-
European Journal of Haematology Mar 2024There are significant disparities in outcomes among Hispanic patients with acute lymphoblastic leukemia (ALL). Recent studies have demonstrated favorable outcomes of...
OBJECTIVE
There are significant disparities in outcomes among Hispanic patients with acute lymphoblastic leukemia (ALL). Recent studies have demonstrated favorable outcomes of pegaspargase-containing ALL regimens (PEG-CAR) in young adults however, outcomes in Hispanic ethnicity continue to be underreported.
METHODS
We evaluated outcomes of newly diagnosed, adult B-cell ALL Hispanic and non-Hispanic patients consecutively treated with a PEG-CAR or HyperCVAD between January 2011 and November 2022. The primary endpoint was event-free survival (EFS) while secondary endpoints included cumulative incidence of relapse and overall survival (OS).
RESULTS
Among 105 included patients, 48 (45.7%) were treated with a PEG-CAR and 57 (54.3%) with HyperCVAD. Median age was 38 years (range, 18-75 years), 61% were Hispanic, and 35.2% had poor-genetic risk. Hispanic patients demonstrated significantly worse 5-year EFS with a PEG-CAR compared to that seen with HyperCVAD (HR, 2.58; 95% CI, 1.32-5.04; p = .006) whereas non-Hispanic patients had better outcomes with PIR (52.4% vs. 42.0%). Hispanic ethnicity (p = .015) and male sex (p = .019) were independent predictors for poor OS.
CONCLUSIONS
Hispanic patients with B-cell ALL had worse EFS with a PEG-CAR as compared with HyperCVAD. Future studies will aim to confirm these findings and establish a tailored treatment approach for this high-risk population.
Topics: Young Adult; Humans; Male; Adult; Asparaginase; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Polyethylene Glycols; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies
PubMed: 37933194
DOI: 10.1111/ejh.14125 -
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 -
Pediatric Blood & Cancer Apr 2024Pegaspargase is a therapeutic enzyme that is utilized in treatment regimens targeting pediatric acute lymphoblastic leukemia. However, many patients experience...
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.
Topics: Child; Humans; Asparaginase; Erwinia; Antineoplastic Agents; Drug Hypersensitivity; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hypersensitivity
PubMed: 38311802
DOI: 10.1002/pbc.30891 -
Annals of Hematology Nov 2023The incorporation of pediatric-inspired regimens in the adolescent-young-adult (AYA) and adult populations have resulted improved survival outcomes (Stock et al. Blood...
The incorporation of pediatric-inspired regimens in the adolescent-young-adult (AYA) and adult populations have resulted improved survival outcomes (Stock et al. Blood 133(14):1548-1559 2019; Dunsmore et al. J Clin Oncol 38(28):3282-3293 2020; DeAngelo et al. Leukemia 29(3):526-534 2015). Nonetheless incorporation of such regimens is limited by increased toxicity to asparaginase. Dosing strategies that reduce the weight-based dose of pegylated-L-asparaginase (PEG-asparaginase) utilizing activity monitoring have been shown to result in better tolerability of these regimens. The purpose of this study was to analyze the efficacy and safety of treating adults with Philadelphia chromosome negative (Ph-) ALL with pediatric-inspired regimens that incorporate PEG-asparaginase dose adjustments and asparaginase activity level monitoring. Patients aged 18-65 years initiated on pediatric-inspired regimens utilizing dose-reduced PEG-asparaginase with therapeutic drug monitoring-guided adjustments were included. The screening of 122 patients treated between 2015 and 2021 resulted in the inclusion of 54 patients. The median age of the cohort was 35 years (16-65 years), and median body mass index (BMI) was 30 kg/m (18.3-53.4 kg/m). The 36-month survival estimate was 62.1% (95% CI 48.1-77.7%), and the median overall survival (OS) was 62.2 months (95% CI 35.1-89.3 months). In the AYA cohort, the 36-month survival was 71.2% (95% CI 55.8-91%) and the median overall survival was not reached. Survival was not significantly affected by immunophenotype or BMI. Discontinuation due to toxicity or hypersensitivity reactions was low at 11% and 9% respectively. The encouraging survival outcomes and favorable tolerability of this older population in the real-world setting support the use of individualized PEG-asparaginase dosing with PharmD-guided therapeutic drug monitoring.
