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Blood and Lymphatic Cancer : Targets... 2022Acute lymphoblastic leukemia (ALL) is a rare hematologic malignancy resulting in the production of abnormal lymphoid precursor cells. Occurring in B-cell and T-cell... (Review)
Review
Acute lymphoblastic leukemia (ALL) is a rare hematologic malignancy resulting in the production of abnormal lymphoid precursor cells. Occurring in B-cell and T-cell subtypes, ALL is more common in children, comprising nearly 30% of pediatric malignancies, but also constitutes 1% of adult cancer diagnoses. Outcomes are age-dependent, with five-year overall survival of greater than 90% in children and less than 20% in older adults. L-asparaginase, an enzyme not found in humans, depletes serum levels of L-asparagine. As leukemic cells are unable to synthesize this amino acid, its deprivation results in cell death. The success of asparaginase-containing regimens in the treatment of pediatric ALL, and poor outcomes with conventional cytotoxic regimens in adults, have led to trials of pediatric or pediatric-inspired regimens incorporating asparaginase in the adolescent and young adult (AYA) and adult populations. Initially purified from , newer formulations of asparaginase have been developed to address short half-life, high immunogenic potential, and manufacturing difficulties. Unfamiliarity with asparaginase use and management of its unique toxicities may result in treatment-decisions that negatively impact outcomes. In this review, we address the current use of asparaginase in the treatment of ALL, with an emphasis on its role in the treatment of adults, key clinical trials, recognition and management of toxicities, and ongoing directions of study.
PubMed: 35669980
DOI: 10.2147/BLCTT.S342052 -
Quantitative Imaging in Medicine and... Apr 2021The prognostic value of interim positron emission tomography/computed tomography (PET/CT) for nasal-type extranodal natural killer/T-cell lymphoma (ENKTL) is...
BACKGROUND
The prognostic value of interim positron emission tomography/computed tomography (PET/CT) for nasal-type extranodal natural killer/T-cell lymphoma (ENKTL) is controversial. We evaluated the prognostic value of interim PET/CT in ENKTL patients to facilitate risk stratification and guide clinical treatment.
METHODS
Patients with ENKTL who received first-line chemotherapy based on L-asparaginase/pegaspargase with/without involved-field radiotherapy were recruited for this study. Pretreatment and interim PET/CT evaluations were performed. Interim PET/CT was evaluated via the maximum standardized uptake value (SUVmax) and the Deauville 5-point scale (DS); and the capacity to predict progression-free survival (PFS) and overall survival (OS) was evaluated. Receiver operating characteristic (ROC) curves were used to determine the optimal SUVmax cutoff. Fisher's exact test was used to analyze relationships between interim PET/CT results and clinical characteristics. Univariate and multivariate analyses were performed to examine the independent effects of interim PET/CT. The Cochran-Mantel-Haenszel test was used to assess the prognostic value of interim PET/CT at different timepoints.
RESULTS
Overall, 129 ENKTL patients were enrolled. The optimal interim PET/CT SUVmax cut-off was 4.95. The median follow-up was 34 [2-90] months, in the low SUVmax group (≤4.95), the 2-year PFS and OS rates were 76.3% and 88.0%, respectively; in the high SUVmax group (>4.95), the PFS and OS rates were 15.6% and 44.5%, respectively. Likewise, for the DS 1-3 group, the PFS and OS rates were 78.9% and 91.2%, respectively; and in the DS 4 or 5 group, the rates of PFS and OS were 49.7% and 69.0%, respectively. In univariate analysis, interim PET/CT evaluation based on SUVmax and DS scores were both PFS and OS predictors. In multivariate analysis, SUVmax was independently significantly associated with PFS (P<0.001) and OS (P=0.002), and DS was independently significantly associated with PFS (P=0.004) but not OS (P=0.204). In the Cochran-Mantel-Haenszel testing, the SUVmax and DS were significantly associated with PFS and OS after adjustments for the interim PET/CT timing.
CONCLUSIONS
Interim PET/CT was of prognostic value concerning ENKTL. The SUVmax is an independent prognostic indicator of PFS and OS, while the DS is an independent prognostic indicator of PFS but not OS. The SUVmax is of greater prognostic value than DS.
