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Haematologica Feb 2022Chemotherapy dosages are often compromised, but most reports lack data on dosages that are actually delivered. In two consecutive acute lymphoblastic leukemia trials...
Chemotherapy dosages are often compromised, but most reports lack data on dosages that are actually delivered. In two consecutive acute lymphoblastic leukemia trials that differed in their asparaginase formulation, native E. coli L-asparaginase in St. Jude Total 15 (T15, n=365) and pegaspargase in Total 16 (T16, n=524), we tallied the dose intensities for all drugs on the low-risk or standard-risk arms, analyzing 504,039 dosing records. The median dose intensity for each drug ranged from 61-100%. Dose intensities for several drugs were more than 10% higher on T15 than on T16: cyclophosphamide (P<0.0001 for the standard- risk arm), cytarabine (P<0.0001 for the standard-risk arm), and mercaptopurine (P<0.0001 for the low-risk arm and P<0.0001 for the standardrisk arm). We attributed the lower dosages on T16 to the higher asparaginase dosages on T16 than on T15 (P<0.0001 for both the low-risk and standard-risk arms), with higher dose-intensity for mercaptopurine in those with anti-asparaginase antibodies than in those without (P=5.62x10-3 for T15 standard risk and P=1.43x10-4 for T16 standard risk). Neutrophil count did not differ between protocols for low-risk patients (P=0.18) and was actually lower for standard-risk patients on T16 than on T15 (P<0.0001) despite lower dosages of most drugs on T16. Patients with low asparaginase dose intensity had higher methotrexate dose intensity with no impact on prognosis. The only dose intensity measure predicting a higher risk of relapse on both studies was higher mercaptopurine dose intensity, but this did not reach statistical significance (P=0.03 T15; P=0.07 T16). In these intensive multiagent trials, higher dosages of asparaginase compromised the dosing of other drugs for acute lymphoblastic leukemia, particularly mercaptopurine, but lower chemotherapy dose intensity was not associated with relapse.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Escherichia coli; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 34196166
DOI: 10.3324/haematol.2021.278411 -
Cancer Chemotherapy and Pharmacology Oct 2021We evaluated effects of asparaginase dosage, schedule, and formulation on CSF asparagine in children with acute lymphoblastic leukemia (ALL). (Comparative Study)
Comparative Study Randomized Controlled Trial
PURPOSE
We evaluated effects of asparaginase dosage, schedule, and formulation on CSF asparagine in children with acute lymphoblastic leukemia (ALL).
METHODS
We evaluated CSF asparagine (2114 samples) and serum asparaginase (5007 samples) in 482 children with ALL treated on the Total XVI study (NCT00549848). Patients received one or two 3000 IU/m IV pegaspargase doses during induction and were then randomized in continuation to receive 2500 IU/m or 3500 IU/m IV intermittently (four doses) on the low-risk (LR) or continuously (15 doses) on the standard/high risk (SHR) arms. A pharmacokinetic-pharmacodynamic model was used to estimate the duration of CSF asparagine depletion below 1 uM.
RESULTS
During induction, CSF asparagine depletion after two doses of pegaspargase was twice as long as one dose (median 30.7 vs 15.3 days, p < 0.001). During continuation, the higher dose increased the CSF asparagine depletion duration by only 9% on the LR and 1% in the SHR arm, consistent with the nonlinear pharmacokinetics of serum asparaginase. Pegaspargase caused a longer CSF asparagine depletion duration (1.3-5.3-fold) compared to those who were switched to erwinase (p < 0.001). The median (quartile range) serum asparaginase activity needed to maintain CSF asparagine below 1 µM was 0.44 (0.20, 0.99) IU/mL. Although rare, CNS relapse was higher with decreased CSF asparagine depletion (p = 0.0486); there was no association with relapse at any site (p = 0.3).
CONCLUSIONS
The number of pegaspargase doses has a stronger influence on CSF asparagine depletion than did dosage, pegaspargase depleted CSF asparagine longer than erwinase, and CSF asparagine depletion may prevent CNS relapses.
