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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 -
Annals of Hematology Jun 2023
Pegaspargase, venetoclax, and nelarabine: a successful bridge to allogeneic hematopoietic stem cell transplantation in a relapsed/refractory T-cell acute lymphoblastic leukemia patient.
Topics: Humans; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Hematopoietic Stem Cell Transplantation; T-Lymphocytes
PubMed: 37099080
DOI: 10.1007/s00277-023-05231-4 -
American Journal of Hematology Jul 2023Novel highly effective and low-toxicity combination therapy for localized extranodal natural-killer/T-cell lymphoma (ENKTL) remains a clinically unmet need. This phase...
A phase II study of sintilimab, anlotinib, and pegaspargase sandwiched with radiotherapy as first-line therapy in patients with newly diagnosed, stage I-II extranodal natural-killer/T-cell lymphoma.
Novel highly effective and low-toxicity combination therapy for localized extranodal natural-killer/T-cell lymphoma (ENKTL) remains a clinically unmet need. This phase II trial (NCT03936452) investigated the efficacy and safety of sintilimab, anlotinib, and pegaspargase sandwiched with radiotherapy as first-line treatment in patients with newly-diagnosed stage I-II ENKTL. The patients received sintilimab 200 mg plus pegaspargase 2500 U/m on day 1 and anlotinib 12 mg once daily on days 1-14 for three 21-day cycles, followed by intensity-modulated radiotherapy and another three cycles of systemic therapy. The primary endpoint was the complete response rate (CRR) after six treatment cycles. The secondary endpoints included progression-free survival (PFS), overall survival (OS), CRR after two cycles, overall response rate (ORR) after six cycles, duration of response (DOR), and safety. Between May 2019 and July 2021, 58 patients were enrolled. The CRR was 55.1% (27/49) after two cycles and 87.8% (43/49) after six cycles. The ORR was 87.8% (43/49; 95% CI, 75.2-95.4) after six cycles. After a median follow-up of 22.5 months (95% CI, 20.4-24.6), the median PFS, OS, and DOR were not reached. The 2-year PFS, OS, and DOR rates were 87.6% (95% CI, 78.8-97.4), 97.9% (95% CI, 94.0-100), and 91.1% (95% CI, 83.2-99.8), respectively. Grade 3-4 treatment-related adverse events occurred in 41.4% (24/58) of patients, with the most common being hypertension (15.5%), hypertriglyceridemia (8.6%), oral mucositis (6.9%), and anemia (5.2%). No treatment-related deaths occurred. First-line sintilimab, anlotinib, and pegaspargase sandwiched with radiotherapy demonstrated promising efficacy in treatment-naïve early-stage ENKTL patients with a favorable safety profile.
Topics: Humans; Lymphoma, Extranodal NK-T-Cell; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine
PubMed: 36970971
DOI: 10.1002/ajh.26922 -
Chinese Medical Journal Mar 2023
Topics: Humans; Gemcitabine; Etoposide; Dexamethasone; Lymphoma, T-Cell; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome; Neoplasm Staging; Lymphoma, Extranodal NK-T-Cell
PubMed: 36939235
DOI: 10.1097/CM9.0000000000002570 -
British Journal of Haematology May 2023Venous thromboembolism (VTE) is a well-known complication in patients with acute lymphoblastic leukaemia (ALL) receiving asparaginase (ASP)-based chemotherapy, including...
Venous thromboembolism incidence associated with pegylated asparaginase (ASP) compared to the native L-ASP: A retrospective analysis with an ASP-based protocol in adult patients with acute lymphoblastic leukaemia.
Venous thromboembolism (VTE) is a well-known complication in patients with acute lymphoblastic leukaemia (ALL) receiving asparaginase (ASP)-based chemotherapy, including the ASP-intensive Dana-Farber Cancer Institute (DFCI) 91-01 protocol for adults. Since 2019, native L-ASP is no longer available in Canada and was replaced by pegylated (PEG)-ASP. To determine whether the incidence of VTE has changed since switching from L-ASP to PEG-ASP, we conducted a single-centred retrospective cohort study. We included 245 adult patients with Philadelphia chromosome negative ALL between 2011 and 2021, with 175 from the L-ASP group (2011-2019) and 70 from the PEG-ASP group (2018-2021). During Induction, 10.29% (18/175) of patients who received L-ASP developed VTE, whereas 28.57% (20/70) of patients who received PEG-ASP developed VTE (p = 0.0035; odds ratio [OR] 3.35, 95% confidence interval [CI] 1.51-7.39), after adjusting for line type, gender, history of VTE, platelets at diagnosis. Similarly, during Intensification, 13.64% (18/132) of patients had VTE on L-ASP while 34.37% (11/32) of patients on PEG-ASP developed VTE (p = 0.0096; OR 3.96, 95% CI 1.57-9.96 with multivariable analysis). We found that PEG-ASP is associated with a higher incidence of VTE compared to L-ASP, both during Induction and Intensification, despite the administration of prophylactic anticoagulation. Further VTE mitigation strategies are needed in particular for adult patients with ALL receiving PEG-ASP.
