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Journal of Clinical Oncology : Official... Jul 2022To improve the outcomes of patients with T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL), the proteasome inhibitor bortezomib was examined... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To improve the outcomes of patients with T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL), the proteasome inhibitor bortezomib was examined in the Children's Oncology Group phase III clinical trial AALL1231, which also attempted to reduce the use of prophylactic cranial radiation (CRT) in newly diagnosed T-ALL.
PATIENTS AND METHODS
Children and young adults with T-ALL/T-LL were randomly assigned to a modified augmented Berlin-Frankfurt-Münster chemotherapy regimen with/without bortezomib during induction and delayed intensification. Multiple modifications were made to the augmented Berlin-Frankfurt-Münster backbone used in the predecessor trial, AALL0434, including using dexamethasone instead of prednisone and adding two extra doses of pegaspargase in an attempt to eliminate CRT in most patients.
RESULTS
AALL1231 accrued 824 eligible and evaluable patients from 2014 to 2017. The 4-year event-free survival (EFS) and overall survival (OS) for arm A (no bortezomib) versus arm B (bortezomib) were 80.1% ± 2.3% versus 83.8% ± 2.1% (EFS, = .131) and 85.7% ± 2.0% versus 88.3% ± 1.8% (OS, = .085). Patients with T-LL had improved EFS and OS with bortezomib: 4-year EFS (76.5% ± 5.1% 86.4% ± 4.0%; = .041); and 4-year OS (78.3% ± 4.9% 89.5% ± 3.6%; = .009). No excess toxicity was seen with bortezomib. In AALL0434, 90.8% of patients with T-ALL received CRT. In AALL1231, 9.5% of patients were scheduled to receive CRT. Evaluation of comparable AALL0434 patients who received CRT and AALL1231 patients who did not receive CRT demonstrated no statistical differences in EFS ( = .412) and OS ( = .600).
CONCLUSION
Patients with T-LL had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. Systemic therapy intensification allowed elimination of CRT in more than 90% of patients with T-ALL without excess relapse.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Child; Disease-Free Survival; Humans; Infant; Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Young Adult
PubMed: 35271306
DOI: 10.1200/JCO.21.02678 -
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 Advances Aug 2023Pediatric-inspired chemotherapy is the standard of care for younger adults with Philadelphia chromosome-negative acute lymphoblastic leukemia/lymphoma (Ph- ALL/LL). In...
Pediatric-inspired chemotherapy is the standard of care for younger adults with Philadelphia chromosome-negative acute lymphoblastic leukemia/lymphoma (Ph- ALL/LL). In LAL1913 trial, the Gruppo Italiano Malattie EMatologiche dell'Adulto added pegaspargase 2000 IU/m2 to courses 1, 2, 5, and 6 of an 8-block protocol for patients aged from 18 to 65 years, with dose reductions in patients aged >55 years. Responders were risk stratified for allogeneic hematopoietic cell transplantation (HCT) or maintenance per clinical characteristics and minimal residual disease (MRD). Of 203 study patients (median age, 39.8 years), 91% achieved a complete remission. The 3-year overall survival, event-free, and disease-free survival (DFS) rates were 66.7%, 57.7%, and 63.3%, respectively, fulfilling the primary study end point of a 2-year DFS >55%. Although based on the intention-to-treat, the DFS being 74% and 50% in the chemotherapy (n = 94) and HCT (n = 91) assignment cohorts, respectively, a time-dependent analysis proved the value of HCT in patients who were eligible (DFS HCT 70% vs no HCT 26%; P <.0001). In multivariate analysis, age and MRD were independent factors predicting DFS rates of 86% (age ≤ 40 and MRD-negative), 64%-65% (MRD-positive or age > 40) and 25% (age > 40 and MRD-positive); P < .0001. Grade ≥2 pegaspargase toxicity was mainly observed at course 1, contributing to induction death in 2 patients but was rare thereafter. This program improved outcomes of patients with Ph- ALL/LL aged up to 65 years in a multicenter national setting. This trial was registered at www.clinicaltrials.gov as #NCT02067143.
