磷酸芦可替尼 依托泊苷联合DDGP方案在NK/T细胞淋巴瘤相关噬血细胞综合征初始诱导治疗的疗效及安全性研究
doi: 10.12354/j.issn.1000-8179.2023.20221557
Efficacy and safety of ruxolitinib phosphate and etoposide combined with DDGP as an initial induction regimen for patients with NK/T-cell lymphoma-associated hemophagocytic syndrome
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摘要:
目的 探讨以磷酸芦可替尼、依托泊苷联合DDGP（RuE-DDGP）方案初始诱导治疗NK/T细胞淋巴瘤相关噬血细胞综合征（NK/T-cell lymphoma-associated hemophagocytic syndrome，NK/T-LAHS）的临床疗效及安全性。 方法 分析郑州大学第一附属医院2021年1月至2022年6月收治的11例采用RuE-DDGP方案治疗的NK/T-LAHS患者的临床资料，对其疗效、不良反应及预后进行回顾性分析。 结果 11例患者中9例为男性，2例为女性，中位年龄为30（20～75）岁。治疗2周后11例均获部分缓解（partial remission，PR），治疗4周后10例评效为PR，1例因死亡未评效。治疗2周后总体缓解率（overall remission rate，ORR）为100%，治疗4周后ORR为90.9%。中位总生存期（median overall survival，mOS）为3.0（0.7～15.5）个月，中位无进展生存期（median progression-free survival，mPFS）为3.0（0.7～15.5）个月。在随访期间未观察到与治疗相关的严重不良事件的发生。 结论 NK/T-LAHS患者在初始诱导治疗中应用RuE-DDGP方案治疗是安全有效的。 Abstract: Objective: To investigate the clinical efficacy and safety of ruxolitinib phosphate and etoposide combined with cisplatin, dexamethasone, gemcitabine, and pegaspargase (RuE-DDGP) as an initial induction regimen for the treatment of natural killer/T-cell lymphoma-associated hemophagocytic syndrome (NK/T-LAHS). Methods: The clinical data for 11 patients with NK/T-LAHS treated with the RuE-DDGP regimen in The First Affiliated Hospital of Zhengzhou University from January 2021 to June 2022 were retrospectively analyzed for treatment efficacy, adverse effects, and prognosis. Results: Among the 11 patients, there were nine males and two females, with a median age of 30 (20–75) years. After 2 weeks of treatment, all 11 patients achieved partial remission (PR), with an overall remission rate (ORR) of 100%. After 4 weeks of treatment, 10 patients achieved PR and one was not evaluated due to death. The median overall survival （mOS) time was 3 (0.7–15.5) months, and the median progression-free survival (mPFS) time was 3 (0.7–15.5) months. No treatment-related serious adverse events were observed during the follow-up period. Conclusions: The RuE-DDGP treatment regimen is safe and effective for patients with NK/T-LAHS during initial induction therapy. -
表 1 患者的临床资料汇总
编号 性别 年龄（岁） 淋巴瘤诊断 Ann Arbor
分期（期）CA
分期（期）PINK-E
评分类型 脾大 NK细胞
活性血清EBV-DNA
治疗前/后骨髓噬血现象
治疗前/后开始治疗后持续