Topics: Humans; Adult; Asparaginase; Retrospective Studies; Venous Thromboembolism; Incidence; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Polyethylene Glycols; Antineoplastic Agents
PubMed: 36794878
DOI: 10.1111/bjh.18683 -
Leukemia & Lymphoma Apr 2023The addition of asparaginase to acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) treatment regimens provides significant patient benefits....
The addition of asparaginase to acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) treatment regimens provides significant patient benefits. Asparaginase therapies vary in origin ( or -derived) and preparation (native or pegylated), conferring distinct pharmacokinetic and immunogenic profiles. Clinical hypersensitivity reactions (HSRs) are commonly reported in patients and range from localized erythema to systemic anaphylaxis. Due to its favorable pharmacokinetic profile and reduced immunogenicity compared to native preparations, pegaspargase is the first-line asparaginase therapeutic option. Switching to an -derived asparaginase is recommended for patients who experience HSRs or antibody-mediated inactivation to achieve the significant clinical benefit observed in patients who complete asparaginase treatment. Previous global shortages of asparaginase necessitated conversion mitigation strategies such as premedication protocols, desensitization, and asparaginase activity level monitoring. Here, we discuss the efficacy, safety, pharmacokinetics, current use, and administration of asparaginase therapies for pediatric and adolescent patients with ALL/LBL.
Topics: Adolescent; Humans; Child; Asparaginase; Escherichia coli; Expert Testimony; Drug Hypersensitivity; Dickeya chrysanthemi; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hypersensitivity; Antineoplastic Agents
PubMed: 36781296
DOI: 10.1080/10428194.2023.2171267 -
Clinical Drug Investigation Feb 2023
PubMed: 36580214
DOI: 10.1007/s40261-022-01236-5 -
Human Cell Mar 2023Extranodal NK/T cell lymphoma, nasal type (ENKTL) is an aggressive and heterogeneous disease. With standard treatment containing pegaspargase-based regimen, patients who...
Extranodal NK/T cell lymphoma, nasal type (ENKTL) is an aggressive and heterogeneous disease. With standard treatment containing pegaspargase-based regimen, patients who were resistant to pegaspargase have rapidly disease progression and worse prognosis. Thus, there is an urgent requirement for constructing ENKTL cell line model to explore the mechanism of pegaspargase resistance and new molecular targeted drugs to improve prognosis. We report here on the establishment of a novel ENKTL cell line, NK-NJ. The cells were isolated from a 52-year-old Chinese man who was diagnosed with relapse/refractory (R/R) ENKTL and grow steadily in vitro. The NK-NJ cells express CD56, CD2, CD45RA with no expression of CD3, CD16, CD57, CD4, CD8, CD26, CD28, CD5, TCR, CD45RO and CD161 and showed a TCR gene unrearrangement, which suggested an origin in the NK-lineage but not T-lineage. The immunophenotypes of NK-NJ cells were consistent with the patient. Moreover, short tandem repeat (STR) profiling results also demonstrated that NK-NJ originated from the patient. NK-NJ showed complex karyotype. Target sequencing method indicated that the main mutation genes of the first-time disease progression of lymph nodal were the same as main mutation genes of the primary nasal lesions. Moreover, NK-NJ was recognized as latency I with EBER positivity and carried high EBV-DNA viral load. The chemosensitivity results suggested synthetic lethality of epigenetic drugs and PD-1 inhibitor for ENKTL patients by reasons of epigenetic drugs promoting PD-L1 expression. In conclusion, we established a new ENKTL cell line in the era of new targeted drugs. We hope that this cell line can help to further understand underlying pathogenesis of ENKTL especially for advanced ENKTL and the functional role of EBV in ENKTL pathogenetic process.
Topics: Male; Humans; Middle Aged; Lymphoma, Extranodal NK-T-Cell; Killer Cells, Natural; Mutation; Disease Progression; Leukemia
PubMed: 36520345
DOI: 10.1007/s13577-022-00841-y -
British Journal of Haematology Feb 2023
Topics: Humans; Asparaginase; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Cell- and Tissue-Based Therapy; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents
PubMed: 36470305
DOI: 10.1111/bjh.18595