019 were retrospectively analyzed. The clinical characteristics, treatment responses, survival rate, and prognostic factors were elucidated. The differences between nasal and non-nasal type and the significance of EBV-DNA in treatment response assessment and prognosis analysis were also evaluated. The male-to-female ratio in the whole group was 2.9∶1 with a median age of 42 years old (range, 14-67 years) . The median follow-up time was 30 months (range, 1-78 months) . The one- and three-year progression-free survival (PFS) rates for the whole cohort were 34.1% and 24.6%, respectively, and the one- and three-year overall survival (OS) rates were 39.9% and 26.6%, respectively. The ratio of nasal to non-nasal type was 1.6∶1. The proportion of hemophagocytic lymphohistiocytosis (HLH) was significantly higher in non-nasal-type patients than nasal-type (=0.039) , and the complete response (CR) rate of first-line chemotherapy is significantly lower in non-nasal type patients (=0.008) . The median OS for nasal and non-nasal types were nine months and four months, respectively. The three-year PFS rates of nasal and non-nasal type patients were 36.0% and 10.0% (=0.029) , respectively, and the three-year OS rates were 37.9% and 11.4% (=0.050) , respectively. The correlation between the Epstein-Barr virus DNA (EBV-DNA) and treatment response were satisfactory. Survival curve between baseline EBV-DNA-negative and EBV-DNA-positive patients showed no significant difference. The three-year OS rates of EBV-DNA-negative and EBV-DNA-positive patients after one cycle of treatment were 77.9% and 8.1% (=0.002) , respectively. In a multivariate analysis, EBV-DNA-positive following one cycle of treatment was an independent adverse prognostic factor for OS. The efficacy of pegaspargase-based chemotherapy and long-term survival of advanced-stage ENKTL patients were still poor. Clinical characteristics, treatment response, and long-term survival of non-nasal-type patients were worse than that of nasal-type patients. In a multivariate analysis, EBV-DNA-positive after one cycle of treatment was an independent adverse prognostic factor for OS. It can be used for early prediction of treatment response and prognosis.
Topics: Adolescent; Adult; Aged; Female; Humans; Lymphoma, Extranodal NK-T-Cell; Male; Middle Aged; Neoplasm Staging; Prognosis; Retrospective Studies; Survival Rate; Young Adult
PubMed: 32654458
DOI: 10.3760/cma.j.issn.0253-2727.2020.06.005 -
Pediatric Blood & Cancer Aug 2019Asparaginase is a critical component of lymphoblastic leukemia therapy, with intravenous pegaspargase (PEG) as the current standard product. Acute adverse events (aAEs)...
BACKGROUND
Asparaginase is a critical component of lymphoblastic leukemia therapy, with intravenous pegaspargase (PEG) as the current standard product. Acute adverse events (aAEs) during PEG infusion are difficult to interpret, representing a mix of drug-inactivating hypersensitivity and noninactivating reactions. Asparaginase Erwinia chrysanthemi (ERW) is approved for PEG hypersensitivity, but is less convenient, more expensive, and yields lower serum asparaginase activity (SAA). We began a policy of universal premedication and SAA testing for PEG, hypothesizing this would reduce aAEs and unnecessary drug substitutions.
PROCEDURE
Retrospective chart review of patients receiving asparaginase before and after universal premedication before PEG was conducted, with SAA performed 1 week later. We excluded patients who had nonallergic asparaginase AEs. Primary end point was substitution to ERW. Secondary end points included aAEs, SAA testing, and cost.
RESULTS
We substituted to ERW in 21 of 122 (17.2%) patients pre-policy, and 5 of 68 (7.4%) post-policy (RR, 0.427; 95% CI, 0.27-0.69, P = 0.028). All completed doses of PEG yielded excellent SAA (mean, 0.90 units/mL), compared with ERW (mean, 0.15 units/mL). PEG inactivation post-policy was seen in 2 of 68 (2.9%), one silent and one with breakthrough aAE. The rate of aAEs pre/post-policy was 17.2% versus 5.9% (RR, 0.342; 95% CI, 0.20-0.58, P = 0.017). Grade 4 aAE rate pre/post-policy was 15% versus 0%. Cost analysis predicts $125 779 drug savings alone per substitution prevented ($12 402/premedicated patient).
