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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 -
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 -
Cancer Management and Research 2019To evaluate the clinical efficacy and safety of the DDGP regimen in treating extranodal NK/T-cell lymphoma and investigate the correlation between Epstein-Barr virus...
Clinical efficacy of cisplatin, dexamethasone, gemcitabine and pegaspargase (DDGP) in the initial treatment of advanced stage (stage III-IV) extranodal NK/T-cell lymphoma, and its correlation with Epstein-Barr virus.
To evaluate the clinical efficacy and safety of the DDGP regimen in treating extranodal NK/T-cell lymphoma and investigate the correlation between Epstein-Barr virus (EBV)-DNA variation after treatment and the clinical efficacy of NK/T-cell lymphoma. Sixty-four patients with extranodal NK/T-cell lymphoma received DDGP regimen-based chemotherapy. Short-term and long-term clinical efficacy and adverse reactions were observed. The relationship between EBV-DNA changes before and after therapy and clinical efficacy was investigated. After the DDGP regimen was used as the initial treatment, the short-term clinical efficacy included 39 complete remission (CR) (60.94%), 12 partial remission (PR) (18.75%), 2 stable disease (SD) (3.13%) and 11 progressive disease (PD) (17.18%). Objective response rate (ORR) was 79.69% and 82.82% for disease control rate (DCR). 3-year progression-free survival (PFS) was 62.00% and 3-year overall survive (OS) was 74.90%. Hemocytopenia was the predominant adverse effect. Between EBV-DNA positive group and its negative counterpart, a significant difference was noted in OS (=0.046), but no difference in ORR, DCR or PFS was observed. In the EBV-DNA positive group, ORR, DCR, PFS and OS were higher for patients whose EBV-DNA copy number decreased within a normal range than patients remained positive (93.33% versus 61.53%, =0.041 for ORR; 93.33% versus 61.53%, =0.041 for DCR, =0.003 for PFS, =0.017 for OS). The main adverse reactions included bone marrow suppression, gastrointestinal reaction and coagulation dysfunction, which were mitigated and treated after expectant or dose-decrement treatment. DDGP regimen can significantly improve the clinical prognosis of NK/T-cell lymphoma patients with tolerable adverse reactions. The variation in EBV-DNA is correlated with clinical efficacy and prognosis, which provides a theoretical basis for NK/T-cell lymphoma therapy. : In November 2011, this clinical trial was registered on the website: www.ClinicalTrials.gov (No. NCT01501149).
PubMed: 31118779
DOI: 10.2147/CMAR.S191929 -
Cancer Management and Research 2018l-asparaginase or pegaspargase-based chemotherapies have shown promising results in the treatment of extranodal NK/T-cell lymphoma. A retrospective study was conducted...
Pegaspargase, gemcitabine, dexamethasone, and cisplatin (P-GDP) combined chemotherapy is effective for newly diagnosed extranodal NK/T-cell lymphoma: a retrospective study.
PURPOSE
l-asparaginase or pegaspargase-based chemotherapies have shown promising results in the treatment of extranodal NK/T-cell lymphoma. A retrospective study was conducted to determine the efficacy and safety of pegaspargase, gemcitabine, dexamethasone, and cisplatin (P-GDP) combined chemotherapy in patients with newly diagnosed extranodal NK/T-cell lymphoma.
PATIENTS AND METHODS
From September 2013 to November 2016, 57 patients with newly diagnosed, stages I to IV, extranodal NK/T-cell lymphoma received P-GDP chemotherapy. Clinical data from these patients were collected and analyzed to evaluate the efficacy and safety of P-GDP.
RESULTS
All patients were subjected to 1-6 cycles of P-GDP chemotherapy, and the median number of cycles of P-GDP regimen administered was 3. The overall response rate was 89.5% (51/57), including a complete response rate of 70.2% (40/59) and a partial response rate of 19.3% (11/57). The median follow-up time was 28 months (range 2-54 months). The 2-year overall survival and progression-free survival (PFS) rates were 82.9% and 75.9%, respectively. For stage I/II patients and stage III/IV patients, 2-year PFS were 80.8% and 66.7%, respectively. The most common grade 3/4 adverse events were neutropenia (42.1%), thrombocytopenia (38.6%), and hypofibrinogenemia (26.3%). No treatment-related deaths were observed.
