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BMC Cancer Oct 2020L-asparaginase (L-ASP) is a key component of acute lymphoblastic leukemia (ALL) treatment, but its use in clinical practice raises challenges to clinicians due to a...
National Italian Delphi panel consensus: which measures are indicated to minimize pegylated-asparaginase associated toxicity during treatment of adult acute lymphoblastic leukemia?
BACKGROUND
L-asparaginase (L-ASP) is a key component of acute lymphoblastic leukemia (ALL) treatment, but its use in clinical practice raises challenges to clinicians due to a relatively high incidence of drug-related adverse events, mainly in adult patients. In the past years the use of ASP in adult population has been mainly limited due to a poor knowledge of its safety profile and to an approximate management of ASP-related toxicity. Recently the development of pediatric-inspired treatment protocols for adult ALL has led to a wider use of ASP and since 2010 in Italy three national treatment protocols including Pegylated asparaginase (Peg-ASP) have been sequentially developed for adolescents, young adults and adults with Philadelphia-negative (Ph-) ALL.
METHODS
With the aim to better understand the approach adopted in Italian centers for the management and prevention of Peg-ASP toxicity in adult ALL and to provide practical, consensus-based recommendations, a board of 6 Italian clinicians, with known expertise in adult ALL, designed 41 consensus statements on current challenges on the management of Peg-ASP associated toxicity. A group of 19 clinical experts in the field then rated these statements using the 5-point Likert-type scale (1 = strongly disagree; 5 = strongly agree).
RESULTS
The main Peg-ASP related issues identified by the board included: 1) clinician's attitudes; 2) toxicity profile; 3) hypersensitivity reactions; 4) hepatic toxicity; 5) hepatic and/or metabolic toxicity; 6) hemorrhagic/thrombotic toxicity; 7) pancreatitis; 8) metabolic toxicity management and prevention; 9) activity levels monitoring. Overall, participants agreed on most statements, except those addressing the potential contraindications to the treatment with Peg-ASP, such as patients with a diagnosis of chronic liver disease or the subsequent administrations of the drug in patients who had previously developed chemical pancreatitis or severe metabolic toxicity. Participants agreed that adult patients with ALL should receive Peg-Asp because this drug is essential to improve treatment results.
CONCLUSIONS
The panel agreed that a critical evaluation of specific risk factors for each patient is crucial in order to reduce the risk of adverse events and specific advices in the management of Peg-ASP toxicities are reported.
Topics: Asparaginase; Delphi Technique; Female; Humans; Italy; Male; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Surveys and Questionnaires
PubMed: 33008391
DOI: 10.1186/s12885-020-07461-5 -
Medicine Aug 2020The optimal treatment strategy of newly diagnosed stage I/II, extranodal nasal-type natural killer/T cell lymphoma (NKTCL) remains unclear. This prospective phase II... (Observational Study)
Observational Study
Long-term outcomes of upfront concurrent chemoradiotherapy followed by P-GDP regimen in newly diagnosed early stage extranodal nasal-type NK/T cell lymphoma: A prospective single-center phase II study.