CONCLUSIONS
Universal premedication reduced substitutions to ERW and aAE rate. SAA testing demonstrated low rates of silent inactivation, and higher SAA for PEG. A substantial savings was achieved. We propose universal premedication for PEG be standard of care.
Topics: Administration, Intravenous; Adolescent; Adult; Antineoplastic Agents; Asparaginase; Child; Child, Preschool; Drug Hypersensitivity; Drug Monitoring; Drug Substitution; Female; Follow-Up Studies; Hematologic Neoplasms; Humans; Infant; Male; Premedication; Prognosis; Retrospective Studies; Tissue Distribution; Young Adult
PubMed: 31099154
DOI: 10.1002/pbc.27797 -
Leukemia & Lymphoma Jul 2019The efficacy of asparaginase in acute lymphoblastic leukemia (ALL) is dependent on depletion of asparagine, an essential amino acid for ALL cells. The target level of... (Randomized Controlled Trial)
Randomized Controlled Trial
The efficacy of asparaginase in acute lymphoblastic leukemia (ALL) is dependent on depletion of asparagine, an essential amino acid for ALL cells. The target level of plasma asparaginase activity to achieve asparagine depletion has been between 0.05 and 0.4 IU/mL. COG AALL07P4 examined the asparaginase activity and plasma and CSF asparagine concentration of pegaspargase when given intravenously in the treatment of NCI high risk ALL. Matched plasma asparaginase/asparagine levels of the clearance of 54 doses of pegaspargase given in induction or consolidation demonstrated that all patients who had a plasma asparaginase level >0.02 IU/mL had undetectable plasma asparagine. No difference was observed in CSF asparagine levels associated with matched plasma asparaginase levels of 0.02-0.049 versus 0.05-0.22 IU/mL ( = .25). Our data suggest that a plasma asparaginase activity level of 0.02 IU/mL can effectively deplete plasma asparagine. The data also indicate that the 95% CI for plasma asparagine depletion after a pegaspargase dose is 22-29 days. clinicaltrials.gov identifier NCT00671034.
Topics: Adolescent; Adult; Antineoplastic Agents; Asparaginase; Asparagine; Biomarkers, Tumor; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Male; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Tissue Distribution; Young Adult
PubMed: 30626253
DOI: 10.1080/10428194.2018.1542146 -
Hematological Oncology Dec 2017The nasal type of extranodal natural killer/T-cell lymphoma is a rare aggressive lymphoma with poor prognosis. To discover a successful treatment, we investigated the...
A phase 2 study of methotrexate, etoposide, dexamethasone, and pegaspargase chemotherapy for newly diagnosed, relapsed, or refractory extranodal natural killer/T-cell lymphoma, nasal type: a multicenter trial in Northwest China.
The nasal type of extranodal natural killer/T-cell lymphoma is a rare aggressive lymphoma with poor prognosis. To discover a successful treatment, we investigated the efficacy and safety of chemotherapy with methotrexate, etoposide, dexamethasone, and polyethylene glycol-asparaginase (MESA). Three cycles of MESA were administered to 46 patients with new or relapsed/refractory natural killer/T-cell lymphoma. Complete response after 3 treatment cycles was 43.5%, the overall response rate was 87%, and 2-year overall survival was 83.4%. Complete response was significantly better for newly diagnosed patients than for patients with relapsed/refractory disease. Patients with newly diagnosed disease had a significantly better overall response rate after 1, but not after 2 or 3 treatment cycles. Overall survival and progression-free survival did not differ over 2 years. Grade 1/2 toxicities were frequent, but MESA was associated with fewer grade 3/4 events or treatment-related deaths. These results will require confirmation in larger prospective trials.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Biomarkers; China; Dexamethasone; Drug Resistance, Neoplasm; Etoposide; Female; Humans; Immunophenotyping; Kaplan-Meier Estimate; Lymphoma, Extranodal NK-T-Cell; Male; Methotrexate; Middle Aged; Neoplasm Staging; Polyethylene Glycols; Prognosis; Recurrence; Retreatment; Treatment Outcome; Young Adult
PubMed: 27723108
DOI: 10.1002/hon.2325