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Journal of Hematology & Oncology Jun 2022Natural killer (NK)/T-cell lymphomas are aggressive malignancies with a predilection for Asian and South American populations. Epstein-Barr virus (EBV) infection in... (Review)
Review
Natural killer (NK)/T-cell lymphomas are aggressive malignancies with a predilection for Asian and South American populations. Epstein-Barr virus (EBV) infection in lymphoma cells is universal. Predominantly extranodal, NK/T-cell lymphomas are divided clinically into nasal (involving the nose and upper aerodigestive tract), non-nasal (involving the skin, gastrointestinal tract, testes, and other organs), and aggressive leukaemia/lymphoma (involving the marrow and multiple organs) subtypes. Initial assessment should include imaging with positron emission tomography computed tomography (PET/CT), quantification of plasma EBV DNA as a surrogate marker of lymphoma load, and bone marrow examination with in situ hybridization for EBV-encoded small RNA. Prognostication can be based on presentation parameters (age, stage, lymph node involvement, clinical subtypes, and EBV DNA), which represent patient factors and lymphoma load; and dynamic parameters during treatment (serial plasma EBV DNA and interim/end-of-treatment PET/CT), which reflect response to therapy. Therapeutic goals are to achieve undetectable plasma EBV DNA and normal PET/CT (Deauville score ≤ 3). NK/T-cell lymphomas express the multidrug resistance phenotype, rendering anthracycline-containing regimens ineffective. Stage I/II nasal cases are treated with non-anthracycline asparaginase-based regimens plus sequential/concurrent radiotherapy. Stage III/IV nasal, and non-nasal and aggressive leukaemia/lymphoma cases are treated with asparaginase-containing regimens and consolidated by allogeneic haematopoietic stem cell transplantation (HSCT) in suitable patients. Autologous HSCT does not improve outcome. In relapsed/refractory cases, novel approaches comprise immune checkpoint blockade of PD1/PD-L1, EBV-specific cytotoxic T-cells, monoclonal antibodies, and histone deacetylase inhibitors. Future strategies may include inhibition of signalling pathways and driver mutations, and immunotherapy targeting the lymphoma and its microenvironment.
Topics: Anthracyclines; Asparaginase; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Leukemia; Lymphoma, Extranodal NK-T-Cell; Positron Emission Tomography Computed Tomography; Tumor Microenvironment
PubMed: 35659326
DOI: 10.1186/s13045-022-01293-5 -
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 -
Future Oncology (London, England) Mar 2022Asparaginase is commonly used in combination therapy of acute lymphoblastic leukemia. However, as an immunogenic protein, hypersensitivity reactions (HSRs) during... (Review)
Review
Asparaginase is commonly used in combination therapy of acute lymphoblastic leukemia. However, as an immunogenic protein, hypersensitivity reactions (HSRs) during asparaginase therapy are frequent, indicating the development of anti-asparaginase antibodies. These can be associated with diminished clinical effectiveness, including poorer survival. Therapeutic drug monitoring of serum asparaginase activity to confirm complete asparagine depletion is therefore crucial during asparaginase therapy. Switching to alternative types of asparaginase is recommended for patients experiencing HSRs or silent inactivation; those with HSRs or silent inactivation on derived asparaginases should switch to another preparation. However, prior global shortages of asparaginase highlight the importance of alternative non- derived asparaginase, including recombinant asparaginase.
Topics: Adolescent; Antineoplastic Agents; Asparaginase; B-Lymphocytes; Child; Drug Hypersensitivity; Drug Monitoring; Female; Humans; Immunoglobulin M; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes, Helper-Inducer
PubMed: 35107320
DOI: 10.2217/fon-2021-1288 -
International Journal of Molecular... May 2022Immunotherapy is a milestone in the treatment of poor-prognosis pediatric acute lymphoblastic leukemia (ALL) and is expected to improve treatment outcomes and reduce... (Review)
Review
Immunotherapy is a milestone in the treatment of poor-prognosis pediatric acute lymphoblastic leukemia (ALL) and is expected to improve treatment outcomes and reduce doses of conventional chemotherapy without compromising the effectiveness of the therapy. However, both chemotherapy and immunotherapy cause side effects, including neurological ones. Acute neurological complications occur in 3.6-11% of children treated for ALL. The most neurotoxical chemotherapeutics are L-asparaginase (L-ASP), methotrexate (MTX), vincristine (VCR), and nelarabine (Ara-G). Neurotoxicity associated with methotrexate (MTX-NT) occurs in 3-7% of children treated for ALL and is characterized by seizures, stroke-like symptoms, speech disturbances, and encephalopathy. Recent studies indicate that specific polymorphisms in genes related to neurogenesis may have a predisposition to MTX toxicity. One of the most common complications associated with CAR T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS). Mechanisms of neurotoxicity in CAR T-cell therapy are still unknown and may be due to disruption of the blood-brain barrier and the effects of elevated cytokine levels on the central nervous system (CNS). In this review, we present an analysis of the current knowledge on the mechanisms of neurotoxicity of standard chemotherapy and the targeted therapy in children with ALL.