The optimal treatment strategy of newly diagnosed stage I/II, extranodal nasal-type natural killer/T cell lymphoma (NKTCL) remains unclear. This prospective phase II trial was conducted to explore the short-term and the long-term efficacy and safety of upfront concurrent chemoradiotherapy (CCRT) followed by pegaspargase, gemcitabine, dexamethasone, cisplatin (P-GDP) regimen in patients newly diagnosed with early stage NKTCL.Thirty patients newly diagnosed with stage I/II NKTCL were enrolled from January 2013 to December 2016, and treated as the following strategy: upfront CCRT with cisplatin weekly (25 mg/m) for 5 weeks, followed by 3 cycles of P-GDP regimen chemotherapy (pegaspargase 2500IU/m capped at 3750IU, intramuscular on day 4, gemcitabine 850 mg/m intravenous on days 1 and 8; dexamethasone 40 mg/day intravenous on days 1 to 4; and cisplatin 20 mg/m intravenous on days 1-3) 3 weeks after the completion of CCRT. The objective response rate (ORR) and the complete response (CR) rate were the primary endpoints, and the secondary endpoints were the overall survival (OS), progression-free survival (PFS), and the adverse event (AE).The median follow-up period was 51.5 months (range, 5-78months). The ORR was 93.3% (28/30) and all these 28 patients attained CR at the end of the treatment. Two patients suffered from lymphoma associated hemophagocytic syndrome (LAHS) during the period of consolidation chemotherapy and died within 2 months. The 5-year OS was 93.3%, and the 5-year PFS was 89.4%Mucositis was the most common grades 3/4 nonhematologic AEs (10%, 3/30) of CCRT. During the P-GDP chemotherapy, vomiting (6.7%, 2/30), neutropenia (43.3%, 13/30) and thrombocytopenia (23.3%, 7/30) were the major grades 3/4 toxicities during chemotherapy. No treatment-related deaths occurred.The upfront CCRT followed by P-GDP regimen chemotherapy is an effective and well-tolerated first-line treatment strategy for patients diagnosed with early stage NKTCL. Further investigation of larger sample size is warranted.
Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Combined Modality Therapy; Consolidation Chemotherapy; Female; Humans; Lymphoma, Extranodal NK-T-Cell; Male; Middle Aged; Nose Neoplasms; Radiotherapy, Intensity-Modulated
PubMed: 32872045
DOI: 10.1097/MD.0000000000021705 -
Journal of Clinical Oncology : Official... Oct 2020Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in those with newly diagnosed disease.
PATIENTS AND METHODS
From 2007 to 2014, Children's Oncology Group trial AALL0434 (ClinicalTrials.gov identifier: NCT00408005) enrolled 1,562 evaluable patients with T-ALL age 1-31 years who received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2 × 2 pseudo-factorial randomization to receive escalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned after induction to receive or not receive six 5-day courses of nelarabine that was incorporated into ABFM. Patients who experienced induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease (CNS3; ≥ 5 WBCs/μL with blasts) received HDMTX and were randomly assigned to receive or not receive nelarabine. All patients, except those with low-risk disease, received cranial irradiation.
RESULTS
The 5-year event-free and overall survival rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. The 5-year disease-free survival (DFS) rates for patients with T-ALL randomly assigned to nelarabine (n = 323) and no nelarabine (n = 336) were 88.2% ± 2.4% and 82.1% ± 2.7%, respectively ( = .029). Differences between DFS in a four-arm comparison were significant ( = .01), with no interactions between the MTX and nelarabine randomizations ( = .41). Patients treated with the best-performing arm, C-MTX plus nelarabine, had a 5-year DFS of 91% (n = 147). Patients who received nelarabine had significantly fewer isolated and combined CNS relapses compared with patients who did not receive nelarabine (1.3% ± 0.63% 6.9% ± 1.4%, respectively; = .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms.
CONCLUSION
The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.
Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Asparaginase; Child; Cohort Studies; Disease-Free Survival; Female; Humans; Leucovorin; Male; Methotrexate; Polyethylene Glycols; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Treatment Outcome
PubMed: 32813610
DOI: 10.1200/JCO.20.00256 -
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 -
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 -
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 -
The Oncologist Nov 2020Concurrent chemoradiotherapy (CCRT) is expected to improve local and systemic disease control and has been established as a standard therapy for several types of solid...
BACKGROUND
Concurrent chemoradiotherapy (CCRT) is expected to improve local and systemic disease control and has been established as a standard therapy for several types of solid tumors. Considering the benefits of frontline radiation and pegaspargase in localized extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL), we conducted a phase II study on pegaspargase-based CCRT to explore an effective treatment.
