A Phase II Study of Methotrexate, Etoposide, Dexamethasone and Pegaspargase Sandwiched with Radiotherapy in the Treatment of Newly Diagnosed, Stage IE to IIE Extranodal Natural-Killer/T-Cell Lymphoma, Nasal-Type

Abstract

BackgroundA phase II study of methotrexate, etoposide, dexamethasone, and pegaspargase (MESA) sandwiched with radiotherapy for newly diagnosed, stage IE-IIE extranodal natural-killer/T-cell lymphoma, nasal-type (ENKTL) was conducted to explore its clinical efficacy and safety, as well as novel serum biomarkers upon anti-metabolic treatment.MethodsFour cycles of MESA sandwiched with radiotherapy were administered. The primary end point was the overall response rate (ORR). Serum metabolomic profiles were assessed by liquid chromatography-mass spectrometry, with specific metabolites quantified by targeted metabolic analysis.FindingsForty patients were enrolled and the ORR was 92.1% (95%CI, 83.1%–100.0%). The 2-year progression-free survival (PFS) rate was 89.1% and overall survival (OS) rate was 92.0%. Grade 3/4 non-hematologic and hematologic toxicities were observed in 17 (42.5%) and 26 patients (65·0%) during chemotherapy, and in 9 (22.5%) and 0 (0.0%) patients during radiotherapy, respectively. Fifty-six significantly decreased and 59 increased metabolites were identified in ENKTL, as compared to healthy volunteers. A predictive principal components analysis model of asparaginase-associated metabolites, asparaginase-associated metabolic score (AspM), was established, including alanine, aspartate, glutamate, and succinic acid. Patients with high AspM score displayed superior survival and prognostic significance of AspM was validated in a historical cohort of early and advanced-stage ENKTL treated with asparaginase-based regimens. Multivariate analysis confirmed AspM as a prognostic score independent of PINK and PINK combined with Epstein-Barr virus DNA.InterpretationMESA sandwiched with radiotherapy is an effective and safe regimen for early-stage ENKTL. AspM score may be a promising prognostic index of serum metabolites in addition to clinical prognostic index in ENKTL.

Advances in multiple omics of natural-killer/T cell lymphoma

“…Serum metabolomic profile of NKTCL patients is distinct from that of healthy volunteers [ 50 ]. Briefly, 115 significantly altered serum metabolites are identified, predominantly involving in pathways of amino acid metabolism [ 50 ].…”

“…Serum metabolomic profile of NKTCL patients is distinct from that of healthy volunteers [ 50 ]. Briefly, 115 significantly altered serum metabolites are identified, predominantly involving in pathways of amino acid metabolism [ 50 ]. As depicted by alanine, aspartate, and glutamate metabolism pathway in KEGG (Kyoto Encyclopedia of Genes and Genomes), nine of them are asparaginase-associated metabolites (alanine, aspartic acid, malic acid, ornithine, glutamate, glutamine, histidine, pantothenic acid, and succinic acid) and differently expressed in patients with good response to asparaginase, suggesting the reliance of malignant NK cells on extracellular amino acids.…”

Oncogenic Network and Hub Genes for Natural Killer/T-Cell Lymphoma Utilizing WGCNA

“…Considering that continuous JAK-STAT pathway activation is a major feature of NKTCL, it would be very interesting to study whether GRB14 promotes the progress of NKTCL by activating STAT3 (3,7). Besides, NKTCL patients have amino acid metabolism disorders, such as alanine, aspartate, and glutamate (30). Asparaginase is the most widely used antimetabolite agent in NKTCL (31).…”

What we should know about natural killer/T‐cell lymphomas

“…We conducted a phase II study of methotrexate, etoposide, dexamethasone, and pegaspargase (MESA) sandwiched with radiotherapy. The ORR is 92.1%, with 2‐year OS, and PFS rates as 92.0% and 89.1%, respectively …”