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维生素 D 缺乏会损害利妥昔单抗介导的细胞毒性,并影响接受利妥昔单抗治疗的弥漫性大 B 细胞淋巴瘤患者的预后,但对未接受利妥昔单抗治疗的患者无影响。

Vitamin D deficiency impairs rituximab-mediated cellular cytotoxicity and outcome of patients with diffuse large B-cell lymphoma treated with but not without rituximab.

机构信息

Jörg Thomas Bittenbring, Frank Neumann, Marina Achenbach, Jörg Reichrath, Jürgen Geisel, Evi Regitz, Gerhard Held, and Michael Pfreundschuh, Klinik für Innere Medizin I, Universitätsklinikum des Saarlandes, Homburg; and Bettina Altmann and Marita Ziepert, University Leipzig, Leipzig, Germany.

出版信息

J Clin Oncol. 2014 Oct 10;32(29):3242-8. doi: 10.1200/JCO.2013.53.4537. Epub 2014 Aug 18.

Abstract

PURPOSE

To investigate the impact and mechanisms of vitamin D deficiency (VDD) on the outcome of elderly patients with diffuse large B-cell lymphoma (DLBCL).

PATIENTS AND METHODS

Three hundred fifty-nine pretreatment 25-hydroxyvitamin D3 (25[OH]D3) serum levels from the RICOVER-60 study (Six Versus Eight Cycles of Biweekly CHOP-14 With or Without Rituximab in Elderly Patients With Aggressive CD20+ B-Cell Lymphomas) and 63 from the RICOVER-noRTh study (an amendment to the RICOVER-60 study in which patients received six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone administered at an interval of 2 weeks plus two cycles of rituximab [R-CHOP-14], but without radiotherapy) were determined by chemoluminescent immunoassay. Rituximab-mediated cellular cytotoxicity (RMCC) was assessed by lactate dehydrogenase release assay of CD20+ Daudi cells.

RESULTS

RICOVER-60 patients with VDD (≤ 8 ng/mL) and vitamin D levels more than 8 ng/mL treated with rituximab had 3-year event-free survival (EFS) of 59% and 79% and 3-year overall survival (OS) of 70% and 82%, respectively. These differences were significant in a multivariable analysis adjusting for International Prognostic Index risk factors with a hazard ratio (HR) of 2.1 (P = .008) for EFS and 1.9 (P = .040) for OS. EFS was not significantly different in patients with vitamin D levels ≤ 8 or more than 8 ng/mL (HR, 1.2; P = .388) treated without rituximab. This was confirmed in an independent validation set of 63 RICOVER-noRTh patients. RMCC increased significantly (P < .001) in seven of seven individuals with VDD after substitution and normalization of their vitamin D levels.

CONCLUSION

VDD is a risk factor for elderly patients with DLBCL treated with R-CHOP. That VDD impairs RMCC and substitution improves RMCC strongly suggests that vitamin D substitution enhances rituximab efficacy, which must be confirmed in appropriately designed prospective trials addressing VDD and substitution not only in DLBCL, but also in malignancies treated with other antibodies, of which the major mechanism of action is antibody-dependent cellular cytotoxicity (eg, trastuzumab in breast cancer and cetuximab in colorectal cancer).

摘要

目的

研究维生素 D 缺乏(VDD)对弥漫性大 B 细胞淋巴瘤(DLBCL)老年患者预后的影响及机制。

方法

对 RICOVER-60 研究(60 岁以上侵袭性 CD20+B 细胞淋巴瘤患者,用 6 或 8 个周期的每周 2 次 CHOP-14 方案,加或不加利妥昔单抗)中 359 例患者治疗前的 25-羟维生素 D3(25[OH]D3)血清水平和 RICOVER-noRTh 研究(对 RICOVER-60 研究的修订,患者接受 6 个周期的环磷酰胺、多柔比星、长春新碱和泼尼松,每 2 周间隔给药,加 2 个周期的利妥昔单抗[R-CHOP-14],但无放疗)中的 63 例患者的 25(OH)D3 血清水平进行化学发光免疫测定。通过 Daudi 细胞的乳酸脱氢酶释放试验评估利妥昔单抗介导的细胞细胞毒性(RMCC)。

结果

在 RICOVER-60 研究中,接受利妥昔单抗治疗且 VDD(≤8ng/ml)和维生素 D 水平>8ng/ml 的患者,3 年无事件生存率(EFS)分别为 59%和 79%,3 年总生存率(OS)分别为 70%和 82%。在多变量分析中,根据国际预后指数危险因素进行调整,EFS 和 OS 的危险比(HR)分别为 2.1(P=0.008)和 1.9(P=0.040),差异具有统计学意义。在未接受利妥昔单抗治疗的维生素 D 水平≤8ng/ml 和>8ng/ml 的患者中,EFS 无显著差异(HR,1.2;P=0.388)。这在 63 例 RICOVER-noRTh 患者的独立验证组中得到了证实。7 例 VDD 患者在补充和正常化维生素 D 水平后,RMCC 显著增加(P<0.001)。

结论

VDD 是接受 R-CHOP 治疗的老年 DLBCL 患者的一个危险因素。VDD 可损害 RMCC,补充维生素 D 可改善 RMCC,这强烈提示维生素 D 替代可增强利妥昔单抗的疗效,这必须在设计合理的前瞻性试验中得到证实,该试验不仅要解决 DLBCL 中的 VDD 和替代问题,还要解决其他用抗体治疗的恶性肿瘤中的 VDD 和替代问题,这些恶性肿瘤的主要作用机制是抗体依赖的细胞毒性(例如,乳腺癌中的曲妥珠单抗和结直肠癌中的西妥昔单抗)。

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