Topics: Antineoplastic Agents; Asparaginase; Asparagine; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Models, Biological; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies
PubMed: 34170389
DOI: 10.1007/s00280-021-04315-0 -
Andes Pediatrica : Revista Chilena de... Apr 2021The treatment of acute lymphoblastic leukemia (ALL) includes the use of asparaginase (ASP), a drug associated with hypersensitivity reactions (HSR) that requires...
INTRODUCTION
The treatment of acute lymphoblastic leukemia (ALL) includes the use of asparaginase (ASP), a drug associated with hypersensitivity reactions (HSR) that requires discontinuing its use.
OBJECTIVE
To determine the incidence of HSR associated with ASP that require discontinuation of its use and des cribe them, and to verify if there is a relationship between HSR incidence and protocols or survival.
PATIENTS AND METHOD
Retrospective study. Clinical records of all patients (1-15 years) diagnosed with ALL between January 2010 and December 2015 at the Hospital Luis Calvo Mackenna were reviewed. The incidence of HSR to ASP was determined and classified according to the CTCAE v5.0 severity score. We analyzed the relative risk of HSR using Fisher's test and the survival with the Kaplan-Meier estimator.
RESULTS
110 patients were collected. During the first treatment (ALL-IC- BFM), the incidence of HSR to L-ASP was 55%, therefore it was changed to PEG-ASP as second-line treatment, and 44% of them had HSR, and ASP should discontinued in 25% of patients. Of all the HSR to ASP, 77% were anaphylactic (CTCAE 3-5). Patients treated with augmented IB protocol were at higher risk of not completing ASP treatment due to HSR, RR 3.81 (95% CI, 1.98-7.31, p = 0.0001). Patients without HSR in ALL-IC-BFM were at lower risk of relapse, HR 0.29 (95% CI, 0.14-0.62, p = 0.0013). Considering all treatments (ALL-IC-BFM and relapse), patients who completed the ASP treatment had higher overall survival, HR 0.20 (95% CI, 0.07-0.57, p = 0.0026).
CONCLUSIONS
HSR to ASP that require discontinuation of treatment are frequent in children with ALL, most of them were severe anaphylactic reactions. This study suggests a better prognosis in patients without HSR to ASP.
Topics: Adolescent; Anaphylaxis; Antineoplastic Agents; Asparaginase; Child; Child, Preschool; Drug Hypersensitivity; Drug Substitution; Female; Humans; Incidence; Infant; Kaplan-Meier Estimate; Male; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Retrospective Studies
PubMed: 34106156
DOI: 10.32641/andespediatr.v92i2.2151 -
Frontiers in Pharmacology 2021Drugs used in oncological diseases are frequently related to adverse drug reactions (ADR). Few studies have analyzed the toxicity of cancer treatments in children in...
Drugs used in oncological diseases are frequently related to adverse drug reactions (ADR). Few studies have analyzed the toxicity of cancer treatments in children in real practice. An observational, longitudinal and prospective study has been carried out in an Oncohematology Service of a tertiary hospital. During 2017, patients exposed to one or more drugs of a previously agreed list were identified and followed-up for at least 6 months each. Characteristics of ADR, incidence, causality and possible preventability, have been evaluated. 72 patients have been treated with at least one study drug, and 159 ADR episodes involving at least one of these drugs have been identified, with a total of 293 ADR. Most episodes required hospital admission (35.2%) or happened during the hospital stay (33%), and 91.2% were severe. Blood disorders were the most frequent ADR (96; 32.8%), related to thioguanine (42) and pegaspargase (39) mainly, followed by infections (86; 29.4%) related to thioguanine (32), pegaspargase (27), asparaginase (14) and rituximab (13). Two ADR were unknown. Most ADR were dose-dependent or expectable (>90%). The global incidence of ADR was 3.1/100 days at risk (95% CI 2.7-3.5), with 3.5 ADR/100 days at risk with pegaspargase (95% CI 2.9-4.2), 1.2/100 days at risk with rituximab (95% CI 0.8-1.8) and 11.6/100 days at risk with thioguanine (95% CI 9.4-14.2). Controversial additional measures of prevention, other than those already used, were identified. ADR are frequent in pediatric oncohematological patients, mainly blood disorders and infectious diseases. Findings regarding incidence and preventability may be useful to compare data between different centers and to evaluate new possibilities for action or prevention.