PubMed: 33816162
DOI: 10.21037/qims-20-620 -
Clinical and Translational Science Jan 2021Extranodal natural killer/T-cell lymphoma, nasal type (ENKL) is a rare peripheral T-cell lymphoma that predominantly occurs in Asian and South American populations. The... (Comparative Study)
Comparative Study
Extranodal natural killer/T-cell lymphoma, nasal type (ENKL) is a rare peripheral T-cell lymphoma that predominantly occurs in Asian and South American populations. The treatment of ENKL has been a challenge for a long time. This study was conducted to compare the clinical efficacy and safety of cisplatin, dexamethasone, gemcitabine, and pegaspargase (DDGP) and methotrexate, dexamethasone, ifosfamide, L-asparaginase, and etoposide (SMILE) regimens for relapsed/refractory ENKL and explore the prognostic factors. From October 2014 to July 2019, 54 patients with relapsed/refractory ENKL who received DDGP or SMILE chemotherapy were retrospectively assessed in this study. Thirty-one patients received DDGP chemotherapy and 23 patients received SMILE chemotherapy. A higher complete response rate was observed in patients treated with DDGP regimen (61.3% vs. 30.4%, P = 0.025). The DDGP group (95% confidence interval (CI) of 5-year progression-free survival (PFS): 24.6-66.2%; 95% CI of 5-year overall survival (OS): 8.5-91.7%) was also significantly associated with longer 5-year PFS and 5-year OS (P = 0.008 for 5-year PFS, P = 0.023 for 5-year OS). More serious leucopenia (P = 0.021), neutropenia (P = 0.041), and allergy (P = 0.040) were observed in the SMILE group. Post-treatment Epstein-Barr virus (EBV)-DNA status (P = 0.001 for PFS, P = 0.018 for OS) was identified as a significant prognostic factor for PFS and OS in multivariate analysis. The present research suggested that compared with SMILE chemotherapy, DDGP chemotherapy can significantly improve the response and survival of relapsed/refractory ENKL with better tolerance. Post-treatment EBV-DNA status was identified as a significant prognostic factor for PFS and OS in relapsed/refractory ENKL.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; DNA, Viral; Drug Resistance, Neoplasm; Epstein-Barr Virus Infections; Female; Follow-Up Studies; Herpesvirus 4, Human; Humans; Lymphoma, Extranodal NK-T-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Progression-Free Survival; Retrospective Studies; Risk Factors; Young Adult
PubMed: 33045134
DOI: 10.1111/cts.12893 -
Annals of Allergy, Asthma & Immunology... Jun 2021
Topics: Anaphylaxis; Antineoplastic Agents; Asparaginase; Child; Drug Hypersensitivity; Female; Humans; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 33716148
DOI: 10.1016/j.anai.2021.03.004 -
JCO Global Oncology Jul 2020Pegylated asparaginase is comparatively safer than native asparaginase in the management of acute lymphoblastic leukemia (ALL). However, the high price and... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Pegylated asparaginase is comparatively safer than native asparaginase in the management of acute lymphoblastic leukemia (ALL). However, the high price and nonavailability in low- and middle-income countries limits its use. In 2014, the first generic of pegaspargase (Hamsyl) was approved in India for use as a second-line treatment option for ALL. The aim of this study was to assess whether the generic pegaspargase (the test product) was bioequivalent with the reference product (Oncaspar).
PATIENTS AND METHODS
This study was an open-label, parallel-group, comparative pharmacokinetic study in pediatric patients with relapsed ALL receiving their first dose (1,000 IU/m) of pegaspargase administered intramuscularly. Patients were randomly assigned 1-to-1 to either the test or the reference product. The 2 formulations were considered equivalent if the 90% CIs for area under the plasma asparaginase activity-time curve (AUC) geometric mean test-to-reference ratio was within 75% to 133%.
