一项新诊断的 IE 期至 IIE 期结外 NK/T 细胞淋巴瘤，鼻型患者接受甲氨蝶呤、依托泊苷、地塞米松和培门冬酶与放疗联合治疗的 II 期研究

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.

机构信息

State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, China.

State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, China; Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.

出版信息

EBioMedicine. 2017 Nov;25:41-49. doi: 10.1016/j.ebiom.2017.10.011. Epub 2017 Oct 12.

BACKGROUND

A 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.

METHODS

Four 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.

FINDINGS

Forty 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.

INTERPRETATION

MESA 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.

背景

一项 II 期研究评估了甲氨蝶呤、依托泊苷、地塞米松和培门冬酶（MESA）联合放疗法治疗新诊断的 I 期和 II 期结外鼻型自然杀伤/T 细胞淋巴瘤（ENKTL）的临床疗效和安全性，以及抗代谢治疗后的新型血清生物标志物。

方法

采用 MESA 联合放疗法进行 4 个周期的治疗。主要终点为总缓解率（ORR）。采用液相色谱-质谱法评估血清代谢组学图谱，并通过靶向代谢分析对特定代谢物进行定量。

结果

共纳入 40 例患者，ORR 为 92.1%（95%CI，83.1%-100.0%）。2 年无进展生存（PFS）率为 89.1%，总生存（OS）率为 92.0%。化疗期间有 17 例（42.5%）和 26 例（65.0%）患者出现 3/4 级非血液学和血液学毒性，放疗期间分别有 9 例（22.5%）和 0 例（0.0%）患者出现毒性。与健康志愿者相比，ENKTL 中发现 56 个显著降低和 59 个升高的代谢物。建立了一个包含丙氨酸、天冬氨酸、谷氨酸和琥珀酸的 asparaginase 相关代谢物的预测主成分分析模型，称为 asparaginase 相关代谢评分（AspM）。高 AspM 评分的患者具有更好的生存，并且在接受 asparaginase 为基础的方案治疗的早期和晚期 ENKTL 的历史队列中验证了 AspM 的预后意义。多变量分析证实 AspM 是除 PINK 和 PINK 联合 EBV-DNA 之外的独立预后评分。