PubMed: 34025429
DOI: 10.3389/fphar.2021.670945 -
Blood and Lymphatic Cancer : Targets... 2021Acute lymphoblastic leukemia (ALL) is a heterogenous hematological malignancy representing 25% of all cancers in children less than 15 years of age. Significant... (Review)
Review
Acute lymphoblastic leukemia (ALL) is a heterogenous hematological malignancy representing 25% of all cancers in children less than 15 years of age. Significant improvements in survival and cure rates have been made over the past four decades in pediatric ALL treatment. Asparaginases, derived from and , have become a critical component of ALL therapy since the 1960s. Asparaginases cause depletion of serum asparagine, leading to deprivation of this critical amino acid for protein synthesis, and hence limit survival of lymphoblasts. Pegaspargase, a conjugate of monomethoxypolyethylene glycol (mPEG) and L-asparaginase, has become an integral component of pediatric upfront and relapsed ALL protocols due to its longer half-life and improved immunogenicity profile compared to native asparaginase preparations. Over the past two decades great strides have been made in outcomes for pediatric ALL due to risk stratification, incorporation of multiagent chemotherapy protocols, and central nervous system prophylaxis with pegaspargase having played an important role in this success. However, adolescents and young adults (AYA) with ALL when treated on contemporaneous trials using adult ALL regimens, continue to have poor outcomes. There is increasing realization of adapting pediatric trial regimens for treating AYAs, especially those incorporating higher intensity of chemotherapeutic agents with pegaspargase being one such agent. Dose or treatment-limiting toxicity is observed in 25-30% of patients, most notable being hypersensitivity reactions. Other toxicities include asparaginase-associated pancreatitis, thrombosis, liver dysfunction, osteonecrosis, and dyslipidemia. Discontinuation or subtherapeutic levels of asparaginase are associated with inferior disease-free survival leading to higher risk of relapse, and in cases of relapse, a higher risk for remission failure. This article provides an overview of available evidence for use of pegaspargase in pediatric acute lymphoblastic leukemia.
PubMed: 33907490
DOI: 10.2147/BLCTT.S245210 -
Frontiers in Oncology 2021fusion is a recurrent event most commonly seen in T-cell acute lymphoblastic leukemia (T-ALL). It is related to resistance to glucocorticoids and chemotherapy; however,...
fusion is a recurrent event most commonly seen in T-cell acute lymphoblastic leukemia (T-ALL). It is related to resistance to glucocorticoids and chemotherapy; however, the reported prognosis of T-ALL with fusion is diverse, and the optimal treatment option remains undetermined. Here, we present the treatment process of an illuminating case of T-ALL with fusion. The patient showed early resistance to routine VICLP chemotherapy (at 15 day, 79.2% blasts), but the leukemia burden was significantly reduced after 28-day induction chemotherapy (18.85% blasts), even though she still didn't achieve complete remission (CR) after a second course of high-dose methotrexate (3 g/m2) and pegaspargase. Ex vivo drug sensitivity screening using a panel of 165 kinds of cytotoxic drugs, targeted therapy drugs, combination chemotherapy drugs, etc., was conducted on the refractory leukemia cells, which showed extensive resistance to various regimens. Surprisingly, AML-like scheme DAE scheme (daunorubicin + cytarabine + etoposide) and carfilzomib showed the highest ex vivo inhibition rate. The patient received DAE regimen chemotherapy, and finally achieved complete remission and received allogenic hematopoietic stem cell transplantation (allo-HSCT). According to our own findings and a literature survey, we found that T-ALL patients with fusion usually shows early resistance to chemotherapy, but they have a delayed response, and the CR rate is not compromised; thus, a chemotherapy regimen featuring a 28-day long course, such as that used in GRAALL 2003 or 2005, is recommended for induction therapy. For refractory patients, AML-like therapy such as DAE or CLAG in combination with asparaginase may be beneficial. In addition, carfilzomib may be a useful therapeutic drug and is worthy of further study. Allo-HSCT improves prognosis and we recommend HSCT if possible. Additional chromosomal or molecular events may affect the prognosis, and further investigation is needed. We believe that through proper treatment, the prognosis of patients with fusion can be greatly improved, at least not worse than that of other T-ALL patients.