发热时间（天）1 男 33 NKTCL Ⅳ Ⅱ 高危组 1 是 正常 阳/阴 有/无 3 2 男 20 NKTCL Ⅳ Ⅱ 高危组 1 是 降低 阳/阴 有/有 16 3 男 64 NKTCL Ⅳ Ⅱ 高危组 1 是 降低 阳/阴 有/无 7 4 男 39 NKTCL Ⅳ Ⅲ 中危组 1 否 正常 阳/阴 有/无 7 5 男 25 NKTCL Ⅲ Ⅲ 中危组 1 否 降低 阳/阴 有/无 2 6 男 75 NKTCL Ⅳ Ⅳ 高危组 1 是 降低 阳/- 有/无 3 7 女 48 NKTCL Ⅳ Ⅳ 高危组 2 是 降低 阳/阴 有/无 3 8 男 34 NKTCL Ⅳ Ⅱ 中危组 1 是 正常 阳/阳 有/有 4 9 男 22 侵袭性NK细胞白血病 Ⅳ Ⅳ 高危组 1 是 正常 阳/阳 有/无 5 10 女 30 NKTCL Ⅳ Ⅳ 高危组 1 是 降低 阳/阳 有/− 21 11 男 24 NKTCL Ⅳ Ⅳ 高危组 1 是 正常 阳/阳 有/无 2 类型1：淋巴瘤诱导的HLH；类型2：化疗期合并的HLH；血清EBV-DNA阳性定义为>5E+02拷贝/mL，阴性定义为<5E+02拷贝/mL 
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表 2 应用RuE-DDGP方案治疗前后的指标变化
指标 正常范围 治疗前
中位数（范围）治疗2周后
中位数（范围）治疗4周后
中位数（范围）Neu（×109/L） 1.80～6.30 1.25（0.36～3.04） 1.72（0.03～8.60） 3.70（1.18～6.45） Hb（g/L） 130.00～175.00 89.00（67.00～128.00） 100.00（85.00～124.00） 102.00（78.00～121.00） PLT（×109/L） 125.00～350.00 39.00（4.00～113.00） 94.00（4.00～210.00） 117.00（38.00～376.00） 铁蛋白（ng/mL） 30.00～400.00 4 370.00（2 203.00～36 844.00） 3 354.00（1 636.00～13 762.00） 1 756.00（726.00～6 324.00） FIB（g/L） 2.00～4.00 1.42（0.45～3.18） 1.48（0.82～3.57） 1.82（0.86～3.01） ALT（U/L） 0～40.00 67.00（33.00～390.00） 67.00（21.00～130.00） 35.00（14.00～74.00） 甘油三酯（mmol/L） <1.70 2.95（1.10～6.57） 1.52（1.20～3.44） 1.23（0.37～2.56） sCD25（pg/mL） <6 400.00 37 816.00（3 164.00～234 790.00） - - Neu：中性粒细胞；Hb：血红蛋白；PLT：血小板；FIB：纤维蛋白原；ALT：谷丙转氨酶。由于编号10的患者在确诊后仅生存0.7个月，因此治疗4周后的数据仅为其余10例。
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表 3 RuE-DDGP方案以及后续治疗方案用于NKT-LAHS患者的疗效
编号 RuE-DDGP方案
治疗2周/4周后续淋巴瘤
治疗方案淋巴瘤
化疗疗效2个
周期4个
周期1 PR/PR DDGP（6） PR CR 2 PR/PR 改良SMILE(1) - - 3 PR/PR DDGP （1） - - 4 PR/PR 改良SMILE （1） - - 5 PR/PR DDGP （1） ，PD-1 （1） CR - 6 PR/PR 无 - - 7 PR/PR DDGP（1），改良SMILE+PD-1（1） PD - 8 PR/PR P-GemOxD （1），DDGP（1） PD - 9 PR/PR DDGP（1），改良SMILE（1） PD - 10 PR/- 无 - - 11 PR/PR DDGP（3） PR - 改良SMILE（甲氨蝶呤+地塞米松+左旋门冬酰胺酶+依托泊苷+异环磷酰胺）；P-GemOxD（培门冬酶+吉西他滨+奥沙利铂+地塞米松）
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表 4 11例RuE-DDGP方案治疗NKT-LAHS患者的不良反应
编号 3～4级中性粒细胞减少持续时间（天） 3～4级血小板减少持续时间（天） 感染情况 3～4级肝功能不全持续时间（天） 胃肠道反应 A B A B A B 1 2 0 5 0 无 9 0 无 2 13 25 28 25 肺部感染 11 5 无 3 15 0 17 0 无 0 0 腹泻 4 4 14 6 16 无 4 0 无 5 0 0 0 0 无 0 0 恶心呕吐 6 0 0 5 0 无 0 0 无 7 0 0 11 3 无 3 0 无 8 0 0 28 20 无 0 0 无 9 13 8 3 8 肺部感染 0 0 无 10 15 - 19 - 无 0 - 无 11 11 0 3 0 无 0 0 无 A：采用RuE-DDGP方案治疗期间；B：治疗结束后随访30天期间
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