Yamaguchi Motoko, Suzuki Ritsuro, Kwong Yok-Lam, Kim Won Seog, Hasegawa Yuichi, Izutsu Koji, Suzumiya Junji, Okamura Takayuki, Nakamura Shigeo, Kawa Keisei, Oshimi Kazuo
Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
Cancer Sci. 2008 May;99(5):1016-20. doi: 10.1111/j.1349-7006.2008.00768.x. Epub 2008 Feb 19.
Extranodal natural killer (NK)/T-cell lymphoma, nasal type, and aggressive NK-cell leukemia are rare, and their standard therapy has not been established. They are Epstein-Barr virus-associated lymphoid malignancies, and tumor cells express P-glycoprotein leading to multidrug resistance of the disease. Patients with stage IV, relapsed or refractory diseases have a dismal prognosis, with survival measured in months only. To develop an efficacious chemotherapeutic regimen, we conducted a dose-escalation feasibility study of a new chemotherapeutic regimen, SMILE, comprising the steroid dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide. The components of SMILE are multidrug resistance-unrelated agents and etoposide. Etoposide shows both in vitro and in vivo efficacy for Epstein-Barr virus-associated lymphoproliferative disorders. Eligible patients had newly diagnosed stage IV, relapsed or refractory diseases after first-line chemotherapy, were 15-69 years of age, and had satisfactory performance scores (0-2). Four dose levels of methotrexate and etoposide were originally planned to be evaluated. At level 1, six patients with extranodal NK/T-cell lymphoma, nasal type, were enrolled. Their disease status was newly diagnosed stage IV (n = 3), first relapse (n = 2), and primary refractory (n = 1). All of the first three patients developed dose-limiting toxicities, and one of them died of sepsis with grade 4 neutropenia. A protocol revision stipulating early granulocyte colony-stimulating factor administration was made. Two out of three additional patients developed dose-limiting toxicities that were all manageable and transient. For the six enrolled patients, the overall response rate was 67% and the complete response rate was 50%. Although its safety and efficacy require further evaluation, we recommend a SMILE chemotherapy dose level of 1 for further clinical studies.
鼻型结外自然杀伤（NK）/T细胞淋巴瘤和侵袭性NK细胞白血病较为罕见，其标准治疗方案尚未确立。它们是与爱泼斯坦-巴尔病毒相关的淋巴系统恶性肿瘤，肿瘤细胞表达P-糖蛋白，导致该疾病产生多药耐药性。IV期、复发或难治性疾病患者的预后很差，生存期仅以月计算。为了开发一种有效的化疗方案，我们对一种新的化疗方案SMILE进行了剂量递增可行性研究，该方案由类固醇地塞米松、甲氨蝶呤、异环磷酰胺、L-天冬酰胺酶和依托泊苷组成。SMILE的成分是与多药耐药无关的药物以及依托泊苷。依托泊苷对爱泼斯坦-巴尔病毒相关的淋巴增殖性疾病在体外和体内均显示出疗效。符合条件的患者为一线化疗后新诊断的IV期、复发或难治性疾病患者，年龄在15至69岁之间，且体能状态评分良好（0至2分）。最初计划评估四个甲氨蝶呤和依托泊苷剂量水平。在1级剂量水平，纳入了6例鼻型结外NK/T细胞淋巴瘤患者。他们的疾病状态为新诊断的IV期（n = 3）、首次复发（n = 2）和原发难治性（n =1）。前三例患者均出现了剂量限制性毒性，其中1例死于4级中性粒细胞减少伴败血症。制定了一项规定早期给予粒细胞集落刺激因子的方案修订。另外3例患者中有2例出现了剂量限制性毒性，均为可控制的短暂毒性。对于这6例入组患者，总缓解率为67%，完全缓解率为50%。尽管其安全性和疗效需要进一步评估，但我们推荐将SMILE化疗剂量水平1用于进一步的临床研究。