Topics: Asparaginase; Child; Drug-Related Side Effects and Adverse Reactions; Humans; Immunologic Factors; Immunotherapy, Adoptive; Methotrexate; Neurotoxicity Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 35628334
DOI: 10.3390/ijms23105515 -
Blood Mar 2020Administering asparaginase has always been problematic in adults because most general oncologists who treat adults are not familiar with its usage and toxicity. The... (Review)
Review
Administering asparaginase has always been problematic in adults because most general oncologists who treat adults are not familiar with its usage and toxicity. The toxicity profile of the drug is unique and is not observed with any other chemotherapy agent. Furthermore, asparaginase is almost exclusively used in acute lymphoblastic leukemia (ALL), which is a very rare cancer in adults. Currently, the long-acting pegylated form (pegasparaginase) is the only Escherichia coli-derived asparaginase available in the United States. The use of pediatric regimens is likely to lead to more adult patients receiving multiple doses of pegasparaginase. However, oncologists who treat adults may be reluctant to use pegasparaginase or may unnecessarily discontinue administering it because of certain adverse effects. As a result, the clinical benefit of multiple doses of pegasparaginase will be missed. Despite the fact that pegasparaginase is associated with unique toxicities, the majority are nonfatal, manageable, and reversible. Here, we describe real-life cases of adults with ALL who were treated with pediatric-inspired regimens that incorporated pegasparaginase to illustrate the management of several pegasparaginase-associated adverse effects and guide whether and how to continue the drug.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Drug-Related Side Effects and Adverse Reactions; Humans; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 31977001
DOI: 10.1182/blood.2019002477 -
Cell Metabolism May 2021Mitochondrial respiration is critical for cell proliferation. In addition to producing ATP, respiration generates biosynthetic precursors, such as aspartate, an...
Mitochondrial respiration is critical for cell proliferation. In addition to producing ATP, respiration generates biosynthetic precursors, such as aspartate, an essential substrate for nucleotide synthesis. Here, we show that in addition to depleting intracellular aspartate, electron transport chain (ETC) inhibition depletes aspartate-derived asparagine, increases ATF4 levels, and impairs mTOR complex I (mTORC1) activity. Exogenous asparagine restores proliferation, ATF4 and mTORC1 activities, and mTORC1-dependent nucleotide synthesis in the context of ETC inhibition, suggesting that asparagine communicates active respiration to ATF4 and mTORC1. Finally, we show that combination of the ETC inhibitor metformin, which limits tumor asparagine synthesis, and either asparaginase or dietary asparagine restriction, which limit tumor asparagine consumption, effectively impairs tumor growth in multiple mouse models of cancer. Because environmental asparagine is sufficient to restore tumor growth in the context of respiration impairment, our findings suggest that asparagine synthesis is a fundamental purpose of tumor mitochondrial respiration, which can be harnessed for therapeutic benefit to cancer patients.
Topics: Activating Transcription Factor 4; Animals; Asparagine; Aspartic Acid; Cell Line, Tumor; Cell Proliferation; Diet; Electron Transport Chain Complex Proteins; Humans; Mechanistic Target of Rapamycin Complex 1; Metformin; Mice; Mice, Inbred NOD; Mitochondria; Neoplasms; Nucleotides; Survival Rate
PubMed: 33609439
DOI: 10.1016/j.cmet.2021.02.001 -
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 -
Journal of Clinical Oncology : Official... Dec 2019Despite contemporary treatment, up to 10% of children with acute lymphoblastic leukemia still experience relapse. We evaluated whether a higher dosage of... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Despite contemporary treatment, up to 10% of children with acute lymphoblastic leukemia still experience relapse. We evaluated whether a higher dosage of PEG-asparaginase and early intensification of triple intrathecal therapy would improve systemic and CNS control.
PATIENTS AND METHODS
Between 2007 and 2017, 598 consecutive patients age 0 to 18 years received risk-directed chemotherapy without prophylactic cranial irradiation in the St Jude Total Therapy Study 16. Patients were randomly assigned to receive PEG-asparaginase 3,500 U/m versus the conventional 2,500 U/m. Patients presenting features that were associated with increased risk of CNS relapse received two extra doses of intrathecal therapy during the first 2 weeks of remission induction.