PubMed: 33869055
DOI: 10.3389/fonc.2021.651494 -
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 Pharmacology and Therapeutics Sep 2021We conducted the first human leukocyte antigen (HLA) allele and genome-wide association study to identify loci associated with hypersensitivity reactions exclusively to...
We conducted the first human leukocyte antigen (HLA) allele and genome-wide association study to identify loci associated with hypersensitivity reactions exclusively to the PEGylated preparation of asparaginase (pegaspargase) in racially diverse cohorts of pediatric leukemia patients: St Jude Children's Research Hospital's Total XVI (TXVI, n = 598) and Children's Oncology Group AALL0232 (n = 2,472) and AALL0434 (n = 1,189). Germline DNA was genotyped using arrays. Genetic variants not genotyped directly were imputed. HLA alleles were imputed using SNP2HLA or inferred using BWAkit. Analyses between genetic variants and hypersensitivity were performed in each cohort first using cohort-specific covariates and then combined using meta-analyses. Nongenetic risk factors included fewer intrathecal injections (P = 2.7 × 10 in TXVI) and male sex (P = 0.025 in AALL0232). HLA alleles DQB1*02:02, DRB1*07:01, and DQA1*02:01 had the strongest associations with pegaspargase hypersensitivity (P < 5.0 × 10 ) in patients with primarily European ancestry (EA), with the three alleles associating in a single haplotype. The top allele HLA-DQB1*02:02 was tagged by HLA-DQB1 rs1694129 in EAs (r = 0.96) and less so in non-EAs. All single nucleotide polymorphisms associated with pegaspargase hypersensitivity reaching genome-wide significance in EAs were in class II HLA loci, and were partially replicated in non-EAs, as is true for other HLA associations. The rs9958628 variant, in ARHGAP28 (previously linked to immune response in children) had the strongest genetic association (P = 8.9 × 10 ) in non-EAs. The HLA-DQB1*02:02-DRB1*07:01-DQA1*02:01 associated with hypersensitivity reactions to pegaspargase is the same haplotype associated with reactions to non-PEGylated asparaginase, even though the antigens differ between the two preparations.
Topics: Alleles; Asparaginase; Cohort Studies; Gene Frequency; Genome-Wide Association Study; Genotype; Haplotypes; Histocompatibility Antigens Class II; Humans; Polyethylene Glycols; Polymorphism, Single Nucleotide
PubMed: 33768542
DOI: 10.1002/cpt.2241 -
Journal of Clinical Oncology : Official... May 2021Children's Oncology Group (COG) AALL0331 tested whether pegaspargase intensification on a low-intensity chemotherapy backbone would improve the continuous complete...
PURPOSE
Children's Oncology Group (COG) AALL0331 tested whether pegaspargase intensification on a low-intensity chemotherapy backbone would improve the continuous complete remission (CCR) rate in a low-risk subset of children with standard-risk B-acute lymphoblastic leukemia (ALL).
METHODS
AALL0331 enrolled 5,377 patients with National Cancer Institute standard-risk B-ALL (age 1-9 years, WBC < 50,000/μL) between 2005 and 2010. Following a common three-drug induction, a cohort of 1,857 eligible patients participated in the low-risk ALL random assignment. Low-risk criteria included no extramedullary disease, < 5% marrow blasts by day 15, end-induction marrow minimal residual disease < 0.1%, and favorable cytogenetics ( fusion or simultaneous trisomies of chromosomes 4, 10, and 17). Random assignment was to standard COG low-intensity therapy (including two pegaspargase doses, one each during induction and delayed intensification) with or without four additional pegaspargase doses at 3-week intervals during consolidation and interim maintenance. The study was powered to detect a 4% improvement in 6-year CCR rate from 92% to 96%.