Topics: Adolescent; Adult; Humans; Asparaginase; Drug Monitoring; Polyethylene Glycols; Body Mass Index
PubMed: 37480389
DOI: 10.1007/s00277-023-05373-5 -
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 -
Leukemia Feb 2024Osteonecrosis is a significant toxicity of acute lymphoblastic leukemia (ALL) therapy. In retrospective analyses, superior event-free survival was noted among affected... (Randomized Controlled Trial)
Randomized Controlled Trial
Osteonecrosis is a significant toxicity of acute lymphoblastic leukemia (ALL) therapy. In retrospective analyses, superior event-free survival was noted among affected adolescents in an earlier trial. We prospectively assessed osteonecrosis incidence, characteristics, and risk factors in patients 1-30 years with newly diagnosed high-risk B-ALL on COG AALL0232. Patients were randomized to induction dexamethasone vs prednisone, and interim maintenance high-dose methotrexate vs escalating-dose Capizzi methotrexate/pegaspargase. Event-free and overall survival were compared between patients with/without imaging-confirmed osteonecrosis. Osteonecrosis developed in 322/2730 eligible, evaluable patients. The 5-year cumulative incidence was 12.2%. Risk was greater in patients ≥10 years (hazard ratio [HR], 7.23; P < 0.0001), particularly females (HR, 1.37; P = 0.0057), but lower in those with asparaginase allergy (HR, 0.60; P = 0.0077). Among rapid early responders ≥10 years, risk was greater with dexamethasone (HR, 1.84; P = 0.0003) and with prednisone/Capizzi (HR, 1.45; P = 0.044), even though neither therapy was independently associated with improved survival. Patients with osteonecrosis had higher 5-year event-free (HR, 0.51; P < 0.0001) and overall survival (HR, 0.42; P < 0.0001), and this was directly attributable to reduced relapse rates (HR, 0.57; P = 0.0014). Osteonecrosis in high-risk B-ALL patients is associated with improved survival, suggesting an important role for host factors in mediating both toxicity and enhanced efficacy of specific therapies.
Topics: Child; Female; Adolescent; Humans; Prednisone; Methotrexate; Retrospective Studies; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Osteonecrosis; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease-Free Survival
PubMed: 38062123
DOI: 10.1038/s41375-023-02099-1 -
Best Practice & Research. Clinical... Dec 2023Asparaginase in various forms is a standard part of the treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. However, its use is more selective... (Review)
Review
Asparaginase in various forms is a standard part of the treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. However, its use is more selective in adults. One of the key reasons is the toxicity observed from this class of agents. In a series of recent post hoc analyses of large prospective studies, obesity has emerged as a key factor that contributes to the challenges with administering regimens that include asparaginase. In this review, the most salient findings are highlighted from these latest publications, both from the pediatric and adult literature. These data are consolidated into recommendations for clinicians who treat adults with ALL, including proposals for how treatment may be modified to try to account for these complications. Lastly, avenues for future investigation are proposed in an attempt to narrow our knowledge gaps in this field, with the goal of safer and more effective treatment for adults with obesity who develop ALL.
Topics: Adult; Adolescent; Humans; Child; Asparaginase; Antineoplastic Agents; Prospective Studies; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Obesity
PubMed: 38092476
DOI: 10.1016/j.beha.2023.101519 -
Journal of Oncology Pharmacy Practice :... Jul 2023While Pegaspargase is an essential component of the treatment of acute lymphoid leukemia (ALL) in children, it causes adverse events (AEs) that sometimes make full use...
BACKGROUND
While Pegaspargase is an essential component of the treatment of acute lymphoid leukemia (ALL) in children, it causes adverse events (AEs) that sometimes make full use impossible.
OBJECTIVE
The objective was to investigate the safety of Pegaspargase biosimilar in pediatric ALL patients undergoing treatment according to ICiCLe ALL-14 protocol.
METHOD AND MATERIALS
A prospective study was carried out in a university teaching hospital located in the state of Maharashtra, India. Data on clinical factors and adverse reaction characteristics were gathered from hospital medical records. Suspected AEs were classified according to causality and severity.
RESULTS
During the study period, 72 children had 52 suspicions of AEs during treatment with biosimilar Pegaspargase. The odds ratio of 1.11 (95%CI, 0.41-2.98) suggested that males and females were both equally likely to experience adverse drug events, despite the fact that the frequency of suspected AEs was higher in boys (66%) than in girls (33%). None of the patients experienced allergic reactions. The high-risk category had the highest number of suspected AEs (56%), followed by intermediate risk (20%) and standard risk (20%). These patients showed a high frequency of suspected AEs during the induction phase (43%) followed by the consolidation phase (26%). Sixty percent of the reactions were classified as grade 1 or 2. ALL cell type ( = 0.02), risk category ( = 0.04) and length of hospitalization ( = 0.003) were significantly correlated with suspected AEs.
CONCLUSION
Bio-similar Pegaspargase in combination with chemotherapy was safe and tolerable in the pediatric ALL patients treated according to ICiCLe ALL-14 protocol. Suspected AEs ranged from mild to moderate and hepatic failure and hyperglycemia being severe.
PubMed: 37501538
DOI: 10.1177/10781552231190827 -
Annals of Allergy, Asthma & Immunology... May 2024
PubMed: 38762055
DOI: 10.1016/j.anai.2024.05.009 -
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