RESULTS
The 5-year event-free survival and overall survival rates for the 598 patients were 88.2% (95% CI, 84.9% to 91.5%) and 94.1% (95% CI, 91.7% to 96.5%), respectively. Cumulative risk of any-isolated or combined-CNS relapse was 1.5% (95% CI, 0.5% to 2.5%). Higher doses of PEG-asparaginase did not affect treatment outcome. T-cell phenotype was the only independent risk factor for any CNS relapse (hazard ratio, 5.15; 95% CI, 1.3 to 20.6; = . 021). Among 359 patients with features that were associated with increased risk for CNS relapse, the 5-year rate of any CNS relapse was significantly lower than that among 248 patients with the same features treated in the previous Total Therapy Study 15 (1.8% [95% CI, 0.4% to 3.3%] 5.7% [95% CI, 2.8% to 8.6%]; = .008). There were no significant differences in the cumulative risk of seizure or infection during induction between patients who did or did not receive the two extra doses of intrathecal treatment.
CONCLUSION
Higher doses of PEG-asparaginase failed to improve outcome, but additional intrathecal therapy during early induction seemed to contribute to improved CNS control without excessive toxicity for high-risk patients.
Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Central Nervous System Neoplasms; Child; Child, Preschool; Cranial Irradiation; Cytarabine; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Male; Methotrexate; Neoplasm Recurrence, Local; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Remission Induction; Survival Rate
PubMed: 31657981
DOI: 10.1200/JCO.19.01692 -
JAMA Oncology Jul 2022The L-asparaginase-based SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy regimen has shown higher response rates and survival... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and Safety of a Pegasparaginase-Based Chemotherapy Regimen vs an L-asparaginase-Based Chemotherapy Regimen for Newly Diagnosed Advanced Extranodal Natural Killer/T-Cell Lymphoma: A Randomized Clinical Trial.
IMPORTANCE
The L-asparaginase-based SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy regimen has shown higher response rates and survival benefit over an anthracycline-containing regimen. However, the safety profile was not satisfied. A well-tolerated regimen with promising efficacy is lacking.
OBJECTIVE
To compare the efficacy and safety of the DDGP (dexamethasone, cisplatin, gemcitabine, and pegaspargase) regimen with the SMILE regimen in newly diagnosed advanced-stage (III/IV) extranodal natural killer/T-cell lymphoma (ENKL).
DESIGN, SETTING, AND PARTICIPANTS
This was an open-label, multicenter, randomized clinical trial that took place across 12 participating hospitals in China from January 2011 to February 2019. Patients were eligible if they were 14 to 70 years old with newly diagnosed ENKL in stages III/IV and had an Eastern Cooperative Oncology Group performance status of 0 to 2. Eligible patients were evenly randomized to either the DDGP or SMILE group.
INTERVENTIONS
Patients in each group were treated with the assigned regimen every 21 days for 6 cycles.
MAIN OUTCOMES AND MEASURES
The primary end point was progression-free survival (PFS), and secondary end points included overall response rate and overall survival (OS). The adverse events between the DDGP and SMILE groups were compared.
RESULTS
Among the 87 randomized patients, 80 received treatment (40 in the DDGP group and 40 in the SMILE group); the median (IQR) age was 43 (12) years, and 51 (64%) were male. The baseline characteristics were similar between the groups. At a median follow-up of 41.5 months, the median PFS was not reached in the DDGP group vs 6.8 months in the SMILE group (HR, 0.42; 95% CI, 0.23-0.77; P = .004), and the median OS was not reached in the DDGP group vs 75.2 months in the SMILE group (HR, 0.41; 95% CI, 0.19-0.89, P = .02). The PFS rate at 3 years and OS rate at 5 years were higher in the DDGP group vs the SMILE group (3-year PFS, 56.6% vs 41.8%; 5-year OS, 74.3% vs 51.7%). The overall response rate was higher in the DDGP group than in the SMILE group (90.0% vs 60.0%; P = .002). Grade 3 and 4 hematologic toxic effects were more frequently reported in the SMILE group vs the DDGP group (leukopenia, 85.0% vs 62.5%; neutropenia, 85.0% vs 65.0%).
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, the DDGP regimen showed promising preliminary results for patients with newly diagnosed local advanced ENKL. A confirmation trial based on larger population is warranted.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01501149.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Dexamethasone; Female; Humans; Killer Cells, Natural; Lymphoma, Extranodal NK-T-Cell; Male; Middle Aged
PubMed: 35708709
DOI: 10.1001/jamaoncol.2022.1968