Phase I study of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy for advanced-stage, relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma and leukemia
Phase I study of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy for advanced-stage, relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma and leukemia
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DOI：
10.1111/j.1349-7006.2008.00768.x
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发表时间：
2008-05-01
期刊：
影响因子：
5.7
通讯作者：
Oshimi, Kazuo
中科院分区：
文献类型：
--
作者：
Yamaguchi, Motoko;Suzuki, Ritsuro;Oshimi, Kazuo
结外自然杀伤 (NK)/T 细胞淋巴瘤、鼻型和侵袭性 NK 细胞白血病很少见，其标准治疗方法尚未建立。它们是 Epstein-Barr 病毒相关的淋巴恶性肿瘤，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，生存期只有几个月。为了开发有效的化疗方案，我们对新的化疗方案 SMILE 进行了剂量递增可行性研究，该方案包含类固醇地塞米松、甲氨蝶呤、异环磷酰胺、L-天冬酰胺酶和依托泊苷。 SMILE的成分是与多药耐药性无关的药物和依托泊苷。依托泊苷在体外和体内均显示出对 Epstein-Barr 病毒相关的淋巴增殖性疾病的功效。符合条件的患者为初诊IV期、一线化疗后复发或难治性疾病、年龄15-69岁、体能评分满意（0-2）。最初计划评估甲氨蝶呤和依托泊苷的四种剂量水平。在 1 级，纳入了 6 名鼻型结外 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)。前三名患者均出现了剂量限制性毒性，其中一名患者死于脓毒症并伴有 4 级中性粒细胞减少症。进行了规定早期粒细胞集落刺激因子施用的方案修订。另外三分之二的患者出现了剂量限制性毒性，这些毒性都是可控且短暂的。对于 6 名入组患者，总体缓解率为 67%，完全缓解率为 50%。尽管其安全性和有效性需要进一步评估，但我们建议 SMILE 化疗剂量水平为 1，以进行进一步的临床研究。
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.