RESULTS
The 6-year CCR and overall survival (OS) rates for the entire low-risk cohort were 94.7% ± 0.6% and 98.7% ± 0.3%, respectively. The CCR rates were similar between arms (intensified pegaspargase 95.3% ± 0.8% standard 94.0% ± 0.8%; = .13) with no difference in OS (98.1% ± 0.5% 99.2% ± 0.3%; = .99). Compared to a subset of standard-risk study patients given identical therapy who had the same early response characteristics but did not have favorable or unfavorable cytogenetics, outcomes were significantly superior for low-risk patients (CCR hazard ratio 1.95; = .0004; OS hazard ratio 5.42; < .0001).
CONCLUSION
Standard COG therapy without intensified pegaspargase, which can easily be given as an outpatient with limited toxicity, cures nearly all children with B-ALL identified as low-risk by clinical, early response, and favorable cytogenetic criteria.
Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Core Binding Factor Alpha 2 Subunit; Female; Humans; Infant; Male; Neoplasm, Residual; Oncogene Proteins, Fusion; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Trisomy
PubMed: 33739852
DOI: 10.1200/JCO.20.02370 -
Medicine Mar 2021There is currently no optimal treatment modality for refractory or relapsed Extranodal NK/T-cell lymphoma, nasal type (ENKTL). In recent years, programmed cell death...
INTRODUCTION
There is currently no optimal treatment modality for refractory or relapsed Extranodal NK/T-cell lymphoma, nasal type (ENKTL). In recent years, programmed cell death protein 1 (PD-1)/programmed cell - ligand 1 pathway blockade and histone deacetylase inhibitors have emerged as promising strategies for refractory or relapsed ENKTL. Accumulating evidence has shown that therapeutic effects of anti-PD-1 antibody could be enhanced by histone deacetylase inhibitors.
PATIENT CONCERNS
A 52-year-old male patient was diagnosed with stage I ENKTL by biopsy on February 2010.
DIAGNOSIS
positron emission tomography-computed tomography (PET-CT) and biopsy were used to diagnose relapsed ENKTL in 2014.
INTERVENTIONS
The patient was treated with radiotherapy and six cycles of etoposide, prednisone, vincristine (Oncovin), cyclophosphamide and doxorubicin hydrochloride and achieved complete remission (CR) by PET-CT in August 2010. In November 2014, the patient was diagnosed with relapsed stage IV ENKTL and was treated with six cycles of alternative chemotherapy with the regimen of steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide and pegaspargase plus Gemcitabine, Oxaliplatin along with radiotherapy. The patient achieved remission and was placed on thalidomide maintenance treatment. Upon suspicion of relapse suggested by PET-CT, Autologous stem cell transplant was performed after BCNU, etoposide, Ara-C, and melphalan preconditioning on February 2016. Following relapse again in December 2016, the lesions of left femur were treated with radiotherapy and he received anti-PD-1 antibody. He was treated with 4 cycles of pegaspargase plus Gemcitabine, Oxaliplatin on August 2017. The patient's condition improved. He received maintenance and consolidation therapy including lenalidomide, radiotherapy of the right nasal cavity and paranasal sinuses and antigen-specific reactive T cell infusions. PET-CT imaging showed there was high metabolic activity signal in the distal end of right femoral on August 2018 and the treatment regimen was adjusted to radiotherapy of the distal end of right femoral and systemic treatment of PD-1 antibody Sintilimab and chidamide 30 mg. After 5 months post-treatment, biopsy of nasopharynx showed no lymphoma cells. The patient continued the treatment of Sintilimab and chidamide 20 mg.
OUTCOMES
PET-CT imaging showed his lesions obtained remission after 8 months post-treatment.
CONCLUSION
Thus, combination of sintilimab and chidamide can be used to treat relapsed ENKTL following treatment failure from chemo-, radio-, and immuno-therapy. A clinical trial has been launched.
Topics: Aminopyridines; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Combined Modality Therapy; Histone Deacetylase Inhibitors; Humans; Lymphoma, Extranodal NK-T-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Nose Neoplasms; Programmed Cell Death 1 Receptor; Remission Induction; Treatment Outcome
PubMed: 33725836
DOI: 10.1097/MD.0000000000024824