CONCLUSION
P-GDP combination chemotherapy is highly effective and safe for newly diagnosed patients with extranodal NK/T-cell lymphoma, nasal type. Additional large sample prospective trials are required to confirm these results.
PubMed: 30464606
DOI: 10.2147/CMAR.S179567 -
Cancer Medicine Nov 2021Pegaspargase (PEG-ASP) is an integral component of therapy for acute lymphoblastic leukemia (ALL) but is associated with hepatotoxicity that may delay or limit future...
BACKGROUND
Pegaspargase (PEG-ASP) is an integral component of therapy for acute lymphoblastic leukemia (ALL) but is associated with hepatotoxicity that may delay or limit future therapy. Obese and adolescent and young adult (AYA) patients are at high risk. Levocarnitine has been described as potentially beneficial for the treatment or prevention of PEG-ASP-associated hepatotoxicity.
METHODS
We collected data for patients age ≥10 years who received levocarnitine during induction therapy for ALL, compared to a similar patient cohort who did not receive levocarnitine. The primary endpoint was conjugated bilirubin (c.bili) >3 mg/dl. Secondary endpoints were transaminases >10× the upper limit of normal and any Grade ≥3 hepatotoxicity.
RESULTS
Fifty-two patients received levocarnitine for prophylaxis (n = 29) or rescue (n = 32) of hepatotoxicity. Compared to 109 patients without levocarnitine, more patients receiving levocarnitine were obese and/or older and had significantly higher values for some hepatotoxicity markers at diagnosis and after PEG-ASP. Levocarnitine regimens varied widely; no adverse effects of levocarnitine were identified. Obesity and AYA status were associated with an increased risk of conjugated hyperbilirubinemia and severe transaminitis. Multivariable analysis identified a protective effect of levocarnitine on the development of c.bili >3 mg/dl (OR 0.12, p = 0.029). There was no difference between groups in CTCAE Grade ≥3 hepatotoxicity. C.bili >3 mg/dl during induction was associated with lower event-free survival.
CONCLUSIONS
This real-world data on levocarnitine supplementation during ALL induction highlights the risk of PEG-ASP-associated hepatotoxicity in obese and AYA patients, and hepatotoxicity's potential impact on survival. Levocarnitine supplementation may be protective, but prospective studies are needed to confirm these findings.
Topics: Adolescent; Adult; Antineoplastic Agents; Asparaginase; Carnitine; Chemical and Drug Induced Liver Injury; Child; Female; Humans; Induction Chemotherapy; Male; Pediatric Obesity; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survival Analysis; Young Adult
PubMed: 34528411
DOI: 10.1002/cam4.4281 -
Medicine Nov 2017Pegaspargase has been used in the treatment of acute lymphoblastic leukemia with promising results. However, it has also been associated with several potentially serious... (Review)
Review
RATIONALE
Pegaspargase has been used in the treatment of acute lymphoblastic leukemia with promising results. However, it has also been associated with several potentially serious complications, including thrombosis. Pegaspargase-induced cerebral venous thrombosis and bone marrow necrosis are very rare.
PATIENT CONCERNS
A 50-year-old female developed headache, weakness of the right lower extremity, fever, and bone pain after chemotherapy including pegaspargase for the treatment of acute lymphoblastic leukemia.
DIAGNOSES
Her imaging studies and bone marrow examinations were compatible with cerebral venous thrombosis and bone marrow necrosis.
INTERVENTIONS
The patient received anticoagulation therapy with rivaroxaban.
OUTCOMES
After treatment with rivaroxaban, she had a good outcome without major or minor bleeding.
LESSONS
Clinicians should be aware of the very rare but possible induction of bone marrow necrosis during pegaspargase treatment when there is necrosis in other organs. Because of its greater safety and convenience, rivaroxaban gains popularity over traditional anticoagulant drugs.
