Final results of nilotinib versus nilotinib combined with pegylated interferon alfa-2a as first-line therapy in chronic phase chronic myeloid leukaemia in France (PETALs): an open-label, multicentre, randomised phase 3 trial.

Phase 2 trials demonstrated increased deep molecular response rates when combining second generation TKIs with pegylated interferon alfa (Peg-IFN).

2期试验显示，将第二代TKIs与聚乙二醇化干扰素α（Peg-IFN）联合使用时，深层分子反应率有所增加。

This trial aimed to evaluate the efficacy and the safety of combining nilotinib with Peg-IFN alfa-2a in patients with newly diagnosed CP-CML.

本试验旨在评估尼洛替尼联合Peg-IFN alfa-2a在新诊断的慢性期慢性髓性白血病（CP-CML）患者中的疗效和安全性。

Methods

In PETALs, this open-label, randomised, multicentre phase 3 trial, we enrolled patients with newly diagnosed CP-CML from 27 French academic institutions via a centrally-generated electronic system in a 1:1 ratio to two groups: 300 mg oral nilotinib alone twice a day (the nilotinib only group) or 300 mg nilotinib twice a day combined with subcutaneous Peg-IFN (30 μg per week for the first month of treatment and 45 μg per week thereafter) for a maximum of 2 years.

在PETALs试验中，这是一项开放标签、随机、多中心的III期试验，我们通过中央生成的电子系统以1:1的比例从27个法国学术机构招募了新诊断的CP-CML患者，分为两组：一组为每天两次口服300 mg尼洛替尼（仅尼洛替尼组），另一组为每天两次口服300 mg尼洛替尼联合皮下注射Peg-IFN（治疗的第一个月每周30 μg，之后每周45 μg），最长治疗期为2年。

The randomly allocated patients were stratified by their Sokal index and European Treatment and Outcome Study long-term survival index.

随机分配的患者根据他们的索卡尔指数和欧洲治疗与结果研究长期生存指数进行了分层。

Eligible patients had major BCR::ABL1 transcripts, an Eastern Cooperative Oncology Group performance score of two or lower, who had never received TKIs, and were aged between 18 and 65 years.

符合条件的患者具有主要的BCR::ABL1转录本，东部肿瘤协作组表现评分为二或更低，从未接受过酪氨酸激酶抑制剂治疗，并且年龄在18至65岁之间。

The primary endpoint was the cumulative rate of molecular response 4·5 (MR4·5; defined as BCR::ABL1 international scale [IS] of 0·0032% and lower), analysed in the intention-to-treatpopulation (n=200).

主要终点是分子反应4·5（MR4·5；定义为BCR::ABL1国际标准[IS]为0·0032%及以下）的累积率，分析在意向治疗人群中（n=200）。

This trial is registered at ClinicalTrials.gov, NCT02201459, and is completed.

该试验已在ClinicalTrials.gov上注册，注册号为NCT02201459，并已完成。

Results

205 patients were enrolled between Aug 6, 2014, and Sept 29, 2016, after which five patients were declared ineligible and excluded, resulting in 200 patients being randomly allocated (99 to the nilotinib group and 101 to the combination group).

2014年8月6日至2016年9月29日期间，共有205名患者被纳入研究，之后有5名患者被判定为不符合条件并被排除，最终有200名患者被随机分配（99名患者分配至尼洛替尼组，101名患者分配至联合治疗组）。

The median age at diagnosis was 45 years (IQR 36-55); 130 patients (65%) were male and 70 (35%) were female.

诊断时的中位年龄为45岁（四分位数间距36-55岁）；130名患者（65%）为男性，70名患者（35%）为女性。

Median follow-up in this cohort was 67 months (IQR 32·6-70·6).

该队列的中位随访时间为67个月（四分位数间距32·6-70·6）。

The primary objective was met, with higher rates of MR4·5 in the combination group (24% [95% CI 16·0-34·1] vs 15% [8·6-24·2], p=0·048) at month 12.

主要目标已实现，在第12个月时，联合治疗组的MR4·5比例更高（24% [95% 置信区间16·0-34·1] 对比 15% [8·6-24·2]，p=0·048）。

There were equivalent grade 3-4 haematological side effects in the both groups (14 vs 14) with a predominance for grade 3-4 thrombocytopenia without haemorrhages (six in the combination group vs five in the nilotinib group).

两组中3-4级血液学副作用的发生率相当（14例对比14例），以3-4级血小板减少症为主，但未出现出血情况（联合治疗组六例对比尼洛替尼组五例）。

Psychiatric grade 3-4 events occurred in six (6%) patients in the combination group (including three unsuccessful suicide attempts) compared with five (5%) in the nilotinib group (including one unsuccessful suicide attempt).

联合治疗组中有6%的患者（六例）出现3-4级精神科事件（包括三例自杀未遂），而尼洛替尼组中则有5%的患者（五例）出现此类事件（包括一例自杀未遂）。

Six vascular events also occurred in six patients in the combination group and seven vascular events in five patients in the nilotinib group (all grades 3-4).

在组合组中，有六名患者发生了六起血管事件，而在尼洛替尼组中，有五名患者发生了七起血管事件（所有均为3-4级）。

interpretation

In this setting, Peg-IFN combined with nilotinib induced higher initial rates of MR4·5 compared to TKI monotherapy, despite additional side effects.

在这种情况下，与酪氨酸激酶抑制剂单药治疗相比，Peg-IFN联合尼洛替尼诱导了更高的初始MR4·5率，尽管伴随有额外的副作用。

The onset of psychiatric events might promote immediate cease of Peg-IFN and psychiatrist advice Whether this early molecular response translates into sustained treatment-free survival should be studied in a randomised trial sufficiently powered for this outcome.

精神事件的发生可能会促进立即停止Peg-IFN治疗，并寻求精神科医生的建议。这种早期的分子反应是否能转化为持续的无治疗生存，应该在一个足够强大以支持这一结果的随机试验中进行研究。

funding

Novartis Pharma.

诺华制药