Topics: Humans; Adult; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hematopoietic Stem Cell Transplantation; Disease-Free Survival; Remission Induction; Acute Disease
PubMed: 37276451
DOI: 10.1182/bloodadvances.2022009596 -
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 -
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 -
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 -
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 -
Innovation (Cambridge (Mass.)) May 2023Methotrexate, etoposide, dexamethasone, and pegaspargase (MESA) with sandwiched radiotherapy is known to be effective for early-stage extranodal natural killer/T-cell...
Methotrexate, etoposide, dexamethasone, and pegaspargase (MESA) with sandwiched radiotherapy is known to be effective for early-stage extranodal natural killer/T-cell lymphoma, nasal type (NKTCL). We explored the efficacy and safety of reduced-intensity, non-intravenous etoposide, dexamethasone, and pegaspargase (ESA) with sandwiched radiotherapy. This multicenter, randomized, phase III trial enrolled patients aged between 14 and 70 years with newly diagnosed early-stage nasal NKTCL from 27 centers in China. Patients were randomly assigned (1:1) to receive ESA (pegaspargase 2,500 IU/m intramuscularly on day 1, etoposide 200 mg orally, and dexamethasone 40 mg orally on days 2-4) or MESA (methotrexate 1 g/m intravenously on day 1, etoposide 200 mg orally, and dexamethasone 40 mg orally on days 2-4, and pegaspargase 2,500 IU/m intramuscularly on day 5) regimen (four cycles), combined with sandwiched radiotherapy. The primary endpoint was overall response rate (ORR). The non-inferiority margin was -10.0%. From March 16, 2016, to July 17, 2020, 256 patients underwent randomization, and 248 (ESA [n = 125] or MESA [n = 123]) made up the modified intention-to-treat population. The ORR was 88.8% (95% confidence interval [CI], 81.9-93.7) for ESA with sandwiched radiotherapy and 86.2% (95% CI, 78.8-91.7) for MESA with sandwiched radiotherapy, with an absolute rate difference of 2.6% (95% CI, -5.6-10.9), meeting the non-inferiority criteria. Per-protocol and sensitivity analysis supported this result. Adverse events of grade 3 or higher occurred in 42 (33.6%) patients in the ESA arm and 81 (65.9%) in the MESA arm. ESA with sandwiched radiotherapy is an effective, low toxicity, non-intravenous regimen with an outpatient design, and can be considered as a first-line treatment option in newly diagnosed early-stage nasal NKTCL.
PubMed: 37181228
DOI: 10.1016/j.xinn.2023.100426 -
IScience Nov 2023Natural killer (NK)/T cell lymphoma (NKTCL) is a rare subtype of Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma characterized by poor clinical outcomes. It is... (Review)
Review
Natural killer (NK)/T cell lymphoma (NKTCL) is a rare subtype of Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma characterized by poor clinical outcomes. It is more common in East Asian and Latin American countries. Despite the introduction of asparaginase/pegaspargase-based chemotherapy, the prognosis of patients with advanced NKTCL needs to be improved, and few salvage treatment options are available for relapsed/refractory patients who fail chemotherapy. Although many unknowns remain, novel treatment strategies to further improve outcomes are urgently needed. Immunotherapy has emerged and shown favorable antitumor activity in NKTCL, including monoclonal antibodies targeting immune checkpoint inhibitors, other receptors on the cellular membrane, and cellular immunotherapy, which could enhance immune cells attack on tumor cells. In this review, we provide an overview of recent immunotherapy in NKTCL, focusing on programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), chimeric antigen receptor (CAR) T cells, EBV-specific cytotoxic T lymphocytes, immunomodulatory agents, and other targeted agents, as well as the current progress and challenges in the field.
PubMed: 38026157
DOI: 10.1016/j.isci.2023.108192