Topics: Antineoplastic Agents; Asparaginase; Bone Marrow; Female; Humans; Middle Aged; Necrosis; Polyethylene Glycols; Remission Induction; Rivaroxaban; Sinus Thrombosis, Intracranial
PubMed: 29145310
DOI: 10.1097/MD.0000000000008715 -
Health Economics Review Dec 2019L-asparaginase is a key component of treatment for patients with acute lymphoblastic leukaemia (ALL) in the UK. Commonly used forms of asparaginase are native E....
BACKGROUND
L-asparaginase is a key component of treatment for patients with acute lymphoblastic leukaemia (ALL) in the UK. Commonly used forms of asparaginase are native E. coli-derived asparaginase (native asparaginase) and pegaspargase in first-line combination therapy, and native Erwinia chrysanthemi-derived asparaginase (Erwinia asparaginase) as second-line treatment. The objective of this study was to evaluate the cost-effectiveness of pegaspargase versus native asparaginase in first-line combination therapy for patients with newly diagnosed ALL. A combined decision tree and health-state transition Markov cost-effectiveness model was developed to assess the relative costs and health outcomes of pegaspargase versus native asparaginase in the UK setting.
RESULTS
In base case analyses, first-line pegaspargase (followed by Erwinia asparaginase in cases of hypersensitivity) dominated first-line native asparaginase followed by Erwinia asparaginase; i.e. resulted in lower costs and more quality-adjusted life year gain. The favourable hypersensitivity rates and administration profile of pegaspargase led to lifetime cost savings of £4741 versus native asparaginase. Pegaspargase remained cost-effective versus all treatment strategies in all scenario analyses, including use of the 2500 IU/m dose, recommended for patients ≤21 years of age.
CONCLUSIONS
Pegaspargase, as part of multi-drug chemotherapy, is a cost-effective option for the treatment of newly diagnosed ALL. Based on this study, The National Institute for Health and Care Excellence Technology Appraisal Committee concluded that it could recommend pegaspargase as a cost-effective use of National Health Service resources in England & Wales for treating ALL in children, young people and adults with untreated, newly diagnosed disease.
TRIAL REGISTRATION
UKALL 2011, EudraCT number 2010-020924-22; UKALL 2003, EudraCT number 2007-004013-34; UKALL14, EudraCT number 2009-012717-22.
PubMed: 31885053
DOI: 10.1186/s13561-019-0257-3 -
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 -
Cancer Medicine Jan 2023Allergic reactions to pegaspargase during ALL therapy are typically due to antibodies against polyethylene glycol (PEG), which is also used as a stabilizing agent in...
OBJECTIVE
Allergic reactions to pegaspargase during ALL therapy are typically due to antibodies against polyethylene glycol (PEG), which is also used as a stabilizing agent in mRNA-based SARS-CoV-2 vaccines. To evaluate the safety of these vaccines in patients with anti-pegaspargase antibodies.
METHODS
We retrospectively reviewed the records of patients treated for ALL who had received SARS-CoV-2 vaccinations. All patients had antibodies against pegaspargase assayed during ALL therapy prospectively and in response to clinical allergies. Symptoms of intolerance to vaccination were gathered retrospectively from chart abstraction.
RESULTS
SARS-CoV-2 vaccination was well tolerated in all 78 patients with prior exposure to pegaspargase as part of their leukemia therapy. No reactions were observed in the 54 patients without a history of anti-pegaspargase antibodies or in 19 patients with antibodies who received mRNA vaccination. 1 patient who received the polysorbate containing Janssen vaccine experienced mild symptoms after vaccination not meeting the criteria of clinical allergy which spontaneously resolved within 25 minutes.
CONCLUSION
SARS-CoV-2 vaccination is safe in this population.
Topics: Humans; Antibodies; Antibodies, Viral; COVID-19; COVID-19 Vaccines; Polyethylene Glycols; Retrospective Studies; RNA, Messenger; SARS-CoV-2; Vaccines
PubMed: 35837830
DOI: 10.1002/cam4.5011