RESULTS
Twenty-nine patients (6-18 years of age) were enrolled in this study, of whom 24 completed the study criteria and were considered for safety analysis (5 patients were ineligible for the assessment). Three patients were excluded from analysis, because of presence of anti-asparaginase antibodies, leaving 21 patients who were considered for bioequivalence pharmacokinetics data. The point estimate of AUC for the test-to-reference ratio was 95.05 (90% CI, 75.07% to 120.33%). Maximum plasma concentration, trough concentrations (day 14), half-life, volume of distribution, drug clearance, and changes in the asparagine and glutamine levels were not significantly different between products. Adverse events were comparable in both groups.
CONCLUSION
Generic and reference pegaspargase had equivalent pharmacokinetics with comparable safety. This could be a safe and cost-effective alternative for patients with ALL, especially in low- and middle-income countries.
Topics: Asparaginase; Child; Humans; India; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Therapeutic Equivalency
PubMed: 32628582
DOI: 10.1200/GO.20.00113 -
Leukemia & Lymphoma Dec 2022A total of 548 patients (age range: 1-22 years, 60.4% Hispanic, 55.8% male) diagnosed with acute lymphoblastic leukemia were reviewed for pegaspargase-associated...
A total of 548 patients (age range: 1-22 years, 60.4% Hispanic, 55.8% male) diagnosed with acute lymphoblastic leukemia were reviewed for pegaspargase-associated hypersensitivity (14.8%), hyperbilirubinemia (9.7%), venous thromboembolism (VTE, 9.7%), and pancreatitis (5.3%). Odds ratios (OR) and 95% confidence intervals (CI) evaluated associations between clinical factors and each toxicity, cumulative number of toxicities, and toxicity clusters identified using k-mode analysis. Most (68.9%) did not experience any toxicity, 24.6% experienced one toxicity, and 6.3% two or more. Age >10 years was associated with hyperbilirubinemia (OR = 3.83; 95% CI: 1.64-8.95), pancreatitis (OR = 3.72; 95% CI: 1.29-10.68), VTE (OR = 4.65; 95% CI: 1.96-11.02), and cumulative toxicity burden (OR = 3.28, 95% CI: 1.97-5.47); high-risk therapy with hypersensitivity (OR 2.25; 95% CI 1.25-4.05); and overweight with cumulative toxicity burden (OR = 1.76, 95% CI: 1.20-2.57). Eight unique toxicity profiles were identified. Older age, overweight, and treatment intensity contribute to pegaspargase-associated toxicities.
Topics: Adolescent; Child; Child, Preschool; Female; Humans; Infant; Male; Young Adult; Antineoplastic Agents; Asparaginase; Demography; Hyperbilirubinemia; Hypersensitivity; Overweight; Pancreatitis; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Venous Thromboembolism
PubMed: 35895075
DOI: 10.1080/10428194.2022.2102621 -
F1000Research 2019PEG-L-asparaginase (pegaspargase) is a critical component of therapy for children and adults with acute lymphoblastic leukemia (ALL). Allergic reactions, which may...
PEG-L-asparaginase (pegaspargase) is a critical component of therapy for children and adults with acute lymphoblastic leukemia (ALL). Allergic reactions, which may occur in up to one third of patients, are the major cause for discontinuation. One study reported lower rates of allergic reactions with premedication. Besides allergy, an unknown number of patients develop silent neutralizing antibodies not associated with allergic reactions. The purpose of this retrospective cohort study was to determine the incidence of silent inactivation of pegasparaginase and compare incidence of allergic reactions with and without premedication. Using a commercial assay, asparaginase activity was monitored following pegaspargase (2500 units/m ) in newly diagnosed children and young adults with B- and T-cell ALL from February 2013 to May 2017. The incidence of allergic reactions before and after initiation of premedication in May 2015 was compared. One patient out of 59 (1.7%) had silent inactivation after the second dose. No patient had silent inactivation after the first pegaspargase dose and no standard risk B-cell ALL patients, who received only two pegaspargase doses in combination with oral dexamethasone, had silent inactivation. The incidence of grade 3 or 4 allergic reactions was 3.7% per dose with premedication (methylprednisolone, acetaminophen and diphenhydramine) versus 5.2% without. The incidence per patient with premedication given for most of the doses was 8.3% versus 17% without. These values are not statistically significant. Premedication did not affect pegaspargase activity. Due to the low incidence of silent inactivation with intravenous pegaspargase and the unlikely event patients receiving only two doses of pegasparaginase would receive erwinase for this possible transient silent inactivation, we recommend routine monitoring of pegaspargase activity only in patients scheduled to receive more than two doses.