MATERIALS AND METHODS
In this study, 30 patients with newly diagnosed nasal ENKTL in stages IE to IIE received CCRT (radiation 50 Gy and two cycles of pegaspargase 2,500 unit/m every 3 weeks). Four courses of pegaspargase were performed after CCRT.
RESULTS
The patients completed CCRT and four cycles of pegaspargase. The complete remission (CR) rate was 90%, with a 95% confidential interval (CI) of 73.5%-97.9% after CCRT. The CR rate was 100% (95% CI, 88.4%-100%) at the end of the treatment. The 2-year overall survival and progression-free survival rates were 90.9% (95% CI, 78.4%-100%) and 92.8% (95% CI, 83.2%-100%), respectively. The major adverse events were in grades 1-2.
CONCLUSION
Preliminary data indicate that pegaspargase combined with concurrent radiotherapy for newly diagnosed patients with nasal ENKTL was efficacious and well tolerated. Registered at www.chictr.org.
CLINICAL TRIAL REGISTRATION NUMBER
ChiCTR-OIC-15007662.
IMPLICATIONS FOR PRACTICE
This clinical trial, evaluating the efficacy and toxicity of concurrent chemoradiotherapy by using single-drug pegaspargase for patients with extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) in stage IE to IIE, showed pegaspargase combined with concurrent radiotherapy was efficacious and well tolerated. Pegaspargase has a long half-life and is easy to administer via intramuscular injection. Consequently, pegaspargase combined with concurrent radiotherapy for patients with ENKTL can be completed in the outpatient clinic.
Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Chemoradiotherapy; Female; Humans; Killer Cells, Natural; Lymphoma, Extranodal NK-T-Cell; Male; Middle Aged; Neoplasm Staging; Polyethylene Glycols; Retrospective Studies; Treatment Outcome
PubMed: 32627928
DOI: 10.1634/theoncologist.2020-0144 -
Journal of Clinical Oncology : Official... Sep 2020The Children's Oncology Group (COG) protocol AALL0434 evaluated the safety and efficacy of multi-agent chemotherapy with Capizzi-based methotrexate/pegaspargase (C-MTX)... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
The Children's Oncology Group (COG) protocol AALL0434 evaluated the safety and efficacy of multi-agent chemotherapy with Capizzi-based methotrexate/pegaspargase (C-MTX) in patients with newly diagnosed pediatric T-cell lymphoblastic lymphoma (T-LL) and gained preliminary data using nelarabine in high-risk patients.
PATIENTS AND METHODS
The trial enrolled 299 patients, age 1-31 years. High-risk (HR) patients had ≥ 1% minimal detectable disease (MDD) in the bone marrow at diagnosis or received prior steroid treatment. Induction failure was defined as failure to achieve a partial response (PR) by the end of the 4-week induction. All patients received the augmented Berlin-Frankfurt-Muenster (ABFM) C-MTX regimen. HR patients were randomly assigned to receive or not receive 6 5-day courses of nelarabine incorporated into ABFM. Patients with induction failure were nonrandomly assigned to ABFM C-MTX plus nelarabine. No patients received prophylactic cranial radiation; however, patients with CNS3 disease (CSF WBC ≥ 5/μL with blasts or cranial nerve palsies, brain/eye involvement, or hypothalamic syndrome) were ineligible.
RESULTS
At end-induction, 98.8% of evaluable participants had at least a PR. The 4-year event-free survival (EFS) and overall survival (OS) were 84.7% ± 2.3% and 89.0% ± 2.0%. The 4-year disease-free survival (DFS) from end-induction was 85.9% ± 2.6%. There was no difference in DFS observed between the HR and standard-risk groups ( = .29) or by treatment regimen ( = .55). Disease stage, tumor response, and MDD at diagnosis did not demonstrate thresholds that resulted in differences in EFS. Nelarabine did not show an advantage for HR patients. CNS relapse occurred in only 4 patients.
CONCLUSION
COG AALL0434 produced excellent outcomes in one of the largest trials ever conducted for patients with newly diagnosed T-LL. The COG ABFM regimen with C-MTX provided excellent EFS and OS without cranial radiation.
