Safety of cladribine tablets in the treatment of patients with multiple sclerosis: An integrated analysis
Safety of cladribine tablets in the treatment of patients with multiple sclerosis: An integrated analysis
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DOI：
10.1016/j.msard.2018.11.021
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发表时间：
2019-04-01
影响因子：
4
通讯作者：
Sylvester, Elke
中科院分区：
文献类型：
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作者：
Cook, Stuart;Leist, Thomas;Sylvester, Elke
背景：用克拉屈滨片治疗复发性多发性硬化症 (MS) 患者（每年两次，每次 4 或 5 天治疗，持续 2 年）可取得持久疗效，许多患者的疗效持续稳定达 4 年或更长时间。克拉屈滨片的个体临床研究的安全性和耐受性结果之前已有报道。 目的：通过对 MS 患者的临床试验和随访进行综合分析来报告安全性数据，以进一步表征克拉屈滨片的安全性。 方法：使用克拉屈滨片 10 mg（MAVENCLAD (R)；2 年累积剂量 3.5 mg/kg，称为克拉屈滨片 3.5 mg/kg）作为单药治疗的患者的数据汇总了 III 期临床试验（CLARITY、CLARITY Extension 和 ORACLE-MS）中的（n=923）或安慰剂（n=641）以及 PREMIERE 登记中的随访（单一疗法口服队列）。为了更好地描述罕见事件，早期研究（涉及 MS 患者肠外使用克拉屈滨）和 ONWARD 研究（其中患者除干扰素 (IFN)-β 或安慰剂加 IFN-β 外还服用克拉屈滨片剂）的额外数据被纳入 All Excessed 队列（克拉屈滨，n=1926；安慰剂，n=802）。计算每 100 患者年的调整后不良事件发生率（每 100 PY 的 Adj-AE）以进行综合分析。结果：单药口服治疗队列中治疗引起的不良事件 (TEAE) 的发生率为 103.29 例，而安慰剂组为每 100 PY 94.26 例 Adj-AE。克拉屈滨片剂更频繁发生的 TEAE 主要由淋巴细胞减少的 TEAE 驱动（Adj-AE 每 100 PY 7.94，安慰剂为 1.06），并且由于克拉屈滨的作用方式，淋巴细胞计数减少（Adj-AE 每 100 PY 0.78，安慰剂为 0.10）。与带状疱疹安慰剂相比，克拉屈滨片 3.5 mg/kg 组的 TEAE 发生率也有所增加（每 100 PY 的 Adj-AE 分别为 0.83 和 0.20）。没有因克拉屈滨片治疗而导致全身性、严重播散性带状疱疹的病例。一般来说，除带状疱疹外，克拉屈滨片与安慰剂相比，感染（包括机会性感染）的风险没有增加。严重淋巴细胞减少症时期（< 0.5x10(9) 细胞/L）与感染频率增加相关，但其性质与用 3.5 mg/kg 克拉屈滨片治疗的整个患者组中观察到的情况没有不同。在有限样本量的限制下，克拉屈滨治疗多发性硬化症的总体临床方案中，与安慰剂治疗的患者相比，没有显示出恶性肿瘤发生率增加的证据，并且克拉屈滨治疗的患者的恶性肿瘤发生率没有随着时间的推移而增加。结论：克拉屈滨片剂 3.5 mg/kg 作为单一疗法的 AE 谱在从早期到晚期复发性多发性硬化症患者的汇总人群中得到了很好的表征。除了带状疱疹发病率较高外，总体感染风险并未增加。淋巴细胞减少症是最常见的 TEAE 之一，克拉屈滨组发生率高于安慰剂组。与安慰剂相比，克拉屈滨的恶性肿瘤发生率也没有增加。
Background: Treating patients with relapsing multiple sclerosis (MS) with cladribine tablets (two times 4 or 5 days of treatment each year for 2 years) results in long-lasting efficacy, with continued stability in many patients for 4 or more years. Safety and tolerability outcomes from individual clinical studies with cladribine tablets have been reported previously.Objective: Report safety data from an integrated analysis of clinical trials and follow-up in patients with MS to further characterize the safety profile of cladribine tablets.Methods: Data for patients treated with cladribine tablets 10 mg (MAVENCLAD (R); 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg) as monotherapy (n=923) or placebo (n=641) in Phase III clinical trials (CLARITY, CLARITY Extension and ORACLE-MS) and followed up in the PREMIERE registry were aggregated (Monotherapy Oral cohort). To better characterize rare events, additional data from earlier studies which involved the use of parenteral cladribine in patients with MS, and the ONWARD study, in which patients were given cladribine tablets in addition to interferon (IFN)-beta or placebo plus IFN-beta were included in an All Exposed cohort (cladribine, n=1926; placebo, n=802). Adjusted adverse events incidences per 100 patient-years (Adj-AE per 100 PY) were calculated for the integrated analyses.Results: The incidence rate of treatment-emergent adverse events (TEAEs) in the Monotherapy Oral cohort was 103.29 vs. 94.26 Adj-AEs per 100 PY for placebo. TEAEs that occurred more frequently with cladribine tablets were mainly driven by the TEAEs of lymphopenia (Adj-AE per 100 PY 7.94 vs. 1.06 for placebo) and lymphocyte count decreased (Adj-AE per 100 PY 0.78 vs. 0.10 for placebo) as anticipated due to the mode of action of cladribine. An increase in TEAE incidence rate was also observed in the cladribine tablets 3.5 mg/kg group vs. placebo for herpes zoster (Adj-AE per 100 PY 0.83 vs. 0.20, respectively). There were no cases of systemic, serious disseminated herpes zoster attributed to treatment with cladribine tablets. In general there was no increase in the risk of infections including opportunistic infections with cladribine tablets versus placebo, except for herpes zoster. Periods of severe lymphopenia (< 0.5x10(9) cells/L) were associated with an increased frequency of infections, but the nature of these was not different to that observed in the overall patient group treated with cladribine tablets 3.5 mg/kg. Within the constraints of a limited sample size, malignancy rates in the overall clinical program for cladribine in MS did not show evidence of an increase compared to placebo-treated patients and there was no increase in the incidence of malignancies over time in cladribine-treated patients.Conclusion: The AE profile for cladribine tablets 3.5 mg/kg as a monotherapy has been well-characterized in a pooled population of patients from early to more advanced relapsing MS. There was no increased risk for infections in general except for a higher incidence of herpes zoster. Lymphopenia was amongst the most frequently observed TEAEs that occurred at a higher incidence with cladribine relative to placebo. There was also no increase in malignancy rates for cladribine relative to placebo.