Topics: Asparaginase; Child; Humans; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Premedication; Retrospective Studies; Young Adult
PubMed: 32089823
DOI: 10.12688/f1000research.19298.2 -
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 -
Frontiers in Oncology 2020Asparaginase-associated pancreatitis (AAP) is one of the most common complications occurring in patients with asparaginase-treated acute lymphoblastic leukemia (ALL)....
BACKGROUND
Asparaginase-associated pancreatitis (AAP) is one of the most common complications occurring in patients with asparaginase-treated acute lymphoblastic leukemia (ALL). Peg-asparaginase (peg-asp), a chemically recombined asparaginase with lower hyposensitivity and better patient tolerance, is now approved as the first line asparaginase formulation in ALL chemotherapy regimens. Due to the differences in pharmacokinetic characteristics and administration procedure between l-asp and peg-asp, this study aimed to investigate the clinical manifestations of peg-asp-associated pancreatitis.
METHOD
Patients with peg-asp-associated pancreatitis diagnosed within a 5-year period (July 2014 to July 2019) were identified and retrospectively studied. The clinical manifestations, laboratory findings, and imaging results of patients with AAP were analyzed. AAP patients were further classified into mild/moderate and severe groups based on criteria used in previous studies. Clinical outcomes were compared between groups.
RESULTS
A total of 38 patients were enrolled in this study. The underlying disease included ALL (n=35) and lymphoma (n=3). The majority of patients developed AAP during the first phase, called remission induction (n=26, 68.4%), after a median of 2 peg-asp doses (range: 1-11). The DVLP regimen (n=23) is the most common peg-asp regimen used in AAP patients. Abdominal pain occurred after a median of 14.5 days (range: 1-50) from the last peg-asp administration, accompanied by abdominal distension (n=14), nausea (n=17), vomiting (n=21), and fever (n=19). Serum amylase elevation was reported in all AAP patients, of whom 65.8% (n=25) exhibited an elevation in the level of this enzyme three times the upper normal level, fulfilling the Atlanta criteria. The level of serum lipase (median days of elevation=23 days, range: 4-75) was significantly elevated compared with that of serum amylase (median days of elevation=9 days, range: 2-71) and persisted at a markedly high level after the level of serum amylase returned to normal. Common local complications included abdominal ascites (n=10) and peripancreatic fluid collection (n=8). Approximately 42.1% (n=16) of patients with severe AAP experienced systemic complications (septic shock or hypovolemic shock) or severe local complications (pseudocyst), among whom 5 failed to recover. Approximately 84.8% (n=28/33) of the remaining patients resumed chemotherapy; among them, peg-asp formulation in 30.3% (n=10/33) of these patients was adjusted, while asparaginase treatment in 39.4% (n=13/33) was permanently discontinued. Five patients experienced an AAP relapse in later stages of asparaginase treatment. Comparison between mild/moderate and severe AAP patients showed a statistically significant difference in the number of pediatric intensive care unit stays (p=0.047), survival rate (p=0.009), AAP prognosis (p=0.047), and impacts on chemotherapy (p=0.024), revealing a better clinical outcome in mild/moderate AAP patients.
CONCLUSION
Early recognition and management of AAP is essential in reversing the severity of AAP. The existing AAP criteria had a low strength in determining the severity of pediatric AAP. A well-defined AAP definition could help distinguish patients with high anticipated risk for redeveloping AAP and ALL relapse, in order to prevent unnecessary withdrawal of asparaginase. Our study could serve as a basis for conducting future large cohort studies and for establishing an accurate definition of pediatric AAP.
PubMed: 33194600
DOI: 10.3389/fonc.2020.538779 -
Blood Dec 2020
Randomized Controlled Trial
Topics: Asparaginase; Drug Elimination Routes; Female; Humans; Male; Metabolic Clearance Rate; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 32750103
DOI: 10.1182/blood.2020006214