Topics: Adolescent; Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Asparaginase; Child; Child, Preschool; Female; Humans; Infant; Male; Methotrexate; Polyethylene Glycols; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Progression-Free Survival; Prospective Studies; Time Factors; United States; Young Adult
PubMed: 32552472
DOI: 10.1200/JCO.20.00531 -
Cancer Medicine Aug 2020The optimal treatment strategies for extranodal natural killer/ T-cell lymphoma (ENKTL) have not been defined. We conducted this prospective, open-label, phase II,...
BACKGROUND
The optimal treatment strategies for extranodal natural killer/ T-cell lymphoma (ENKTL) have not been defined. We conducted this prospective, open-label, phase II, single-center study aimed to explore the efficacy and safety of radiotherapy followed by DICEP (Dexamethasone, ifosfamide, cisplatin, etoposide, and pegaspargase) regimen in the treatment of patients with untreated, stage IE/IIE, extranodal NK/T-cell lymphoma.
METHODS
Thirty eligible patients were enrolled in this study, receiving radiotherapy of 50Gy/25fx, and followed by chemotherapy with DICEP regimen for 3 cycles if tolerated. Median follow-up time of this study was 70.8 months. We constructed Kaplan-Meier survival curves for survival analyses.
RESULTS
The most common manifestations at the onset of disease were nasal obstruction (80%), with or without fever, and pharyngalgia (20%). The overall response rate (ORR) was 96.7% (29/30). Four patients (13.3%) had progression of the disease (PD), the estimated 5-year progression-free survival (PFS) rate was 86%. Four patients (13.3%) died of disease, and the estimated 5-year cumulative overall survival (OS) was 87%. The most common hematological toxicity was grade 3 or grade 4 neutropenia, which could be successfully managed via using growth-stimulating factors or dose modifications. Hypoalbuminemia and decreased fibrinogen are the top two nonhematologic toxicities. No treatment-related death occurred in this study.
CONCLUSIONS
Our present study showed that radiotherapy followed by DICEP chemotherapy could be an effective and tolerable treatment modality for newly diagnosed, stage IE/IIE ENKTL patients. Adverse events were predictable and manageable.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01667302. Registered: 1 July 2012.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Etoposide; Female; Humans; Lymphoma, Extranodal NK-T-Cell; Male; Middle Aged; Neoplasm Staging; Progression-Free Survival; Survival Analysis; Treatment Outcome
PubMed: 32519518
DOI: 10.1002/cam4.3207 -
International Journal of Clinical and... 2020Natural killer T-cell lymphoma (NKTCL) is a highly aggressive tumor that usually affects the nasal cavity and/or paranasal sinuses. Primary orbital NKTCL is extremely...
Natural killer T-cell lymphoma (NKTCL) is a highly aggressive tumor that usually affects the nasal cavity and/or paranasal sinuses. Primary orbital NKTCL is extremely rare, with only a few cases reported in the literature. The clinical presentation of orbital involvement by NKTCL is atypical and usually misdiagnosed as orbital cellulitis or orbital pseudotumor. A 23-year-old male patient was admitted to our hospital complaining of severe eye pain and manifested as acute orbital hemorrhage. Isolated orbital natural killer T-cell lymphoma (NKTCL) was confirmed by biopsy. This patient's orbital NKTCL did not respond to CHOP (cyclophosphamide, epirubicin, vincristine, prednisone) chemotherapy, but shrank significantly after receiving 1 cycle of C-SMILE (chidamide, steroid, methotrexate, isophosphamide, L-pegaspargase, etoposide). However, he still died after 3 cycles of C-SMILE chemotherapy at a follow-up time of 4 months. Primary orbital NKTCL can present clinically as a rare acute orbital hemorrhage, and the disease is aggressive and has a poor prognosis.
PubMed: 32509082
DOI: No ID Found